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Astigarraga CC, Mpms K, Iovino L, Milano F. Haploidentical transplantation: An optimal platform for graft manipulation and cellular therapies. Blood Rev 2025:101286. [PMID: 40133165 DOI: 10.1016/j.blre.2025.101286] [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: 11/27/2024] [Revised: 03/11/2025] [Accepted: 03/20/2025] [Indexed: 03/27/2025]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a curative therapeutic option for patients with high-risk hematologic malignancies. When a fully matched donor is unavailable, haploidentical hematopoietic stem cell transplantation (haplo-HCT) provides a viable alternative. Over time, haplo-HCT procedures have significantly evolved, improving outcomes in treatment related mortality (TRM), especially in graft-versus-host disease (GvHD). However, challenges such as delayed immune reconstitution and disease relapse persist. Advances in in vivo graft manipulation techniques, such as post-transplant cyclophosphamide (PTCy) and ex vivo approaches, including TCRα/β and CD19 depletion, have shown promise in reducing the risk of severe GvHD without increasing the relapse rates. Innovative strategies, such as haploidentical donor lymphocyte infusions, "suicide-switch" mechanisms, ORCA-Q product infusions, and CAR based therapies offer potential to further optimize outcomes. This review examines the graft manipulation modalities in the haplo-HCT setting, highlighting their role in advancing cellular therapies and providing new hope in the fight against life-threatening diseases.
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Affiliation(s)
- C C Astigarraga
- Fred Hutchinson Cancer Center, Seattle, WA, USA; Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; Universidade Federal do Rio grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Klauberg Mpms
- Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil
| | - L Iovino
- Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - F Milano
- Fred Hutchinson Cancer Center, Seattle, WA, USA.
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Mancusi A, Ruggeri L, Pierini A. Novel conditioning and prophylaxis regimens for relapse prevention. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:627-634. [PMID: 39644026 DOI: 10.1182/hematology.2024000590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
The last 20 years witnessed relevant clinical advancements in the field of hematopoietic cell transplantation (HCT) for leukemia patients. The introduction of novel conditioning regimens, a better prophylaxis and management of graft- versus-host disease, and an ameliorated posttransplant support system improved safety and, therefore, outcomes. On the other hand, leukemia relapse remains the major cause of allogeneic HCT failure. Efforts have been made to understand the mechanisms of leukemia relapse, and new insights that clarify how donor immunity exerts graft-versus- leukemia (GVL) activity are available. Such studies set the base to design novel transplant strategies that can improve disease control. In our review we begin by discussing the most relevant criteria to choose a donor that provides a strong GVL effect. We also report some of the novel conditioning regimens that aim to deliver and extend myeloablation in order to reduce the disease burden at time of graft infusion. Finally, we discuss how the graft can be manipulated to limit the use of immune suppression and ensure potent antileukemic activity.
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Affiliation(s)
- Antonella Mancusi
- Division of Hematology, Department of Medicine and Surgery, University of Perugia, Italy
| | | | - Antonio Pierini
- Division of Hematology, Department of Medicine and Surgery, University of Perugia, Italy
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Meade MG, Bolaños-Meade J. The history of haploidentical stem cell transplantation: a trip from the bench to the bedside. Hematology 2024; 29:2346401. [PMID: 38687632 PMCID: PMC11285319 DOI: 10.1080/16078454.2024.2346401] [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: 03/26/2024] [Accepted: 04/17/2024] [Indexed: 05/02/2024] Open
Abstract
Allogeneic bone marrow transplantation is a curative intervention for both neoplastic and non-malignant conditions. However, not all patients have an HLA-matched donor. Therefore, the development of an approach that expand the donor pool was of paramount relevance. The development of post-transplantation cyclophosphamide as graft versus host disease prophylaxis allows the safe use of haploidentical donors, solving the donor availability problem to the vast majority of patients in need. The present paper reviews the history of the development of haploidentical transplantation at Johns Hopkins University, from the bench to the bedside.
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Affiliation(s)
| | - Javier Bolaños-Meade
- Johns Hopkins University School of Medicine, Clinical Director, BMT Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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Rambaldi B, Rizzuto G, Rambaldi A, Introna M. Genetically modified and unmodified cellular approaches to enhance graft versus leukemia effect, without increasing graft versus host disease: the use of allogeneic cytokine-induced killer cells. Front Immunol 2024; 15:1459175. [PMID: 39512351 PMCID: PMC11540647 DOI: 10.3389/fimmu.2024.1459175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 09/30/2024] [Indexed: 11/15/2024] Open
Abstract
Although allogeneic hematopoietic cell transplantation (HCT) represents a curative approach for many patients with hematological diseases, post-transplantation relapse occurs in 20-50% of cases, representing the primary cause of treatment failure and mortality. Alloreactive donor T cells are responsible for the graft versus leukemia (GvL) effect, which represents the key mechanism for the long-term curative effect of HCT. However, the downside is represented by graft versus host disease (GvHD), largely contributing to transplant-related mortality (TRM). Multiple factors play a role in regulating the delicate balance between GvL and GvHD, such as the optimization of the donor HLA and KIR match, the type of graft source, and the adaptive use of post-transplant cellular therapy. In addition to the standard donor lymphocyte infusion (DLI), several attempts were made to favor the GvL effect without increasing the GvHD risk. Selected DLI, NK DLI, activated DLI and more sophisticated genetically engineered cells can be employed. In this scenario, cytokine-induced killer (CIK) cells represent a suitable tool to boost GvL while minimizing GvHD. CIK cells are T lymphocytes activated in culture in the presence of monoclonal antibodies against CD3 (OKT3), interferon-gamma (IFN-g), and interleukin-2 (IL-2), characterized by the expression of markers typical of NK cells and T cells (CD3+, CD56+, with a prevalent CD8+ phenotype). CIK cells can mediate cytotoxicity through both MHC and non-MHC restricted recognition, which is the so-called "dual-functional capability" and display minimum alloreactivity. Allogeneic CIK cells showed a favorable rate of response, especially in the setting of minimal residual disease, with a rate of GvHD not exceeding 25%. Finally, the CIK cell platform can be adapted for chimeric antigen receptor (CAR) cell strategy, showing promising results in both preclinical and clinical settings. In this review, we describe the main immunological basis for the development of the GvL and the possible cellular therapy approaches used to boost it, with a particular focus on the use of CIK cells.
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Affiliation(s)
- Benedetta Rambaldi
- Dipartimento di Oncologia ed Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Giuliana Rizzuto
- Dipartimento di Oncologia ed Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy
- Molecular and Translational Medicine Doctoral Program (DIMET), University of Milano-Bicocca, Monza, Italy
| | - Alessandro Rambaldi
- Dipartimento di Oncologia ed Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy
- Department of Oncology and Hematology, Università degli Studi di Milano, Milan, Italy
| | - Martino Introna
- Dipartimento di Oncologia ed Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy
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Fonseca-Santos M, Bailen R, Lopez-Godino O, Herruzo-Delgado B, Bermudez MA, García-Cadenas I, Huguet-Mas M, Ferra-Coll C, Esquirol A, Cortés-Rodriguez M, Yañez-Sansegundo L, Pascual-Cascon MJ, Heras I, Kwon M, Lopez-Corral L. Characterization of Chronic Graft-versus-host Disease After Haploidentical Stem Cell Transplantation With Posttransplant Cyclophosphamide: A Study on Behalf of GETH-TC. Transplantation 2024; 108:2134-2143. [PMID: 38685204 DOI: 10.1097/tp.0000000000005034] [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: 05/02/2024]
Abstract
BACKGROUND Chronic graft-versus-host disease (cGVHD) is a cause of late morbidity and nonrelapse mortality (NRM) after allogenic hematopoietic stem cell transplantation (allo-HSCT). Although studies evaluating haploidentical allo-HSCT (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) demonstrate lower cGVHD rates, comprehensive data describing the clinical profile, risk factors, or outcomes of cGVHD within this platform are scarce. METHODS We conducted a retrospective multicenter analysis of 389 consecutive patients who underwent haplo-HSCT PTCy in 7 transplant centers of the Spanish Group Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) between 2008 and 2020 describing incidence, clinical profile, risk factors, and cGVHD outcomes. RESULTS Ninety-five patients of 389 developed cGVHD. Our data revealed that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis and that the strongest predictor for cGVHD was previous acute GVHD ( P = 0.031). Also, recipient age ≥60 y ( P = 0.044) was protective against cGVHD. Moreover, patients with moderate cGVHD had longer event-free survival at 3 y than other patients ( P = 0.016) and a lower relapse rate at 3 y ( P = 0.036). CONCLUSIONS Our results support the fact that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis. In this series, patients who develop moderate cGVHD after haplo-HSCT PTCy had a higher overall survival and event-free survival, and lower relapse, suggesting higher graft-versus-leukemia effect. Although this is the largest series focused on characterizing cGVHD in haplo-HSCT PTCy, further prospective studies are needed to confirm the findings.
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Affiliation(s)
- Marta Fonseca-Santos
- Hematology Department, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - Rebeca Bailen
- Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Oriana Lopez-Godino
- Hematology Department, Hospital Universitario Morales Meseguer, Murcia, Spain
| | | | - Maria Aranzazu Bermudez
- Servicio de Hematologia y Hemoterapia, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | | | - María Huguet-Mas
- Hematology Department, Hospital Germans Trias i Pujol, Barcelona, Spain
| | | | - Albert Esquirol
- Hematology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - María Cortés-Rodriguez
- Hematology Department, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
- Statistical Department, Universidad de Salamanca, Salamanca, Spain
| | - Lucrecia Yañez-Sansegundo
- Servicio de Hematologia y Hemoterapia, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | | | - Inmaculada Heras
- Hematology Department, Hospital Universitario Morales Meseguer, Murcia, Spain
| | - Mi Kwon
- Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Lucía Lopez-Corral
- Hematology Department, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
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Morales E, Pulsipher MA. A better approach to mismatched HSCT than PTCY? Blood 2024; 144:474-476. [PMID: 39088235 DOI: 10.1182/blood.2024025060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024] Open
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7
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Ma R, Zhu DP, Zhang XH, Xu LP, Wang Y, Mo XD, Lv M, Zhang YY, Cheng YF, Yan CH, Chen YH, Chen Y, Wang JZ, Wang FR, Han TT, Kong J, Wang ZD, Han W, Chen H, Chang YJ, He Y, Xu ZL, Zheng FM, Fu HX, Liu KY, Huang XJ, Sun YQ. Salvage haploidentical transplantation for graft failure after first haploidentical allogeneic stem cell transplantation: an updated experience. Bone Marrow Transplant 2024; 59:991-996. [PMID: 38565964 DOI: 10.1038/s41409-024-02276-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/04/2024]
Abstract
Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33-215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8-24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9-140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p < 0.001) and platelet engraftment (75.8% versus 32.3%, p < 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p = 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation.
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Affiliation(s)
- Rui Ma
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Dan-Ping Zhu
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Xiao-Dong Mo
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Meng Lv
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Yuan-Yuan Zhang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Yi-Fei Cheng
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Chen-Hua Yan
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Yu-Hong Chen
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Yao Chen
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Jing-Zhi Wang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Feng-Rong Wang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Ting-Ting Han
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Jun Kong
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Zhi-Dong Wang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Wei Han
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Huan Chen
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Ying-Jun Chang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Yun He
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Zheng-Li Xu
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Feng-Mei Zheng
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Hai-Xia Fu
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Kai-Yan Liu
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Beijing, China
- Peking University Institute of Hematology, Beijing, China
- National Clinical Research Center for Hematologic Disease, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Yu-Qian Sun
- Peking University People's Hospital, Beijing, China.
- Peking University Institute of Hematology, Beijing, China.
- National Clinical Research Center for Hematologic Disease, Beijing, China.
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China.
