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Jain MD, Abramson JS, Ansell SM. Easy as ABC: Managing Toxicities of Antibody-Drug Conjugates, Bispecific Antibodies, and CAR T-Cell Therapies. Am Soc Clin Oncol Educ Book 2025; 45:e473916. [PMID: 40294348 DOI: 10.1200/edbk-25-473916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Antibody-drug conjugates (ADCs), bispecific antibodies that engage T cells (BsAbs), and chimeric antigen receptor (CAR) T cells are widely used standard-of-care therapies that have revolutionized the treatment of lymphoid and plasma cell malignancies. With recent regulatory approvals, these therapies are poised to also revolutionize the treatment of common solid tumors and become a part of the everyday lexicon, the ABCs, of the practicing oncologist. Drawing from experience in hematology, we review the early, late, and rare toxicities of ADCs, BsAbs, and CAR T cells and provide general principles for their management.
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Chen DT, Goloubeva O, Rapoport AP, Dahiya S, Atanackovic D, Hardy N, Kocoglu M, Lutfi F, Alkhaldi H, Claiborne JP, Lee ST, Kline K, Law JY, Yared JA. CD19 CAR-T With Axicabtagene Ciloleucel in R/R Large B-Cell Lymphoma With/Without Prior Autologous Stem Cell Transplant. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025; 25:432-439. [PMID: 39865000 DOI: 10.1016/j.clml.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 12/24/2024] [Accepted: 12/28/2024] [Indexed: 01/28/2025]
Abstract
BACKGROUND Anti-CD19 CAR-T therapy has been a breakthrough in treatment of primary refractory or relapsed large B-cell lymphoma (r/r LBCL) and is poised to supplant previous second line of high dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). However, in clinical practice, high risk patients with chemoimmunotherapy sensitive disease continue to receive salvage chemoimmunotherapy or cannot access CAR-T in a timely manner and thus may still proceed to HDT/ASCT. Little is known about clinical outcomes of CAR-T in patients who receive HDT/ASCT compared to those who are transplant-naïve. DESIGN We conducted a retrospective study of patients with r/r LBCL who previously underwent HDT/ASCT or were transplant-naïve (n = 97) and received axicabtagene ciloleucel after at least 2 prior therapy lines between 1/1/2018 to 12/31/2021. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse/progression. RESULTS 82 (84.5%) patients were transplant-naïve and 15 (15.5%) previously received HDT/ASCT. No differences were found in the incidence of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, length of hospital admission, or incidence of cytopenia at day 30. 90-day response, PFS, OS, cumulative incidence of relapse/progression, and NRM were not different. Factors that adversely affected outcomes were prior bridging therapy, elevated LDH or thrombocytopenia at time of lymphodepleting chemotherapy, and worse ECOG performance status. CONCLUSION Prior treatment with HDT/ASCT does not compromise the safety and efficacy of anti-CD19 CAR-T therapy, suggesting a continued role for HDT/ASCT in treatment of select patients with r/r DLBCL.
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Immunotherapy, Adoptive/methods
- Retrospective Studies
- Antigens, CD19/immunology
- Antigens, CD19/therapeutic use
- Transplantation, Autologous/methods
- Aged
- Adult
- Hematopoietic Stem Cell Transplantation/methods
- Biological Products/therapeutic use
- Biological Products/pharmacology
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Affiliation(s)
- David T Chen
- Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD.
| | - Olga Goloubeva
- Department of Epidemiology and Public Health, Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD
| | - Aaron P Rapoport
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Saurabh Dahiya
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Djordje Atanackovic
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Nancy Hardy
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Mehmet Kocoglu
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Forat Lutfi
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Hanan Alkhaldi
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - John Preston Claiborne
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Seung Tae Lee
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Kathryn Kline
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Jennie Y Law
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
| | - Jean A Yared
- Transplantation & Cellular Therapy Program, Division of Hematology/Oncology, Department of Internal Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, MD
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3
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Cheloni G, Karagkouni D, Pita-Juarez Y, Torres D, Kanata E, Liegel J, Avigan Z, Saldarriaga I, Chedid G, Rallis K, Miles B, Tiwari G, Kim J, Mattie M, Rosenblatt J, Vlachos IS, Avigan D. Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire. Nat Commun 2025; 16:4819. [PMID: 40410132 DOI: 10.1038/s41467-025-59904-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 05/02/2025] [Indexed: 05/25/2025] Open
Abstract
While Chimeric Antigen Receptor (CAR) T cell therapy may result in durable remissions in recurrent large B cell lymphoma, persistence is limited and the mechanisms underlying long-term response are not fully elucidated. Using longitudinal single-cell immunoprofiling, here we compare the immune landscape in durable remission versus early relapse patients following CD19 CAR T cell infusion in the NCT02348216 (ZUMA-1) trial. Four weeks post-infusion, both cohorts demonstrate low circulating CAR T cells. We observe that long-term remission is associated with elevated native cytotoxic and proinflammatory effector cells, and post-infusion clonotypic expansion of effector memory T cells. Conversely, early relapse is associated with impaired NK cell cytotoxicity and elevated immunoregulatory cells, potentially dampening native T cell activation. Thus, we suggest that durable remission to CAR T is associated with a distinct T cell signature and pattern of clonotypic expansion within the native T cell compartment post-therapy, consistent with their contribution to the maintenance of response.
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MESH Headings
- Humans
- Immunotherapy, Adoptive/methods
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- T-Lymphocytes, Cytotoxic/immunology
- Lymphocyte Activation/immunology
- Antigens, CD19/immunology
- Killer Cells, Natural/immunology
- Male
- Female
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/immunology
- Middle Aged
- Receptors, Antigen, T-Cell
- Remission Induction
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Affiliation(s)
- Giulia Cheloni
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Dimitra Karagkouni
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Yered Pita-Juarez
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Daniela Torres
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Eleni Kanata
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Jessica Liegel
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Zachary Avigan
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Isabella Saldarriaga
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Georges Chedid
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Kathrine Rallis
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | | | | | - Jenny Kim
- Kite, a Gilead Company, Santa Monica, CA, USA
| | - Mike Mattie
- Kite, a Gilead Company, Santa Monica, CA, USA
| | - Jacalyn Rosenblatt
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Ioannis S Vlachos
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Spatial Technologies Unit, Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
| | - David Avigan
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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4
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Frigault MJ, Yao N, Berger TR, Wehrli M, Gallagher KME, Horick N, Graham CE, Jacobson CA, Chen YB, Leick MB, DeFilipp Z, El-Jawahri AR, Johnson PC, Dolaher M, Katsis K, Kim AI, Crombie J, Merryman RW, Cook D, Trailor M, Cho H, Jeffrey R, Shen R, Filosto S, Nater J, Getz G, Haradhvala NJ, Maus MV. Single-cell dynamics of breakthrough toxicities after anakinra prophylaxis for axicabtagene ciloleucel in lymphoma. Blood Adv 2025; 9:2122-2135. [PMID: 39928957 PMCID: PMC12051123 DOI: 10.1182/bloodadvances.2024015161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/09/2025] [Accepted: 01/22/2025] [Indexed: 02/12/2025] Open
Abstract
ABSTRACT Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy is limited by cytokine release syndrome (CRS) and neurotoxicity (NT). We sought to use once-daily prophylactic anakinra, an interleukin-1 (IL-1) receptor antagonist, to prevent CRS/NT that would require hospitalization (grade ≥2) in patients receiving axicabtagene ciloleucel for large-cell lymphoma, with the goal of facilitating outpatient therapy and management. Our study, in line with others, demonstrates that once-daily prophylactic anakinra is insufficient to prevent the development of toxicities that would require hospitalization in most patients. As part of the initial study design, we prospectively incorporated single-cell RNA sequencing to gain insight into the molecular immune signaling associated with breakthrough CRS and NT despite anakinra prophylaxis. In patients who developed breakthrough CRS or NT, we found that interferon gamma (IFN-γ) pathways and ligand-receptor activities were significantly enriched, as were cytokine levels of IFN-γ and CXCL10 in CD14+ monocytes. This correlated with increased IFN-γ and other cytokines in the peripheral blood. In infused CAR-T products, IL-4 and IL-10 anti-inflammatory pathways were negatively associated with grade ≥2 toxicities, regardless of anakinra treatment. These data identify IFN-γ as a potential key mechanism in CAR-T-associated toxicities, which is not inhibited by anakinra but may be otherwise targetable. This trial was registered at www.ClinicalTrials.gov as #NCT04150913.
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Affiliation(s)
- Matthew J. Frigault
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Ning Yao
- Harvard Medical School, Boston, MA
| | - Trisha R. Berger
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Marc Wehrli
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Kathleen M. E. Gallagher
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Nora Horick
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Charlotte E. Graham
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
| | - Caron A. Jacobson
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Yi-Bin Chen
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Mark B. Leick
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Zachariah DeFilipp
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Areej R. El-Jawahri
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - P. Connor Johnson
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Maria Dolaher
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Katelin Katsis
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Austin I. Kim
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Jennifer Crombie
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Reid W. Merryman
- Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA
| | - Daniella Cook
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Michael Trailor
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Hana Cho
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Richard Jeffrey
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
| | - Rhine Shen
- Kite, a Gilead Company, Santa Monica, CA
| | | | | | - Gad Getz
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | | | - Marcela V. Maus
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
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5
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Locke FL, Munoz JL, Tees MT, Lekakis LJ, de Vos S, Nath R, Stevens DA, Malik SA, Shouse GP, Hamadani M, Oluwole OO, Perales MA, Miklos DB, Fisher PW, Feng A, Navale L, Le Gall JB, Neelapu SS. Allogeneic Chimeric Antigen Receptor T-Cell Products Cemacabtagene Ansegedleucel/ALLO-501 in Relapsed/Refractory Large B-Cell Lymphoma: Phase I Experience From the ALPHA2/ALPHA Clinical Studies. J Clin Oncol 2025; 43:1695-1705. [PMID: 39946666 PMCID: PMC12058369 DOI: 10.1200/jco-24-01933] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 01/17/2025] [Accepted: 01/31/2025] [Indexed: 04/16/2025] Open
Abstract
PURPOSE Off-the-shelf, allogeneic CD19 chimeric antigen receptor (CAR) T-cell products may improve access to treatment versus autologous ones. We report the phase I experience of the allogeneic CD19 CAR T-cell product cemacabtagene ansegedleucel (cema-cel) and its predecessor, ALLO-501, in CD19 CAR T-naïve patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). METHODS In the ALPHA2/ALPHA studies, the safety and efficacy of allogeneic CD19 CAR T cells were evaluated in CD19 CAR T treatment-naïve patients with R/R LBCL. Patients received healthy donor-derived, human leukocyte antigen-unmatched cema-cel/ALLO-501 following a 3-day lymphodepletion regimen of fludarabine (30 mg/m2 once daily), cyclophosphamide (300 or 500 mg/m2 once daily), and escalating doses of the anti-CD52 monoclonal antibody, ALLO-647. RESULTS As of September 26, 2024, 33 CD19 CAR T-naïve patients with LBCL (median age, 66 years; median number of previous therapies, 3) received allogeneic CAR T cells. CAR T-cell expansion was observed following infusion, with persistence observed up to 4 months. The overall and complete response (CR) rates were 58% and 42%, respectively; the median duration of response in patients with a CR was 23.1 months. The most common treatment-emergent adverse events were hematologic toxicities. No cases of graft-versus-host disease, immune effector cell-associated neurotoxicity syndrome, or grade ≥3 cytokine release syndrome were reported. CONCLUSION Allogeneic CD19 CAR T cells demonstrated promising overall and durable CR rates with a manageable safety profile in CD19 CAR T-naïve patients with R/R LBCL, supporting additional evaluation of cema-cel in patients with LBCL.
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MESH Headings
- Adult
- Aged
- Female
- Humans
- Male
- Middle Aged
- Antigens, CD19/immunology
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplasm Recurrence, Local/immunology
- Receptors, Chimeric Antigen/immunology
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Affiliation(s)
| | | | - Michael T. Tees
- Colorado Blood Cancer Institute/Sarah Cannon Research Institute, Denver, CO
| | - Lazaros J. Lekakis
- University of Miami Health System, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Sven de Vos
- University of California, Los Angeles, Los Angeles, CA
| | | | | | | | | | | | | | | | | | | | - Amy Feng
- Allogene Therapeutics, San Francisco, CA
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6
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Zhang Z, Zheng J, Liang Y, Wu Q, Ding C, Ma L, Su L. Hematologic and lymphatic disorders associated with chimeric antigen receptor T-cell therapy: a pharmacovigilance analysis of the FDA adverse event reporting system (FAERS) database. BMC Cancer 2025; 25:846. [PMID: 40346502 PMCID: PMC12063233 DOI: 10.1186/s12885-025-14227-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 04/25/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND As the application of Chimeric Antigen Receptor T-cell (CAR-T) therapy in cancer treatment becomes increasingly widespread, associated hematologic and lymphatic system adverse events pose significant challenges to its clinical use. Therefore, we aim to comprehensively investigate and summarize the hematologic and lymphatic system AEs associated with CAR-T therapy. METHODS We extracted CAR-T-related adverse event reports from the FDA Adverse Event Reporting System (FAERS) database for the period from August 2017 to December 2023. Disproportionality analysis using the Reporting Odds Ratio (ROR) and Information Component (IC) was performed to identify CAR-T-associated hematologic and lymphatic system AEs. We employed LASSO regression analysis to identify hematologic and lymphatic system AEs associated with mortality. RESULTS In the FAERS database, we identified 1,600 individual case safety reports of hematologic and lymphatic system AEs related to CAR-T therapy. The median age of patients was 57 years (interquartile range [IQR] 32-67), with fatal outcomes in 15.3% of cases. We identified 25 significant adverse event signals associated with CAR-T therapy. B-cell aplasia (ROR025 = 1054.56, IC025 = 4.74), cytopenia (ROR025 = 17.27, IC025 = 3.81), hypofibrinogenemia (ROR025 = 100.18, IC025 = 2.46), anemia (ROR025 = 1.87, IC025 = 0.59), febrile bone marrow aplasia (ROR025 = 55.32, IC025 = 2.70), and pancytopenia (ROR025 = 7.18, IC025 = 1.42) were the most significant hematologic and lymphatic system AEs for tisa-cel, axi-cel, brexu-cel, liso-cel, ide-cel, and cilta-cel, respectively. Most hematologic and lymphatic system AEs occurred within 10 days post-CAR-T infusion. Hematologic and lymphatic system AEs were associated with a mortality rate of 15.3%. Our analysis revealed 15 hematologic and lymphatic system AEs closely associated with mortality in CAR-T-treated patients, including splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia. CONCLUSIONS Our study found that hematologic and lymphatic system AEs were more closely associated with anti-CD19 CAR-T and CAR-T containing CD28. Splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia were identified as hematologic and lymphatic system AEs that, while less frequently reported clinically, were highly associated with mortality.
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Affiliation(s)
- Zhenpo Zhang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Jingping Zheng
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Yankun Liang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Qimin Wu
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Chufeng Ding
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Lin Ma
- School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China.
- Medical Department, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, China.
| | - Ling Su
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China.
