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Gao D. The role of non-malignant B cells in malignant hematologic diseases. Hematology 2025; 30:2466261. [PMID: 39964954 DOI: 10.1080/16078454.2025.2466261] [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: 06/02/2024] [Accepted: 02/08/2025] [Indexed: 02/20/2025] Open
Abstract
The tumor microenvironment (TME) represents a heterogeneous, complicated ecosystem characterized by intricate interactions between tumor cells and immune cells. During the past decade, immune cells especially T cells were found to play an important role in the progression of tumor and many related immune checkpoints drugs were created. In recent years, more and more scientists revealed the critical role of B-cells within the TME, particularly various populations of non-malignant B cells. Some studies indicated that non-malignant B cells may exert a 'double-edged sword' role in solid tumors. However, there has been comparatively less focus on the role of non-malignant B cells in hematologic malignancies. In this review, we characterized the development of B cells and summarized its functions of antitumor immunity within TME, with an emphasis on elucidating the roles and potential mechanisms of non-malignant B cells in the progression of hematologic diseases including classical Hodgkin's lymphoma, non-Hodgkin's B-cell lymphoma, non-Hodgkin's T-cell lymphoma, leukemia and multiple myeloma.
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Affiliation(s)
- Daquan Gao
- Department of Hematology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, People's Republic of China
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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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Li X, Zhang Y, Mixdorf JC, Wu Q, Lee SJ, Engle JW, Barnhart TE, Kenney SC, Rui L, Wei W, Cai W. Development and Preclinical Evaluation of [ 64Cu]Cu-NOTA-ABDB6: A CD70 and Albumin Dual-Binding Tracer with Improved Pharmacokinetics. J Nucl Med 2025; 66:552-558. [PMID: 40015924 PMCID: PMC11960615 DOI: 10.2967/jnumed.124.268835] [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: 09/19/2024] [Accepted: 02/03/2025] [Indexed: 03/01/2025] Open
Abstract
CD70 is an emerging biomarker for both solid tumors and hematologic malignancies, highlighting the urgent need for a molecular imaging tracer capable of visualizing CD70 with favorable pharmacokinetics. Methods: ABDB6 was prepared by fusing the albumin-binding domain ABD035 with the CD70-targeting single-domain antibody RCCB6, which we previously reported. The resulting ABDB6 was then conjugated to the bifunctional chelator p-SCN-NOTA and labeled with 64Cu to produce [64Cu]Cu-NOTA-ABDB6. Flow cytometry was used to screen 6 lymphoma cell lines with varying CD70 expression levels. Cell uptake and in vivo immuno-PET imaging studies were conducted to fully evaluate the pharmacokinetic properties and tumor-targeting efficacy of [64Cu]Cu-NOTA-ABDB6. An ABDB6 blocking study was performed to validate the targeting specificity of [64Cu]Cu-NOTA-ABDB6, followed by immunohistochemistry and fluorescent immunostaining studies to correlate tracer uptake with CD70 expression. Results: 64Cu labeling of ABDB6 achieved a high radiochemical yield and specific activity. Significant CD70 expression was observed in 5 lymphoma cell lines (TMD8, HBL1, OCI-LY10, LCL-EBV, and type III latency Burkitt lymphoma [BL] cells) but not in type I latency BL cells, which served as the negative control. [64Cu]Cu-NOTA-ABDB6 exhibited good affinity for CD70 protein at the nanomolar level (inhibitory concentration of 50%, 91.57 nM) and specificity in binding to human CD70. Immuno-PET imaging of [64Cu]Cu-NOTA-ABDB6 demonstrated excellent tumor uptake and retention in various CD70-positive lymphoma models (TMD8, type III latency BL, and LCL-EBV), with the highest tumor uptake values recorded as 24.67 ± 1.36, 18.02 ± 4.29, and 14.68 ± 1.20 percentage injected dose per gram of tissue (%ID/g) at 48 h after injection, respectively. These tumor uptake values were significantly higher than that of the CD70-negative type I latency BL tumor, which had an uptake of 3.59 ± 0.28 %ID/g at the same scanning time point (P < 0.05). In the TMD8 blocking group, tumor uptake was 5.99 ± 1.20 %ID/g at 48 h after injection, significantly lower than in the TMD8 control group (P < 0.01). Both biodistribution and histology results corroborated these imaging findings. Conclusion: [64Cu]Cu-NOTA-ABDB6 immuno-PET effectively visualized varying levels of CD70 in different lymphoma models. Its clinical potential may provide insights into CD70 expression in lymphoma patients.
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Affiliation(s)
- Xiaoyan Li
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - You Zhang
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jason C Mixdorf
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Qianyun Wu
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Sophia J Lee
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Jonathan W Engle
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Todd E Barnhart
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Shannon C Kenney
- Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin; and
| | - Lixin Rui
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin; and
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Weijun Wei
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;
| | - Weibo Cai
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin;
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
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Chen K, Liang H, Yu Z, Guo G, Zheng H, Huang Y, Liu L, Lin J, Long J, Pan R, Chen X, Wang C, Zhang W, Xu Z. Analysis of early efficacy and immune reconstitution after autologous hematopoietic stem cell transplantation in multiple myeloma. Sci Rep 2025; 15:1222. [PMID: 39775096 PMCID: PMC11707290 DOI: 10.1038/s41598-024-84047-2] [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: 07/21/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
This retrospective study aimed to stress the advantages of autologous hematopoietic stem cell transplantation (auto-HSCT) in treating primary MM. Ninety-four MM patients who underwent initial parallel sequential auto-HSCT were selected. Data on efficacy (efficacy evaluation, renal function and hemoglobin recovery), immune reconstitution (B-cell subsets, immunoglobulin levels, T-cell subsets, NK cells, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR)) and hematopoietic reconstitution times were collected and analyzed. Whether in all selected patients or in groups R-ISS II-III, there was a notable increase in the proportion of patients achieving in a very good partial response (VGPR) or better (P < 0.001, P = 0.02) and a complete response (CR) or better (P = 0.007, P = 0.014) after transplantation compared to the pre-transplant status. Post-Transplant Immune Reconstitution Analysis (Baseline vs. Pre-Transplant and Pre-Transplant vs. Post-Transplant): The level of CD19 + B cells, CD20 + B cells, CD22 + B cells, CD3 + T cells, IgG and LMR showed the same change trend, that is, it decreased before transplantation (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P<0.007, P < 0.001) and then increased significantly after transplantation(P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001). CD3 + CD4 + T cells from 545.97 (342.11,708.60)/µL to 342.93 (168.38, 475.52)/µL (P < 0.001) and then to 251.48 (188.52, 406.98)/µL (P = 0.348); CD3 + CD8 + T cells from 391.36 (242.19, 563.37)/µL to 337.23 (192.54, 505.96)/µL (P = 0.065) and then to 797.96 (514.49, 1198.03)/µL (P < 0.001), so the CD3 + CD4+/CD3 + CD8 + T cell ratio still remained inverted post-transplant. NK cells changed from 309.86 (206.33, 460.96)/µL to 258.31 (160.75, 436.68)/ µL (P = 0.229) and then to 151.08 (108.17, 240.84)/µL (P = 0.007). Auto-HSCT can promote prolonged remission in patients with MM and also overcome some high-risk factors to achieve superior efficacy in group R-ISS II-III. Patients were immunodeficient before transplantation and auto-HSCT facilitated immune reconstitution.