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Alqathami MS, Khan MA, Yoosuf ABM. Global research trends in Total Body Irradiation: a bibliometric analysis. Front Oncol 2024; 14:1370059. [PMID: 38737901 PMCID: PMC11082912 DOI: 10.3389/fonc.2024.1370059] [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: 01/13/2024] [Accepted: 04/01/2024] [Indexed: 05/14/2024] Open
Abstract
Objectives This manuscript presents a bibliometric and visualization analysis of Total Body Irradiation (TBI) research, aiming to elucidate trends, gaps, and future directions in the field. This study aims to provide a comprehensive overview of the global research landscape of TBI, highlighting its key contributions, evolving trends, and potential areas for future exploration. Methods The data for this study were extracted from the Web of Science Core Collection (WoSCC), encompassing articles published up to May 2023. The analysis included original studies, abstracts, and review articles focusing on TBI-related research. Bibliometric indicators such as total publications (TP), total citations (TC), and citations per publication (C/P) were utilized to assess the research output and impact. Visualization tools such as VOS Viewer were employed for thematic mapping and to illustrate international collaboration networks. Results The analysis revealed a substantial body of literature, with 7,315 articles published by 2,650 institutions involving, 13,979 authors. Full-length articles were predominant, highlighting their central role in the dissemination of TBI research. The authorship pattern indicated a diverse range of scholarly influences, with both established and emerging researchers contributing significantly. The USA led in global contributions, with significant international collaborations observed. Recent research trends have focused on refining TBI treatment techniques, investigating long-term patient effects, and advancing dosimetry and biomarker studies for radiation exposure assessments. Conclusions TBI research exhibits a dynamic and multifaceted landscape, driven by global collaboration and innovation. It highlights the clinical challenges of TBI, such as its adverse effects and the need for tailored treatments in pediatric cases. Crucially, the study also acknowledges the fundamental science underpinning TBI, including its effects on inflammatory and apoptotic pathways, DNA damage, and the varied sensitivity of cells and tissues. This dual focus enhances our understanding of TBI, guiding future research toward innovative solutions and comprehensive care.
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Affiliation(s)
- Mamdouh Saud Alqathami
- Department of Oncology, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | | | - Ahamed Badusha Mohamed Yoosuf
- Department of Oncology, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
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9
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Petersdorf EW, McKallor C, Malkki M, He M, Spellman SR, Gooley T, Stevenson P. HLA Haplotypes and Relapse After Hematopoietic Cell Transplantation. J Clin Oncol 2024; 42:886-897. [PMID: 38051980 PMCID: PMC10927336 DOI: 10.1200/jco.23.01264] [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: 06/12/2023] [Revised: 09/25/2023] [Accepted: 10/06/2023] [Indexed: 12/07/2023] Open
Abstract
PURPOSE Recurrence of blood malignancy is the major cause of hematopoietic cell transplant failure. HLA class II molecules play a fundamental role in antitumor responses but the role of class II haplotypes is not known. METHODS HLA-DR, -DQ, -DM, and -DO allele variation was determined in 1,629 related haploidentical transplants to study the clinical significance of individual molecules and haplotypes. RESULTS Outcome correlated with patient and donor variation for HLA-DRβ residue 86 (Gly/Val), HLA-DQ (G1/G2) heterodimers, and donor HLA-DM (DM11,11/nonDM11,11) molecules, and depended on patient-donor mismatching. Risks of relapse were lower for DRβ-86 GlyGly patients when the donor was GlyVal (hazard ratio [HR], 0.46 [95% CI, 0.30 to 0.68]; P < .001); GlyVal patients benefited from HLA-DRB1-matched donors, whereas no donor was superior to another for ValVal patients. G1G2 patients with G1G2-mismatched donors had lower relapse. Transplantation from donors with DMα residue 184 ArgHis was associated with higher risk of relapse (HR, 1.60 [95% CI, 1.09 to 2.36]; P = .02) relative to ArgArg. Relapse and mortality risks differed across HLA-DR-DQ-DM haplotypes. CONCLUSION HLA class II haplotypes may be functional constituents of the transplantation barrier, and their consideration in patients and donors may improve the success of transplantation.
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Affiliation(s)
- Effie W. Petersdorf
- Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA
- University of Washington School of Medicine, Seattle, WA
| | - Caroline McKallor
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
| | - Mari Malkki
- Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA
| | - Meilun He
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN
| | - Stephen R. Spellman
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN
| | - Theodore Gooley
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
| | - Philip Stevenson
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
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Velardi A, Mancusi A, Ruggeri L, Pierini A. How adoptive transfer of components of the donor immune system boosts GvL and prevents GvHD in HLA-haploidentical hematopoietic transplantation for acute leukemia. Bone Marrow Transplant 2024; 59:301-305. [PMID: 38212671 DOI: 10.1038/s41409-024-02199-1] [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: 11/14/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/13/2024]
Abstract
Why a new Perspective in allogeneic hematopoietic transplantation? A summary. Nowadays, for high-risk acute leukemia patients without an HLA-matched donor (sibling or volunteer), hematopoietic transplants that use HLA-haploidentical grafts combined with enhanced post transplant immune suppression (i.e., high-dose cyclophosphamide) are widely used. They are associated with low TRM rates. However, they are also associated with significant chronic GvHD while they only partially abrogate leukemia relapse rates. One may speculate that post-transplant immune suppression, required for GvHD prophylaxis, weakens the anti-leukemic potential of the graft. Historically, haploidentical transplants became feasible for the first time through transplantation of T cell-depleted peripheral blood hematopoietic progenitor cells. Lack of post-transplant immune suppression allowed the emergence of donor-versus-recipient NK-cell alloreactions that eradicated AML. In an attempt to improve these results we recently combined an age-adapted, irradiation-based conditioning regimen with transplant of T-cell-depleted grafts and infusion of regulatory and conventional T cells, without any post transplant immune suppression. With the obvious limitations of a single center experience, this protocol resulted in extremely low relapse and chronic GvHD rates and, consequently, in a remarkable 75% chronic GvHD/relapse-free survival in over 50 AML patients up to the age of 65 many of whom at high risk of relapse.
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Affiliation(s)
- Andrea Velardi
- Department of Medicine and Surgery, Division of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy.
| | - Antonella Mancusi
- Department of Medicine and Surgery, Division of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy
| | - Loredana Ruggeri
- Department of Medicine and Surgery, Division of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy
| | - Antonio Pierini
- Department of Medicine and Surgery, Division of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy
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Di Ianni M, Liberatore C, Santoro N, Ranalli P, Guardalupi F, Corradi G, Villanova I, Di Francesco B, Lattanzio S, Passeri C, Lanuti P, Accorsi P. Cellular Strategies for Separating GvHD from GvL in Haploidentical Transplantation. Cells 2024; 13:134. [PMID: 38247827 PMCID: PMC10814899 DOI: 10.3390/cells13020134] [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: 12/02/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
GvHD still remains, despite the continuous improvement of transplantation platforms, a fearful complication of transplantation from allogeneic donors. Being able to separate GvHD from GvL represents the greatest challenge in the allogeneic transplant setting. This may be possible through continuous improvement of cell therapy techniques. In this review, current cell therapies are taken into consideration, which are based on the use of TCR alpha/beta depletion, CD45RA depletion, T regulatory cell enrichment, NK-cell-based immunotherapies, and suicide gene therapies in order to prevent GvHD and maximally amplify the GvL effect in the setting of haploidentical transplantation.
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Affiliation(s)
- Mauro Di Ianni
- Hematology Unit, Pescara Hospital, 65124 Pescara, Italy; (C.L.); (N.S.); (P.R.)
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, 66100 Chieti, Italy; (F.G.); (G.C.); (S.L.); (P.L.)
- Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
| | - Carmine Liberatore
- Hematology Unit, Pescara Hospital, 65124 Pescara, Italy; (C.L.); (N.S.); (P.R.)
| | - Nicole Santoro
- Hematology Unit, Pescara Hospital, 65124 Pescara, Italy; (C.L.); (N.S.); (P.R.)
| | - Paola Ranalli
- Hematology Unit, Pescara Hospital, 65124 Pescara, Italy; (C.L.); (N.S.); (P.R.)
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, 66100 Chieti, Italy; (F.G.); (G.C.); (S.L.); (P.L.)
- Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
| | - Francesco Guardalupi
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, 66100 Chieti, Italy; (F.G.); (G.C.); (S.L.); (P.L.)
- Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
| | - Giulia Corradi
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, 66100 Chieti, Italy; (F.G.); (G.C.); (S.L.); (P.L.)
- Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
| | - Ida Villanova
- Blood Bank Unit, Pescara Hospital, 65124 Pescara, Italy; (I.V.); (B.D.F.); (C.P.); (P.A.)
| | - Barbara Di Francesco
- Blood Bank Unit, Pescara Hospital, 65124 Pescara, Italy; (I.V.); (B.D.F.); (C.P.); (P.A.)
| | - Stefano Lattanzio
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, 66100 Chieti, Italy; (F.G.); (G.C.); (S.L.); (P.L.)
- Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
| | - Cecilia Passeri
- Blood Bank Unit, Pescara Hospital, 65124 Pescara, Italy; (I.V.); (B.D.F.); (C.P.); (P.A.)
| | - Paola Lanuti
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, 66100 Chieti, Italy; (F.G.); (G.C.); (S.L.); (P.L.)
- Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, 66100 Chieti, Italy
| | - Patrizia Accorsi
- Blood Bank Unit, Pescara Hospital, 65124 Pescara, Italy; (I.V.); (B.D.F.); (C.P.); (P.A.)
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To NH, Pilon C, Moatti A, Debesset A, Debbi K, Coraggio G, Ksouri W, Massaria V, Cohen JL, Belkacemi Y, Thiolat A. Effect of lethal total body irradiation on bone marrow chimerism, acute graft-versus-host disease, and tumor engraftment in mouse models: impact of different radiation techniques using low- and high-energy X-rays. Strahlenther Onkol 2023; 199:1242-1254. [PMID: 36932237 DOI: 10.1007/s00066-023-02066-w] [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: 08/31/2022] [Accepted: 02/19/2023] [Indexed: 03/19/2023]
Abstract
PURPOSE Effects of X‑ray energy levels used for myeloablative lethal total body irradiation (TBI) delivery prior to bone marrow transplantation (BMT) in preclinical mouse models were examined. MATERIALS AND METHODS In mouse models, single-fraction myeloablative TBI at a lethal dose was delivered using two different X‑ray devices, either low (160 kV cabinet irradiator) or high energy (6 MV linear accelerator), before semi-allogeneic hematopoietic stem-cell transplantation (HSCT) to ensure bone marrow (BM) chimerism, graft-versus-host disease (GVHD), and tumor engraftment. Recipient mice were clinically followed for 80 days after bone marrow transplantation (BMT). Flow cytometry was performed to assess donor chimerism and tumor engraftment in recipient mice. RESULTS Both X‑ray irradiation techniques delivered a 10 Gy single fraction of TBI, presented a lethal effect, and could allow near-complete early donor chimerism on day 13. However, low-energy irradiation increased T cells' alloreactivity compared to high-energy irradiation, leading to clinical consequences for GVHD and tumor engraftment outcomes. The alloreactive effect differences might be attributed to the distinction in inflammatory status of irradiated recipients at donor cell infusion (D0). Delaying donor cell administration (D1 after lethal TBI) attenuated T cells' alloreactivity and clinical outcomes in GVHD mouse models. CONCLUSION Different X‑ray irradiation modalities condition T cell alloreactivity in experimental semi-allogeneic BMT. Low-energy X‑ray irradiator induces a post-TBI inflammatory burst and exacerbates alloreactive reactions. This technical and biological information should be considered in interpreting GVHD/ graft-versus-leukemia effect results in mice experimental models of BMT.
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Affiliation(s)
- Nhu Hanh To
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France.