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7
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Cao G, Hu Y, Pan T, Tang E, Asby N, Althaus T, Wan J, Riedell PA, Bishop MR, Kline JP, Huang J. Two-stage CD8 + CAR T-cell differentiation in patients with large B-cell lymphoma. Nat Commun 2025; 16:4205. [PMID: 40328775 PMCID: PMC12055983 DOI: 10.1038/s41467-025-59298-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/16/2025] [Indexed: 05/08/2025] Open
Abstract
Advancements in chimeric antigen receptor (CAR) T-cell therapy for treating diffuse large B-cell lymphoma (DLBCL) have been limited by an incomplete understanding of CAR T-cell differentiation in patients. Here, we show via single-cell, multi-modal, and longitudinal analyses, that CD8+ CAR T cells from DLBCL patients successfully treated with axicabtagene ciloleucel undergo two distinct waves of clonal expansion in vivo. The first wave is dominated by an exhausted-like effector memory phenotype during peak expansion (day 8-14). The second wave is dominated by a terminal effector phenotype during the post-peak persistence period (day 21-28). Importantly, the two waves have distinct ontogeny from the infusion product and are biologically uncoupled. Precursors of the first wave exhibit more effector-like signatures, whereas precursors of the second wave exhibit more stem-like signatures. We demonstrate that CAR T-cell expansion and persistence are mediated by clonally, phenotypically, and ontogenically distinct CAR T-cell populations that serve complementary clinical purposes.
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Affiliation(s)
- Guoshuai Cao
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA
| | - Yifei Hu
- Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Tony Pan
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA
| | - Erting Tang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA
| | - Nicholas Asby
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA
| | - Thomas Althaus
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, 60637, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Peter A Riedell
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
- Committee on Cancer Biology, University of Chicago, Chicago, IL, 60637, USA
| | - Michael R Bishop
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Justin P Kline
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
- Committee on Cancer Biology, University of Chicago, Chicago, IL, 60637, USA
- Committee on Immunology, University of Chicago, Chicago, IL, 60637, USA
| | - Jun Huang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA.
- Committee on Cancer Biology, University of Chicago, Chicago, IL, 60637, USA.
- Committee on Immunology, University of Chicago, Chicago, IL, 60637, USA.
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8
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Zhang D, Wang Z, Inuzuka H, Wei W. Proximity-induced membrane protein degradation for cancer therapies. RSC Med Chem 2025:d5md00141b. [PMID: 40365034 PMCID: PMC12066958 DOI: 10.1039/d5md00141b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
The selective modulation of membrane proteins presents a significant challenge in drug development, particularly in cancer therapies. However, conventional small molecules and biologics often face significant hurdles in effectively targeting membrane-bound proteins, largely due to the structural complexity of these proteins and their involvement in intricate cellular processes. In light of these limitations, proximity-induced protein modulation has recently emerged as a transformative approach. It leverages molecule-induced proximity strategies to commandeer endogenous cellular machinery for precise protein manipulation. One of these modulatory strategies is protein degradation, wherein membrane-targeting degraders derived from proximity-induction approaches offer a unique therapeutic avenue by inducing the irreversible removal of key oncogenic and immune-regulatory proteins to combat cancer. This review explores the fundamental principles underlying proximity-driven membrane protein degradation, highlighting key strategies such as LYTACs, PROTABs, TransTACs, and IFLD that are reshaping targeted cancer therapy. We discuss recent technological advancements in the application of proximity-induced degraders across breast cancer, lung cancer, immunotherapy, and other malignancies, underscoring how these innovative approaches have demonstrated significant therapeutic potential. Lastly, while these emerging technologies offer significant promise, they still face substantial limitations, including drug delivery, selectivity, and resistance mechanisms that need to be addressed to achieve successful clinical translation.
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Affiliation(s)
- Dingpeng Zhang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
| | - Zhen Wang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
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9
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Canelo-Vilaseca M, Sabbah M, Di Blasi R, Cristinelli C, Sureda A, Caillat-Zucman S, Thieblemont C. Lymphodepletion chemotherapy in chimeric antigen receptor-engineered T (CAR-T) cell therapy in lymphoma. Bone Marrow Transplant 2025; 60:559-567. [PMID: 40148484 PMCID: PMC12061774 DOI: 10.1038/s41409-025-02539-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/29/2024] [Accepted: 02/17/2025] [Indexed: 03/29/2025]
Abstract
The development of chimeric antigen receptor (CAR) T-cells, engineered from peripheral T-lymphocytes of a patient with lymphoma, in order to specifically target tumor cells, has been a revolution in adoptive cell therapy (ACT). As outlined in this review, ACT was initiated by hematopoietic cell transplantation (HSCT) and re-injection of interleukin-boosted tumor-infiltrating lymphocytes (TIL). The innovative venture of genetically modifying autologous peripheral T-cells to target them to cell-surface tumoral antigens through an antibody-derived structure (i.e. independent of major histocompatibility antigen presentation, physiologically necessary for T-cell activation), and intracytoplasmic T-cell costimulatory peptides, via a novel membrane CAR, has been an outstanding breakthrough. Here, focusing on B-cell hematological malignancies and mostly non-Hodgkin lymphoma, attention is brought to the importance of providing an optimal microenvironment for such therapeutic cells to proliferate and positively develop anti-tumoral cytotoxicity. This, perhaps paradoxically, implies a pre-infusion step of deep lymphopenia and deregulation of immunosuppressive mechanisms enhanced by tumoral cells. Fludarabine and cyclophosphamide appear to be the most efficient lymphodepletive drugs in this context, dosage being of importance, as will be illustrated by a thorough literature review.
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Affiliation(s)
- Marta Canelo-Vilaseca
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
| | - Mohamad Sabbah
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
- Université Paris Cité, Paris, France
| | - Roberta Di Blasi
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
| | - Caterina Cristinelli
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
| | - Anna Sureda
- Clinical Hematology Department, Institut Català d'Oncologia-L'Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
| | - Sophie Caillat-Zucman
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Laboratoire d'Immunologie, Paris, France
| | - Catherine Thieblemont
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France.
- Université Paris Cité, Paris, France.
- Inserm U1153, Hôpital Saint Louis, Paris, France.
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10
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Ossami Saidy A, Peczynski C, Thieblemont C, Daskalakis M, Wehrli M, Beauvais D, Finke J, Schorb E, Vandenberghe P, Berning P, Stelljes M, Ayuk F, Ram R, Von Bonin M, Dreger P, Bethge W, Kuhnl A, Jost L, Stölzel F, von Tresckow B, Renner C, Fuhrmann S, Galimard J, Michel E, Bazarbachi A, Balari AS, Schmitz N, Glass B. Efficacy and safety of CAR T-cell therapy in patients with primary or secondary CNS lymphoma: A study on behalf of the EBMT and the GoCART coalition. Hemasphere 2025; 9:e70146. [PMID: 40400509 PMCID: PMC12093105 DOI: 10.1002/hem3.70146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/13/2025] [Accepted: 04/04/2025] [Indexed: 05/23/2025] Open
Abstract
Patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary central nervous system (CNS) lymphoma (SCNSL) face a dismal prognosis. They have been excluded from most clinical CAR T-cell trials as investigators feared an increased risk for severe immune effector cell-associated neurotoxicity (ICANS). To investigate the potential of anti-CD19 CAR T-cell therapy (CART) in such patients, we analyzed data of 100 patients with CNS manifestation treated with CART between January 2018 and July 2023 and reported to European Society for Blood and Marrow Transplantation. Median age was 62 years. Of patients, 58% had failed ≥3 treatment lines, and 40% had received autologous stem-cell transplantation before CART. Fifty-nine patients received axicabtagene ciloleucel, 38 patients were treated with tisagenlecleucel, three patients received other products. At the time of CART, 67 patients had active CNS disease. Overall and progression-free survival (PFS) at 24 months were 37% and 28%. Relapse incidence (RI) at 24 months was 59%, whereas non-relapse mortality at 1 year was 7%. Cytokine release syndrome (CRS) and ICANS of any grade occurred in 83% and 42% of patients, respectively. CRS grade 3 occurred in 11 and ICANS grades 3-4 in 17 patients. Two patients died of neurotoxicity. Elevated lactate dehydrogenase was an independent risk factor for RI and PFS (hazard ratio [HR] 2.4, p = 0.003; HR: 1.9, p = 0.016). Patients with ECOG 2-3 had a significantly increased risk for the development of ICANS (HR 2.68, p = 0.002). These data support the implementation of CART as treatment for patients with r/r PCNSL and SCNSL.
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Affiliation(s)
- Anna Ossami Saidy
- Department of Hematology and Cell TherapyHelios Klinikum Berlin‐BuchBerlinGermany
| | - Christophe Peczynski
- EBMT Paris Study OfficeEuropean Society for Blood and Marrow TransplantationParisFrance
| | - Catherine Thieblemont
- University Paris Cité, Assistance Publique‐Hôpitaux de Paris Hemato‐oncology, INSERM U1153, Hôpital Saint‐LouisParisFrance
| | - Michael Daskalakis
- Department of Hematology and Central Hematology LaboratoryInselspital, Bern University HospitalBernSwitzerland
| | - Marc Wehrli
- Department of Medical OncologyInselspital, Bern University HospitalBernSwitzerland
| | - David Beauvais
- Department of HematologyCentre Hospitalier Universitaire de LilleLilleFrance
| | - Jürgen Finke
- Department of Medicine I, Faculty of Medicine, Medical Center‐University of FreiburgUniversity of FreiburgFreiburgGermany
| | - Elisabeth Schorb
- Department of Medicine I, Faculty of Medicine, Medical Center‐University of FreiburgUniversity of FreiburgFreiburgGermany
| | | | - Philipp Berning
- Department of HematologyUniversity Hospitals LeuvenLeuvenBelgium
| | | | - Francis Ayuk
- Department of Stem Cell TransplantationUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Ron Ram
- Bone Marrow Transplantation Unit, Faculty of Medicine, Tel Aviv Sourasky Medical CenterTel Aviv UniversityTel AvivIsrael
| | - Malte Von Bonin
- Medical Clinic IUniversity Hospital Carl Gustav Carus, Technische Universität DresdenDresdenGermany
| | - Peter Dreger
- Department of Medicine VUniversity of HeidelbergHeidelbergGermany
| | - Wolfgang Bethge
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology, and RheumatologyUniversity Hospital TübingenTübingenGermany
| | - Andrea Kuhnl
- Department of HaematologyKing's College HospitalLondonUnited Kingdom
| | - Lasse Jost
- Department of Medicine II, Division for Stem Cell Transplantation and Cellular ImmunotherapyUniversity Cancer Center Schleswig‐Holstein, University Hospital Schleswig‐Holstein KielKielGermany
| | - Friedrich Stölzel
- Department of Medicine II, Division for Stem Cell Transplantation and Cellular ImmunotherapyUniversity Cancer Center Schleswig‐Holstein, University Hospital Schleswig‐Holstein KielKielGermany
| | - Bastian von Tresckow
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer Consortium (DKTK partner site Essen)University Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Christoph Renner
- Division of Hematology/OncologyClinic HirslandenZurichSwitzerland
| | | | | | - Eva Michel
- EBMT Paris Study OfficeEuropean Society for Blood and Marrow TransplantationParisFrance
| | - Ali Bazarbachi
- Department of Internal Medicine, Bone Marrow Transplantation ProgramUniversity of BeirutBeirutLebanon
| | - Anna Sureda Balari
- Clinical Hematology Department, Institut Català d'Oncologia‐Hospitalet, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)University of BarcelonaBarcelonaSpain
| | - Norbert Schmitz
- Department of Medicine AUniversity Hospital MuensterMuensterGermany
| | - Bertram Glass
- Department of Hematology and Cell TherapyHelios Klinikum Berlin‐BuchBerlinGermany
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11
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Mulvey A, Trueb L, Coukos G, Arber C. Novel strategies to manage CAR-T cell toxicity. Nat Rev Drug Discov 2025; 24:379-397. [PMID: 39901030 DOI: 10.1038/s41573-024-01100-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 02/05/2025]
Abstract
The immune-related adverse events associated with chimeric antigen receptor (CAR)-T cell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-T cell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on-off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloid cell-intrinsic druggable targets and cellular engineering strategies to develop safer CAR-T cells.
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Affiliation(s)
- Arthur Mulvey
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Lionel Trueb
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - George Coukos
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Caroline Arber
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland.
- Departments of Oncology UNIL-CHUV and Laboratory Medicine and Pathology, Service and Central Laboratory of Hematology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
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12
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Shu J, Xie W, Mei C, Ren A, Ke S, Ma M, Zhou Z, Hu Y, Mei H. Safety and clinical efficacy of Relmacabtagene autoleucel (relma-cel) for systemic lupus erythematosus: a phase 1 open-label clinical trial. EClinicalMedicine 2025; 83:103229. [PMID: 40386685 PMCID: PMC12083988 DOI: 10.1016/j.eclinm.2025.103229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 04/15/2025] [Accepted: 04/15/2025] [Indexed: 05/20/2025] Open
Abstract
Background Systemic lupus erythematosus (SLE) is a classic systemic autoimmune disease mediated by autoantibodies. Chimeric antigen receptor T (CAR-T) cell therapy, known for its success in cancer, has shown promise in achieving durable B cell depletion and long-term remission in SLE. Relmacabtagene autoleucel (relma-cel) is the second anti-CD19 CAR-T product approved for marketing by the National Medical Products Administration (NMPA) in China and demonstrates its long-term efficacy in relapsed/refractory (r/r) large B cell lymphoma (LBCL). We report the results from a phase I open-label clinical trial of relma-cel in treating patients with moderately to severely active SLE. Methods Eligible patients were aged 18-70 years, a ≥6-month history of SLE, and the disease had to remain active after at least 2 months of stable SLE standard treatment prior to screening. We evaluated four dose levels (DL) of relma-cel in a dose-escalation scheme: total dose of 25 × 106, 50 × 106, 75 × 106, and 100 × 106 anti-CD19 CAR-T cells. All patients received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. The primary endpoints were the incidence of dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included the evaluation of standard cellular pharmacokinetic parameters, the SLE Responder Index (SRI) response rate, and changes from baseline in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI), British Isles Lupus Assessment Group 2004 (BILAG-2004) and Physician's Global Assessment (PGA) scores post-treatment. This trial is registered with ClinicalTrials.gov, NCT05765006. Findings Between March 28, 2023 and April 8, 2024, a total of 12 patients were screened for study inclusion, of whom 8 patients were enrolled and assigned to different dose levels: 25 × 106 cells (n = 3), 50 × 106 cells (n = 2), 75 × 106 cells (n = 2), and 100 × 106 cells (n = 1). No DLT was observed. The most common AEs included cytopenia (n = 8, 100%), cytokine release syndrome (CRS) (n = 7, 88%) and hypogammaglobulinemia (n = 5, 63%). No Grade 3 or higher immune effector cell-associated hematotoxicity (ICAHT) occurred. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. CRS was predominantly grade 1, characterized mainly by mild fever and muscle soreness. A rare severe adverse event, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), was observed in one patient. The median time to reach maximum CAR-T cell expansion (Cmax) was 9.5 days (range: 8-22 days). The median Cmax was 18.74 CD3+CAR+ cells/μL (range: 7.94-228.36) by flow cytometry and 81766.5 copies/μg DNA (range: 50,979-1,140,893) by quantitative real-time PCR (qPCR). In all patients treated with relma-cel, CD19+ B cells in peripheral blood were almost completely depleted within 11-15 days and gradually recovered within 2-6 months. All patients achieved SRI response. Four patients achieved Definition of Remission in SLE (DORIS) remission criteria and seven patients reached the Lupus Low Disease Activity State (LLDAS) criteria within 1-4 months following relma-cel infusion. Interpretation This study preliminarily demonstrated that relma-cel is an effective and safe CAR-T product for the treatment of patients with moderately to severely active SLE, providing valuable clinical insights into the management of rare complications. Further studies with larger sample sizes are warranted. Funding National Natural Science Foundation of China.