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Affiliation(s)
- Kaili Chen
- Department of Blood Transfusion, Affiliated Hospital of Putian University, Putian, 351100, China
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Huixin Liang
- Department of infectious diseases, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Zezhong Yu
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Guangyao Guo
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Huijian Zheng
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Yun Huang
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Liping Liu
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Jie Lin
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Jinlan Long
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Renyao Pan
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Xi Chen
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Changgui Wang
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China
| | - Wenjie Zhang
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China.
| | - Zhenshu Xu
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, 29 Xinquan Rd, Fuzhou, 350001, China.
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Gupta A, Dagar G, Rehmani MU, Prasad CP, Saini D, Singh M, Shankar A. CAR T-cell therapy in cancer: Integrating nursing perspectives for enhanced patient care. Asia Pac J Oncol Nurs 2024; 11:100579. [PMID: 39315365 PMCID: PMC11417177 DOI: 10.1016/j.apjon.2024.100579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy represents a significant advancement in cancer treatment, particularly for hematologic malignancies. Various cancer immunotherapy strategies are presently being explored, including cytokines, cancer vaccines, immune checkpoint inhibitors, immunomodulators monoclonal antibodies, etc. The therapy has shown impressive efficacy in treating conditions such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma, often leading to complete remission in refractory cases. However, the clinical application of CAR T-cell therapy is accompanied by challenges, notably severe side effects. Effective management of these adverse effects requires meticulous monitoring and prompt intervention, highlighting the critical role of nursing in this therapeutic process. Nurses play a crucial role in patient education, monitoring, symptom management, care coordination, and psychosocial support, ensuring safe and effective treatment. As research advances and new CAR T-cell therapies are developed, the role of nursing professionals remains pivotal in optimizing patient outcomes. The continued evolution of CAR T-cell therapy promises improved outcomes, with nursing professionals integral to its success.
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Affiliation(s)
- Ashna Gupta
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Gunjan Dagar
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Mohd Umar Rehmani
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Deepak Saini
- Indian Society of Clinical Oncology, Delhi, India
| | - Mayank Singh
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Abhishek Shankar
- Department of Radiation Oncology, Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
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Ma R, Li Y, Yin S, Gao Y, Zhao G. Interstitial pneumonia development after chemotherapy in B-cell non-hodgkin's lymphoma patients: clinical profiles and risk factors. Am J Cancer Res 2024; 14:4484-4494. [PMID: 39417196 PMCID: PMC11477814 DOI: 10.62347/btgq7302] [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: 05/13/2024] [Accepted: 08/30/2024] [Indexed: 10/19/2024] Open
Abstract
Interstitial pneumonia (IP) is a significant adverse effect of chemotherapy in B-cell non-Hodgkin's lymphoma (NHL) patients. This study aimed to identify the clinical characteristics, risk factors, and treatment outcomes associated with IP in these patients. A retrospective review of 615 NHL patients treated at the Fourth Hospital of Hebei Medical University from 2016 to 2021 identified 50 patients with IP post-chemotherapy as the case group. A propensity score matched control group of 55 patients without pneumonia was established. Clinical profiles, risk factors, and treatment outcomes were evaluated. The IP incidence was 8.13% (50/615) in B-cell NHL patients. Multivariate analysis revealed liposomes, elevated lactate dehydrogenase (LDH), and erythrocyte sedimentation rate (ESR) as independent risk factors for IP. Receiver Operating Characteristic (ROC) curve analyses suggested that alterations in LDH and ESR could predict IP risk. The conclusion suggests that IP is associated with liposomal doxorubicin-induced lung injury and other cytotoxic chemotherapy, possibly due to Rituximab (RTX)-induced immune imbalance. Given the potential of IP with pulmonary infections, high-risk patients may need prophylactic antibiotics and appropriate corticosteroid therapy.
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Affiliation(s)
- Ruijuan Ma
- Department of Hematology, The Fourth Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Yuan Li
- Department of Hematology, The Fourth Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Shaoning Yin
- Department of Hematology, The Fourth Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Yuhuan Gao
- Department of Hematology, The Fourth Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Guimin Zhao
- Department of Hematology, The Fourth Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
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Anurogo D, Luthfiana D, Anripa N, Fauziah AI, Soleha M, Rahmah L, Ratnawati H, Wargasetia TL, Pratiwi SE, Siregar RN, Sholichah RN, Maulana MS, Ikrar T, Chang YH, Qiu JT. The Art of Bioimmunogenomics (BIGs) 5.0 in CAR-T Cell Therapy for Lymphoma Management. Adv Pharm Bull 2024; 14:314-330. [PMID: 39206402 PMCID: PMC11347730 DOI: 10.34172/apb.2024.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 01/13/2024] [Accepted: 03/03/2024] [Indexed: 09/04/2024] Open
Abstract
Purpose Lymphoma, the most predominant neoplastic disorder, is divided into Hodgkin and Non-Hodgkin Lymphoma classifications. Immunotherapeutic modalities have emerged as essential methodologies in combating lymphoid malignancies. Chimeric Antigen Receptor (CAR) T cells exhibit promising responses in chemotherapy-resistant B-cell non-Hodgkin lymphoma cases. Methods This comprehensive review delineates the advancement of CAR-T cell therapy as an immunotherapeutic instrument, the selection of lymphoma antigens for CAR-T cell targeting, and the conceptualization, synthesis, and deployment of CAR-T cells. Furthermore, it encompasses the advantages and disadvantages of CAR-T cell therapy and the prospective horizons of CAR-T cells from a computational research perspective. In order to improve the design and functionality of artificial CARs, there is a need for TCR recognition investigation, followed by the implementation of a quality surveillance methodology. Results Various lymphoma antigens are amenable to CAR-T cell targeting, such as CD19, CD20, CD22, CD30, the kappa light chain, and ROR1. A notable merit of CAR-T cell therapy is the augmentation of the immune system's capacity to generate tumoricidal activity in patients exhibiting chemotherapy-resistant lymphoma. Nevertheless, it also introduces manufacturing impediments that are laborious, technologically demanding, and financially burdensome. Physical, physicochemical, and physiological limitations further exacerbate the challenge of treating solid neoplasms with CAR-T cells. Conclusion While the efficacy and safety of CAR-T cell immunotherapy remain subjects of fervent investigation, the promise of this cutting-edge technology offers valuable insights for the future evolution of lymphoma treatment management approaches. Moreover, CAR-T cell therapies potentially benefit patients, motivating regulatory bodies to foster international collaboration.