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France.
| | - Caroline Pilon
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
| | - Audrey Moatti
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
| | - Anaïs Debesset
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
| | - Kamel Debbi
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
| | - Gabriele Coraggio
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
| | - Wassim Ksouri
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
| | - Virginie Massaria
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
| | - José L Cohen
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
| | - Yazid Belkacemi
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
| | - Allan Thiolat
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
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Wiercinska E, Quade-Lyssy P, Hümmer C, Beifuß J, Akarkach K, Poppe C, Olevska V, Dzionek J, Lahnor H, Bosio A, Papanikolaou E, Bonig H. Automatic generation of alloreactivity-reduced donor lymphocytes and hematopoietic stem cells from the same mobilized apheresis product. J Transl Med 2023; 21:849. [PMID: 38007485 PMCID: PMC10675913 DOI: 10.1186/s12967-023-04738-8] [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: 09/15/2023] [Accepted: 11/17/2023] [Indexed: 11/27/2023] Open
Abstract
INTRODUCTION In vitro or in vivo depletion of alloreactive T cells can facilitate haplo-identical hematopoietic stem cell transplantation (HSCT). Very satisfactory transplant outcomes were thus reported for TCRαβ/CD19-depleted hematopoietic stem/progenitor cell (HSPC) grafts. The current semi-automatic manufacturing process on the CliniMACS Plus, although robust, still requires a significant amount of manual labor to be completed. Towards advancing and further facilitating large scale cell processing, a new TCRαβ/CD19 depletion module combined with the previously described CD45RA depletion module (to serve as allo-reactivity attenuated donor lymphocyte infusion) was established on the CliniMACS Prodigy. METHODS We evaluated six apheresis products from G-CSF-mobilized volunteer donors which were split automatically by the Prodigy, one portion each depleted of CD45RA+ or of TCRαβ+ and CD19+ cells. We investigated critical quality attributes for both products. Products were assessed for recovery of HSPCs and mature subsets, as well as depletion efficiency of targeted cells using flow cytometry. Effects of apheresis and product age post 48 h storage at 2-6 °C as well as freeze-thawing on product viability and recovery of WBC and HPSCs were assessed by flow cytometry. RESULTS Ten sequential automatic processes were completed with minimal hands-on time beyond tubing set installation. Depletion efficiency of CD45RA+ resp. TCRαβ+ and CD19+ cells was equivalent to previous reports, achieving mean depletions of 4 log of targeted cells for both products. HSPC products retained TCRγδ+ and NK cells. 48 h storage of apheresis product was associated with the expected modest loss of HSPCs, but depletions remained efficient. Depleted products were stable until at least 72 h after apheresis with stem cell viabilities > 90%. Freeze-thawing resulted in loss of NK cells; post-thaw recovery of viable CD45+ and HSPCs was > 70% and in line with expectation. CONCLUSION The closed, GMP-compatible process generates two separate medicinal products from the same mobilized apheresis product. The CD45RA-depleted products contained functional memory T cells, whereas the TCRαβ/CD19-depleted products included HSPCs, TCRγδ+ and NK cells. Both products are predicted to be effectively depleted of GVH-reactivity while providing immunological surveillance, in support of haplo-identical HSCT.
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Affiliation(s)
- E Wiercinska
- Department of Cellular Therapeutics (GMP), German Red Cross Blood Service BaWü-He, Institute Frankfurt, Frankfurt, Germany
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany
| | - P Quade-Lyssy
- Department of Cellular Therapeutics (GMP), German Red Cross Blood Service BaWü-He, Institute Frankfurt, Frankfurt, Germany
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany
| | - C Hümmer
- Department of Cellular Therapeutics (GMP), German Red Cross Blood Service BaWü-He, Institute Frankfurt, Frankfurt, Germany
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany
| | - J Beifuß
- Department of Cellular Therapeutics (GMP), German Red Cross Blood Service BaWü-He, Institute Frankfurt, Frankfurt, Germany
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany
| | - K Akarkach
- Department of Cellular Therapeutics (GMP), German Red Cross Blood Service BaWü-He, Institute Frankfurt, Frankfurt, Germany
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany
| | - C Poppe
- Department of Cellular Therapeutics (GMP), German Red Cross Blood Service BaWü-He, Institute Frankfurt, Frankfurt, Germany
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany
| | - V Olevska
- Miltenyi Biotec B.V. & CO. KG, Bergisch Gladbach, Germany
| | - J Dzionek
- Miltenyi Biotec B.V. & CO. KG, Bergisch Gladbach, Germany
| | - H Lahnor
- Miltenyi Biomedicine GmbH, Bergisch Gladbach, Germany
| | - A Bosio
- Miltenyi Biotec B.V. & CO. KG, Bergisch Gladbach, Germany
| | - E Papanikolaou
- Miltenyi Biotec B.V. & CO. KG, Bergisch Gladbach, Germany
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Halvard Bonig
- Department of Cellular Therapeutics (GMP), German Red Cross Blood Service BaWü-He, Institute Frankfurt, Frankfurt, Germany.
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany.
- Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA.
- DRK-BSD BaWüHe, Sandhofstraße 1, 60528, Frankfurt, Germany.
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14
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Gooptu M, Bolaños-Meade J, Koreth J. Expanding post-transplant cyclophosphamide to matched unrelated donor transplants and beyond. Blood Rev 2023; 62:101053. [PMID: 36822991 DOI: 10.1016/j.blre.2023.101053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/23/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Affiliation(s)
- Mahasweta Gooptu
- Adult Stem-Cell Transplantation, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston 02215, USA
| | - Javier Bolaños-Meade
- Blood and Marrow Transplant Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N Broadway, Baltimore MD 21231, USA
| | - John Koreth
- Adult Stem-Cell Transplantation, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston 02215, USA.
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15
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Flaadt T, Ebinger M, Schreiber M, Ladenstein RL, Simon T, Lode HN, Hero B, Schuhmann MU, Schäfer J, Paulsen F, Timmermann B, Eggert A, Lang P. Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse. J Clin Med 2023; 12:6196. [PMID: 37834840 PMCID: PMC10573405 DOI: 10.3390/jcm12196196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 10/15/2023] Open
Abstract
Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1-21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m2/day × 5 days for 5-6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse.
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Affiliation(s)
- Tim Flaadt
- Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany; (M.E.); (M.S.); (P.L.)
| | - Martin Ebinger
- Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany; (M.E.); (M.S.); (P.L.)
| | - Malin Schreiber
- Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany; (M.E.); (M.S.); (P.L.)
| | - Ruth L. Ladenstein
- Department of Pediatrics, St Anna Children’s Hospital, Medical University, 1090 Vienna, Austria;
- Studies and Statistics of Integrated Research and Projects, Children’s Cancer Research Institute, 1090 Vienna, Austria
| | - Thorsten Simon
- Department of Pediatric Oncology and Hematology, University Hospital, University of Cologne, 50937 Köln, Germany; (T.S.); (B.H.)
| | - Holger N. Lode
- Department of Pediatric Hematology and Oncology, University Medicine Greifswald, 17489 Greifswald, Germany;
| | - Barbara Hero
- Department of Pediatric Oncology and Hematology, University Hospital, University of Cologne, 50937 Köln, Germany; (T.S.); (B.H.)
| | - Martin U. Schuhmann
- Section of Pediatric Neurosurgery, Department of Neurosurgery, University Hospital of Tuebingen, 72076 Tuebingen, Germany;
| | - Jürgen Schäfer
- Department for Diagnostic and Interventional Radiology, University Hospital, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany;
| | - Frank Paulsen
- Department of Radiation Oncology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany;
| | - Beate Timmermann
- Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), German Cancer Consortium (DKTK), 45147 Essen, Germany;
| | - Angelika Eggert
- Department of Pediatric Oncology/Hematology, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany;
| | - Peter Lang
- Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany; (M.E.); (M.S.); (P.L.)
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16
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Xu J, Miao W, Yuan H, Liu Y, Chen G, Wang H, Aizezi G, Qu J, Duan X, Yang R, Muhashi M, Han C, Ding L, Abulaiti N, Pang N, Zhang L, Jiang M. Unique Reduced-Intensity Conditioning Haploidentical Peripheral Blood Stem Cell Transplantation Protocol for Patients with Hematologic Malignancy. Transplant Cell Ther 2023; 29:331.e1-331.e8. [PMID: 36775200 DOI: 10.1016/j.jtct.2023.02.005] [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: 09/09/2022] [Revised: 02/03/2023] [Accepted: 02/03/2023] [Indexed: 02/12/2023]
Abstract
Reduced-intensity conditioning (RIC) haploidentical (haplo-) hematopoietic stem cell transplantation (HSCT) requires more hematopoietic progenitor and stem cells (HPSCs) to promote engraftment and immune reconstitution and needs a stronger graft-versus-leukemia effect. Peripheral blood stem cells (PBSCs) offer advantages over bone marrow; however, the use of higher-dose non-T cell-depleted (non-TCD) in vitro PBSCs may increase the occurrence of severe graft-versus-host disease (GVHD). This prospective, single-arm clinical study was performed to investigate using high-dose non-TCD in vitro PBSCs as the graft source, using fludarabine/Ara-C/busulfan (FAB) as the conditioning regimen, using rabbit antithymocyte globulin to remove T cells in vivo, and enhancing GVHD prophylaxis with an IL-2 receptor antagonist in RIC-haplo-HSCT in patients with hematologic malignancies age 50 to 70 years or <50 years with comorbidities (Hematopoietic Cell Transplantation Comorbidity Index score ≥2) classified as intermediate to high risk. The primary endpoint was day 100 acute GVHD (aGVHD). A total of 47 patients were enrolled; the median age was 52 years (range, 30 to 68 years), the median duration of follow-up was 34 months (range, 2 to 99 months), and the medium-infused doses of mononuclear cells, CD34+ cells, and CD3+ cells were 15.93 × 108/kg, 8.68 × 106/kg, and 5.57 × 108/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day 100 was 30.3% (95% confidence interval [CI], 15.9% to 44.8%), and that of grade III-IV aGVHD was 10.2% (95% CI, .6% to 19.8%). The 2-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI, 19.0% to 50.8%). The 2-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI, 11.80% to 40.40%) and 8.7% (95% CI, 3.26% to 20.65%), respectively. The 2-year cumulative incidence of relapse was 17.3% (95% CI, 5.1% to 29.5%), the 2-year overall survival rate was 71.2% (95% CI, 57.9% to 84.5%), and the 2-year disease-free survival rate was 66.2% (95% CI, 52.1% to 80.3%). The incidence of aGVHD was not high, and the overall efficacy was good. This study demonstrates that this unique RIC-haplo-PBSC transplantation protocol was effective in treating hematologic malignancies. Nonetheless, larger prospective multicenter clinical trials and experimental studies should be performed to further confirm our findings.
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Affiliation(s)
- Jianli Xu
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Wenyan Miao
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Hailong Yuan
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Ying Liu
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Gang Chen
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Hongbo Wang
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Gulibadanmu Aizezi
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Jianhua Qu
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Xianlin Duan
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Ruixue Yang
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Maliya Muhashi
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Chunxia Han
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Linglu Ding
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Nadiya Abulaiti
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Nannan Pang
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Le Zhang
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China
| | - Ming Jiang
- Hematologic Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology, Urumqi 830061, Xinjiang, China.