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Affiliation(s)
- Jinhui Shu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Wei Xie
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Chunli Mei
- Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Anqi Ren
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Sha Ke
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Meilin Ma
- JW Therapeutics (Shanghai) Co. Ltd, Shanghai, China
| | - Zisong Zhou
- JW Therapeutics (Shanghai) Co. Ltd, Shanghai, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Heng Mei
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
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13
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Pagliuca S, Malard F, Mooyaart JE, Daskalakis M, Gabellier L, Yakoub-Agha I, Ram R, Besley C, Forcade E, Vucinic V, Corral LL, Vydra J, von Tresckow B, Amat P, Amrolia P, Vandenberghe P, Stölzel F, Sica S, Rubio MT, Hoogenboom JD, Ortiz-Maldonado V, Nagler A, Kuball J, Chabannon C, Ruggeri A. The landscape of immune monitoring in CAR-T cell therapy: A comprehensive review and survey study by the Cellular Therapy and Immunobiology Working Party of the EBMT. Blood Rev 2025; 71:101272. [PMID: 39986989 DOI: 10.1016/j.blre.2025.101272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/20/2025] [Accepted: 02/13/2025] [Indexed: 02/24/2025]
Abstract
Immune monitoring of cell therapies is a complex and evolving topic, particularly in the rapid expanding field of chimeric antigen receptor T (CAR-T) cell applications. Defining essential, recommended, and optional immune monitoring data post-CAR-T cell infusion is crucial to improve patient outcomes and inform post-treatment decisions. To address this gap, we conducted a survey-based study across centers affiliated with the European Society for Blood and Marrow Transplantation (EBMT), focusing on patients treated with European Medicines Agency (EMA)-approved CAR-T products. Building on a thorough review of the literature, we mapped the current landscape of immune monitoring practices and assessed their impact on clinical management. By defining the state of the art in the field, this work marks an initial step towards a structured harmonization process potentially able to enhance the management and outcomes of patients undergoing these immune cell therapies.
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Affiliation(s)
- Simona Pagliuca
- Hematology department, Nancy University Hospital, UMR 7365, CNRS, University of Lorraine, Vandoeuvre-lès-Nancy, France.
| | - Florent Malard
- Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France
| | | | | | | | | | - Ron Ram
- Tel Aviv Sourasky Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Caroline Besley
- University Hospitals Bristol and Weston NHSFT, Bristol, United Kingdom
| | | | | | - Lucía López Corral
- Hospital Clínico, CIBERONC. Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - Jan Vydra
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Bastian von Tresckow
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Paula Amat
- Hospital Clínico Universitario-INCLIVA de, Valencia, Spain
| | - Persis Amrolia
- Great Ormond Street Children's Hospital Paediatrics, London, United Kingdom
| | | | - Friedrich Stölzel
- University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany
| | | | - Marie Thérèse Rubio
- Hematology department, Nancy University Hospital, UMR 7365, CNRS, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | | | | | - Arnon Nagler
- Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Jürgen Kuball
- University Medical Center Utrecht, Utrecht, the Netherlands
| | - Christian Chabannon
- Institut Paoli-Calmettes Comprehensive Cancer Centre and Module Biothérapies du Centre d'Investigations Cliniques de Marseille, INSERM-Aix-Marseille Université-AP-HM-IPC, CBT-1409 Marseille, France
| | - Annalisa Ruggeri
- San Raffaele Scientific Institute, Hematology and Bone Marrow Transplantation Unit, Milan, Italy
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14
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Gile JJ, Mondello P, Wang Z, Li Y, Bansal R, Gandhi S, Zhang H, Babadi E, Martinez K, McCoy G, Shao Z, Regan K, Hathcock MA, Wang P, Wang J, Al Saleh AS, Ruan G, Ansell SM, Bennani NN, Johnston PB, Paludo J, Villasboas-Bisneto JC, Khurana A, Durani U, Wang Y, Hampel PJ, Rosenthal A, Munoz J, Moreno E, Castro JE, Murthy HS, Kharfan-Dabaja M, Kenderian SS, Kim JJ, Shen R, Mattie M, Lin Y, Witzig TE. Hypomagnesemia in lymphoma patients receiving CAR T therapy correlates with immune dysfunction and decreased survival. Exp Hematol Oncol 2025; 14:63. [PMID: 40307941 PMCID: PMC12044716 DOI: 10.1186/s40164-025-00623-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/24/2025] [Indexed: 05/02/2025] Open
Abstract
BACKGROUND Hypomagnesemia has been correlated with inferior outcomes in patients with large B cell lymphoma (LBCL) undergoing stem cell transplants. As T-cell and myeloid cell dysfunction have been associated with low magnesium conditions, we investigated whether serum magnesium (Mg) levels could predict clinical outcomes in LBCL patients who received chimeric antigen receptor T-cell therapy. METHODS Patients with LBCL who received axi-cel under the ZUMA-1 trial or as FDA approved therapy at Mayo Clinic were examined. Serum samples were obtained at specified time points and cytokine analysis was performed. Single cell RNA sequencing was performed on peripheral blood mononuclear cells. The Student T-test, Kruskal Wallis, or Fisher's Exact Tests were used to compare differences in demographics across Mg levels. Survival curves were plotted using the Kaplan-Meier methodology and compared using the Wilcoxon test. RESULTS We found that hypomagnesemia before lymphodepletion chemotherapy predicted inferior progression-free and overall survival in the pivotal study ZUMA-1 (NCT02348216). These results were validated in an independent cohort of LBCL patients receiving axicabtagene ciloleucel (axi-cel) at Mayo Clinic. Hypomagnesemia correlated with increased inflammatory serum markers and cytokine levels including ferritin, IL-6, IL1Ra, IL-8, and MIP1a. scRNAseq analysis unveiled altered immune interactions between monocytes and T cells with a concordant immune suppressive transcriptome. CONCLUSIONS Hypomagnesemia at the time of CAR-T infusion is associated with an unfavorable inflammatory profile and decreased response and survival in LBCL patients receiving axi-cel. These findings suggest a potentially actionable prognostic factor for patients with large cell lymphoma undergoing CAR-T.
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Affiliation(s)
- Jennifer J Gile
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Patrizia Mondello
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Zixing Wang
- KITE, a Gilead Company, Santa Monica, CA, 90404, USA
| | - Ying Li
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Radhika Bansal
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Sangeetha Gandhi
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Henan Zhang
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Elham Babadi
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Kodi Martinez
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Gabrielle McCoy
- Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Zuoyi Shao
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Kevin Regan
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Matthew A Hathcock
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Panwen Wang
- Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Junwen Wang
- Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Abdullah S Al Saleh
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Gordon Ruan
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Stephen M Ansell
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - N Nora Bennani
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Patrick B Johnston
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Jonas Paludo
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | | | - Arushi Khurana
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Urshila Durani
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Yucai Wang
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Paul J Hampel
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Allison Rosenthal
- Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Javier Munoz
- Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Eider Moreno
- Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Januario E Castro
- Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Hemant S Murthy
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
| | | | - Saad S Kenderian
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA
| | - Jenny J Kim
- KITE, a Gilead Company, Santa Monica, CA, 90404, USA
| | - Rhine Shen
- KITE, a Gilead Company, Santa Monica, CA, 90404, USA
| | - Mike Mattie
- KITE, a Gilead Company, Santa Monica, CA, 90404, USA
| | - Yi Lin
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA.
- Division of Experimental Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
| | - Thomas E Witzig
- Division of Hematology, Mayo Clinic, 200 SW First Street, Rochester, MN, 55905, USA.
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15
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Azmal M, Miah MM, Prima FS, Paul JK, Haque ASNB, Ghosh A. Advances and challenges in cancer immunotherapy: Strategies for personalized treatment. Semin Oncol 2025; 52:152345. [PMID: 40305928 DOI: 10.1016/j.seminoncol.2025.152345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 05/02/2025]
Abstract
Cancer immunotherapy has transformed oncology by harnessing the immune system to specifically target cancer cells, offering reduced systemic toxicity compared to traditional therapies. This review highlights key strategies, including adoptive cell transfer (ACT), immune checkpoint inhibitors, oncolytic viral (OV) therapy, monoclonal antibodies (mAbs), and mRNA-based vaccines. ACT reinfuses enhanced immune cells like tumor-infiltrating lymphocytes (TILs) to combat refractory cancers, while checkpoint inhibitors (eg, PD-1 and CTLA-4 blockers) restore T-cell activity. OV therapy uses engineered viruses (eg, T-VEC) to selectively lyse cancer cells, and advanced mAbs improve targeting precision. mRNA vaccines introduce tumor-specific antigens to trigger robust immune responses. Despite significant progress, challenges like immune-related side effects, high costs, and immunosuppressive tumor microenvironments persist. This review underscores the need for combination strategies and precision medicine to overcome these barriers and maximize the potential of immunotherapy in personalized cancer treatment.
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Affiliation(s)
- Mahir Azmal
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Md Munna Miah
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Fatema Sultana Prima
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Jibon Kumar Paul
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Anm Shah Newaz Been Haque
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Ajit Ghosh
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh.
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16
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Milunović V, Dragčević D, Bogeljić Patekar M, Mandac Smoljanović I, Gašparov S. The Improving Outcomes in Relapsed-Refractory Diffuse Large B Cell Lymphoma: The Role of CAR T-Cell Therapy. Curr Treat Options Oncol 2025:10.1007/s11864-025-01305-9. [PMID: 40293655 DOI: 10.1007/s11864-025-01305-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 04/30/2025]
Abstract
OPINION STATEMENT Diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) is the most common aggressive lymphoma and can be cured with CHOP-R immunochemotherapy in 60% of cases. The second-line therapy includes salvage regimens followed by autologous stem cell transplantation (ASCT), which offers a cure to a minority of patients due to limitations in efficacy and eligibility. These data present the unmet need in the field, and this review article focuses on how second-generation chimeric antigen receptor T (CAR T) cell therapy targeting CD19 antigen may improve the outcomes with relapsed/refractory DLBCL. In heavily pretreated patients, who have dismal outcomes with conventional therapy, all three approved products-tisangenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel) have shown durable, unprecedented complete responses with the potential for cure. When compared to salvage regimens and ASCT as the standard of care, axi-cel and liso-cel, unlike tisa-cel, have demonstrated superiority in long-term control. In ASCT-ineligible r/r DLBCL, liso-cel has shown a favourable benefit-risk ratio. Regarding safety, two adverse events of interest have emerged: cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, both of which are manageable. Real-world evidence reflects the results of pivotal trials while favouring axi-cel in heavily pretreated patients, albeit with higher toxicity. The main barrier to the implementation of this treatment modality is the cost associated with the process of CAR T therapy, along with complications and reimbursement issues. However, the barriers can be overcome, and CAR T therapy has the potential to become the standard of care in relapsed/refractory DLBCL. Furthermore, with advances in the scientific engineering of CAR products and the understanding of novel treatment modalities currently being tested in clinical trials, we believe that targeted cellular therapy will become the future of relapsed/refractory DLBCL treatment.
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Affiliation(s)
- Vibor Milunović
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia.
| | - Dora Dragčević
- Division of Hematology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia
| | | | | | - Slavko Gašparov
- School of Medicine in Zagreb, University of Zagreb, Zagreb, Croatia
- Clinical Department of Cytology and Pathology, Clinical Hospital Merkur, Zagreb, Croatia
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17
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Lynch SM, Richards CE, Ui Mhaonaigh A, Lynam-Lennon N, Eustace AJ, Allott EH, Robson T, Marcone S. Translating Basic Science Discoveries into Clinical Advances: Highlights from the EACR-AACR-IACR 2024 Conference in Celebration of Irish Association for Cancer Research's 60th Anniversary. Cancers (Basel) 2025; 17:1420. [PMID: 40361346 PMCID: PMC12071098 DOI: 10.3390/cancers17091420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
The EACR-AACR-IACR 2024 Basic and Translational Research Conference, held in Dublin, Ireland, from 27th-29th February, 2024, marked a significant milestone as part of the 60th anniversary celebrations of the Irish Association for Cancer Research (IACR). Organized in collaboration with the European Association for Cancer Research (EACR) and the American Association for Cancer Research (AACR), this prestigious event brought together leading experts in oncology research from around the world. The conference provided a platform for cutting-edge discussions on the latest advancements in immunotherapy, drug combinations, cell-based therapies, liquid biopsies, epigenetics, tumour microenvironment, and novel drug targets. With keynote lectures from esteemed researchers such as Kevan Shokat, Jerome Galon, Suzanne Topalian, and Scott Lowe, the conference facilitated knowledge exchange and fostered international collaboration in the pursuit of improved cancer treatments. The report highlights the key sessions, research breakthroughs, and discussions that shaped this landmark event.
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Affiliation(s)
- Seodhna M. Lynch
- Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Altnagelvin Area Hospital, Glenshane Road, Londonderry BT47 6SB, UK;
| | - Cathy E. Richards
- School of Dentistry, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Aisling Ui Mhaonaigh
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland; (A.U.M.); (N.L.-L.)
| | - Niamh Lynam-Lennon
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland; (A.U.M.); (N.L.-L.)
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, W23 NPY6 Maynooth, Ireland
| | - Alex J. Eustace
- Life Science Institute, School of Biotechnology, Dublin City University, D09 NR58 Dublin, Ireland;
| | - Emma H. Allott
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK;
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Simone Marcone
- UCD School of Biology and Environmental Science, University College Dublin, D04 N2E5 Dublin, Ireland;
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18
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Wu A, Zhang T, Yu H, Cao Y, Zhang R, Shao R, Liu B, Chen L, Xu K, Chen W, Ho J, Shi X. Mechanisms underlying resistance to CAR-T cell therapy and strategies for enhancement. Cytokine Growth Factor Rev 2025:S1359-6101(25)00045-0. [PMID: 40340171 DOI: 10.1016/j.cytogfr.2025.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/19/2025] [Accepted: 04/19/2025] [Indexed: 05/10/2025]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a revolutionary approach in the treatment of hematological malignancies, including acute lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. Despite its promise, the clinical efficacy is often hampered by transient efficacy and subsequent relapse, which curtail the long-term success of this treatment. Current research focuses on overcoming these obstacles by exploring multitarget strategies and optimizing CAR-T cell design. This review summarizes recent insights into the resistance mechanisms associated with CAR-T cell therapy, and delineates emerging strategies for optimized CAR construction, including targeting multiple antigens, improving CAR design, and enhancing T-cell persistence. The goal is to provide a comprehensive overview of the field's current landscape to guide future research and the clinical application of CAR-T cell therapies.