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Affiliation(s)
- Dito Anurogo
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Faculty of Medicine and Health Sciences, Muhammadiyah University of Makassar, Makassar, South Sulawesi, 90221, Indonesia
| | - Dewi Luthfiana
- Bioinformatics Research Center, Indonesian Institute of Bioinformatics (INBIO), Malang, East Java, 65162, Indonesia
| | - Nuralfin Anripa
- Department of Environmental Science, Dumoga University, Kotamobagu, South Sulawesi, 95711, Indonesia
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Apriliani Ismi Fauziah
- MSc Program in Tropical Medicine, Kaohsiung Medical University, Kaohsiung City, 807378, Taiwan
| | - Maratu Soleha
- National Research and Innovation Agency (BRIN), Central Jakarta, 10340, Indonesia
- IKIFA College of Health Sciences, East Jakarta, Special Capital Region of Jakarta, 13470, Indonesia
| | - Laila Rahmah
- Department of Digital Health, School of Medicine, Tehran University of Medical Sciences, Tehran, 1416634793, Iran
- Faculty of Medicine, Muhammadiyah University of Surabaya, Surabaya, East Java, 60113, Indonesia
| | - Hana Ratnawati
- Faculty of Medicine, Maranatha Christian University, Bandung, West Java, 40164, Indonesia
| | | | - Sari Eka Pratiwi
- Department of Biology and Pathobiology, Faculty of Medicine, Tanjungpura University, Pontianak, West Kalimantan, 78115, Indonesia
| | - Riswal Nafi Siregar
- National Research and Innovation Agency (BRIN), Central Jakarta, 10340, Indonesia
| | - Ratis Nour Sholichah
- Department of Biotechnology, Postgraduate School of Gadjah Mada University, Yogyakarta, 55284, Indonesia
| | - Muhammad Sobri Maulana
- Community Health Center (Puskesmas) Temon 1, Kulon Progo, Special Region of Yogyakarta, 55654, Indonesia
| | - Taruna Ikrar
- Director of Members-at-Large, International Association of Medical Regulatory Authorities (IAMRA), Texas, 76039, USA
- Aivita Biomedical Inc., Irvine, California, 92612, USA
- Chairman of Medical Council, The Indonesian Medical Council (KKI), Central Jakarta, 10350, Indonesia
- Adjunct Professor, School of Military Medicine, The Republic of Indonesia Defense University (RIDU), Jakarta Pusat, 10440, Indonesia
- Department of Pharmacology, Faculty of Medicine, Malahayati University, Bandar Lampung, Lampung, 35152, Indonesia
| | - Yu Hsiang Chang
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Locus Cell Co., LTD., Xizhi Dist., New Taipei City, 221, Taiwan
| | - Jiantai Timothy Qiu
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, 110301, Taiwan
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Lee AA, Godwin AK, Abdelhakim H. The multifaceted roles of extracellular vesicles for therapeutic intervention with non-Hodgkin lymphoma. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2024; 5:329-343. [PMID: 39639879 PMCID: PMC11618822 DOI: 10.20517/evcna.2024.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Extracellular vesicles (EVs) contribute to the development of cancer in various ways. Non-Hodgkin lymphoma (NHL) is a cancer of mature lymphocytes and the most common hematological malignancy globally. The most common form of NHL, diffuse large B-cell lymphoma (DLBCL), is primarily treated with chemotherapy, autologous stem cell transplantation (ASCT), and/or chimeric antigen receptor T-cell (CAR-T) therapy. With NHL disease progression and its treatment, extracellular vesicles play remarkable roles in influencing outcomes. This finding can be utilized for therapeutic intervention to improve patient outcomes for NHL. This review focuses on the multifaceted roles of EVs with NHL and its potential for guiding patient care.
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Affiliation(s)
- Arthur A. Lee
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Bioengineering Program, The University of Kansas, Lawrence, KS 64111, USA
| | - Andrew K. Godwin
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Bioengineering Program, The University of Kansas, Lawrence, KS 64111, USA
- Kansas Institute for Precision Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Haitham Abdelhakim
- The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Ho M, Bonavida B. Cross-Talks between Raf Kinase Inhibitor Protein and Programmed Cell Death Ligand 1 Expressions in Cancer: Role in Immune Evasion and Therapeutic Implications. Cells 2024; 13:864. [PMID: 38786085 PMCID: PMC11119125 DOI: 10.3390/cells13100864] [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: 03/10/2024] [Revised: 05/11/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
Innovations in cancer immunotherapy have resulted in the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies in immune checkpoint inhibitors (ICIs), which have shown significant clinical efficacy and increased survival rates in patients with various therapy-resistant cancers. This immune intervention consists of monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or against corresponding ligands (e.g., PD-L1/PD-L2) overexpressed on cancer cells and other cells in the tumor microenvironment (TME). However, not all cancer cells respond-there are still poor clinical responses, immune-related adverse effects, adaptive resistance, and vulnerability to ICIs in a subset of patients with cancer. This challenge showcases the heterogeneity of cancer, emphasizing the existence of additional immunoregulatory mechanisms in many patients. Therefore, it is essential to investigate PD-L1's interaction with other oncogenic genes and pathways to further advance targeted therapies and address resistance mechanisms. Accordingly, our aim was to investigate the mechanisms governing PD-L1 expression in tumor cells, given its correlation with immune evasion, to uncover novel mechanisms for decreasing PD-L1 expression and restoring anti-tumor immune responses. Numerous studies have demonstrated that the upregulation of Raf Kinase Inhibitor Protein (RKIP) in many cancers contributes to the suppression of key hyperactive pathways observed in malignant cells, alongside its broadening involvement in immune responses and the modulation of the TME. We, therefore, hypothesized that the role of PD-L1 in cancer immune surveillance may be inversely correlated with the low expression level of the tumor suppressor Raf Kinase Inhibitor Protein (RKIP) expression in cancer cells. This hypothesis was investigated and we found several signaling cross-talk pathways between the regulations of both RKIP and PD-L1 expressions. These pathways and regulatory factors include the MAPK and JAK/STAT pathways, GSK3β, cytokines IFN-γ and IL-1β, Sox2, and transcription factors YY1 and NFκB. The pathways that upregulated PD-L1 were inhibitory for RKIP expression and vice versa. Bioinformatic analyses in various human cancers demonstrated the inverse relationship between PD-L1 and RKIP expressions and their prognostic roles. Therefore, we suspect that the direct upregulation of RKIP and/or the use of targeted RKIP inducers in combination with ICIs could result in a more targeted anti-tumor immune response-addressing the therapeutic challenges related to PD-1/PD-L1 monotherapy alone.