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17
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Naik S, Triplett BM. Selective depletion of naïve T cells by targeting CD45RA. Front Oncol 2023; 12:1009143. [PMID: 36776371 PMCID: PMC9911795 DOI: 10.3389/fonc.2022.1009143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/22/2022] [Indexed: 01/28/2023] Open
Affiliation(s)
- Swati Naik
- *Correspondence: Swati Naik, ; Brandon M. Triplett,
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18
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Handgretinger R, Arendt AM, Maier CP, Lang P. Ex vivo and in vivo T-cell depletion in allogeneic transplantation: towards less or non-cytotoxic conditioning regimens. Expert Rev Clin Immunol 2022; 18:1285-1296. [PMID: 36220154 DOI: 10.1080/1744666x.2022.2134857] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Although tremendous progress has been made since the introduction of allogeneic hematopoietic stem cell transplantation (HSCT) decades ago, there are still many obstacles to overcome. A major obstacle is the presence of T-lymphocytes in the recipient and in the donor. Recipient-derived T-lymphocytes not eliminated by the conditioning regimen are a major barrier and can lead to mixed chimerism or to complete rejection of the graft. Donor-derived T-lymphocytes can induce severe acute and chronic Graft-versus-Host Disease (GvHD). AREAS COVERED Currently published strategies for in vivo depletion of recipient-derived T-lymphocytes are discussed including the increase of the intensity of the conditioning regimen, the addition of anti-thymocyte globulin (ATG) or the anti-CD52 monoclonal antibody Campath. For the depletion or tolerization of the donor-derived T-lymphocytes, ex vivo-T-cell depletion methods, such as positive selection of CD34+ stem cells, negative depletion of CD3+ or TcRαβ+ T-lymphocytes or the use of post-transplant cyclophosphamide (PTCy) have been developed. EXPERT COMMENTARY All these currently used approaches have their disadvantages and new approaches should be investigated. In this review, we discuss current and propose new possible strategies to overcome the HLA barrier by using more specific T-cell directed therapies and/or by the combinations of current methods.
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Affiliation(s)
- Rupert Handgretinger
- Department of Hematology/Oncology. Children's University Hospital, University of Tuebingen, Germany.,Abu Dhabi Stem Cells Center, Abu Dhabi, UAE
| | - Anne-Marie Arendt
- Department of Hematology/Oncology. Children's University Hospital, University of Tuebingen, Germany
| | - Claus-Philipp Maier
- Department of Hematology/Oncology. Children's University Hospital, University of Tuebingen, Germany.,Department of Hematology, Oncology, Clinical Immunology and Rheumatology, Center for Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany
| | - Peter Lang
- Department of Hematology/Oncology. Children's University Hospital, University of Tuebingen, Germany
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19
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Mendoza-Valderrey A, Alvarez M, De Maria A, Margolin K, Melero I, Ascierto ML. Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity. Cells 2022; 11:3147. [PMID: 36231109 PMCID: PMC9562848 DOI: 10.3390/cells11193147] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/06/2022] [Accepted: 10/02/2022] [Indexed: 11/19/2022] Open
Abstract
In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors.
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Affiliation(s)
- Alberto Mendoza-Valderrey
- Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
| | - Maite Alvarez
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Andrea De Maria
- Department of Health Sciences, University of Genoa, 16126 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Kim Margolin
- Borstein Family Melanoma Program, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
| | - Ignacio Melero
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Maria Libera Ascierto
- Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
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20
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Zu Y, Li Z, Gui R, Liu Y, Zhang Y, Yu F, Zhao H, Fu Y, Zhan X, Wang Z, Xing P, Wang X, Wang H, Zhou J, Song Y. Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA-matched unrelated donor peripheral blood stem cell transplants: a multicentre, randomized controlled trial. Bone Marrow Transplant 2022; 57:1573-1580. [PMID: 35840747 PMCID: PMC9532243 DOI: 10.1038/s41409-022-01754-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/16/2022] [Accepted: 06/28/2022] [Indexed: 11/09/2022]
Abstract
The most widely used regimens of graft-versus-host disease (GVHD) prophylaxis in HLA-matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT) are based on anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). To improve the efficiency of GVHD prophylaxis, a novel regimen, composed of low-dose PTCy (20 mg/kg on day +3 and +4) and low-dose ATG (6 mg/kg), was evaluted in patients with hematological malignancies ungoing 10/10 HLA MUD-PBSCT in first remission (CR1). In our prospective, multicenter study, 104 patients were randomly assigned one-to-one to low-dose PTCy-ATG (n = 53) or standard-dose ATG (10 mg/kg, n = 51). Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; P = 0.017; 14.1% vs. 33.3%; P = 0.013). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%; P = 0.049) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%; P = 0.032). The low-dose PTCy-ATG based GVHD prophylaxis is a promising strategy for patients in CR1 after 10/10 HLA MUD-PBSCT.
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Affiliation(s)
- Yingling Zu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Zhen Li
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China
| | - Ruirui Gui
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China
| | - Yanyan Liu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China
| | - Yanli Zhang
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China
| | - Fengkuan Yu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China
| | - Huifang Zhao
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China
| | - Yuewen Fu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China
| | - Xinrong Zhan
- Department of Hematology, Central Hospital of Xinxiang, Xinxiang, 453000, Henan, China
| | - Zhongliang Wang
- Department of Hematology, Central Hospital of Xinxiang, Xinxiang, 453000, Henan, China
| | - Pengtao Xing
- Department of Hematology, Central Hospital of Xinxiang, Xinxiang, 453000, Henan, China
| | - Xianjing Wang
- Department of Hematology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Huili Wang
- Department of Hematology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Jian Zhou
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China.
| | - Yongping Song
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450000, Henan, China. .,Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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21
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Bernard NF, Alsulami K, Pavey E, Dupuy FP. NK Cells in Protection from HIV Infection. Viruses 2022; 14:v14061143. [PMID: 35746615 PMCID: PMC9231282 DOI: 10.3390/v14061143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 02/05/2023] Open
Abstract
Some people, known as HIV-exposed seronegative (HESN) individuals, remain uninfected despite high levels of exposure to HIV. Understanding the mechanisms underlying their apparent resistance to HIV infection may inform strategies designed to protect against HIV infection. Natural Killer (NK) cells are innate immune cells whose activation state depends on the integration of activating and inhibitory signals arising from cell surface receptors interacting with their ligands on neighboring cells. Inhibitory NK cell receptors use a subset of major histocompatibility (MHC) class I antigens as ligands. This interaction educates NK cells, priming them to respond to cells with reduced MHC class I antigen expression levels as occurs on HIV-infected cells. NK cells can interact with both autologous HIV-infected cells and allogeneic cells bearing MHC antigens seen as non self by educated NK cells. NK cells are rapidly activated upon interacting with HIV-infected or allogenic cells to elicit anti-viral activity that blocks HIV spread to new target cells, suppresses HIV replication, and kills HIV-infected cells before HIV reservoirs can be seeded and infection can be established. In this manuscript, we will review the epidemiological and functional evidence for a role for NK cells in protection from HIV infection.
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Affiliation(s)
- Nicole F. Bernard
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC H4A3J1, Canada; (K.A.); (E.P.); (F.P.D.)
- Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada
- Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- Division of Clinical Immunology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- Correspondence: ; Tel.: +1-(514)-934-1934 (ext. 44584)
| | - Khlood Alsulami
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC H4A3J1, Canada; (K.A.); (E.P.); (F.P.D.)
- Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada
- Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Erik Pavey
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC H4A3J1, Canada; (K.A.); (E.P.); (F.P.D.)
- Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Franck P. Dupuy
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC H4A3J1, Canada; (K.A.); (E.P.); (F.P.D.)
- Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
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22
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He L, Wang Y, Suolitiken D, Zhang R, Liu M, Hua Z, Yao S, Zou H, Wang Z. Outcomes of allogeneic hematopoietic stem cell transplantation for primary hemophagocytic lymphohistiocytosis in adults. Hematol Oncol 2022; 40:390-399. [PMID: 35526261 DOI: 10.1002/hon.3014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/06/2022] [Accepted: 05/04/2022] [Indexed: 11/07/2022]
Affiliation(s)
- Lingbo He
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Yini Wang
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
- Department of General Practice Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Dina Suolitiken
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Ruoxi Zhang
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Menghan Liu
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Zhengjie Hua
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Shuyan Yao
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Heshan Zou
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
| | - Zhao Wang
- Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing China100050
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23
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Teramoto M, Maruyama S, Tamaki H, Kaida K, Mayumi A, Fukunaga K, Inoue T, Yoshihara K, Yoshihara S, Ikegame K, Okada M, Osugi Y, Ogawa H, Higasa S, Morita K, Matsumoto K, Kijima T. Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation. Int J Hematol 2022; 116:248-257. [PMID: 35522381 DOI: 10.1007/s12185-022-03342-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 11/24/2022]
Abstract
Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5 mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0-41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0-7 (AUC0-7) and 0-32 (AUC0-32) than the grade 0-I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738-1.000). The high C0 (≥ 27.8 µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8 µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.
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Affiliation(s)
- Masahiro Teramoto
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Satoshi Maruyama
- Department of Hematology-Oncology, Chiba Cancer Center, Chiba, Japan
| | - Hiroya Tamaki
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Katsuji Kaida
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Azusa Mayumi
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiko Fukunaga
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Takayuki Inoue
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Kyoko Yoshihara
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Satoshi Yoshihara
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
- Department of Transfusion Medicine and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kazuhiro Ikegame
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Masaya Okada
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yuko Osugi
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hiroyasu Ogawa
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Satoshi Higasa
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Kunihiko Morita
- Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan
| | - Kana Matsumoto
- Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan
| | - Takashi Kijima
- Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
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24
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Outcomes of Different Haploidentical Transplantation Strategies from the Taiwan Blood and Marrow Transplantation Registry. Cancers (Basel) 2022; 14:cancers14041097. [PMID: 35205845 PMCID: PMC8870072 DOI: 10.3390/cancers14041097] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/08/2022] [Accepted: 02/19/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The two most noteworthy strategies for haploidentical stem cell transplantation (haplo-HSCT) are posttransplantation cyclophosphamide (PTCy) with or without thymoglobulin (ATG) and granulocyte colony stimulating factor-primed bone marrow plus peripheral blood stem cells (GIAC). We aimed to compare these approaches in patients with hematological malignancies. METHODS We enrolled 178 patients undergoing haplo-HSCT, including modified GIAC (mGIAC), PTCy without ATG, and PTCy with ATG. RESULTS The patients in the mGIAC group had the most favorable platelet and neutrophil engraftment kinetics. Although the grade III-IV acute graft-versus-host-disease (GvHD) rates were similar, those receiving mGIAC had a significantly higher extensive chronic GvHD rate. The patients receiving mGIAC had a similar cumulative incidence of relapse (CIR) to that in the patients receiving PTCy with ATG, but this was lower than that in the patients receiving PTCy without ATG. The patients receiving mGIAC had the lowest nonrelapse mortality (NRM) and the highest overall survival (OS) rates. The differences in CIR, NRM, and OS remained significant when focusing on patients with low/intermediate-risk diseases before haplo-HSCT. Intriguingly, among patients with high/very-high-risk diseases before haplo-HSCT, no differences were observed in the CIR, NRM, OS, or GvHD/relapse-free survival. CONCLUSION the mGIAC approach may yield a better outcome in Taiwanese patients with hematologic malignancies, especially for those with low/intermediate-risk diseases.
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25
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Ye Y, Yang L, Yuan X, Huang H, Luo Y. Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering. Front Oncol 2022; 11:790299. [PMID: 35155192 PMCID: PMC8829143 DOI: 10.3389/fonc.2021.790299] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/28/2021] [Indexed: 12/19/2022] Open
Abstract
Donor lymphocyte infusion (DLI) is a key strategy for the treatment of AML relapse after allogeneic hematopoietic cell transplantation (allo-HCT) and has been used for either prophylactic, pre-emptive, or therapeutic purposes. However, the prognosis of these patients remains dismal even after DLI infusion (2-year overall survival, ~25%), and the efficacy is achieved at the cost of toxicities such as graft-versus-host (GVH) disease. Attempts to optimize DLI efficacy and safety, such as dose/timing modification and the use of cytoreduction, before DLI have been performed previously. Recently, a great number of novel targeted and immunomodulatory agents have emerged. Some of them, such as hypomethylating agents, FLT3 and Bcl-2 inhibitors, have been used in combination with DLI, aiming to enhance the graft-versus-leukemia effect. Moreover, manipulation of the DLI graft through cell selection (e.g., donor NK cells) or cell engineering (donor CAR-T cells) has shown potentially superior anti-tumor effects but less GVH effect than conventional DLI in clinical trials. This review summarizes the recent advances on the use of DLI for the prophylaxis/treatment of AML relapse and discusses future strategies which may further improve the treatment efficacy.