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Affiliation(s)
- Anran Wu
- Department of Hematology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China; The Second Clinical Medical School of Nanjing Medical University, Nanjing 210011, China
| | - Tingying Zhang
- Department of Hematology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China; The Second Clinical Medical School of Nanjing Medical University, Nanjing 210011, China
| | - Hongkai Yu
- Department of Hematology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China; The Second Clinical Medical School of Nanjing Medical University, Nanjing 210011, China
| | - Yuyue Cao
- Department of Hematology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China; The Second Clinical Medical School of Nanjing Medical University, Nanjing 210011, China
| | - Rui Zhang
- Department of Hematology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China; The Second Clinical Medical School of Nanjing Medical University, Nanjing 210011, China
| | - Ruonan Shao
- Department of Hematology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China
| | - Bofeng Liu
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Liting Chen
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Xu
- Department of Hematology, Blood Diseases Institute, Key Laboratory of Bone Marrow Stem Cells, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Wei Chen
- Department of Hematology, Blood Diseases Institute, Key Laboratory of Bone Marrow Stem Cells, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
| | - Jinyuan Ho
- Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, China.
| | - Xiaofeng Shi
- Department of Hematology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China; The Second Clinical Medical School of Nanjing Medical University, Nanjing 210011, China.
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19
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Mokhtari S, Asquith JM, Kareem SS, Bachmeier CA, Pina Y, Faramand RG, Kim Y, Peguero EN, Sahebjam S, Jaffer MH, Iacono DP, Jain MD, Vogelbaum MA, Davila ML, Forsyth PA, Locke FL, Lazaryan A. Intravenous Immunoglobulin (IVIG) for Patients with Severe Neurotoxicity Associated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy. Int J Mol Sci 2025; 26:3904. [PMID: 40332772 PMCID: PMC12028060 DOI: 10.3390/ijms26083904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
Severe immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in about 30% of all patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel). There are currently limited treatment strategies other than the standard corticosteroids, and it is essential to find additional therapies to manage severe ICANS. We conducted a retrospective study of neurologic outcomes among patients who received axi-cel for LBCL from May 2015 to February 2019. We identified patients who developed severe ICANS and were treated with glucocorticoids followed by intravenous immunoglobulin (IVIG) (n = 9) or glucocorticoids alone (n = 10). There was no statistically significant difference in the time to resolution (TTR) of severe ICANS between groups; however, patients in the IVIG had more severe grades of ICANS with a lower performance status at baseline. The cumulative steroid days were 11.2 in the IVIG arm and 13.5 in the glucocorticoids-only arm. The use of IVIG for severe ICANS after axi-cel therapy was tolerable and safe and is generally recommended in the CAR-T setting in patients with hypogammaglobinemia. The use of IVIG as a potential therapeutic agent for severe ICANS can be further explored in future prospective studies.
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Affiliation(s)
- Sepideh Mokhtari
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - Justin M. Asquith
- Department of Medical Oncology, Aspirus Cancer Care, Wausau, WI 54401, USA
| | - Syeda Saba Kareem
- Department of Bone Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Christina A. Bachmeier
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - Yolanda Pina
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - Rawan G. Faramand
- Department of Bone Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Youngchul Kim
- Department of Biostatistics, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Edwin N. Peguero
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - Solmaz Sahebjam
- Department of Medical Oncology, John Hopkins Hospital, Washington, DC 20016, USA
| | - Mohammad H. Jaffer
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - David P. Iacono
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - Michael D. Jain
- Department of Medical Oncology, Aspirus Cancer Care, Wausau, WI 54401, USA
| | - Michael A. Vogelbaum
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - Marco L. Davila
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Peter A. Forsyth
- Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA (E.N.P.); (P.A.F.)
| | - Frederick L. Locke
- Department of Medical Oncology, Aspirus Cancer Care, Wausau, WI 54401, USA
| | - Aleksandr Lazaryan
- Department of Medical Oncology, Aspirus Cancer Care, Wausau, WI 54401, USA
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20
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Xue F, Liu R, Fu Z, Zheng P, Yang F, Feng S, Guo Y, Shi H, Ma L, Deng B, Ke X, Hu K. Sequential CD19-20 CAR T-cell therapy for refractory/relapsed diffuse large B-cell lymphoma. Cytotherapy 2025:S1465-3249(25)00686-3. [PMID: 40340294 DOI: 10.1016/j.jcyt.2025.04.063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/05/2025] [Accepted: 04/14/2025] [Indexed: 05/10/2025]
Abstract
Loss or mutation of antigen and limited chimeric antigen receptor (CAR) T-cell persistence in vivo are essential determinants of recurrence in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Sequential infusion of CD19 and CD20 CAR Tcells (sequential CD19-20 CAR T-cell therapy) have been proposed as a potential solution. From March 2019 to January 2022 in Beijing Gobroad Boren Hospital, a total of 21 patients with r/r DLBCL received the CD19-20 CAR T-cell therapy in the prospective study (Clinical Trials Number: ChiCTR1900020980).Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in 9.5% (2/21) and 0% (0/21) of patients, respectively. The CD20 CAR T-cell infusion did not increase severe toxicity. There were no treatment-related deaths. Of 21 patients, 13 (61.9%) attained partial responses (PRs) and 8 (38.1%) attained complete responses (CRs) within 90 days after CD19 CAR T-cell infusion. Subsequent treatment with CD20 CAR T-cell infusion resulted in 10 of the 13 initial PR patients converting to CR, with a median time to achieving CR of 30 days (range, 30-90). With a median follow-up of 24.7 months (range, 11.6-45.86), 71.4% (15/21) of patients maintained ongoing responses at the data cutoff date. Overall, sequential CD19-CD20 CAR T-cell therapy demonstrated a favorable safety profile and might enhance long-term clinical outcomes.
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Affiliation(s)
- Fei Xue
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Rui Liu
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Zhonghua Fu
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Peihao Zheng
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Fan Yang
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Shaomei Feng
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Yuelu Guo
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Hui Shi
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Lixia Ma
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China
| | - Biping Deng
- Cytology Laboratory, Beijing Gobroad Boren Hospital, Beijing, China
| | - Xiaoyan Ke
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China.
| | - Kai Hu
- Department of Lymphoma and Myeloma Research Center, Beijing Gobroad Boren Hospital, Beijing, China.
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21
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Farolfi A, Casadei B, Malizia C, Ussia R, Rocchi V, Paccagnella A, Gentilini M, Nanni C, Argnani L, Zinzani PL, Fanti S. Semiquantitative PET Parameters Refine Prognosis in CAR T-Treated Lymphoma After 1 and 3 Months: A Prospective Single-Center Study. J Nucl Med 2025:jnumed.125.269670. [PMID: 40246539 DOI: 10.2967/jnumed.125.269670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/31/2025] [Indexed: 04/19/2025] Open
Abstract
Chimeric antigen receptor T-cell (CAR T) therapy has shown remarkable efficacy in treating relapsed or refractory large B-cell lymphoma. However, for nearly half of these patients, the therapy eventually does not achieve durable remission. We investigated whether semiquantitative PET parameters (namely, SUVmax, metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) could improve risk stratification 1 mo (PET1m) and 3 mo (PET3m) after CAR T infusion. Methods: In this prospective, single-center cohort study, patients with large B-cell lymphoma received axicabtagene ciloleucel or tisagenlecleucel. [18F]FDG PET/CT scans were acquired at baseline, 1 mo, and 3 mo after infusion. MTV and TLG were calculated using a threshold SUVmax of 4 or greater. Patients were followed for overall survival (OS), progression-free survival (PFS), and duration of response (DoR). The imaging assessment was based on the Lugano recommendation for response assessment. Prognostic factors were identified using univariate and multivariate Cox regression. Results: Sixty-one patients were enrolled, with a median follow-up of 18 mo. Twenty-eight (46%) patients died. Kaplan-Meier analysis with log-rank tests indicated a significant association of elevated Deauville score (DS), SUVmax, MTV, and TLG with OS (all P < 0.05). DS cutoff was arbitrarily fixed at 4. The optimal SUVmax, MTV, and TLG cutoffs at PET1m were 9.1, 60.8, and 97.0, respectively; whereas at PET3m, they were 6.3, 120.1, and 436.9, respectively. Patients with an SUVmax of 6.3 or greater at PET3m had an 8-fold increase in risk of death (hazard ratio [HR], 8.15; 95% CI, 2.81-23.6; P < 0.01) compared with those below this cutoff. Similarly, higher MTV (≥120.1) at PET3m yielded a nearly 10-fold risk (HR, 9.87; 95% CI, 3.65-26.7; P < 0.01). DS, SUVmax, MTV, and TLG at both PET1m and PET3m were associated with OS and PFS (all P < 0.05), whereas PET3m parameters also correlated with DoR (P < 0.05). Harrell C-index values were higher for PET3m measures than for PET1m, though differences were not statistically significant (P > 0.05). On multivariable analysis, older age (HR, 1.10), bridging therapy (HR, 10.91), elevated lactate dehydrogenase (HR, 6.43), increased fibrinogen (HR, 5.27), and higher SUVmax at PET3m (HR, 11.03) independently predicted poorer OS. There were no significant associations between SUVmax, MTV, and TLG with CAR T-related toxicities. Conclusion: Semiquantitative PET parameters, such as SUVmax, MTV, and TLG, at 1 mo and 3 mo after CAR T-cell therapy correlate significantly with OS, PFS, and DoR. [18F]FDG PET/CT at 3 mo may offer slightly stronger prognostic discrimination, but both time points can be used for early risk stratification.
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Affiliation(s)
- Andrea Farolfi
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy;
| | - Beatrice Casadei
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seragnoli", Bologna, Italy
| | - Claudio Malizia
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Riccardo Ussia
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Veronica Rocchi
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea Paccagnella
- Nuclear Medicine Unit, "M. Bufalini" Hospital, AUSL Romagna, Cesena, Italy; and
| | - Marianna Gentilini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seragnoli", Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Cristina Nanni
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Lisa Argnani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seragnoli", Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Pier Luigi Zinzani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seragnoli", Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Stefano Fanti
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
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22
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Zhao L, Yan F, Tang D, Li W, An N, Ren C, Wang Y, Xu K, Zhao K. The transition between M1 and M2 macrophage phenotypes is associated with the disease status following CD19 CAR-T therapy for B cell lymphoma/leukemia. Cell Death Dis 2025; 16:275. [PMID: 40216772 PMCID: PMC11992075 DOI: 10.1038/s41419-025-07610-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/19/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025]
Abstract
Although anti-CD19 chimeric antigen receptor (CAR-T) cells demonstrate high response rates in relapsed/refractory B-cell lymphomas, a considerable proportion of patients eventually encounter disease progression or relapse. The short-term and long-term outcomes of CAR-T treatment are intricately linked to the tumor microenvironment (TME), wherein macrophages with polarized characteristics can exhibit either anti-tumorigenic or pro-tumorigenic roles. Despite evidence implicating the crucial involvement of macrophages in CAR-T cell-treated lymphoma, their dynamic distribution and immune function related to lymphoma progression remain poorly understood. Immunocompetent mice were utilized to establish syngeneic A20 lymphoma/leukemia models. The distribution and polarization of macrophages were detected using immunohistochemistry (IHC) and flow cytometry techniques. We observed that CD19 CAR-T therapy exhibited significant efficacy in protecting mice against lymphoma, leading to increased infiltration of macrophages into the tumor tissue. Notably, during remission stages, M1-like macrophages (CD11b+F4/80+C206-CD80+) were predominant, whereas in relapsed mice, there was a shift towards M2-like phenotypes (CD11b+F4/80+C206+CD80+). The transition from remissive to relapsed status was accompanied by a reduction in the M1/M2 ratio and a decrease in pro-inflammatory cytokines. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed differential expression levels of CD206 and CD163 between remissive and relapsed mice, while signaling pathways involving PI3K and STAT3 may contribute to the skewing towards M2 polarization. In summary, our findings highlight the dynamic transformation of macrophage polarization during different stages of lymphoma progression and underscore its potential implications for immunotherapeutic interventions.
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Affiliation(s)
- Li Zhao
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fen Yan
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Donghai Tang
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wenwen Li
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Na An
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chunxiao Ren
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ying Wang
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kailin Xu
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Kai Zhao
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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23
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Gao P, Zhang Y, Ma J, Zhang Y. Immunotherapy in chronic lymphocytic leukemia: advances and challenges. Exp Hematol Oncol 2025; 14:53. [PMID: 40211406 PMCID: PMC11984025 DOI: 10.1186/s40164-025-00644-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/19/2025] [Indexed: 04/14/2025] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized as a clonal proliferation of mature B lymphocytes with distinct immunophenotypic traits, predominantly affecting the middle-aged and elderly population. This condition is marked by an accumulation of lymphocytes within the peripheral blood, bone marrow, spleen, and lymph nodes. The associated immune dysregulation predisposes CLL patients to a higher risk of secondary malignancies and infections, which significantly contribute to morbidity and mortality rates. The advent of immunotherapy has revolutionized the prognosis of CLL, advancing treatment modalities and offering substantial benefits to patient outcomes. This review endeavors to synthesize and scrutinize the efficacy, merits, and limitations of the current immunotherapeutic strategies for CLL. The aim is to inform the selection of optimal treatment regimens tailored to individual patient needs. Furthermore, the review juxtaposes various therapeutic combinations to elucidate the comparative advantages of each approach, with the ultimate objective of enhancing patient prognosis and quality of life.
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Affiliation(s)
- Pan Gao
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Yang Zhang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Jun Ma
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Ya Zhang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China.
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24
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Roex G, Gordon KS, Lion E, Birnbaum ME, Anguille S. Expanding the CAR toolbox with high throughput screening strategies for CAR domain exploration: a comprehensive review. J Immunother Cancer 2025; 13:e010658. [PMID: 40210240 PMCID: PMC11987143 DOI: 10.1136/jitc-2024-010658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/06/2025] [Indexed: 04/12/2025] Open
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy has been highly successful in the treatment of B-cell hematological malignancies. CARs are modular synthetic molecules that can redirect immune cells towards target cells with antibody-like specificity. Despite their modularity, CARs used in the clinic are currently composed of a limited set of domains, mostly derived from IgG, CD8α, 4-1BB, CD28 and CD3ζ. The current low throughput CAR screening workflows are labor-intensive and time-consuming, and lie at the basis of the limited toolbox of CAR building blocks available. High throughput screening methods facilitate simultaneous investigation of hundreds of thousands of CAR domain combinations, allowing discovery of novel domains and increasing our understanding of how they behave in the context of a CAR. Here we review the growing body of reports that employ these high throughput screening and computational methods to advance CAR design. We summarize and highlight the important differences between the different studies and discuss their limitations and future considerations for further improvements. In conclusion, while still in its infancy, high throughput screening of CARs has the capacity to vastly expand the CAR domain toolbox and improve our understanding of CAR design. This knowledge could be foundational for translating CAR therapy beyond hematological malignancies and push the frontiers in personalized medicine.