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Affiliation(s)
| | - Benjamin Bonavida
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer, University of California, Los Angeles, CA 90095, USA;
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10
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Maqbool S, Baloch MF, Khan MAK, Khalid A, Naimat K. Autologous hematopoietic stem cell transplantation conditioning regimens and chimeric antigen receptor T cell therapy in various diseases. World J Transplant 2024; 14:87532. [PMID: 38576761 PMCID: PMC10989471 DOI: 10.5500/wjt.v14.i1.87532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/21/2023] [Accepted: 01/08/2024] [Indexed: 03/15/2024] Open
Abstract
Conditioning regimens employed in autologous stem cell transplantation have been proven useful in various hematological disorders and underlying malig nancies; however, despite being efficacious in various instances, negative consequences have also been recorded. Multiple conditioning regimens were extracted from various literature searches from databases like PubMed, Google scholar, EMBASE, and Cochrane. Conditioning regimens for each disease were compared by using various end points such as overall survival (OS), progression free survival (PFS), and leukemia free survival (LFS). Variables were presented on graphs and analyzed to conclude a more efficacious conditioning regimen. In multiple myeloma, the most effective regimen was high dose melphalan (MEL) given at a dose of 200/mg/m2. The comparative results of acute myeloid leukemia were presented and the regimens that proved to be at an admirable position were busulfan (BU) + MEL regarding OS and BU + VP16 regarding LFS. In case of acute lymphoblastic leukemia (ALL), BU, fludarabine, and etoposide (BuFluVP) conferred good disease control not only with a paramount improvement in survival rate but also low risk of recurrence. However, for ALL, chimeric antigen receptor (CAR) T cell therapy was preferred in the context of better OS and LFS. With respect to Hodgkin's lymphoma, mitoxantrone (MITO)/MEL overtook carmustine, VP16, cytarabine, and MEL in view of PFS and vice versa regarding OS. Non-Hodgkin's lymphoma patients were administered MITO (60 mg/m2) and MEL (180 mg/m2) which showed promising results. Lastly, amyloidosis was considered, and the regimen that proved to be competent was MEL 200 (200 mg/m2). This review article demonstrates a comparison between various conditioning regimens employed in different diseases.
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Affiliation(s)
- Shahzaib Maqbool
- Department of Medicine, Holy Family Hospital, Rawalpindi 46000, Pakistan
| | - Maryam Farhan Baloch
- Department of Community Medicine, Allama Iqbal Medical College, Lahore 45000, Pakistan
| | | | - Azeem Khalid
- Department of Medicine, Allama lqbal Medical College, Lahore 45000, Pakistan
| | - Kiran Naimat
- Department of MedicineLiaquat University of Medical and Health Sciences, Karachi 43000, Pakistan
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11
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Ramalingam TR, Vaidhyanathan L, Muthu A, Swaminathan VV, Uppuluri R, Raj R. Deciphering stage 0 hematogones by flow cytometry in follow-up bone marrow samples of pediatric B-Acute lymphoblastic leukemia cases: A potential mimicker of residual disease after anti CD19 therapy. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2024; 106:92-98. [PMID: 38243626 DOI: 10.1002/cyto.b.22159] [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: 08/24/2023] [Revised: 11/21/2023] [Accepted: 12/27/2023] [Indexed: 01/21/2024]
Abstract
CD19 is frequently targeted for immunotherapy in B cell malignancies, which may result in loss of CD19 expression in leukemic cells as an escape mechanism. Stage 0 hematogones (Hgs) are normal CD19-negative very early B cell precursors that can be potentially mistaken for CD19 negative residual leukemic cells by flow cytometry (FCM) in B cell acute lymphoblastic leukemia (BCP-ALL) cases treated with anti CD19 therapy. Our main objective was to characterize and study the incidence of stage 0 hematogones in follow-up bone marrow samples of pediatric BCP-ALL cases. We analyzed the flow cytometry standard files of 61 pediatric BCP-ALL cases treated with conventional chemotherapy and targeted anti-CD19 therapy, for identifying the residual disease and normal B cell precursors including stage 0 Hgs. A non-CD19 alternate gating strategy was used to isolate the B cells for detecting the residual disease and stage 0 Hgs. The stage 0 Hgs were seen in 95% of marrow samples containing CD19+ Hgs. When compared with controls and posttransplant marrow samples, the fraction of stage 0 Hgs was higher in patients receiving anti CD19 therapy (p = 0.0048), but it was not significant when compared with patients receiving chemotherapy (p = 0.1788). Isolated stage 0 Hgs are found in samples treated with anti-CD19 therapy simulating CD19 negative residual illness. Our findings aid in understanding the stage 0 Hgs and its association with CD19+ Hgs in anti CD19 therapy and conventional chemotherapy. This is crucial as it can be potentially mistaken for residual disease in patients treated with anti CD19 therapy.
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Affiliation(s)
| | | | - Anurekha Muthu
- Department of Hematology, Apollo Cancer Centre, Chennai, India
| | | | - Ramya Uppuluri
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Cancer Centre, Chennai, India
| | - Revathi Raj
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Cancer Centre, Chennai, India
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12
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Lin Y, Chen Y, Luo Z, Wu YL. Recent advances in biomaterial designs for assisting CAR-T cell therapy towards potential solid tumor treatment. NANOSCALE 2024; 16:3226-3242. [PMID: 38284230 DOI: 10.1039/d3nr05768b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
Chimeric antigen receptor T (CAR-T) cells have shown promising outcomes in the treatment of hematologic malignancies. However, CAR-T cell therapy in solid tumor treatment has been significantly hindered, due to the complex manufacturing process, difficulties in proliferation and infiltration, lack of precision, or poor visualization ability. Fortunately, recent reports have shown that functional biomaterial designs such as nanoparticles, polymers, hydrogels, or implantable scaffolds might have potential to address the above challenges. In this review, we aim to summarize the recent advances in the designs of functional biomaterials for assisting CAR-T cell therapy for potential solid tumor treatments. Firstly, by enabling efficient CAR gene delivery in vivo and in vitro, functional biomaterials can streamline the difficult process of CAR-T cell therapy manufacturing. Secondly, they might also serve as carriers for drugs and bioactive molecules, promoting the proliferation and infiltration of CAR-T cells. Furthermore, a number of functional biomaterial designs with immunomodulatory properties might modulate the tumor microenvironment, which could provide a platform for combination therapies or improve the efficacy of CAR-T cell therapy through synergistic therapeutic effects. Last but not least, the current challenges with biomaterials-based CAR-T therapies will also be discussed, which might be helpful for the future design of CAR-T therapy in solid tumor treatment.