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Affiliation(s)
- Yishan Ye
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Luxin Yang
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Xiaolin Yuan
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - He Huang
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yi Luo
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
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26
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HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning with very low-dose antithymocyte globulin for relapsed/refractory acute leukemia in pediatric patients: a single-institution retrospective analysis. Int J Hematol 2022; 115:406-413. [PMID: 35028882 DOI: 10.1007/s12185-021-03270-z] [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: 07/02/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 10/19/2022]
Abstract
The prognosis of relapsed/refractory (R/R) pediatric acute leukemia is extremely poor. We retrospectively reviewed 20 consecutive pediatric patients with R/R acute leukemia who underwent a first HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning (haplo-RIC-PBSCT) with very low-dose antithymocyte globulin (ATG) between 2012 and 2019. Of these 20 patients, 7 patients had acute lymphoblastic leukemia, and 13 had acute myeloid leukemia. At the time of haplo-RIC-PBSCT, 15 patients had active disease. The median follow-up duration for survivors was 56 months (range 22-108 months). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, short-term methotrexate, methylprednisolone, and ATG 1.25 mg/kg on day-2. The 2-year cumulative incidence of transplant-related mortality and relapse were 5.0% [95% confidence interval (CI) 0.7-30.5%)] and 57.8% (95% CI 37.4-79.6%), respectively. Among the 20 patients, 16 (80.0%) developed grade III-IV acute GVHD, and 2 developed severe chronic GVHD. The 2-year event-free survival and overall survival rates were 40.0% (95% CI 19.3-60.0%) and 50.0% (95% CI 27.1-69.2%), respectively. Although the sample size is small, the survival outcomes of the present study are encouraging.
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27
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Singh A, Dandoy CE, Chen M, Kim S, Mulroney CM, Kharfan-Dabaja MA, Ganguly S, Maziarz RT, Kanakry CG, Kanakry JA, Patel SS, Hill JA, De Oliveir S, Taplitz R, Hematti P, Lazarus HM, Abid MB, Goldsmith SR, Romee R, Komanduri KV, Badawy SM, Friend BD, Beitinjaneh A, Politikos I, Perales MA, Riches M. Post-Transplantation Cyclophosphamide Is Associated with an Increase in Non-Cytomegalovirus Herpesvirus Infections in Patients with Acute Leukemia and Myelodysplastic Syndrome. Transplant Cell Ther 2022; 28:48.e1-48.e10. [PMID: 34587551 PMCID: PMC9717499 DOI: 10.1016/j.jtct.2021.09.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 01/03/2023]
Abstract
The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.
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Affiliation(s)
- Anurag Singh
- University of Kansas, University of Kansas Cancer Center, Westwood, Kansas.
| | - Christopher E Dandoy
- Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio
| | - Min Chen
- Center for International Blood and Marrow Transplantation Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Soyoung Kim
- Center for International Blood and Marrow Transplantation Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Carolyn M Mulroney
- Division of Blood and Marrow Transplant. University of California, San Diego, La Jolla, California
| | - Mohamed A Kharfan-Dabaja
- Division of Hematology-Oncology, Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, Florida
| | - Siddhartha Ganguly
- Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City, Kansas
| | - Richard T Maziarz
- Adult Blood and Marrow Stem Cell Transplant Program, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
| | - Christopher G Kanakry
- Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jennifer A Kanakry
- Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sagar S Patel
- Blood and Marrow Transplant Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Joshua A Hill
- Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, Washington
| | - Satiro De Oliveir
- Divsion of Pediatric Hematology/Oncology, University of California, Los Angeles (UCLA), Los Angeles, California
| | - Randy Taplitz
- Division of Infectious Diseases, City of Hope National Medical Center, Duarte, California
| | - Peiman Hematti
- Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin, Madison, Wisconsin
| | - Hillard M Lazarus
- University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio
| | - Muhammad Bilal Abid
- Divisions of Hematology/Oncology & Infectious Diseases, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Scott R Goldsmith
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Rizwan Romee
- Department of Medical Oncology, Dana farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Krishna V Komanduri
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Sherif M Badawy
- Division of Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Brian D Friend
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
| | - Amer Beitinjaneh
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Ioannis Politikos
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Miguel-Angel Perales
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marcie Riches
- Division of Hematology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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28
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Takahashi T, Prockop SE. T-cell depleted haploidentical hematopoietic cell transplantation for pediatric malignancy. Front Pediatr 2022; 10:987220. [PMID: 36313879 PMCID: PMC9614427 DOI: 10.3389/fped.2022.987220] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Access to allogenic hematopoietic cell transplantation (HCT), a potentially curative treatment for chemotherapy-resistant hematologic malignancies, can be limited if no human leukocyte antigen (HLA) identical related or unrelated donor is available. Alternative donors include Cord Blood as well as HLA-mismatched unrelated or related donors. If the goal is to minimize the number of HLA disparities, partially matched unrelated donors are more likely to share 8 or 9 of 10 HLA alleles with the recipient. However, over the last decade, there has been success with haploidentical HCT performed using the stem cells from HLA half-matched related donors. As the majority of patients have at least one eligible and motivated haploidentical donor, recruitment of haploidentical related donors is frequently more rapid than of unrelated donors. This advantage in the accessibility has historically been offset by the increased risks of graft rejection, graft-versus-host disease and delayed immune reconstitution. Various ex vivo T-cell depletion (TCD) methods have been investigated to overcome the immunological barrier and facilitate immune reconstitution after a haploidentical HCT. This review summarizes historical and contemporary clinical trials of haploidentical TCD-HCT, mainly in pediatric malignancy, and describes the evolution of these approaches with a focus on serial improvements in the kinetics of immune reconstitution. Methods of TCD discussed include in vivo as well as ex vivo positive and negative selection. In addition, haploidentical TCD as a platform for post-HCT cellular therapies is discussed. The present review highlights that, as a result of the remarkable progress over half a century, haploidentical TCD-HCT can now be considered as a preferred alternative donor option for children with hematological malignancy in need of allogeneic HCT.
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Affiliation(s)
- Takuto Takahashi
- Pediatric Stem Cell Transplantation, Boston Children's Hospital/Dana-Farber Cancer Institute, Boston, MA, United States.,Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, United States
| | - Susan E Prockop
- Pediatric Stem Cell Transplantation, Boston Children's Hospital/Dana-Farber Cancer Institute, Boston, MA, United States
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29
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Chang YJ, Zhao XY, Huang XJ. Haploidentical Stem Cell Transplantation for Acute Myeloid Leukemia: Current Therapies, Challenges and Future Prospective. Front Oncol 2021; 11:758512. [PMID: 34778077 PMCID: PMC8581046 DOI: 10.3389/fonc.2021.758512] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/05/2021] [Indexed: 01/01/2023] Open
Abstract
Haploidentical stem cell transplantation (haplo-SCT), an alternative donor source, offers a curative therapy for patients with acute myeloid leukemia (AML) who are transplant candidates. Advances in transplantation techniques, such as donor selection, conditioning regimen modification, and graft-versus-host disease prophylaxis, have successfully improved the outcomes of AML patients receiving haplo-SCT and extended the haploidentical transplant indictions for AML. Presently, treating de novo AML, secondary AML, therapy-related AML and refractory and relapsed AML with haplo-SCT can achieve comparable outcomes to those of human leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT), unrelated donor transplantation or umbilical cord blood transplantation. For some subgroups of AML subjects, such as patients with positive pretransplantation minimal/measurable residual disease, recent studies suggest that haplo-SCT might be superior to MSDT in decreasing relapse and improving survival. Unfortunately, for patients with AML after haplo-SCT, relapse and infections remain the causes of death that restrict further improvement in clinical outcomes. In this review, we discuss the recent advances and challenges in haplo-SCT for AML treatment, mainly focusing on unmanipulated haplo-SCT protocols. We provide an outlook on future prospects and suggest that relapse prophylaxis, intervention, and treatment, as well as infection prevention and therapy, are areas of active research in AML patients who receive haploidentical allografts.
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Affiliation(s)
- Ying-Jun Chang
- Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiang-Yu Zhao
- Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China
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30
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Xu Z, Huang X. Optimizing allogeneic grafts in hematopoietic stem cell transplantation. Stem Cells Transl Med 2021; 10 Suppl 2:S41-S47. [PMID: 34724721 PMCID: PMC8560196 DOI: 10.1002/sctm.20-0481] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/23/2021] [Accepted: 03/04/2021] [Indexed: 12/19/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of hematological diseases. It is well known that allogeneic grafts play a key role in predicting transplantation prognosis. Hematopoietic stem cells (HSCs) are a functional part of grafts and are capable of reconstructing hematopoiesis and immunity, but purified HSCs have not been identified or isolated to date. In clinical practice, allogeneic grafts have been optimized to improve transplantation outcomes. The optimized grafts are considered to engraft successfully, reconstruct immunity rapidly, and exert a graft-vs-leukemia (GVL) effect without causing severe graft-vs-host disease (GvHD). In the last several decades, considerable efforts have been made in searching for optimized grafts based on different graft manipulation approaches and different graft sources. Currently, there is no uniform standard for optimized grafts in allogeneic transplantation. In the future, sorting out the cellular elements responsible for the effects of allo-HSCT might be a research direction for further optimization of grafts. In this review, we propose the concept of optimized grafts and summarize the recent advances made in the process of optimizing grafts.
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Affiliation(s)
- Zheng‐Li Xu
- Peking University People's HospitalPeking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijingPeople's Republic of China
| | - Xiao‐Jun Huang
- Peking University People's HospitalPeking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijingPeople's Republic of China
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31
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Xu Z, Zhou X, Zhao X, Lu X, Tang L, Shi W, Yan H, You Y, Wang H. Cytokine release syndrome after haploidentical hematopoietic stem cell transplantation with antithymocyte globulin: risk factors analysis and poor impact on outcomes for non-remisssion patients. Hematology 2021; 26:809-817. [PMID: 34602023 DOI: 10.1080/16078454.2021.1978752] [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: 10/20/2022] Open
Abstract
INTRODUCTION Cytokine release syndrome (CRS) is a common complication after T-replete HLA haploidentical hematopoietic cell transplantation (haplo-HCT) with PTCy. We aim to assess the incidence, severity, and impact of CRS on clinical outcomes of patients who received haplo-HCT using Beijing Protocol. METHODS This was a single-enter retrospective analysis of 286 subjects who received haplo-HCT with Antithymocyte Globulin (ATG). RESULTS We identified 147/268 (54.9%) patients who developed CRS, grade 1 CRS (32.5%) and grade ≥2 CRS (22.4%). Eight patients developed severe CRS. The incidence and severity of CRS did not show significant discrimination among patients who received different doses of ATG. By multivariable analysis, age and the disease status at transplantation were significantly associated with the occurrence of CRS (p =.000 and p = .021). In the univariate analysis for the severity of CRS, compared with CRS grade ≥2, patients with CRS grade 0-1 had higher 1-year overall survival (OS) (p = .009). The cumulative incidence of 100-day grades II-IV acute GVHD was 12.4%. The incidence did not show significant differences between patients with CRS or not. The devolvement of CRS is associated with worse OS, inferior disease-free survival, and higher nonrelapse mortality significantly. But the result appeared to be limited to patients in uncomplete remission status before transplantation. DISCUSSION AND CONCLUSIONS CRS is less frequent and milder with a protocol based on ATG. CRS can potentially affect the outcomes after haplo-HCT especially for patients in an uncomplete remission. Prospective clinical trials are needed to provide an appropriate scheme for CRS prophylaxis.