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Affiliation(s)
- Gils Roex
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium
| | - Khloe S Gordon
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
| | - Eva Lion
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium
- Center for Cell Therapy and Regenerative Medicine, University Hospital Antwerp, Edegem, Belgium
| | - Michael E Birnbaum
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
- Ragon Institute of Mass General MIT and Harvard, Cambridge, Massachusetts, USA
| | - Sébastien Anguille
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium
- Center for Cell Therapy and Regenerative Medicine, University Hospital Antwerp, Edegem, Belgium
- Division of Hematology, University Hospital Antwerp, Edegem, Belgium
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25
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Yang J, Cheng X, Wei G, Chen T, Zhao Y. Safety and Efficacy of Pharmacotherapy Containing the Second-Generation Integrase Inhibitors and Chemotherapy Drugs in AIDS-Related Diffuse Large B-Cell Lymphoma: A Single-Center Retrospective Analysis. Oncol Res Treat 2025:1-10. [PMID: 40179836 PMCID: PMC12068825 DOI: 10.1159/000545644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 03/28/2025] [Indexed: 04/05/2025]
Abstract
INTRODUCTION Previous research indicates that combining antiviral and anti-tumor drugs may lead to compounded toxic side effects and risks of drug-drug interactions. Our study aimed to investigate the safety and effectiveness of pharmacotherapy combining second-generation integrase inhibitors (INSTIs) with chemotherapy drugs in patients with AIDS-related diffuse large B-cell lymphoma (AR-DLBCL). METHODS We conducted a retrospective cohort study of newly diagnosed AR-DLBCL patients at the Public Health Clinical Center of Chengdu from February 2020 to May 2023. All patients received a second-generation INSTI-based regimen alongside chemotherapy. Primary endpoints included the frequency and severity of adverse effects (AEs), while secondary endpoints encompassed CD4 count, CD4/CD8 ratio, HIV viral load, and complete response (CR), partial response (PR), and overall response rate (ORR) at the end of treatment. Evaluations were performed at each chemotherapy cycle, with AEs assessed using Common Terminology Criteria for Adverse Events, version 4.02. RESULTS We enrolled 96 AR-DLBCL patients with a median follow-up of 15.5 months (range: 5-33). Of these patients, 60 received bictegravir/tenofovir alafenamide/emtricitabine, while 36 were treated with dolutegravir/lamivudine/albuvirtide as their antiretroviral therapy regimen. Regarding chemotherapy, 75 patients underwent R±CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), while 21 received R±EPOCH (rituximab, etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone). The most common grade 3 or higher AEs during treatment were neutropenia (32.29%) and thrombocytopenia (20.83%). Seven patients experienced serious complications during treatment, including pulmonary tuberculosis (2), multiple organ dysfunction (1), intracranial infection (1), renal failure (1), and severe COVID-19 (2), resulting in 3 deaths. CD4 count and CD4/CD8 ratio showed slight decreases from baseline (251.76 ± 188.53 cells/μL and 0.71 ± 0.69, respectively) to the 6th month (233.44 ± 140.53 cells/μL and 0.66 ± 0.55, respectively), with no statistical significance observed (p = 0.375 and p = 0.608). Viral load rebound was not observed. The objective response rate was 85.41%, with a CR rate of 51.04%. As of June 2024, 15 patients had died from severe infections or progressive disease. CONCLUSION Second-generation INSTIs seem to be a safe and effective first-line treatment option for AR-DLBCL patients undergoing chemotherapy, regardless of the chemotherapy type.
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Affiliation(s)
- Jing Yang
- Department of General Surgery and Oncology Surgery, Public Health Clinical Center of Chengdu, Chengdu, China
| | - Xingzhen Cheng
- Department of General Surgery and Oncology Surgery, Public Health Clinical Center of Chengdu, Chengdu, China
| | - Guo Wei
- Department of General Surgery and Oncology Surgery, Public Health Clinical Center of Chengdu, Chengdu, China
| | - Tingyu Chen
- Department of General Surgery and Oncology Surgery, Public Health Clinical Center of Chengdu, Chengdu, China
| | - Yong Zhao
- Department of General Surgery and Oncology Surgery, Public Health Clinical Center of Chengdu, Chengdu, China
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26
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Yu W, Li P, Zhou L, Yang M, Ye S, Zhu D, Huang J, Yao X, Zhang Y, Li L, Zhao J, Zhu K, Li J, Zheng C, Lan L, Wan H, Yao Y, Zhang H, Zhou D, Jin J, Liang A. A phase 1 trial of prizloncabtagene autoleucel, a CD19/CD20 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. Blood 2025; 145:1526-1535. [PMID: 39813680 DOI: 10.1182/blood.2024026401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/09/2024] [Accepted: 12/09/2024] [Indexed: 01/18/2025] Open
Abstract
ABSTRACT Prizloncabtagene autoleucel (prizlon-cel), a novel bispecific chimeric antigen receptor T cell, targets and eliminates CD19/CD20-positive tumor cells. This phase 1, open-label study investigated the safety and efficacy of prizlon-cel in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Patients with CD19 and/or CD20-positive R/R B-NHL received a 3-day lymphodepletion (cyclophosphamide: 300 mg/m2 per day; fludarabine: 30 mg/m2 per day) followed by an IV dose of prizlon-cel. The primary end points were dose-limiting toxicity (DLT) and incidence and severity of treatment-emergent adverse events (TEAEs). Secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of the 48 patients infused prizlon-cel, 44 had large B-cell lymphoma (LBCL). No patient experienced DLT. Cytokine release syndrome occurred in 93.8% of the patients, with only 1 case of grade 3. Immune effector cell-associated neurotoxicity syndrome occurred in 6.3% of patients, with no grade 3 or higher events. The most common grade 3 or higher TEAEs were neutropenia (83.3%) and leukopenia (50%). The ORR and complete response (CR) rates in all patients were 91.5% and 85.1%, respectively, and in LBCL patients, ORR was 90.7% with 86.0% CR. With median follow-up of 30.0 months, median DOR, PFS, and OS were all not reached. Kaplan-Meier estimate of 2-year DOR, PFS, and OS rates were 66.0%, 62.6%, and 76.5%, respectively. Prizlon-cel had a favorable safety profile and a high and durable response in patients with R/R B-NHL, suggesting a promising treatment option for patients with R/R B-NHL. These trials were registered at www.clinicaltrials.gov as #NCT04317885, #NCT04655677, #NCT04696432, and #NCT04693676.
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Affiliation(s)
- Wenjuan Yu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ping Li
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
| | - Lili Zhou
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
| | - Min Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shiguang Ye
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
| | - Dan Zhu
- Shanghai AbelZeta Ltd, Shanghai, China
| | | | - Xin Yao
- Shanghai AbelZeta Ltd, Shanghai, China
| | - Yan Zhang
- Department of Hematology, Peking Union Medical College Hospital, Beijing, China
| | - Lanfang Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jing Zhao
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Kevin Zhu
- University of Maryland School of Medicine, Baltimore, MD
| | - Jing Li
- Shanghai AbelZeta Ltd, Shanghai, China
| | | | | | - Hui Wan
- Shanghai AbelZeta Ltd, Shanghai, China
| | | | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Daobin Zhou
- Department of Hematology, Peking Union Medical College Hospital, Beijing, China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Aibin Liang
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
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27
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Caloian AD, Cristian M, Calin E, Pricop AR, Mociu SI, Seicaru L, Deacu S, Ciufu N, Suceveanu AI, Suceveanu AP, Mazilu L. Epigenetic Symphony in Diffuse Large B-Cell Lymphoma: Orchestrating the Tumor Microenvironment. Biomedicines 2025; 13:853. [PMID: 40299416 PMCID: PMC12024808 DOI: 10.3390/biomedicines13040853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/18/2025] [Accepted: 03/21/2025] [Indexed: 04/30/2025] Open
Abstract
DLBCL is a testament to the complexity of nature. It is characterized by remarkable diversity in its molecular and pathological subtypes and clinical manifestations. Despite the strides made in DLBCL treatment and the introduction of innovative drugs, around one-third of patients face a relapse or develop refractory disease. Recent findings over the past ten years have highlighted the critical interplay between the evolution of DLBCL and various epigenetic mechanisms, including chromatin remodeling, DNA methylation, histone modifications, and the regulatory roles of non-coding RNAs. These epigenetic alterations are integral to the pathways of oncogenesis, tumor progression, and the development of therapeutic resistance. In the past decade, the identification of dysregulated epigenetic mechanisms in lymphomas has paved the way for an exciting field of epigenetic therapies. Crucially, these epigenetic transformations span beyond tumor cells to include the sophisticated network within the tumor microenvironment (TME). While the exploration of epigenetic dysregulation in lymphoma cells is thriving, the mechanisms affecting the functions of immune cells in the TME invite further investigation. This review is dedicated to weaving together the narrative of epigenetic alterations impacting both lymphoma cells with a focus on their infiltrating immune companions.
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Affiliation(s)
- Andreea-Daniela Caloian
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Miruna Cristian
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology-CEDMOG, “Ovidius” University of Constanta, 900470 Constanta, Romania
- Department of Forensic Medicine, “Sf. Apostol Andrei” Emergency County Hospital, 900439 Constanta, Romania
| | - Elena Calin
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Andreea-Raluca Pricop
- Department of Dermatology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania;
| | - Stelian-Ilie Mociu
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Liliana Seicaru
- Department of Clinical Patology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania;
| | - Sorin Deacu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Clinical Patology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania;
| | - Nicolae Ciufu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
| | - Andra-Iulia Suceveanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Gastroenterology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
| | - Adrian-Paul Suceveanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Gastroenterology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
| | - Laura Mazilu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (E.C.); (S.D.); (N.C.); (A.-I.S.); (A.-P.S.); (L.M.)
- Department of Hemato-Oncology, “Ovidius” Clinical Hospital, 900470 Constanta, Romania;
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28
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Shumilov E, Levien L, Mazzeo P, Jung W, Leha A, Koch R, Hasenkamp J, Wulf G. Allogeneic stem cell transplantation against aggressive lymphomas: graft-versus-lymphoma effects in peripheral T-cell lymphoma and diffuse large B-cell lymphoma after myeloablative conditioning. Leuk Lymphoma 2025; 66:668-679. [PMID: 39660415 DOI: 10.1080/10428194.2024.2438805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/23/2024] [Accepted: 12/01/2024] [Indexed: 12/12/2024]
Abstract
Allogeneic stem cell transplantation (alloSCT) represents a curative option for patients with relapsed/refractory (r/r) aggressive lymphomas. We compared outcomes of alloSCT in r/r PTCL and r/r DLBCL pts (n = 150) who underwent identical myeloablative conditioning chemotherapy, GvHD prophylaxis, and relapse management. 5-year PFS and OS were significantly superior in PTCL compared to DLBCL (56% vs. 24%; 56% vs. 28%; p ≤ 0.005). A landmark analysis (day≥ +100 post-alloSCT) markedly favored outcomes in PTCL vs. DLBCL: 5-year PFS and OS of 76% vs. 30% and 76% and 35%, respectively (p ≤ 0.003). Non-relapse mortality was comparable (35% PTCL vs. 34% DLBCL, p = 0.894), whereas post-alloSCT relapse mortality was significantly higher in DLBCL (36% vs. 10%, p = 0.0007). The occurence of limited chronic GvHD did not improve outcomes in DLBCL, whereas extensive chronic GvHD was a negative risk factor for both (HR 2.09 and 2.80, p ≤ 0.006). In conclusion, we gained evidence for strong graft-versus-lymphoma activity against PTCL but not DLBCL.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/pathology
- Male
- Female
- Middle Aged
- Transplantation Conditioning/methods
- Transplantation Conditioning/adverse effects
- Hematopoietic Stem Cell Transplantation/adverse effects
- Hematopoietic Stem Cell Transplantation/methods
- Graft vs Host Disease/etiology
- Graft vs Host Disease/prevention & control
- Adult
- Lymphoma, T-Cell, Peripheral/therapy
- Lymphoma, T-Cell, Peripheral/mortality
- Lymphoma, T-Cell, Peripheral/pathology
- Transplantation, Homologous
- Aged
- Graft vs Tumor Effect/immunology
- Young Adult
- Treatment Outcome
- Retrospective Studies
- Adolescent
- Myeloablative Agonists/therapeutic use
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Affiliation(s)
- Evgenii Shumilov
- Department of Hematology and Medical Oncology, University Medical Center Goettingen (UMG), Goettingen, Germany
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster (UKM), Muenster, Germany
| | - Lena Levien
- Department of Hematology and Medical Oncology, University Medical Center Goettingen (UMG), Goettingen, Germany
| | - Paolo Mazzeo
- Department of Hematology and Medical Oncology, INDIGHO Laboratory, University Medical Center Goettingen (UMG), Goettingen, Germany
| | - Wolfram Jung
- Department of Hematology and Medical Oncology, University Medical Center Goettingen (UMG), Goettingen, Germany
| | - Andreas Leha
- Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany
| | - Raphael Koch
- Department of Hematology and Medical Oncology, University Medical Center Goettingen (UMG), Goettingen, Germany
| | - Justin Hasenkamp
- Department of Hematology and Medical Oncology, University Medical Center Goettingen (UMG), Goettingen, Germany
| | - Gerald Wulf
- Department of Hematology and Medical Oncology, University Medical Center Goettingen (UMG), Goettingen, Germany
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29
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Raj SS, Fei T, Fried S, Ip A, Fein JA, Leslie LA, Alarcon Tomas A, Leithner D, Peled JU, Corona M, Dahi PB, Danylesko I, Epstein-Peterson Z, Funnell T, Giralt SA, Jacoby E, Kedmi M, Landego I, Lin RJ, Parascondola A, Pascual L, Orozco N, Park JH, Palomba ML, Salles G, Saldia A, Schöder H, Sdayoor I, Shah GL, Scordo M, Shem-Tov N, Shimoni A, Slingerland J, Yerushalmi R, Nagler A, Greenbaum BD, Vickers AJ, Suh HC, Avigdor A, Perales MA, van den Brink MRM, Shouval R. An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma. Nat Med 2025; 31:1183-1194. [PMID: 40169864 PMCID: PMC12003198 DOI: 10.1038/s41591-025-03532-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/23/2025] [Indexed: 04/03/2025]
Abstract
Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60-4.91; P < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy.
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Grants
- P01 CA023766 NCI NIH HHS
- R01 CA228308 NCI NIH HHS
- R01 HL147584 NHLBI NIH HHS
- K08 CA282987 NCI NIH HHS
- UL1 TR002384 NCATS NIH HHS
- R01 CA228358 NCI NIH HHS
- K08 HL143189 NHLBI NIH HHS
- R01 HL123340 NHLBI NIH HHS
- P30 CA008748 NCI NIH HHS
- P01 AG052359 NIA NIH HHS
- The reported research was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) award number P01CA023766 and Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748). Dr. Roni Shouval reports grant support from an NIH-NCI K08CA282987, the Long Island Sound Chapter, Swim Across America, the Robert Hirschhorn Award, Comedy vs. Cancer, and the MSK Steven Greenberg Lymphoma Research.