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Affiliation(s)
- Yuting Lin
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
| | - Ying Chen
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
| | - Zheng Luo
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
- Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research), Singapore 138634, Singapore
| | - Yun-Long Wu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
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13
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Ostojska M, Nowak E, Twardowska J, Lejman M, Zawitkowska J. CAR-T Cell Therapy in the Treatment of Pediatric Non-Hodgkin Lymphoma. J Pers Med 2023; 13:1595. [PMID: 38003910 PMCID: PMC10672004 DOI: 10.3390/jpm13111595] [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: 10/01/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Non-Hodgkin lymphomas (NHL) are a group of cancers that originate in the lymphatic system, especially from progenitor or mature B-cells, T-cells, or natural killer (NK) cells. NHL is the most common hematological malignancy worldwide and also the fourth most frequent type of cancer among pediatric patients. This cancer can occur in children of any age, but it is quite rare under the age of 5 years. In recent decades, available medicines and therapies have significantly improved the prognosis of patients with this cancer. However, some cases of NHL are treatment resistant. For this reason, immunotherapy, as a more targeted and personalized treatment strategy, is becoming increasingly important in the treatment of NHL in pediatric patients. The objective of the following review is to gather the latest available research results, conducted among pediatric and/or adult patients with NHL, regarding one immunotherapy method, i.e., chimeric antigen receptor (CAR) T cell therapy. We focus on assessing the effectiveness of CAR-T cell therapy, which mainly targets B cell markers, CD19, CD20, and CD22, their connections with one another, sequential treatment, or connections with co-stimulatory molecules. In addition, we also evaluate the safety, aftermath (especially neurotoxicities) and limitations of CAR-T cell therapy.
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Affiliation(s)
- Magdalena Ostojska
- Student’s Scientific Association of the Department of Pediatric Hematology, Oncology and Transplantation, Medical University of Lublin, 20-093 Lublin, Poland; (M.O.); (E.N.); (J.T.)
| | - Emilia Nowak
- Student’s Scientific Association of the Department of Pediatric Hematology, Oncology and Transplantation, Medical University of Lublin, 20-093 Lublin, Poland; (M.O.); (E.N.); (J.T.)
| | - Julia Twardowska
- Student’s Scientific Association of the Department of Pediatric Hematology, Oncology and Transplantation, Medical University of Lublin, 20-093 Lublin, Poland; (M.O.); (E.N.); (J.T.)
| | - Monika Lejman
- Independent Laboratory of Genetic Diagnostics, Faculty of Medicine, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Joanna Zawitkowska
- Department of Pediatric Hematology, Oncology and Transplantation, Medical University of Lublin, 20-093 Lublin, Poland
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Cai Y, Lv L, Lu T, Ding M, Yu Z, Chen X, Zhou X, Wang X. α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis. Cell Death Discov 2023; 9:182. [PMID: 37308557 DOI: 10.1038/s41420-023-01475-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 05/11/2023] [Accepted: 05/19/2023] [Indexed: 06/14/2023] Open
Abstract
Metabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of reactive oxygen species (ROS) contributed to ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.
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Affiliation(s)
- Yiqing Cai
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Liemei Lv
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Tiange Lu
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Mengfei Ding
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Zhuoya Yu
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Xiaomin Chen
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Xiangxiang Zhou
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China.
- Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China.
- National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China.
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China.
- Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China.
- National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China.
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15
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Robak T, Robak P. Refractory and relapsed hairy-cell leukemia (HCL): casting light on promising experimental drugs in clinical trials. Expert Opin Investig Drugs 2023; 32:311-324. [PMID: 36931901 DOI: 10.1080/13543784.2023.2193323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2023]
Abstract
INTRODUCTION Hairy cell leukemia (HCL) is a rare subtype of indolent lymphoid leukemia originating from a mature B lymphocyte. The standard first-line treatment for classic HCL, and HCL variant (HCLv), consists of purine nucleoside analogs (PNA), with or without rituximab. However, almost half of patients relapse and require subsequent therapy. AREAS COVERED This article summarizes recent achievements in the treatment of relapsed and refractory HCL. A literature search was conducted of the PubMed and MEDLINE database for articles in English. Publications from 2010 through January 2023 were scrutinized. The search terms used were hairy cell leukemia in conjunction with BRAF inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CD20 monoclonal antibodies, relapsed, refractory and variant.The growing understanding of HCL biology has allowed the design of several new, chemotherapy-free targeted drugs which have demonstrated encouraging efficacy in early clinical trials. EXPERT OPINION Novel drugs will soon be available to assist standard therapy for HCL and HCLv among patients with suboptimal results following PNA treatment. In particular, the BRAF inhibitors vemurafenib and dabrafenib, with or without rituximab, have revolutionized treatment of patients with relapsed or refractory disease.
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Affiliation(s)
- Tadeusz Robak
- Department of Hematology, Medical University of Lodz, Łódź, Poland
- Department of General Hematology, Copernicus Memorial Hospital, Lodz, Poland
| | - Paweł Robak
- Department of Experimental Hematology, Medical University of Lodz, Lodz, Poland
- Department of Hematooncology, Copernicus Memorial Hospital, Lodz, Poland
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16
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Abstract
INTRODUCTION New methods in cancer immunotherapy, such as chimeric antigen receptor (CAR)-T cells, have shown promising results in destroying malignant cells. However, limitations and side effects of CAR-T cell therapy, such as graft-versus-host disease (GVHD), neurotoxicity, and cytokine release syndrome, have motivated researchers to investigate safer alternative cells like natural killer (NK) cells. AREA COVERED NK cells can effectively recognize hematologic malignant cells and destroy them. Many clinical and preclinical studies investigate the efficacy of CAR-NK cells in treating lymphoma and other hematologic malignancies. The results of published clinical trials and preclinical studies have shown that CAR-NK cells could be an appropriate choice for treating lymphoma. In this review, we discuss the characteristics of CAR-NK cells, their role in treating B-cell and T-cell lymphoma, and the challenges faced by using them. We also highlight clinical trials using CAR-NK cells for treating lymphoma. EXPERT OPINION CAR-NK cells have shown promising results in cancer therapy, especially B-cell lymphoma, with a much lower risk for GVHD, cytokine release syndrome, and neurotoxicity than CAR-T cells. Further investigations are required to overcome the obstacles of CAR-NK cell therapy, both generally, and in cancers like T-cell lymphoma.
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Affiliation(s)
- Shaghayegh Khanmohammadi
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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17
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Cheke RS, Bagwe P, Bhange S, Kharkar PS. Biologicals and small molecules as target-specific cancer chemotherapeutic agents. MEDICINAL CHEMISTRY OF CHEMOTHERAPEUTIC AGENTS 2023:615-646. [DOI: 10.1016/b978-0-323-90575-6.00018-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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18
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Su L, Wu L, Lobb RR, Rennert PD, Ambrose C. CAR-T Engager proteins optimize anti-CD19 CAR-T cell therapies for lymphoma. Oncoimmunology 2022; 11:2111904. [PMID: 35990518 PMCID: PMC9387338 DOI: 10.1080/2162402x.2022.2111904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
B cell lymphoma therapy has been transformed by CD19-targeting cellular therapeutics that induce high clinical response rates and impressive remissions in relapsed and refractory patients. However, approximately half of all patients who respond to CD19-directed cell therapy relapse, the majority within 6 months. One characteristic of relapse is loss or reduction of CD19 expression on malignant B cells. We designed a unique therapeutic to prevent and reverse relapses due to lost or reduced CD19 expression. This novel biologic, a CAR T Engager, binds CD20 and displays the CD19 extracellular domain. This approach increases the apparent CD19 antigen density on CD19-positive/CD20-positive lymphoma cells, and prevents antigen-loss induced relapse, as CD19 bound to CD20 remains present on the cell surface. We demonstrate that this novel therapeutic prevents and reverses lymphoma relapse in vitro and prevents CD19-negative lymphoma growth and relapse in vivo.