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Affiliation(s)
- Ziwei Xu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xi Zhou
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xiaoyan Zhao
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xuan Lu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Liang Tang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Wei Shi
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Han Yan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yong You
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Huafang Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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32
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Esquirol A, Pascual MJ, Kwon M, Pérez A, Parody R, Ferra C, Garcia Cadenas I, Herruzo B, Dorado N, Hernani R, Sanchez-Ortega I, Torrent A, Sierra J, Martino R. Severe infections and infection-related mortality in a large series of haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. Bone Marrow Transplant 2021; 56:2432-2444. [PMID: 34059802 PMCID: PMC8165955 DOI: 10.1038/s41409-021-01328-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/10/2021] [Accepted: 04/22/2021] [Indexed: 12/12/2022]
Abstract
Severe infections and their attributable mortality are major complications in recipients of allogeneic hematopoietic stem cell transplantation (alloSCT). We herein report 236 adult patients who received haploSCT with PTCy. The median follow-up for survivors was 37 months. The overall incidence of bloodstream infections by gram-positive and gram-negative bacteria at 37 months was 51% and 46%, respectively. The incidence of cytomegalovirus infection was 69%, while Epstein Barr virus infections occurred in 10% of patients and hemorrhagic cystitis in 35% of cases. Invasive fungal infections occurred in 11% at 17 months. The 3-year incidence of infection-related mortality was 19%. The median interval from transplant to IRM was 3 months (range 1-30), 53% of IRM occurred >100 days post-haploSCT. Risk factors for IRM included age >50 years, lymphoid malignancy, and developing grade III-IV acute GvHD. Bacterial infections were the most common causes of IRM (51%), mainly due to gram-negative bacilli BSI. In conclusion, severe infections are the most common causes of NRM after haploSCT with PTCy, with a reemergence of gram-negative bacilli as the most lethal pathogens. More studies focusing on the severe infections after haploSCT with PTCy and differences with other types of alloSCT in adults are clearly warranted.
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Affiliation(s)
- Albert Esquirol
- Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau and Jose Carreras Leukemia Research Institutes, Universitat Autonoma of Barcelona (Departament de medicina), Barcelona, Spain.
| | | | - Mi Kwon
- Hematology Department, Hospital Gregorio Marañón, Madrid, Spain
| | - Ariadna Pérez
- Hematology Department, Hospital Clinico Universitario, Valencia, Spain
| | - Rocio Parody
- Hematology Department, Hospital de Bellvitge, Barcelona, Spain
| | - Christelle Ferra
- Hematology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Irene Garcia Cadenas
- Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau and Jose Carreras Leukemia Research Institutes, Universitat Autonoma of Barcelona (Departament de medicina), Barcelona, Spain
| | - Beatriz Herruzo
- Hematology Department, Hospital Regional Universitario, Malaga, Spain
| | - Nieves Dorado
- Hematology Department, Hospital Gregorio Marañón, Madrid, Spain
| | - Rafael Hernani
- Hematology Department, Hospital Clinico Universitario, Valencia, Spain
| | | | - Anna Torrent
- Hematology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Jorge Sierra
- Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau and Jose Carreras Leukemia Research Institutes, Universitat Autonoma of Barcelona (Departament de medicina), Barcelona, Spain
| | - Rodrigo Martino
- Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau and Jose Carreras Leukemia Research Institutes, Universitat Autonoma of Barcelona (Departament de medicina), Barcelona, Spain
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33
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Hakki M, Aitken SL, Danziger-Isakov L, Michaels MG, Carpenter PA, Chemaly RF, Papanicolaou GA, Boeckh M, Marty FM. American Society for Transplantation and Cellular Therapy Series: #3-Prevention of Cytomegalovirus Infection and Disease After Hematopoietic Cell Transplantation. Transplant Cell Ther 2021; 27:707-719. [PMID: 34452721 DOI: 10.1016/j.jtct.2021.05.001] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 05/02/2021] [Indexed: 11/20/2022]
Abstract
The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious diseases guidelines for the care of hematopoietic cell transplant (HCT) recipients. A new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The third topic in the series focuses on the prevention of cytomegalovirus infection and disease in HCT recipients by reviewing prophylaxis and preemptive therapy approaches; key definitions, relevant risk factors, and diagnostic monitoring considerations are also reviewed.
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Affiliation(s)
- Morgan Hakki
- Division of Infectious Diseases, Department of Medicine, Oregon Health and Science University, Portland, Oregon.
| | - Samuel L Aitken
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lara Danziger-Isakov
- Division of Infectious Disease, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Marian G Michaels
- Division of Pediatric Infectious Diseases, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Paul A Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Michael Boeckh
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Vaccine and Infectious Disease Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Francisco M Marty
- Division of Infectious Diseases, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts
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34
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Seitz CM, Flaadt T, Mezger M, Lang AM, Michaelis S, Katz M, Syring D, Joechner A, Rabsteyn A, Siebert N, Troschke-Meurer S, Zumpe M, Lode HN, Yang SF, Atar D, Mast AS, Scheuermann S, Heubach F, Handgretinger R, Lang P, Schlegel P. Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment. Front Immunol 2021; 12:690467. [PMID: 34367149 PMCID: PMC8339919 DOI: 10.3389/fimmu.2021.690467] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/16/2021] [Indexed: 11/14/2022] Open
Abstract
Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.
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Affiliation(s)
- Christian Martin Seitz
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Tim Flaadt
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Markus Mezger
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Anne-Marie Lang
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Sebastian Michaelis
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Marie Katz
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Desireé Syring
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Alexander Joechner
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Cellular Cancer Therapeutics Unit, Children's Medical Research Institute, Westmead, NSW, Australia
| | - Armin Rabsteyn
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Nikolai Siebert
- Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Sascha Troschke-Meurer
- Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Maxi Zumpe
- Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Holger N Lode
- Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Sile F Yang
- Cellular Cancer Therapeutics Unit, Children's Medical Research Institute, Westmead, NSW, Australia
| | - Daniel Atar
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Anna-Sophia Mast
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Sophia Scheuermann
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Florian Heubach
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Rupert Handgretinger
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Peter Lang
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Patrick Schlegel
- Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany.,Cellular Cancer Therapeutics Unit, Children's Medical Research Institute, Westmead, NSW, Australia.,School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.,Department of Pediatric Hematology and Oncology, Westmead Children's Hospital, Westmead, NSW, Australia
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35
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Agrawal V, Gbolahan OB, Stahl M, Zeidan AM, Zaid MA, Farag SS, Konig H. Vaccine and Cell-based Therapeutic Approaches in Acute Myeloid Leukemia. Curr Cancer Drug Targets 2021; 20:473-489. [PMID: 32357813 DOI: 10.2174/1568009620666200502011059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 03/05/2020] [Accepted: 03/29/2020] [Indexed: 12/13/2022]
Abstract
Over the past decade, our increased understanding of the interactions between the immune system and cancer cells has led to paradigm shifts in the clinical management of solid and hematologic malignancies. The incorporation of immune-targeted strategies into the treatment landscape of acute myeloid leukemia (AML), however, has been challenging. While this is in part due to the inability of the immune system to mount an effective tumor-specific immunogenic response against the heterogeneous nature of AML, the decreased immunogenicity of AML cells also represents a major obstacle in the effort to design effective immunotherapeutic strategies. In fact, AML cells have been shown to employ sophisticated escape mechanisms to evade elimination, such as direct immunosuppression of natural killer cells and decreased surface receptor expression leading to impaired recognition by the immune system. Yet, cellular and humoral immune reactions against tumor-associated antigens (TAA) of acute leukemia cells have been reported and the success of allogeneic stem cell transplantation and monoclonal antibodies in the treatment of AML clearly provides proof that an immunotherapeutic approach is feasible in the management of this disease. This review discusses the recent progress and persisting challenges in cellular immunotherapy for patients with AML.
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Affiliation(s)
- Vaibhav Agrawal
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Olumide B Gbolahan
- Division of Hematology and Oncology, University of Alabama School of Medicine, Birmingham, AL 35294, United States
| | - Maximilian Stahl
- Department of Medicine, Division of Hematology and Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
| | - Amer M Zeidan
- Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Mohammad Abu Zaid
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Sherif S Farag
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Heiko Konig
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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36
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Mulroney CM, Abid MB, Bashey A, Chemaly RF, Ciurea SO, Chen M, Dandoy CE, Diaz Perez MA, Friend BD, Fuchs E, Ganguly S, Goldsmith SR, Kanakry CG, Kim S, Komanduri KV, Krem MM, Lazarus HM, Ljungman P, Maziarz R, Nishihori T, Patel SS, Perales MA, Romee R, Singh AK, Reid Wingard J, Yared J, Riches M, Taplitz R. Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation. Br J Haematol 2021; 194:145-157. [PMID: 34124796 PMCID: PMC8853845 DOI: 10.1111/bjh.17563] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 12/26/2022]
Abstract
Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.
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Affiliation(s)
- Carolyn M Mulroney
- Department of Medicine, Division of Blood and Marrow Transplant, University of California San Diego, La Jolla, CA, USA
| | | | - Asad Bashey
- Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stefan O Ciurea
- Department of Medicine, University of California Irvine, Irvine, CA, USA
| | - Min Chen
- Department of Medicine, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Christopher E Dandoy
- Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH, USA
| | - Miguel A Diaz Perez
- Department of Hematology/Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Brian D Friend
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX, USA
| | - Ephraim Fuchs
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | | | - Scott R Goldsmith
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Christopher G Kanakry
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Soyoung Kim
- Department of Medicine, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
- Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Maxwell M Krem
- Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Hillard M Lazarus
- University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Per Ljungman
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Richard Maziarz
- Adult Blood and Marrow Stem Cell Transplant Program, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
| | - Taiga Nishihori
- Department of Blood and Marrow Transplant and Cellular Immunotherapy (BMT CI), Moffitt Cancer Center, Tampa, FL, USA
| | - Sagar S Patel
- Utah Blood and Marrow Transplant Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Miguel-Angel Perales
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rizwan Romee
- Division of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, MA, USA
| | - Anurag K Singh
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Fairway, KS, USA
| | - John Reid Wingard
- Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL, USA
| | - Jean Yared
- Blood and Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA
| | - Marcie Riches
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Randy Taplitz
- Department of Medicine, City of Hope, Duarte, CA, USA
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37
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Modi D, Kondrat K, Kim S, Deol A, Ayash L, Ratanatharathorn V, Uberti JP. Post-transplant Cyclophosphamide Versus Thymoglobulin in HLA-Mismatched Unrelated Donor Transplant for Acute Myelogenous Leukemia and Myelodysplastic Syndrome. Transplant Cell Ther 2021; 27:760-767. [PMID: 34174469 DOI: 10.1016/j.jtct.2021.06.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/11/2021] [Accepted: 06/16/2021] [Indexed: 10/21/2022]
Abstract
Limited information is available on the efficacy of post-transplantation cyclophosphamide (PTcy) or thymoglobulin for graft-versus-host disease (GVHD) prophylaxis in mismatched unrelated donor (MMUD) transplants. We retrospectively compared outcomes of 76 adult patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who underwent 7/8 HLA-MMUD transplantation and received either PTcy (50 mg/kg on day 3 and 4) or thymoglobulin (total dose 4.5 mg/kg) for GVHD prophylaxis. In addition, tacrolimus and mycophenolate were used in both groups. Propensity score-based multivariable analyses (PSCA) were performed to adjust confounding effects of patient characteristics between both groups. Between January 2006 and June 2019, 25 patients received PTcy, and 51 received thymoglobulin. Median age of the population was 57 years, 78% of patients had AML, most common graft source was peripheral blood (96%), and 46% received myeloablative conditioning regimens. Median time to neutrophil (15 versus 11 days, P < .001) and platelet engraftment (21 versus 15 days, P = .002) was prolonged in the PTcy group. The cumulative incidence of grade III-IV acute GVHD at day 100 was similar (12% versus 19.6%, P = .38), whereas chronic GVHD at 1 year was lower with PTcy compared to thymoglobulin (16% versus 49%, P = .006). Using PSCA, no difference in survival, relapse, relapse-free survival, and GVHD-free relapse-free survival was seen between groups. However, thymoglobulin was associated with higher incidence of acute (hazard ratio [HR] = 2.63, P = .01) and chronic GVHD (HR = 4.43, P = .03), and non-relapse mortality (HR 3.38, P = .04) compared to PTcy. Our study demonstrated that PTcy resulted in significantly lower rates of acute and chronic GVHD and non-relapse mortality compared to thymoglobulin in 7/8 HLA-MMUD transplants for AML and MDS.