- Dr. Sandeep S. Raj reports funding from the American Society for Transplantation and Cellular Therapy (ASTCT) New Investigator Award, the Louis V. Gerstner, Jr. Physician Scholars Award, and the Weill Cornell Medicine Clinical and Translational Science Center Grant 2UL1-TR-2384.
- Dr. Jonathan U. Peled reports funding from NHLBI NIH Award K08HL143189.
- Dr. Magdalena Corona’s work was supported by a grant from the Alfonso Martin Escudero Foundation.
- Dr. Marcel van den Brink reports funding from the National Cancer Institute (NCI; R01-CA228358, R01-CA228308, and P01-CA023766); National Heart, Lung, and Blood Institute (NHLBI; R01-HL123340 and R01-HL147584); National Institute on Aging (NIA; P01-AG052359), and Tri-Institutional Stem Cell Initiative. Additional funding was received from the Lymphoma Foundation, the Susan and Peter Solomon Family Fund, the Solomon Microbiome Nutrition and Cancer Program, Cycle for Survival, Parker Institute for Cancer Immunotherapy, Paula and Rodger Riney Multiple Myeloma Research Initiative, Starr Cancer Consortium, and Seres Therapeutics.
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Affiliation(s)
- Sandeep S Raj
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Teng Fei
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shalev Fried
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Andrew Ip
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Joshua A Fein
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Lori A Leslie
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Ana Alarcon Tomas
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Hematology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Doris Leithner
- Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan U Peled
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Magdalena Corona
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Parastoo B Dahi
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ivetta Danylesko
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Zachary Epstein-Peterson
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tyler Funnell
- Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Sergio A Giralt
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elad Jacoby
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Meirav Kedmi
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ivan Landego
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Internal Medicine, Max Rady Faculty of Health Sciences, Section of Medical Oncology and Hematology, University of Manitoba, Winnipeg, MB, Canada
| | - Richard J Lin
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Allison Parascondola
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lauren Pascual
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Natali Orozco
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Jae H Park
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - M Lia Palomba
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Gilles Salles
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amethyst Saldia
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Heiko Schöder
- Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Inbal Sdayoor
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gunjan L Shah
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Scordo
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Noga Shem-Tov
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Avichai Shimoni
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Ronit Yerushalmi
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Arnon Nagler
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Benjamin D Greenbaum
- Halvorsen Center for Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
| | - Andrew J Vickers
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hyung C Suh
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Abraham Avigdor
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Miguel-Angel Perales
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Roni Shouval
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Zhang Q, Dai J, Liu T, Rao W, Li D, Gu Z, Huang L, Wang J, Hou X. Targeting cardiac fibrosis with Chimeric Antigen Receptor-Engineered Cells. Mol Cell Biochem 2025; 480:2103-2116. [PMID: 39460827 DOI: 10.1007/s11010-024-05134-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 10/04/2024] [Indexed: 10/28/2024]
Abstract
Cardiac fibrosis poses a significant challenge in cardiovascular diseases due to its intricate pathogenesis, and there is currently no standardized and effective treatment approach. The fibrotic process entails the involvement of various cell types and molecular mechanisms, such as fibroblast activation and proliferation, increased collagen synthesis, and extracellular matrix rearrangement. Traditional therapies often fall short in efficacy or carry substantial side effects. However, recent studies have shown that Chimeric Antigen Receptor T (CAR-T) cells can selectively target and eliminate activated cardiac fibroblasts (CFs) in mice, leading to reduced cardiac fibrosis and improved myocardial tissue compliance. This breakthrough presents a new and promising avenue for treating cardiac fibrosis. Currently, CAR-T cell-based therapy for cardiac fibrosis is undergoing animal experimentation, indicating ample scope for enhancement. Future investigations could explore the application of CAR cell therapy in cardiac fibrosis treatment, including the potential of CAR-natural killer (CAR-NK) cells and CAR macrophages (CAR-M), offering novel insights and strategies for combating cardiac fibrosis.
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Affiliation(s)
- Qinghang Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Jinjie Dai
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Tianbao Liu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Wutian Rao
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Dan Li
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Zhengying Gu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Lin Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Jiayi Wang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Xumin Hou
- Hospital's Office, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
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31
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Grady CB, Li Y, Maude SL, Hexner EO, Frey NV, Porter DL, Hwang WT. Inconsistent Reporting and Definitions of Time-to-Event Endpoints in CAR T Clinical Trials: A Review. Transplant Cell Ther 2025; 31:271.e1-271.e13. [PMID: 39603418 PMCID: PMC11957941 DOI: 10.1016/j.jtct.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/05/2024] [Accepted: 11/17/2024] [Indexed: 11/29/2024]
Abstract
Clinical trials evaluating chimeric antigen receptor T-cell therapy (CAR T) commonly report time-to-event (TTE) endpoints. However, definitions are not necessarily comparable across studies and variability can lead to misinterpretation of results or inappropriate comparisons across products and studies. Amid the rapidly increasing number of published CAR T trials-many of which were used for regulatory approval-this study aims to summarize the variation in the use and reporting of TTE endpoints in CAR T trials. We include CAR T trials published January 2008 to January 2023 on PubMed that reported at least one of these TTE endpoints: overall survival (OS), progression-free survival (PFS), duration of response/remission (DOR), disease-free survival, event-free survival (EFS), relapse-free survival (RFS), time to relapse, time to progression, or time to treatment failure. We abstracted and summarized endpoint definitions, including the time origin, events, competing events, and censoring. We assessed the completeness of endpoint reporting, overall and by subgroups such as study phase, publication year, and the journal's impact factor. We included 116 publications in the analysis. The most frequently reported TTEs were OS (83%,), PFS (56%), DOR (55%), and EFS (23%). Complete reporting of endpoints was poor overall: 32%, 24%, 25%, and 56% for OS, PFS, DOR, and EFS respectively. Complete reporting was lower in articles published before 2018, in lower impact factor journals, and in phase I trials. There was also a large variability in TTE definitions among those reported. For example, among 64 studies reporting DOR, 48% used the date of response as the time origin while 20% used the date of infusion, and 31% did not report a time origin. There is substantial heterogeneity and incompleteness of TTE endpoint definitions in CAR T trials that could impact the interpretation of the study results. Improving TTE reporting, by stating the time origin, event(s) of interest, competing event(s) if any, and censoring, is required to ensure valid assessment of clinical benefit and cross-trial comparison.
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Affiliation(s)
- Connor B Grady
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yimei Li
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Shannon L Maude
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Elizabeth O Hexner
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine and the Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Noelle V Frey
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine and the Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David L Porter
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine and the Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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Bayly-McCredie E, Prince HM, Yannakou CK, Fiorenza S. An evaluation of odronextamab for the treatment of multiple subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma. Expert Opin Biol Ther 2025; 25:331-343. [PMID: 40106587 DOI: 10.1080/14712598.2025.2479631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/11/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
INTRODUCTION Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) have a poor median survival rate when treated with traditional salvage therapies. Bispecific antibodies (BsAbs) are an emerging class of 'off-the-shelf' immunotherapies that show promising efficacy in this population. Odronextamab is a CD20×CD3 targeting bispecific antibody that is being investigated in multiple subtypes of relapsed/refractory B-NHL. AREAS COVERED This article describes the development of odronextamab from pre-clinical work through to ongoing clinical trials in relapsed/refractory B-NHL. The structure, safety, efficacy, and administration of odronextamab are discussed. Studies were selected for inclusion by performing a search in PubMed, EMBASE, Cochrane Library, and relevant conference abstracts from 2014 to 2024. The clinicaltrials.gov website and reference lists of the included studies were also reviewed. EXPERT OPINION Odronextamab has demonstrated manageable safety and promising efficacy in multiple subtypes of relapsed/refractory B-NHL. The low rates of immune effector cell-associated neurotoxicity syndrome (ICANS) and high response rates in rare aggressive subtypes of B-NHL are particularly noteworthy. High rates of severe infections remain a challenge with BsAbs, with further prophylactic efforts required to reduce the risk. Clinical trials of combination therapies with odronextamab are required to improve the utility of this BsAb across a wider range of settings and subtypes of B-NHL.
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MESH Headings
- Humans
- Lymphoma, B-Cell/drug therapy
- Lymphoma, B-Cell/pathology
- Lymphoma, B-Cell/immunology
- Antibodies, Bispecific/adverse effects
- Antibodies, Bispecific/administration & dosage
- Antibodies, Bispecific/pharmacology
- Antibodies, Bispecific/therapeutic use
- Animals
- Immunotherapy/methods
- Recurrence
- Salvage Therapy
- Survival Rate
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/pharmacology
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Affiliation(s)
| | - Henry Miles Prince
- Epworth HealthCare, East Melbourne, Australia
- The University of Melbourne, Melbourne, Australia
- Monash University, Melbourne, Australia
- Sir Peter MacCallum Cancer Centre, Melbourne, Australia
| | | | - Salvatore Fiorenza
- Epworth HealthCare, East Melbourne, Australia
- Department of Clinical Haematology, Alfred Health, Melbourne, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, Australia
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Goel U, Mian A, Sauter CS. SOHO State of the Art Updates and Next Questions | Contemporary Role of Autologous Stem Cell Transplantation for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma in the Era of Cellular Therapies. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025; 25:219-225. [PMID: 39214752 DOI: 10.1016/j.clml.2024.07.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024]
Abstract
Since the 1990s, the standard of care for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) had been salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) in patients with a chemotherapy-sensitive remission. However, promising results from the recent TRANSFORM and ZUMA-7 trials evaluating the efficacy of CAR T-cell therapy versus HDT-ASCT for second line relapsed/refractory DLBCL have sought to challenge this standard of care. While these studies have established a new standard for the treatment of early relapsed and primary refractory DLBCL, significant differences in the trial design between these studies and limitations with the timing of randomization during the disease course warrant a thoughtful interpretation of the results. Additionally, the financial burden and logistic challenges of CAR T-cell administration and limited access to these therapies continue to be ongoing issues. Despite the encouraging results from these trials, HDT-ASCT continues to have a role in the treatment of DLBCL, especially in disease relapsing ≥12 months after initial therapy, and in chemo sensitive disease with a good response to salvage chemotherapy. Ongoing studies evaluating novel salvage regimens for use prior to HDT-ASCT, and future studies evaluating the role of CAR T-cell therapy in chemo sensitive disease will help determine the continued role of HDT-ASCT for relapsed/refractory DLBCL.
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Affiliation(s)
- Utkarsh Goel
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH
| | - Agrima Mian
- Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Craig S Sauter
- Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH.
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34
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Bock TJ, Colonne CK, Fiorenza S, Turtle CJ. Outcome correlates of approved CD19-targeted CAR T cells for large B cell lymphoma. Nat Rev Clin Oncol 2025; 22:241-261. [PMID: 39966627 DOI: 10.1038/s41571-025-00992-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2025] [Indexed: 02/20/2025]
Abstract
CD19-targeted chimeric antigen receptor (CAR) T cells have provided a breakthrough in the treatment of patients with relapsed and/or refractory large B cell lymphoma (LBCL). Currently, three CD19-targeted CAR T cell products are approved by the FDA and various other regulators for the treatment of patients with LBCL: axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel. Response rates following infusion of these CD19-targeted CAR T cells have been promising; however, approximately half of treated patients show relapse within 2 years. Furthermore, receiving these agents can be associated with serious toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. In this Review, we summarize the factors associated with the efficacy, including response and survival outcomes, and toxicity of CD19-targeted CAR T cells in pivotal clinical trials and large real-world datasets describing the outcomes of patients with LBCL who received treatment with these products.
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MESH Headings
- Humans
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Antigens, CD19/immunology
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/therapeutic use
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/therapeutic use
- Treatment Outcome
- Biological Products
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Affiliation(s)
- Tamara J Bock
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
| | - Chanukya K Colonne
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Salvatore Fiorenza
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Cameron J Turtle
- Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
- Royal North Shore Hospital, Sydney, New South Wales, Australia
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
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Kordic A, Phillips TJ, Weiss J. The Current State of Bispecific Antibodies and T-Cell Directed Therapy in NHL. Cancers (Basel) 2025; 17:1192. [PMID: 40227768 PMCID: PMC11988123 DOI: 10.3390/cancers17071192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 03/10/2025] [Accepted: 03/25/2025] [Indexed: 04/15/2025] Open
Abstract
Relapsed/refractory non-Hodgkin lymphoma (r/r/NHL) is an aggressive disease with overall poor response rates to chemo-immunotherapy and autologous stem-cell transplant, especially in patients with diffuse large B-cell lymphoma. Major improvements in this disease space have come through the incorporation of novel immune therapies, including CD19/CD20 directed CAR-T cells and bispecific antibodies. These exciting new therapies continue to change the landscape of treatment for r/r NHL and have been incorporated in earlier lines of therapy with demonstrated efficacy and patient safety. In this review, the role of these treatments in the management of relapsed/refractory NHL is discussed in detail along with future directions of research.
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Affiliation(s)
- Austin Kordic
- City of Hope Comprehensive Cancer Center, Department of Hematology and Hematopoietic Cell Transplantation, Division of Lymphoma, Duarte, CA 91010, USA;
| | - Tycel Jovelle Phillips
- City of Hope Comprehensive Cancer Center, Department of Hematology and Hematopoietic Cell Transplantation, Division of Lymphoma, Duarte, CA 91010, USA;
| | - Jonathan Weiss
- Rogel Comprehensive Cancer Center, University of Michigan-Ann Arbor, Ann Arbor, MI 48109, USA;
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36
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Davila M, Lee SB, Kang YP, Boucher J, Mandula J, Roselli E, Chang D, Jimenez R, Kotani H, Reid K, Vazquez-Martinez J, Beatty N, Goala P, Sierra-Mondragon R, Liu M, Koomen J, Nguyen J, Hussaini M, Shaw T, Wang X, Faramand R, Jain M, Locke F, Rodriguez P, Sailer C, McSain S, Hamid S, Tariq M, Wang J, Abraham-Miranda J. CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma. RESEARCH SQUARE 2025:rs.3.rs-3481746. [PMID: 40235478 PMCID: PMC11998770 DOI: 10.21203/rs.3.rs-3481746/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients' intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. CAR T cell-produced interferon-gamma (IFN-γ) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, iNOS-expressing macrophages upregulated the p53 pathway, mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating the MYC pathway involved in ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs) by blocking IFN-γ secretion from CAR T cells will improve outcomes for LBCL patients.