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Affiliation(s)
- Lihe Su
- Department of Research & Development, Aleta Biotherapeutics, Natick, MA, USA
| | - Lan Wu
- Department of Research & Development, Aleta Biotherapeutics, Natick, MA, USA
| | - Roy R. Lobb
- Department of Research & Development, Aleta Biotherapeutics, Natick, MA, USA
| | - Paul D. Rennert
- Department of Research & Development, Aleta Biotherapeutics, Natick, MA, USA
| | - Christine Ambrose
- Department of Research & Development, Aleta Biotherapeutics, Natick, MA, USA
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19
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Tannoury M, Garnier D, Susin SA, Bauvois B. Current Status of Novel Agents for the Treatment of B Cell Malignancies: What's Coming Next? Cancers (Basel) 2022; 14:6026. [PMID: 36551511 PMCID: PMC9775488 DOI: 10.3390/cancers14246026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/29/2022] [Accepted: 12/03/2022] [Indexed: 12/13/2022] Open
Abstract
Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today's commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of inhibitors of anti-apoptotic proteins from the B-cell lymphoma/leukemia 2 family and the B-cell receptor (BCR) signaling pathway. Orally administered small-molecule inhibitors of Bcl-2 protein and BCR partners (e.g., Bruton's tyrosine kinase and phosphatidylinositol-3 kinase) have already been included (as monotherapies or combination therapies) in the standard of care for selected B cell malignancies. Agonistic monoclonal antibodies and their derivatives (antibody-drug conjugates, antibody-radioisotope conjugates, bispecific T cell engagers, and chimeric antigen receptor-modified T cells) targeting tumor-associated antigens (TAAs, such as CD19, CD20, CD22, and CD38) are indicated for treatment (as monotherapies or combination therapies) of patients with B cell tumors. However, given that some patients are either refractory to current therapies or relapse after treatment, novel therapeutic strategies are needed. Here, we review current strategies for managing B cell malignancies, with a focus on the ongoing clinical development of more effective, selective drugs targeting these molecules, as well as other TAAs and signaling proteins. The observed impact of metabolic reprogramming on B cell pathophysiology highlights the promise of targeting metabolic checkpoints in the treatment of these disorders.
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Affiliation(s)
| | | | | | - Brigitte Bauvois
- Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, F-75006 Paris, France
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20
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Shen J, Liu J. Bruton's tyrosine kinase inhibitors in the treatment of primary central nervous system lymphoma: A mini-review. Front Oncol 2022; 12:1034668. [PMID: 36465385 PMCID: PMC9713408 DOI: 10.3389/fonc.2022.1034668] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/31/2022] [Indexed: 09/19/2023] Open
Abstract
Primary central nervous system lymphoma (PCNSL) is a highly aggressive brain tumor with poor prognosis if no treatment. The activation of the NF-κB (nuclear factor kappa-B) is the oncogenic hallmark of PCNSL, and it was driven by B cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways. The emergence of Bruton's tyrosine kinase inhibitors (BTKis) has brought the dawn of life to patients with PCNSL. This review summarizes the management of PCNSL with BTKis and potential molecular mechanisms of BTKi in the treatment of PCNSL. And the review will focus on the clinical applications of BTKi in the treatment of PCNSL including the efficacy and adverse events, the clinical trials currently being carried out, the underlying mechanisms of resistance to BTKi and possible solutions to drug resistance.
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Affiliation(s)
- Jing Shen
- Department of Hematology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Jinghua Liu
- Department of Hematology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Hematology, Northern Theater General Hospital, Shenyang, China
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21
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Wen H, Lou X, Qu Z, Qin C, Jiang H, Yang Y, Kang L, Geng X, Yu L, Huang Y. Pre-clinical efficacy of CD20-targeted chimeric antigen receptor T cells for non-Hodgkin's lymphoma. Discov Oncol 2022; 13:122. [PMID: 36352168 PMCID: PMC9646688 DOI: 10.1007/s12672-022-00588-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND A 4-1BB/CD3-ζ-costimulated CAR-T against CD20 (CAR-T20) was subjected to a systemic efficacy evaluation in a cell co-culture model, and NOD-SCID IL-2 receptor gamma null mice (short for NSG mice) were xenografted with human Burkitt's lymphoma Raji cells. METHODS CAR-T20 cells were incubated with target cells (K562, K562 CD20 or Raji cells) at ratios of 10:1 and 5:1 for 24 h, and the killing rate was estimated by an LDH cytotoxicity assay. To evaluate the effect of CAR-T20 on the survival time of tumor-bearing animals, 30 NSG mice were employed, and Raji-Luc cells (5 × 105 cells per mouse) were administered prior to CAR-T20 administration. The survival time, optical intensity of Raji-Luc cells, clinical symptoms, and body mass of the animals were observed. Another 144 male NSG mice were employed to investigate the proliferation and antitumor effects of CAR-T20. Human cytokine and murine cytokines were detected at 1, 7, 14, 21, 28, 42, 56 and 90 days post-CAR-T administration, while biochemistry index analysis, T-cell and CAR-T-cell detection in peripheral blood, and histopathological examination were performed at 14, 28, 56 and 90 days post-administration. RESULTS CAR-T20 cells had a specific killing effect on CD20-expressing cells in vitro. At a dose of 1 × 106 per mouse or above, CAR-T20 prolonged the median survival time from 14 days to more than 3 months, inhibited the proliferation of Raji cells in mice, and alleviated the clinical manifestations and weight loss caused by the Raji-Luc cell load. CAR-T20 at a dose of 2 × 106 per mouse or above inhibited the proliferation of Raji cells in mice for up to 111 days post-administration without recurrence. The numbers of T cells and CAR-T cells in the animals administered CAR-T20 increased significantly when Raji cells were markedly proliferated and subsequently decreased when Raji cells were predominantly inhibited. CAR-T20 increased human IFN-γ, murine TNF and murine IL-6 levels and decreased human IL-10 levels in tumor-bearing mice. The incidences of xenografted tumors in organs/tissues were also reduced effectively by CAR-T20. CONCLUSION The effective dose of CAR-T20 in mice starts from 1 × 106 per mouse, equivalent to a clinical dose of 5 × 106/kg. Together, our data support the clinical translation of CAR-T20 for R/R B-cell NHL patients.