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Affiliation(s)
- Dipenkumar Modi
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
| | - Kyle Kondrat
- Department of Internal Medicine and Pediatrics, DMC and Children's Hospital of Michigan, Detroit, Michigan
| | - Seongho Kim
- Biostatistics Core, Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, Michigan
| | - Abhinav Deol
- Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Lois Ayash
- Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Voravit Ratanatharathorn
- Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Joseph P Uberti
- Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
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38
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Sun YQ, Wang Y, Wang FR, Yan CH, Cheng YF, Chen YH, Zhang YY, Han TT, Han W, Suo P, Xu LP, Zhang XH, Liu KY, Huang XJ. Graft Failure in Patients With Hematological Malignancies: A Successful Salvage With a Second Transplantation From a Different Haploidentical Donor. Front Med (Lausanne) 2021; 8:604085. [PMID: 34150785 PMCID: PMC8212968 DOI: 10.3389/fmed.2021.604085] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 04/27/2021] [Indexed: 11/13/2022] Open
Abstract
Graft failure (GF) is a fatal complication of allogeneic stem cell transplantation, especially after haploidentical transplantation. The mortality of GF is nearly 100% without an effective salvage method. A second transplantation is usually necessary to save the patient's life. However, there is no standardized regimen, and the outcome is usually disappointing. We report on a prospective single-center study using a reduced-intensity conditioning regimen with different haploidentical donors (HIDs). Patients with GF after the first transplantation were enrolled in a prospective single-arm clinical trial (ClinicalTrials.Gov ID: NCT03717545) at the Peking University Institute of Hematology. The conditioning regimen consisted of fludarabine (30 mg/m2) (days-6 to-2) and cyclophosphamide (1,000 mg/m2/day) (days-5 to-4). Patients underwent a second transplant from a different HID using a granulocyte colony-stimulating factor primed bone marrow and peripheral blood stem cells. The primary outcome was neutrophil engraftment at day 28. The secondary outcomes included platelet engraftment at day 100, transplant-related mortality (TRM) at day 30, TRM at day 100, and overall survival (OS) at 1 year. From March 2018 to June 2020, 13 patients were enrolled in this clinical trial. Of the 13 patients, five had acute myeloid leukemia, five had acute lymphoblastic leukemia, two had myelodysplastic syndromes, and one had a non-Hodgkin lymphoma. The median age at first transplantation was 38 years (range, 8-55 years). As for the first transplantation, 11 patients underwent haploidentical transplantations and two underwent unrelated donor transplantations. At the time of GF, three patients had complete donor chimerism, five had mixed chimerism, and five had complete recipient chimerism. The median time from the first transplantation to the second transplantation was 49 (range 35-120) days. The medians of infused cell doses were as follows: mononuclear cells 7.93 (5.95-12.51) × 108/kg and CD34 + cells 2.28 (0.75-5.57) × 106/kg. All 13 patients achieved neutrophil engraftment after the second transplantation, with a median engraftment time of 11 (range 10-20) days after transplantation. The platelet engraftment rate on day 100 after transplantation was 76.9%. The TRMs at day 30, day 100, and 1-year were 0, 0, and 23.1%, respectively. The OS and disease-free survival at 1-year were 56.6 and 48.4%, respectively. For patients with GF after first transplantation, a second transplantation using a fludarabine/cyclophosphamide regimen from a different HID was a promising salvage option. Further investigation is needed to confirm the suitability of this method.
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Affiliation(s)
- Yu-Qian Sun
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yu Wang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Feng-Rong Wang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Chen-Hua Yan
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yi-Fei Cheng
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yu-Hong Chen
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Yuan-Yuan Zhang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Ting-Ting Han
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Wei Han
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Pan Suo
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Lan-Ping Xu
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Xiao-Hui Zhang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Kai-Yan Liu
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Xiao-Jun Huang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
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39
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Nagler A, Kanate AS, Labopin M, Ciceri F, Angelucci E, Koc Y, Gülbas Z, Arcese W, Tischer J, Pioltelli P, Ozdogu H, Afanasyev B, Wu D, Arat M, Peric Z, Giebel S, Savani B, Mohty M. Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia. Haematologica 2021; 106:1591-1598. [PMID: 32354866 PMCID: PMC8168508 DOI: 10.3324/haematol.2020.247296] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 04/28/2020] [Indexed: 11/16/2022] Open
Abstract
Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG.
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Affiliation(s)
- Arnon Nagler
- Chaim Sheba Medical Center, Tel Aviv University, Tel-Hashomer, Israel
| | | | - Myriam Labopin
- Haematology and EBMT Paris study office / CEREST-TC, Saint Antoine Hospital, Paris, France
| | | | | | - Yener Koc
- Medical Park Hospitals, Stem Cell Transplant Unit, Antalya, Turkey
| | - Zafer Gülbas
- Anadolu Medical Center Hospital, Bone Marrow Transplantation Department, Kocaeli, Turkey
| | - William Arcese
- Tor Vergata University of Rome, Stem Cell Transplant Unit, Rome, Italy
| | | | - Pietro Pioltelli
- Ospedale San Gerardo, Clinica Ematologica dell`Universita Milano-Biocca, Monza, Italy
| | - Hakan Ozdogu
- Baskent University Hospital, Haematology Division, BMT Unit, Adana, Turkey
| | - Boris Afanasyev
- First State Pavlov Medical University of St. Petersburg, Russia
| | - Depei Wu
- First Affiliated Hospital of Soochow University, Department of Hematology, Suzhou, China
| | - Mutlu Arat
- Florence Nightingale Sisli Hospital, Hematopoietic SCT Unit, Istanbul, Turkey
| | - Zinaida Peric
- University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sebastian Giebel
- Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Bipin Savani
- Department of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mohamad Mohty
- Saint Antoine Hospital and Université Pierre et Marie Curie, Paris, France
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40
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Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia. Blood Adv 2021; 5:1199-1208. [PMID: 33646302 DOI: 10.1182/bloodadvances.2020003739] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/28/2020] [Indexed: 11/20/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment in eradicating high-risk acute myeloid leukemia (AML). Here, we present data from a novel HLA-haploidentical HSCT protocol that addressed the 2 remaining major unmet medical needs: leukemia relapse and chronic graft-versus-host disease (cGVHD). Fifty AML patients were enrolled in the study. The conditioning regimen included total body irradiation for patients up to age 50 years and total marrow/lymphoid irradiation for patients age 51 to 65 years. Irradiation was followed by thiotepa, fludarabine, and cyclophosphamide. Patients received an infusion of 2 × 106/kg donor regulatory T cells on day -4 followed by 1 × 106/kg donor conventional T cells on day -1 and a mean of 10.7 × 106 ± 3.4 × 106/kgpurified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GVHD prophylaxis was administered posttransplantation. Patients achieved full donor-type engraftment. Fifteen patients developed grade ≥2 acute GVHD (aGVHD). Twelve of the 15 patients with aGVHD were alive and no longer receiving immunosuppressive therapy. Moderate/severe cGVHD occurred in only 1 patient. Nonrelapse mortality occurred in 10 patients. Only 2 patients relapsed. Consequently, at a median follow-up of 29 months, the probability of moderate/severe cGVHD/relapse-free survival was 75% (95% confidence interval, 71%-78%). A novel HLA-haploidentical HSCT strategy that combines an age-adapted myeloablative conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy resulted in an unprecedented cGVHD/relapse-free survival rate in 50 AML patients with a median age of 53 years. This trial was registered with the Umbria Region Institutional Review Board Public Registry as identification code 02/14 and public registry #2384/14 and at www.clinicaltrials.gov as #NCT03977103.
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41
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Zheng X, Tian Z. Which is better, HLA-matched sibling or haploidentical transplantation? Cell Mol Immunol 2021; 18:1347. [PMID: 33879863 PMCID: PMC8093214 DOI: 10.1038/s41423-021-00640-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 01/09/2021] [Indexed: 12/11/2022] Open
Affiliation(s)
- Xiaodong Zheng
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.
- Institue of Immunology, University of Science and Technology of China, Hefei, China.
| | - Zhigang Tian
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Institue of Immunology, University of Science and Technology of China, Hefei, China
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42
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Pelosi A, Besi F, Tumino N, Merli P, Quatrini L, Li Pira G, Algeri M, Moretta L, Vacca P. NK Cells and PMN-MDSCs in the Graft From G-CSF Mobilized Haploidentical Donors Display Distinct Gene Expression Profiles From Those of the Non-Mobilized Counterpart. Front Immunol 2021; 12:657329. [PMID: 33986748 PMCID: PMC8111072 DOI: 10.3389/fimmu.2021.657329] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/06/2021] [Indexed: 11/13/2022] Open
Abstract
A recent approach of hematopoietic stem cell (HSC) transplantation from haploidentical donors "mobilized" with G-CSF is based on the selective depletion of αβ T and B lymphocytes from the graft. Through this approach, the patient receives both HSC and mature donor-derived effector cells (including NK cells), which exert both anti-leukemia activity and protection against infections. We previously showed that donor HSC mobilization with G-CSF results in accumulation in the graft of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), capable of inhibiting in vitro the anti-leukemia activity of allogeneic NK cells. Here, we performed a detailed gene expression analysis on NK cells and PMN-MDSCs both derived from mobilized graft. Cytotoxicity assays and real time PCR arrays were performed in NK cells. Microarray technology followed by bioinformatics analysis was used for gene expression profiling in PMN-MDSCs. Results indicate that NK cells from the graft have a lower cytolytic activity as compared to those from non-mobilized samples. Further, mobilized PMN-MDSCs displayed a peculiar transcriptional profile distinguishing them from non-mobilized ones. Differential expression of pro-proliferative and immune-modulatory genes was detected in mobilized PMN-MDSCs. These data strengthen the concept that G-CSF-mobilized PMN-MDSCs present in the graft display unique molecular characteristics, in line with the strong inhibitory effect on donor NK cells.