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Xu J, Zhang X, Li Y, Meng F, Zhang Y, Zheng M. Efficacy and safety of zanubrutinib combined with chimeric antigen receptor T-cell therapy targeting CD19 in refractory or relapsed diffuse large B cell lymphoma: A retrospective analysis. Cancer Treat Res Commun 2025; 43:100902. [PMID: 40158266 DOI: 10.1016/j.ctarc.2025.100902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND While chimeric antigen receptor T-cell (CAR T) therapy has shown promise in treating B-cell non-Hodgkin lymphoma, its efficacy is variable in patients with poor initial responses. This study investigates the efficacy and safety of zanubrutinib combined with CAR T therapy targeting CD19 in refractory/relapsed diffuse large B cell lymphoma (DLBCL). METHODS We conducted a retrospective study of 17 patients with R/R DLBCL who received zanubrutinib combined with anti-CD19 CAR T-cell therapy. We assessed overall survival (OS) and progression-free survival (PFS) and conducted subgroup analyses. We also monitored CAR T-cell expansion by quantifying vector copy numbers (VCN). Safety and tolerability were assessed by documenting adverse events, including cytokine release syndrome and neurotoxicity. RESULTS The median follow-up was 30 months (range, 4-36). The overall response rate(ORR) was 88.2 %, with 70.5 % achieving complete remission. At 24 months, the estimated PFS was 59 % (95 %CI, 40-88 %), and the OS was 71 % (95 %CI, 52-90 %). At 36 months, the estimated OS was 65 % (95 %CI, 46-92 %). Patients with non-elevated lactate dehydrogenase(LDH) levels showed a higher PFS probability (100 %) compared to those with elevated LDH (42 %, 95 %CI: 21 %-81 %) (log-rank, p = 0.071). The area under the receiver-operating characteristic (ROC) curve for peak CAR T-cell expansion was 0.773, suggesting an optimal cutoff at day 13 for enhancing survival (sensitivity 66.7 %, specificity 90.9 %; p = 0.07). Early peak expansion (before day 13) correlated with better PFS and OS (log-rank, p = 0.0018 and p = 0.0053, respectively). The total VCN AUC was 0.636, with a cutoff of 12,690 significantly predicting survival (sensitivity 83.3 %, specificity 72.7 %; p = 0.366). Kaplan-Meier analysis indicated statistically significant differences in OS for patients with VCN below 12,690 (log-rank, p = 0.017) in comparison to those exceeding 12,690, though trends in PFS did not reach statistical significance (log-rank, p = 0.12). Safety profiles indicated manageable cytokine release syndrome, with no severe neurotoxicity reported. CONCLUSIONS Zanubrutinib combined with CAR T-cell therapy offers an effective treatment option for patients with R/R DLBCL, enhancing response rates and survival. Detailed analysis of CAR T-cell expansion provides insight into the dynamics of cellular responses, underscoring the potential for tailored therapeutic approaches based on biological markers.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/pathology
- Female
- Male
- Middle Aged
- Retrospective Studies
- Aged
- Antigens, CD19/immunology
- Adult
- Pyrimidines/therapeutic use
- Pyrimidines/pharmacology
- Pyrimidines/adverse effects
- Pyrimidines/administration & dosage
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Pyrazoles/therapeutic use
- Pyrazoles/pharmacology
- Pyrazoles/adverse effects
- Pyrazoles/administration & dosage
- Receptors, Chimeric Antigen
- Piperidines/therapeutic use
- Piperidines/pharmacology
- Neoplasm Recurrence, Local/therapy
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
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Affiliation(s)
- Jinhuan Xu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China
| | - Xiaoying Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China
| | - Yun Li
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China
| | - Fankai Meng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China
| | - Yicheng Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China
| | - Miao Zheng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China.
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38
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Georgiadis C, Preece R, Qasim W. Clinical development of allogeneic chimeric antigen receptor αβ-T cells. Mol Ther 2025:S1525-0016(25)00214-X. [PMID: 40156192 DOI: 10.1016/j.ymthe.2025.03.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/10/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025] Open
Abstract
Ready-made banks of allogeneic chimeric antigen receptor (CAR) T cells, produced to be available at the time of need, offer the prospect of accessible and cost-effective cellular therapies. Various strategies have been developed to overcome allogeneic barriers, drawing on cell engineering platforms including RNA interference, protein-based restriction, and genome editing, including RNA-guided CRISPR-Cas and base editing tools. Alloreactivity and the risk of graft-versus-host disease from non-matched donor cells have been mitigated by disruption of αβ-T cell receptor expression on the surface of T cells and stringent removal of any residual αβ-T cell populations. In addition, host-mediated rejection has been tackled through a combination of augmented lymphodepletion and cell engineering strategies that have allowed infused cells to evade immune recognition or conferred resistance to lymphodepleting agents to promote persistence and expansion of effector populations. Early-phase studies using off-the-shelf universal donor CAR T cells have been undertaken mainly in the context of blood malignancies, where emerging data of clinical responses have supported wider adoption and further applications. These developments offer the prospect of alternatives to current autologous approaches through the emerging application of genome engineering solutions to improve safety, persistence, and function of universal donor products.
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Affiliation(s)
- Christos Georgiadis
- University College London Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, London WC1N 1DZ, UK
| | - Roland Preece
- University College London Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, London WC1N 1DZ, UK
| | - Waseem Qasim
- University College London Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, London WC1N 1DZ, UK.
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39
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Karmali R, Shouse G, Torka P, Moyo TK, Romancik J, Barta SK, Bhansali R, Cohen JB, Shah NN, Zurko J, Kenkre VP, Hess B, Stephens DM, Fitzgerald L, Ollila T, Tabiti B, Roy I, Ma S, Winter J, Pro B, Moreira J, Danilov AV, David K, Gordon LI, Epperla N. Double hit & double expressor lymphomas: a multicenter analysis of survival outcomes with CD19-directed CAR T-cell therapy. Blood Cancer J 2025; 15:43. [PMID: 40140360 PMCID: PMC11947441 DOI: 10.1038/s41408-025-01250-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 02/04/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Double-hit (DHL) and double expressor (DEL) DLBCL have poor prognosis with standard therapy but CART may overcome this poor prognostic impact. In this multicenter retrospective study, we sought to confirm this observation by evaluating survival outcomes among patients with relapsed/refractory DHL and DEL treated with CART and evaluate outcomes of relapse post-CART. A total of 408 adult patients with relapsed/refractory DLBCL from 13 academic centers were included based on the availability of DHL and DEL. All 408 patients were included in the DHL (n = 80) vs non-DHL (n = 328) analysis, while 333 patients were included in the analysis of DHL (n = 80) vs DEL (n = 74) vs non (n = 179). On MVA, there were no differences for PFS for DHL vs non-DHL (HR 0.8, 95%CI 0.5-1.3, p = 0.35) or DHL vs DEL vs other (three-way p value, p = 0.5). Response rates and toxicities were similar among groups. Patients with DEL had the highest relapse rates post-CART, while DHL had the worst overall survival after CART relapse. In sum, our data support the notion that CART cell therapy can overcome the poor prognostic impact of DHL and DEL DLBCL in the relapsed/refractory setting. Additionally, patients with DHL that relapse after CART have a very poor prognosis.
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MESH Headings
- Humans
- Female
- Male
- Middle Aged
- Adult
- Aged
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Antigens, CD19/immunology
- Retrospective Studies
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/immunology
- Prognosis
- Aged, 80 and over
- Treatment Outcome
- Young Adult
- Receptors, Chimeric Antigen
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Affiliation(s)
- Reem Karmali
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
| | | | - Pallawi Torka
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tamara K Moyo
- Levine Cancer Institute, Atrium Health, Charlotte, NC, USA
| | - Jason Romancik
- Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Stefan K Barta
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Rahul Bhansali
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Nirav N Shah
- MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Joanna Zurko
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Vaishalee P Kenkre
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Brian Hess
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Deborah M Stephens
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | | | - Thomas Ollila
- Lifespan Cancer Institute, Brown University, Providence, RI, USA
| | - Bukky Tabiti
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Ishan Roy
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
- Shirley Ryan Ability Lab, Chicago, IL, USA
| | - Shuo Ma
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Jane Winter
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Barbara Pro
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Jonathan Moreira
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | | | - Kevin David
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA
| | - Leo I Gordon
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Narendranath Epperla
- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA
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40
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Huang Y, Wang H. Tonic signaling in CAR-T therapy: the lever long enough to move the planet. Front Med 2025:10.1007/s11684-025-1130-x. [PMID: 40117019 DOI: 10.1007/s11684-025-1130-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/16/2024] [Indexed: 03/23/2025]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.
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Affiliation(s)
- Yuwei Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Lingang Laboratory, Shanghai, 200031, China
| | - Haopeng Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- Shanghai Clinical Research and Trial Center, Shanghai, 201210, China.
- State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, 201210, China.
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41
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Wang L, Yue C, Zhou X, Yang J, Jin B, Wang B, Huang M, Chen H, Zhou L, Tu S, Li Y. Efficacy and safety of chimeric antigen receptor T cell therapy combined with zanubrutinib in the treatment of relapsed/refractory diffuse large B-cell lymphoma. Chin Med J (Engl) 2025; 138:748-750. [PMID: 39981563 PMCID: PMC11925414 DOI: 10.1097/cm9.0000000000003504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Indexed: 02/22/2025] Open
Affiliation(s)
- Langqi Wang
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510000, China
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42
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Renninger J, Kurz L, Stein H. Mitigation and Management of Common Toxicities Associated with the Administration of CAR-T Therapies in Oncology Patients. Drug Saf 2025:10.1007/s40264-025-01538-5. [PMID: 40108072 DOI: 10.1007/s40264-025-01538-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2025] [Indexed: 03/22/2025]
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapies are one of the main approaches among targeted cellular therapies. Despite the potential benefit and durable responses observed in some patients receiving CAR-T therapies, serious and potentially fatal toxicities remain a major challenge. The most common CAR-T-associated toxicities include cytokine release syndrome (CRS), neurotoxicity, cytopenias, and infections. While CRS and neurotoxicity are generally managed with tocilizumab and corticosteroids, respectively, high-grade toxicities can be life-threatening. Close postinfusion monitoring and assessment of clinical laboratory parameters, patient-related and clinical risk factors (e.g., age, tumor burden, comorbidities, baseline laboratory parameters, and underlying abnormalities), and therapy-related risk factors (e.g., CAR-T type, dose, and CAR-T-induced toxicity) are effective strategies to mitigate the toxicities. Clinical laboratory parameters, including various cytokines, have been identified for CRS (interleukin [IL]-1, IL-2, IL-5, IL-6, IL-8, IL-10, C-reactive protein [CRP], interferon [IFN]-γ, ferritin, granulocyte-macrophage colony-stimulating factor [GM-CSF], and monocyte chemoattractant protein-1), neurotoxicity (IL-1, IL-2, IL-6, IL-15, tumor necrosis factor [TNF]-α, GM-CSF, and IFN-γ), cytopenias (IL-2, IL-4, IL-6, IL-10, IFN-γ, ferritin, and CRP), and infections (IL-8, IL-1β, CRP, IFN-γ, and procalcitonin). CAR-T-associated toxicities can be monitored and treated to mitigate the risk to patients. Assessment of alterations in clinical laboratory parameter values that are correlated with CAR-T-associated toxicities may predict development and/or severity of a given toxicity, which can improve patient management strategies and ultimately enable the patients to better tolerate these therapies.
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Affiliation(s)
- Jonathan Renninger
- GSK Safety Evaluation and Risk Management, Global Safety, Philadelphia, PA, USA.
| | - Lisa Kurz
- GSK Safety Evaluation and Risk Management, Global Safety, Upper Providence, PA, USA
| | - Heather Stein
- GSK Safety Evaluation and Risk Management, Global Safety, Cambridge, MA, USA
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43
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Laverdure E, Mollica L, Ahmad I, Cohen S, Lachance S, Veilleux O, Bernard M, Marchand EL, Delisle JS, Bernard L, Boileau M, Petrella T, Pilon SJ, Bouchard P, Roy DC, Busque L, Fleury I. Enhancing CAR-T Efficacy in Large B-Cell Lymphoma with Radiation Bridging Therapy: A Real-World Single-Center Experience. Curr Oncol 2025; 32:173. [PMID: 40136377 PMCID: PMC11941054 DOI: 10.3390/curroncol32030173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/25/2025] [Accepted: 03/09/2025] [Indexed: 03/27/2025] Open
Abstract
One challenge of chimeric antigen receptor T-cell therapy (CAR-T) for relapsed or refractory large B-cell lymphoma (LBCL) is achieving disease control during manufacturing. We report real-word outcomes of 100 patients treated with axicabtagene ciloleucel (axi-cel, n = 50) or tisagenlecleucel (tisa-cel, n = 50) at our center. Most patients received bridging therapy (BT) with 48 undergoing radiation BT (RBT) and 32 receiving systemic BT (SBT). The best overall response rate (ORR) was 84% (78% complete response (CR)) for axi-cel and 60% (42% CR) for tisa-cel. At a median follow-up of 16 months, 12-month progression-free survival (PFS) and overall survival (OS) were 72% and 82% for axi-cel, compared to 35% and 57% for tisa-cel. By the bridging approach, 12-month PFS was 60% with RBT, 59% without BT and 35% with SBT (p = 0.06). Notably, axi-cel patients without lymphoma progression during manufacturing (n = 24) achieved 12-month PFS and OS rates of 91% and 96%, respectively. Axi-cel was associated with more cytokine release syndrome (92% vs. 66%, p = 0.003) and neurotoxicity (all-grade 56% vs. 10%, p < 0.001, grade ≥ 328% vs. 4%, p = 0.002). Multivariate analysis identified RBT as independently associated with improved PFS (HR 0.46, 95% CI 0.22-0.96). Pending prospective validation, RBT shows promise for improving CAR-T outcomes in LBCL.
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MESH Headings
- Humans
- Female
- Male
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/radiotherapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Middle Aged
- Aged
- Immunotherapy, Adoptive/methods
- Adult
- Aged, 80 and over
- Receptors, Chimeric Antigen
- Receptors, Antigen, T-Cell/therapeutic use
- Treatment Outcome
- Young Adult
- Biological Products
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Affiliation(s)
- Eva Laverdure
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Department of Hemato-Oncology, Hôpital Fleurimont, Centre Hospitalier Universitaire de Sherbrooke, CIUSSS de l’Estrie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Luigina Mollica
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Imran Ahmad
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Sandra Cohen
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Silvy Lachance
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Olivier Veilleux
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Maryse Bernard
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
- Department of Radiation Therapy, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, Montréal, QC H1T 2M4, Canada
| | - Eve-Lyne Marchand
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
- Department of Radiation Therapy, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, Montréal, QC H1T 2M4, Canada
| | - Jean-Sébastien Delisle
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Lea Bernard
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Mélissa Boileau
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Tony Petrella
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
- Department of Pathology, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, Montréal, QC H1T 2M4, Canada
| | - Sarah-Jeanne Pilon
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
- Department of Pathology, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, Montréal, QC H1T 2M4, Canada
| | - Philippe Bouchard
- Department of Pharmacy, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, Montréal, QC H1T 2M4, Canada
| | - Denis-Claude Roy
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Lambert Busque
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
| | - Isabelle Fleury
- Department of Medicine, Institut Universitaire d’Hémato-Oncologie et de Thérapie Cellulaire, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, l, Montréal, QC HIT 2M4, Canada; (E.L.); (L.M.); (I.A.); (S.C.); (S.L.); (O.V.); (J.-S.D.); (D.-C.R.)