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Affiliation(s)
- Hairuo Wen
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People's Republic of China
| | - Xiaoyan Lou
- Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, No 1525 Minqiang Road, Shanghai, People's Republic of China
| | - Zhe Qu
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People's Republic of China
| | - Chao Qin
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People's Republic of China
| | - Hua Jiang
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People's Republic of China
| | - Ying Yang
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People's Republic of China
| | - Liqing Kang
- Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, No 1525 Minqiang Road, Shanghai, People's Republic of China
| | - Xingchao Geng
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People's Republic of China
| | - Lei Yu
- Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, No 1525 Minqiang Road, Shanghai, People's Republic of China.
| | - Ying Huang
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People's Republic of China.
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22
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Chen Z, Liu Y, Chen N, Xing H, Tian Z, Tang K, Rao Q, Xu Y, Wang Y, Wang M, Wang J. Loop CD20/CD19 CAR-T cells eradicate B-cell malignancies efficiently. SCIENCE CHINA LIFE SCIENCES 2022; 66:754-770. [PMID: 36251156 DOI: 10.1007/s11427-022-2173-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 07/27/2022] [Indexed: 11/05/2022]
Abstract
CD19 chimeric antigen receptor (CAR) T cells have shown robust efficacy in relapsed and refractory acute lymphoblastic leukemia (R/R ALL), but compromising result in chronic lymphoblastic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). CD19 relapse and the lack of CAR-T cell persistence which result in treatment failure are considerable obstacles to overcome. CAR-T targeting CD20 is an option for salvaging CD19 CAR-T failure. Previous studies have established variant structures of bispecific CAR-T which could avoid antigen-loss and immune escape. Here, we constructed tandem and loop CAR structures targeting both CD19 and CD20 antigen. Bispecific CAR-T cells could eliminate either CD19 or CD20 negative lymphoma cells, suggesting they exhibited dual antigen targeting of CD19 and CD20. By comparing the efficiency of four bispecific CAR modified T cells, it was found that loop2019 CAR was the best structure among them to eradicate lymphoma cell lines and patients' primary lymphoma or CLL cells in a very low dose in vitro and prolong the survival time dramatically in lymphoma xenograft mice model. These data highlighted the potential of loop2019 CAR-T in clinical treatment.
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Chen L, Xie T, Wei B, Di DL. Current progress in CAR-T cell therapy for tumor treatment. Oncol Lett 2022; 24:358. [PMID: 36168313 PMCID: PMC9478623 DOI: 10.3892/ol.2022.13478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Chimeric antigen receptor T (CAR-T) cells are a type of tumor immunotherapy that is a breakthrough technology in the clinical treatment of tumors. The basic principle of this method is to extract the patient's T cells and equip them with targeting recognition receptors of tumor cells and return them to the patient's body to recognize and kill tumor cells specifically. Most CAR-T cell therapies treat hematological diseases such as leukemia or lymphoma and achieved encouraging results. The safety and effectiveness of CAR-T cell technology in solid tumor treatment require to be improved, although it has demonstrated promising efficacy in treating hematological malignancies. It is worth noting that certain patients may experience fatal adverse reactions after receiving CAR-T cell therapy. At present, the difficulty of this therapy mainly lies in how to reduce adverse reactions and target escape effects during the course of treatment. The improvement of CAR-T cell therapy mainly focuses on improving CAR-T structure, finding suitable tumor targets and combining them with immune checkpoint inhibitors to the enhance efficacy and safety of treatment. The problems in the rapid development of CAR-T cell therapy provide both obstacles and opportunities. The present review elaborates on the clinical application of CAR-T cell technology to provide a reference for clinical practice and research on tumor treatment.
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Affiliation(s)
- Lei Chen
- Department of Hematology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Ting Xie
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Bing Wei
- Department of Immunology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Da-Lin Di
- Department of Immunology, Weifang Medical University, Weifang, Shandong 261053, P.R. China
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Liang T, Wang X, Liu Y, Ai H, Wang Q, Wang X, Wei X, Song Y, Yin Q. Decreased TCF1 and BCL11B expression predicts poor prognosis for patients with chronic lymphocytic leukemia. Front Immunol 2022; 13:985280. [PMID: 36211334 PMCID: PMC9539190 DOI: 10.3389/fimmu.2022.985280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/08/2022] [Indexed: 11/29/2022] Open
Abstract
T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the TCF7 gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.
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Sheikh IN, Elgehiny A, Ragoonanan D, Mahadeo KM, Nieto Y, Khazal S. Management of Aggressive Non-Hodgkin Lymphomas in the Pediatric, Adolescent, and Young Adult Population: An Adult vs. Pediatric Perspective. Cancers (Basel) 2022; 14:2912. [PMID: 35740580 PMCID: PMC9221186 DOI: 10.3390/cancers14122912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/04/2022] [Accepted: 06/08/2022] [Indexed: 02/01/2023] Open
Abstract
Non-Hodgkin lymphoma (NHL) is a broad entity which comprises a number of different types of lymphomatous malignancies. In the pediatric and adolescent population, the type and prognosis of NHL varies by age and gender. In comparison to adults, pediatric and adolescent patients generally have better outcomes following treatment for primary NHL. However, relapsed/refractory (R/R) disease is associated with poorer outcomes in many types of NHL such as diffuse large B cell lymphoma and Burkitt lymphoma. Newer therapies have been approved in the use of primary NHL in the pediatric and adolescent population such as Rituximab and other therapies such as chimeric antigen receptor T-cell (CAR T-cell) therapy are under investigation for the treatment of R/R NHL. In this review, we feature the characteristics, diagnosis, and treatments of the most common NHLs in the pediatric and adolescent population and also highlight the differences that exist between pediatric and adult disease. We then detail the areas of treatment advances such as immunotherapy with CAR T-cells, brentuximab vedotin, and blinatumomab as well as cell cycle inhibitors and describe areas where further research is needed. The aim of this review is to juxtapose established research regarding pediatric and adolescent NHL with recent advancements as well as highlight treatment gaps where more investigation is needed.