- Faculty of Medicine, Université de Montréal, Montréal, QC H2V 0B3, Canada; (M.B.); (E.-L.M.); (T.P.); (S.-J.P.)
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44
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Cao G, Hu Y, Pan T, Tang E, Asby N, Althaus T, Wan J, Riedell PA, Bishop MR, Kline JP, Huang J. Two-Stage CD8 + CAR T-Cell Differentiation in Patients with Large B-Cell Lymphoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.05.641715. [PMID: 40161759 PMCID: PMC11952315 DOI: 10.1101/2025.03.05.641715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has expanded therapeutic options for patients with diffuse large B-cell lymphoma (DLBCL). However, progress in improving clinical outcomes has been limited by an incomplete understanding of CAR T-cell differentiation in patients. To comprehensively investigate CAR T-cell differentiation in vivo, we performed single-cell, multimodal, and longitudinal analyses of CD28-costimulated CAR T cells from infusion product and peripheral blood (day 8-28) of patients with DLBCL who were successfully treated with axicabtagene ciloleucel. Here, we show that CD8+ CAR T cells undergo two distinct waves of clonal expansion. The first wave is dominated by CAR T cells with an exhausted-like effector memory phenotype during the peak expansion period (day 8-14). The second wave is dominated by CAR T cells with a terminal effector phenotype during the post-peak persistence period (day 21-28). Importantly, the two waves have distinct ontogeny and are biologically uncoupled. Furthermore, lineage tracing analysis via each CAR T cell's endogenous TCR clonotype demonstrates that the two waves originate from different effector precursors in the infusion product. Precursors of the first wave exhibit more effector-like signatures, whereas precursors of the second wave exhibit more stem-like signatures. These findings suggest that pre-infusion heterogeneity mediates the two waves of in vivo clonal expansion. Our findings provide evidence against the intuitive idea that the post-peak contraction in CAR abundance is solely apoptosis or extravasation of short-lived CAR T cells from peak expansion. Rather, our findings demonstrate that CAR T-cell expansion and persistence are mediated by clonally, phenotypically, and ontogenically distinct CAR T-cell populations that serve complementary clinical purposes.
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Affiliation(s)
- Guoshuai Cao
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Yifei Hu
- Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Tony Pan
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Erting Tang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Nick Asby
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Thomas Althaus
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL 60637, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Peter A. Riedell
- Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL 60637, USA
| | - Michael R. Bishop
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL 60637, USA
| | - Justin P. Kline
- Committee on Immunology, University of Chicago, Chicago, IL 60637, USA
- Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
- The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL 60637, USA
| | - Jun Huang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
- Committee on Immunology, University of Chicago, Chicago, IL 60637, USA
- Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA
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45
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Li N, An N, Ma S, Cao J, Zhu F, Qi K, Yan Z, Cheng H, Sang W, Chen W, Li D, Li Z, Xu K, Wang Y. Lymphocyte/monocyte to lactate dehydrogenase ratio prior to lymphodepletion impact the outcomes of patients with diffused large B cell lymphoma undergoing CAR-T cell therapy. Cancer Immunol Immunother 2025; 74:148. [PMID: 40088299 PMCID: PMC11910468 DOI: 10.1007/s00262-025-03987-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/17/2025] [Indexed: 03/17/2025]
Abstract
Factors associated with outcomes of chimeric antigen receptor (CAR)-T cell therapy in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have not been fully elucidated. We explored the impact of the prelymphodepletion (pre-LD) lymphocyte to monocyte ratio (LMR) and its ratio to lactate dehydrogenase (LDH) (LMR/LDH) on the efficacy and prognosis of 60 patients with R/R DLBCL undergoing CAR-T cell therapy. The optimal cutoff values for pre-LD LMR and LMR/LDH were 3.583 and 0.0103, respectively. The overall response rate (ORR)s were higher in patients with high pre-LD LMR or LMR/LDH than those with low pre-LD LMR or LMR/LDH (ORR, 100% vs. 65.79%, P = 0.006 and 96.15% vs. 38.24%, P < 0.0001, respectively). Pre-LD LMR/LDH was an independent factor associated with ORR (P = 0.010, odds ratio = 18.757; 95% confidence interval [CI] 2.046-171.975) by multivariate logistic regression analysis. Patients with high pre-LD LMR/LDH had significantly longer progression-free survival (PFS) (median PFS, 29.73 vs. 2.47 months, P < 0.0001) and overall survival (OS) (median OS, not reached vs. 7.4 months, P = 0.0002) than those with low pre-LD LMR/LDH. Multivariate Cox regression analysis showed that pre-LD LMR/LDH and ORR were independent factors affecting PFS (P = 0.030, hazard ratio [HR] = 2.561; 95% CI 1.093-5.999 and P = 0.024, HR = 2.202; 95% CI 1.22-4.369, respectively); pre-LD LMR/LDH was an independent factor affecting OS (P = 0.029, HR = 3.331; 95% CI 1.131-9.807). In conclusion, the pre-LD LMR/LDH was an independent factor associated with ORR and an independent prognostic factor in patients with R/R DLBCL undergoing CAR-T cell therapy.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/blood
- Female
- Male
- Middle Aged
- Immunotherapy, Adoptive/methods
- Monocytes/immunology
- L-Lactate Dehydrogenase/blood
- L-Lactate Dehydrogenase/metabolism
- Aged
- Prognosis
- Adult
- Lymphocytes/immunology
- Receptors, Chimeric Antigen
- Lymphocyte Depletion
- Aged, 80 and over
- Treatment Outcome
- Retrospective Studies
- Young Adult
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Affiliation(s)
- Na Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Na An
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Sha Ma
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Jiang Cao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Feng Zhu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Kunming Qi
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Zhiling Yan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Hai Cheng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Wei Sang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Wei Chen
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Depeng Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Zhenyu Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
| | - Ying Wang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
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Sun J, Song S, Liu J, Chen F, Li X, Wu G. Gut microbiota as a new target for anticancer therapy: from mechanism to means of regulation. NPJ Biofilms Microbiomes 2025; 11:43. [PMID: 40069181 PMCID: PMC11897378 DOI: 10.1038/s41522-025-00678-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 03/04/2025] [Indexed: 03/15/2025] Open
Abstract
In order to decipher the relationship between gut microbiota imbalance and cancer, this paper reviewed the role of intestinal microbiota in anticancer therapy and related mechanisms, discussed the current research status of gut microbiota as a biomarker of cancer, and finally summarized the reasonable means of regulating gut microbiota to assist cancer therapy. Overall, our study reveals that the gut microbiota can serve as a potential target for improving cancer management.
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Affiliation(s)
- Jiaao Sun
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shiyan Song
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jiahua Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Feng Chen
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Xiaorui Li
- Department of oncology, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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Riedell PA, Grady CB, Nastoupil LJ, Luna A, Ahmed N, Maziarz RT, Hu M, Brower J, Hwang WT, Schuster SJ, Chen AI, Oluwole OO, Bachanova V, McGuirk JP, Perales MA, Bishop MR, Porter DL. Lisocabtagene maraleucel for relapsed/refractory large B-cell lymphoma: a cell therapy consortium real-world analysis. Blood Adv 2025; 9:1232-1241. [PMID: 39657136 PMCID: PMC11993828 DOI: 10.1182/bloodadvances.2024014164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/19/2024] [Accepted: 11/19/2024] [Indexed: 12/17/2024] Open
Abstract
ABSTRACT Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed chimeric antigen receptor T-cell therapy approved for the treatment of relapsed/refractory large B-cell lymphoma. We present a multicenter retrospective study evaluating safety, efficacy, and resource use of liso-cel in the standard-of-care setting. Patients received commercial liso-cel at 7 US medical centers, and patient selection, toxicity management, and disease assessment followed institutional practices. Among 101 patients who received infusion, the median age was 71 years (35% aged ≥75 years), 68% had a Charlson comorbidity index score of ≥3, and 10% had secondary central nervous system involvement. Median number of prior therapies was 3; and because of comorbidities, 33% would have been ineligible for the TRANSCEND study. Bridging therapy was used in 60% (43% received polatuzumab-based treatment). Any-grade cytokine-release syndrome occurred in 49% (3% grade ≥3) with any-grade immune effector cell-associated neurotoxicity syndrome occurring in 26% (10% grade ≥3). The overall response rate (ORR) to bridging therapy was 45%, with 18% achieving a complete response (CR). Following liso-cel infusion, the day 90 ORR was 66% (60% CR); and with a median follow-up of 15.5 months, 12-month progression-free survival (PFS) and overall survival (OS) were 55% and 68%, respectively. A normal lactate dehydrogenase level before lymphodepletion was associated with improved PFS and OS. These analyses confirm similar efficacy and safety of commercial liso-cel compared with pivotal trial results. Notably, these outcomes were achieved in patients predominantly of advanced age and with significant comorbidities. Results also likely reflect advancements in patient selection, toxicity management, and the use of novel bridging strategies.
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Affiliation(s)
- Peter A. Riedell
- David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL
| | - Connor B. Grady
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA
| | - Loretta J. Nastoupil
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alejandro Luna
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
- Adult Bone Marrow Transplantation Unit, Hematology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Nausheen Ahmed
- Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Cancer Center, Westwood, KS
| | - Richard T. Maziarz
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Marie Hu
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN
| | - Jamie Brower
- Center for Cell Therapy and Transplant, University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA
| | - Stephen J. Schuster
- Center for Cell Therapy and Transplant, University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA
| | - Andy I. Chen
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Olalekan O. Oluwole
- Division of Hematology Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN
| | - Veronika Bachanova
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN
| | - Joseph P. McGuirk
- Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Cancer Center, Westwood, KS
| | - Miguel-Angel Perales
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Michael R. Bishop
- David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL
| | - David L. Porter
- Center for Cell Therapy and Transplant, University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA
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Almawash S. Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2025; 17:880. [PMID: 40075727 PMCID: PMC11899125 DOI: 10.3390/cancers17050880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].
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Affiliation(s)
- Saud Almawash
- Department of Pharmaceutics, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
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49
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Ye X, Ge M, Tan M, Wu Y, Zhang H, Fu Z. CD19 -targeted CAR T therapy treating hematologic malignancies: hidden danger is the next neighbor to security? Front Immunol 2025; 16:1490491. [PMID: 40103829 PMCID: PMC11914092 DOI: 10.3389/fimmu.2025.1490491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025] Open
Abstract
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has achieved marvelous results in the treatment of patients with relapsed and/or refractory B-cell lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. As a new treatment method that has changed the existing treatment paradigm, there has been a short time from its emergence to FDA approval. However, with the increasing number of cases and the passage of time, hidden problems have gradually been exposed. In this review, we summarize the short- and long-term toxicity, such as secondary T-cell tumors and lethal CAR tumors, of patients with hematologic malignancies treated with CD19-CAR-T cells, including cytokine release syndrome (CRS), ICANS, and secondary malignancies with low occurrence rates but high mortality, such as secondary T cell tumors and lethal CAR tumors, which may be related to the gene modification mechanism of viral vectors currently approved for CAR-T cells. We also discuss potential investigational strategies designed to improve the safety of CAR-T-cell therapy.
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Affiliation(s)
- Xueshuai Ye
- Affiliated Hospital of Hebei Engineering University and School of Clinical Medicine, Hebei University of Engineering, Handan, China
| | - Min Ge
- Affiliated Hospital of Hebei Engineering University and School of Clinical Medicine, Hebei University of Engineering, Handan, China
| | - Mengtian Tan
- Affiliated Hospital of Hebei Engineering University and School of Clinical Medicine, Hebei University of Engineering, Handan, China
| | - Yongqiang Wu
- Gene Editing Research Center, Hebei University of Science and Technology, Shijiazhuang, China
| | - Haiqiang Zhang
- Department of Gastrointestinal Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zexian Fu
- Medical College, Hebei University of Engineering, Handan, China
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50
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Bastin DJ, Kilgour MK, Shorr R, Sabri E, Delluc A, Ardolino M, McComb S, Lee SH, Allan D, Ramsay T, Visram A. Efficacy of chimeric antigen receptor engineered natural killer cells in the treatment of hematologic malignancies: a systematic review and meta-analysis of preclinical studies. Cytotherapy 2025; 27:350-364. [PMID: 39692673 DOI: 10.1016/j.jcyt.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/29/2024] [Accepted: 11/03/2024] [Indexed: 12/19/2024]
Abstract
BACKGROUND Chimeric antigen receptor (CAR) engineered NK cells (CAR-NK) are a novel approach to the immunotherapy of hematologic malignancies which seeks to overcome some of the challenges faced by CAR-T cells (CAR-T). With few published clinical studies, preclinical studies can identify strategies to accelerate clinical translation. We conducted a systematic review on the preclinical in vivo use of CAR-NK for the treatment of hematologic malignancies to assess these therapies in a holistic and unbiased manner. METHODS Our protocol was registered with PROSPERO (ID: CRD42023438375). We performed a search of OVID MEDLINE, OVID Embase, and Embase for animal studies employing human CAR-NK cells in the treatment of hematologic malignancies. Screening of studies for eligibility criteria was performed in duplicate. Our primary outcomes were survival and reduction in tumor volume. Data extraction from individual experiments was performed by one reviewer using DigitizeitTM software and verified by a second reviewer. Meta-analysis and subgroup analyses were performed using Comprehensive Meta-AnalysisTM software. Information for descriptive outcomes was extracted in duplicate by two independent reviewers. Risk of bias was assessed using the SYRCLE Risk of Bias Tool for Animal Studies. RESULTS A total of 34 papers met eligibility criteria. Overall, CD19 was the most common antigen targeted however there was substantial diversity in antigenic targets, source material for generating CAR-NK cells, and NK cell modifications. Mice treated with CAR-NK therapy survived significantly longer than untreated mice (median survival ratio of 1.18, 95% CI: 1.10-1.27, P < 0.001), and mice treated with nonengineered NK cells (median survival ratio 1.13, 95% CI: 1.03-1.23, P < 0.001). Similarly, treatment with CAR-NK significantly reduced the tumor burden when compared to untreated mice (ratio of mean tumor volume 0.23, 95% CI: 0.17-0.32, P < 0.001) or mice treated with nonengineered NK cells (ratio of mean tumor volume 0.37, 95% CI: 0.28-0.51, P < 0.001). Subgroup analysis showed that cotreatment with IL-15 reduced tumor volume but did not increase survival. In general, CAR-NK cell persistence was short but was increased by IL-15. CONCLUSIONS CAR-NK shows promise for the treatment of hematologic malignancies in preclinical models.
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Affiliation(s)
- Donald J Bastin
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Marisa K Kilgour
- Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Risa Shorr
- Learning Services, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Elham Sabri
- Methods Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Aurélien Delluc
- Department of Medicine (Hematology), The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Michele Ardolino
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada; CI3, University of Ottawa, Ottawa, Ontario, Canada
| | - Scott McComb
- Human Health Therapeutics Research Center, National Research Council, Ottawa, Ontario, Canada
| | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - David Allan
- Department of Medicine (Hematology), The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Tim Ramsay
- Methods Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Alissa Visram
- Department of Medicine (Hematology), The Ottawa Hospital, Ottawa, Ontario, Canada.
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