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Affiliation(s)
- Irtiza N. Sheikh
- Department of Pediatrics, Pediatric Hematology Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Amr Elgehiny
- Department of Pediatrics, McGovern Medical School, The University of Texas at Houston Health Science Center, Houston, TX 77030, USA;
| | - Dristhi Ragoonanan
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
| | - Kris M. Mahadeo
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
| | - Yago Nieto
- Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Sajad Khazal
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
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Guo R, Li W, Li Y, Li Y, Jiang Z, Song Y. Generation and clinical potential of functional T lymphocytes from gene-edited pluripotent stem cells. Exp Hematol Oncol 2022; 11:27. [PMID: 35568954 PMCID: PMC9107657 DOI: 10.1186/s40164-022-00285-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 04/26/2022] [Indexed: 12/16/2022] Open
Abstract
Engineered T cells have been shown to be highly effective in cancer immunotherapy, although T cell exhaustion presents a challenge for their long-term function. Additional T-cell sources must be exploited to broaden the application of engineered T cells for immune defense and reconstitution. Unlimited sources of pluripotent stem cells (PSCs) have provided a potential opportunity to generate precise-engineered therapeutic induced T (iT) cells. Single-cell transcriptome analysis of PSC-derived induced hematopoietic stem and progenitor cells (iHSPC)/iT identified the developmental pathways and possibilities of generating functional T cell from PSCs. To date, the PSC-to-iT platforms encounter several problems, including low efficiency of conventional T subset specification, limited functional potential, and restrictions on large-scale application, because of the absence of a thymus-like organized microenvironment. The updated PSC-to-iT platforms, such as the three-dimensional (3D) artificial thymic organoid (ATO) co-culture system and Runx1/Hoxa9-enforced iT lymphopoiesis, provide fresh perspectives for coordinating culture conditions and transcription factors, which may greatly improve the efficiency of T-cell generation greatly. In addition, the improved PSC-to-iT platform coordinating gene editing technologies will provide various functional engineered unconventional or conventional T cells. Furthermore, the clinical applications of PSC-derived immune cells are accelerating from bench to bedside.
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Affiliation(s)
- Rongqun Guo
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Wei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yadan Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Academy of Medical Science, Henan Medical College of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yingmei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zhongxing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Yongping Song
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Ying Z, Song Y, Zhu J. Effectiveness and Safety of Anti-CD19 Chimeric Antigen Receptor-T Cell Immunotherapy in Patients With Relapsed/Refractory Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis. Front Pharmacol 2022; 13:834113. [PMID: 35548364 PMCID: PMC9081610 DOI: 10.3389/fphar.2022.834113] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Aim: To investigate the effectiveness and safety of using chimeric antigen receptor (CAR) T cell therapies targeting CD19 in patients with diffuse large B-cell lymphoma (DLBCL). Methods: PubMed, Embase, and the Cochrane Library were searched for reports published from database inception up to July 2021. The present meta-analysis included clinical response outcomes, survival outcomes, and safety analyses. For qualitative analysis that could not be combined, the data were presented in a tabular form. Subgroup analyses were also performed according to the costimulatory domains, generic names, and study designs. Results: Twenty-seven studies (1,687 patients) were included. The pooled 12-months overall survival (OS) rate was 63% (95%CI: 56-70%). The pooled best overall response (BOR) was 74.0% (95%CI: 67-79%), with a best complete response (BCR) of 48% (95%CI: 42-54%) and a 3-months CR rate (CRR) of 41% (95%CI: 35-47%). The subgroup analyses by costimulatory domain suggested statistically significant differences in BOR and BCR, whereas not in the 12-months OS rate and 3-months CRR. Among the patients evaluable for safety, 78% (95%CI: 68-87%), 6% (95%CI: 3-10%), 41% (95%CI: 31-52%), and 16% (95%CI: 10-24%) experienced cytokine release syndrome (CRS), severe CRS, neurotoxicity, and severe neurotoxicity, respectively. Compared with the CD28 costimulatory domain, the 4-1BB-based products showed a better safety profile on any-grade CRS (p < 0.01), severe CRS (p = 0.04), any-grade neurotoxicity (p < 0.01), and severe neurotoxicity (p < 0.01). Conclusion: Anti-CD19 CAR-T cell immunotherapy has promising effectiveness and tolerable severe AE profile in DLBCL patients. 4-1BB-based CAR-T cells have a similar 12-months OS rate and 3-months CRR with CD28-based products but a better safety profile. The costimulatory domain might not affect the survival outcomes.
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Affiliation(s)
| | - Yuqin Song
- Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jun Zhu
- Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Peking University Cancer Hospital & Institute, Beijing, China
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Bohn JP, Dietrich S. Treatment of Classic Hairy Cell Leukemia: Targeting Minimal Residual Disease beyond Cladribine. Cancers (Basel) 2022; 14:cancers14040956. [PMID: 35205704 PMCID: PMC8869886 DOI: 10.3390/cancers14040956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/03/2022] [Accepted: 02/11/2022] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Standard treatment with purine analogues facilitates a near normal life expectancy in the majority of patients with classic hairy cell leukemia (HCL), a rare chronic B-cell malignancy. However, nearly all patients ultimately relapse and require retreatment, while drug-induced myelotoxicity accumulates predisposing to infectious complications and, possibly, secondary malignancies. Persistence of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. New insights into disease biology initiated design and investigation of several new, chemotherapy-free, targeted drugs with encouraging efficacy in early clinical trials aimed at enhancing eradication of MRD and optimizing drug tolerability. This review provides an update on recent clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome. Abstract Classic hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder characterized by profound pancytopenia and frequent infectious complications due to progressive infiltration of the bone marrow and spleen. Lacking effective treatment options, affected patients were confronted with a dismal survival prognosis of less than 5 years when the disease was first described in 1958. Tremendous therapeutic advances were accomplished with the introduction of purine analogues such as cladribine in the 1990s, facilitating a near-normal life expectancy in most HCL patients. Nevertheless, nearly all patients eventually relapse and require successive retreatments, while drug-associated myelotoxicity may accumulate and secondary malignancies may evolve. Detection of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. In the last decade, novel biologic insights such as identification of the driver mutation BRAF V600E have initiated the development and clinical investigation of new, chemotherapy-free, targeted drugs in HCL treatment, with encouraging efficacy in early clinical trials aimed at boosting eradication of MRD while optimizing drug tolerability. This review summarizes current clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome.
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Affiliation(s)
- Jan-Paul Bohn
- Department of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, A-6020 Innsbruck, Austria
- Correspondence:
| | - Sascha Dietrich
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120 Heidelberg, Germany;
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New actionable targets and investigational drugs in chronic lymphocytic leukemia. MEMO - MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2022. [DOI: 10.1007/s12254-021-00755-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
SummaryThe treatment landscape of chronic lymphocytic leukemia (CLL) has shifted from chemotherapy-based approaches to targeted agents in the last decade. However, evolving drug resistance and accumulating toxicity remain challenges that still limit patients’ clinical outcomes. Furthermore, currently licensed targeted agents such as inhibitors of Bruton’s tyrosine kinase (BTK) and anti-apoptotic protein B‑cell lymphoma 2 (BCL2) do not adequately compensate for the poor clinical outcomes associated with high-risk genetics such as TP53 alterations. New insights into disease biology facilitated design and investigation of several new targeted agents with encouraging results in early clinical trials. This short review focuses on novel actionable targets and investigational drugs aimed at circumventing acquired resistance and avoiding accumulating toxicity.
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