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Affiliation(s)
- Andrea Pelosi
- Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Francesca Besi
- Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Nicola Tumino
- Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Pietro Merli
- Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Linda Quatrini
- Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giuseppina Li Pira
- Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Mattia Algeri
- Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Lorenzo Moretta
- Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Paola Vacca
- Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Kerbauy MN, Ribeiro AAF, Arcuri LJ, Kerbauy LN, da Silva CC, Camargo LFA, Machado CM, Hamerschlak N. Clinical impact of multiple DNA virus infections in nondepleted haploidentical and unrelated allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2021; 23:e13626. [PMID: 33900012 DOI: 10.1111/tid.13626] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/26/2021] [Accepted: 04/15/2021] [Indexed: 12/16/2022]
Abstract
Few studies have compared the clinical impact of multiple DNA-virus infections in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with posttransplant cyclophosphamide (PTCy) and unrelated donor allogeneic hematopoietic stem cell transplantation (UD-HSCT) with thymoglobulin, so we retrospectively analyzed viral infections in the first 6 mo posttransplant in these scenarios. Fifty-nine patients underwent to haplo-HSCT, and 68 to UD-HSCT. The most frequent infection was cytomegalovirus (CMV) (76.3% in haplo-HSCT and 69.1% in UD-HSCT) (P = .878) and in the group of patients with CMV reactivation, maximal CMV viral load over 2500 UI/ml correlated with worse overall survival-hazard ratio (HR) 1.93 (95% confidence interval [CI] 1.04-3.59) P = .03. The cumulative incidence of multiple DNA virus within 180 d of posttransplant was 78.7% for one virus and 28.4% for two or more viruses with no difference regarding the type of transplant. Viral infections, age, and acute graft versus host disease (GVHD) grades II-IV were risk factors for worse overall survival in multivariate analyses: one virus HR 2.53 (95% CI 1.03-6.17) P = .04, two or more viruses HR 3.51 (95% CI 1.37-9) P < .01, age HR 1.03 (95% CI 1.02-1.05) P < .01 and acute GVHD II-IV HR 1.97 (95% CI 1.13-3.43) P = .01. Also, age over 50 y HR 4.25 (95% CI 2.01-8.97) P < .001, second CMV reactivation or having both CMV and BK polyomavirus (BKV) HR 2.65 (95% CI 1.26-5.56) P = .01 and acute GVHD grades II-IV HR 2.23 (95% CI 1.12-4.43) P = .022 were risk factors for nonrelapse mortality in the multivariate analyses. In conclusion, multiple DNA-virus infections are frequent in both haplo-HSCT and UD-HSCT and a risk factor for worse overall survival.
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Affiliation(s)
- Mariana N Kerbauy
- Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Andreza A F Ribeiro
- Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Leonardo J Arcuri
- Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Lucila N Kerbauy
- Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Cinthya C da Silva
- Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Luis Fernando A Camargo
- Instituto Israelita de Ensino e Pesquisa (IIEP), Hospital Israelita Albert Einstein, São Paulo, Brazil.,Department of Infectious Diseases, Hospital Israelita Albert Einstein, São Paulo, Brazil.,Department of Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Clarisse M Machado
- Instituto Israelita de Ensino e Pesquisa (IIEP), Hospital Israelita Albert Einstein, São Paulo, Brazil.,Virology Laboratory, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil
| | - Nelson Hamerschlak
- Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, São Paulo, Brazil
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44
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Rubio MT, Dhuyser A, Nguyen S. Role and Modulation of NK Cells in Multiple Myeloma. HEMATO 2021. [DOI: 10.3390/hemato2020010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
Abstract
Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.
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45
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Tanzi M, Consonni M, Falco M, Ferulli F, Montini E, Pasi A, Cacciatore R, Brugnatelli S, Pedrazzoli P, Zecca M, Boghen S, Dellabona P, Casorati G, Montagna D. Cytokine-Induced Memory-Like NK Cells with High Reactivity against Acute Leukemia Blasts and Solid Tumor Cells Suitable for Adoptive Immunotherapy Approaches. Cancers (Basel) 2021; 13:1577. [PMID: 33808051 PMCID: PMC8036252 DOI: 10.3390/cancers13071577] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 03/23/2021] [Accepted: 03/23/2021] [Indexed: 01/03/2023] Open
Abstract
The limited efficacy of Natural Killer (NK) cell-based immunotherapy results in part from the suboptimal expansion and persistence of the infused cells. Recent reports suggest that the generation of NK cells with memory-like properties upon in vitro activation with defined cytokines might be an effective way of ensuring long-lasting NK cell function in vivo. Here, we demonstrate that activation with IL-12, IL-15 and IL-18 followed by a one-week culture with optimal doses of Interleukin (IL-2) and IL-15 generates substantial numbers of memory-like NK cells able to persist for at least three weeks when injected into NOD scid gamma (NSG) mice. This approach induces haploidentical donor-derived memory-like NK cells that are highly lytic against patients' myeloid or lymphoid leukemia blasts, independent of the presence of alloreactive cell populations in the donor and with negligible reactivity against patients' non-malignant cells. Memory-like NK cells able to lyse autologous tumor cells can also be generated from patients with solid malignancies. The anti-tumor activity of allogenic and autologous memory-like NK cells is significantly greater than that displayed by NK cells stimulated overnight with IL-2, supporting their potential therapeutic value both in patients affected by high-risk acute leukemia after haploidentical hematopoietic stem cell transplantation and in patients with advanced solid malignancies.
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Affiliation(s)
- Matteo Tanzi
- Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.T.); (F.F.); (E.M.)
- Laboratory of Immunology Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Michela Consonni
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; (M.C.); (P.D.); (G.C.)
| | - Michela Falco
- Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy;
| | - Federica Ferulli
- Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.T.); (F.F.); (E.M.)
- Laboratory of Immunology Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Enrica Montini
- Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.T.); (F.F.); (E.M.)
- Laboratory of Immunology Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.Z.); (S.B.)
| | - Annamaria Pasi
- Immunohematology and Transfusion Service and Cell Therapy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (A.P.); (R.C.)
| | - Rosalia Cacciatore
- Immunohematology and Transfusion Service and Cell Therapy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (A.P.); (R.C.)
| | - Silvia Brugnatelli
- Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.B.); (P.P.)
| | - Paolo Pedrazzoli
- Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.B.); (P.P.)
- Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy
| | - Marco Zecca
- Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.Z.); (S.B.)
| | - Stella Boghen
- Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.Z.); (S.B.)
| | - Paolo Dellabona
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; (M.C.); (P.D.); (G.C.)
| | - Giulia Casorati
- Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; (M.C.); (P.D.); (G.C.)
| | - Daniela Montagna
- Cell Factory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.T.); (F.F.); (E.M.)
- Laboratory of Immunology Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Sciences Clinic-Surgical, Diagnostic and Pediatric, University of Pavia, 27100 Pavia, Italy
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Ruggeri L, Vago L, Eikema DJ, de Wreede LC, Ciceri F, Diaz MA, Locatelli F, Jindra P, Milone G, Diez-Martin JL, Pérez-Simón JA, Merluzzi M, Koster L, van der Werf S, van Biezen A, Toubert A, Nagler A, Chabannon C, Bonini C, Velardi A. Natural killer cell alloreactivity in HLA-haploidentical hematopoietic transplantation: a study on behalf of the CTIWP of the EBMT. Bone Marrow Transplant 2021; 56:1900-1907. [PMID: 33767404 DOI: 10.1038/s41409-021-01259-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 02/04/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022]
Abstract
Human leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute myeloid leukemia patients after T-cell-depleted HLA-haplotype mismatched ("haploidentical") hematopoietic transplantation. In murine graft-versus-host disease (GvHD) models, alloreactive NK-cells also prevent GvHD. Here we report the results of a non-interventional, prospective study performed on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. The study was aimed at re-assessing the role of NK-cell alloreactivity in a cohort of haploidentical transplants performed in Europe between 2012 and 2015 and composed of unmanipulated, as well as T-cell-depleted transplants. One hundred thirty-eight patients with acute myeloid or lymphoid leukemias were analyzed. Eighty-six patients received ex-vivo T-cell-depleted transplants, 52 patients received unmanipulated transplants. Fifty patients were transplanted from NK alloreactive donors, 88 from non-NK alloreactive donors. NK cell alloreactivity did not impact on GvHD/relapse-free survival (GRFS) in unmanipulated transplants (HR: 1.66 (0.9-3.1), p = 0.1). In contrast, it did impact beneficially on GRFS in T-cell-depleted transplants (HR: 0.6, (0.3-1.2), p = 0.14, interaction p < 0.001). This effect was the consequence of reduced incidences of acute and chronic GvHD and non-relapse mortality.
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Affiliation(s)
| | - Luca Vago
- Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milano, Italy
| | | | - Liesbeth C de Wreede
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Fabio Ciceri
- Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milano, Italy
| | | | | | - Pavel Jindra
- Charles University Hospital, Pilsen, Czech Republic
| | | | | | | | | | - Linda Koster
- EBMT Data Office Leiden, Leiden, The Netherlands
| | | | | | - Antoine Toubert
- Hôpital Saint-Louis, APHP, INSERM U1160, Université Paris Diderot, Paris, France
| | - Arnon Nagler
- Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Christian Chabannon
- Institut Paoli-Calmettes, Centre de Lutte Contre le Cancer; Centre d'Investigations Cliniques en Biothérapie, Université d'Aix-Marseille, Inserm CBT, Marseille, France
| | - Chiara Bonini
- Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milano, Italy
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47
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Contemporary haploidentical stem cell transplant strategies in children with hematological malignancies. Bone Marrow Transplant 2021; 56:1518-1534. [PMID: 33674791 DOI: 10.1038/s41409-021-01246-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/01/2021] [Accepted: 02/15/2021] [Indexed: 12/14/2022]
Abstract
The barriers to HLA-mismatched or haploidentical hematopoietic stem cell transplantation (HSCT), namely GvHD and graft failure, have been overcome with novel transplant platforms. Post-transplant Cyclophosphamide (PTCy) is widely available, feasible and easy to implement. TCRαβ T and B cell depletion comes with consistent GvHD preventive benefits irrespective of age and indication. Naive T-cell depletion helps prevention of severe viral reactivations. The Beijing protocol shows promising outcomes in patients with poor remission status at the time of transplantation. For children, the toxicities and late outcomes related to these transplants are truly relevant as they suffer the most in the long run from transplant-related toxicities, especially chronic GvHD. While comparing the outcomes of different Haplo-HSCT approaches, one must understand the transplant immunobiology and factors affecting the transplant outcomes. Leukemia remission status at the time of conditioning is a consistent factor affecting the transplant outcomes using any of these platforms. Prospective comparison of these platforms lacks in a homogenous population; however, the evidence is growing, and this review highlights the areas of research gaps.
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Elmariah H, Brunstein CG, Bejanyan N. Immune Reconstitution after Haploidentical Donor and Umbilical Cord Blood Allogeneic Hematopoietic Cell Transplantation. Life (Basel) 2021; 11:102. [PMID: 33572932 PMCID: PMC7911120 DOI: 10.3390/life11020102] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/19/2021] [Accepted: 01/25/2021] [Indexed: 02/07/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for a variety of hematologic diseases. However, this therapeutic platform is limited by an initial period when patients are profoundly immunocompromised. There is gradual immune recovery over time, that varies by transplant platform. Here, we review immune reconstitution after allogeneic HCT with a specific focus on two alternative donor platforms that have dramatically improved access to allogeneic HCT for patients who lack an HLA-matched related or unrelated donor: haploidentical and umbilical cord blood HCT. Despite challenges, interventions are available to mitigate the risks during the immunocompromised period including antimicrobial prophylaxis, modified immune suppression strategies, graft manipulation, and emerging adoptive cell therapies. Such interventions can improve the potential for long-term overall survival after allogeneic HCT.
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Affiliation(s)
- Hany Elmariah
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Claudio G. Brunstein
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Nelli Bejanyan
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 33612, USA;
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Rambaldi B, Kim HT, Reynolds C, Chamling Rai S, Arihara Y, Kubo T, Buon L, Gooptu M, Koreth J, Cutler C, Nikiforow S, Ho VT, Alyea EP, Antin JH, Wu CJ, Soiffer RJ, Ritz J, Romee R. Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide. Blood Adv 2021; 5:352-364. [PMID: 33496734 PMCID: PMC7839379 DOI: 10.1182/bloodadvances.2020003005] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 11/25/2020] [Indexed: 12/18/2022] Open
Abstract
Administration of posttransplant cyclophosphamide (PTCy) has significantly expanded the number of patients undergoing HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). To examine immune reconstitution in these patients, we monitored T- and natural killer (NK)-cell recovery in 60 patients receiving bone marrow or peripheral blood stem cell (PBSC) grafts after haplo-HCT with PTCy and 35 patients receiving HLA-matched donor PBSC grafts with standard graft-versus-host disease (GVHD) prophylaxis. Compared with HLA-matched recipients, early T-cell recovery was delayed in haplo-HCT patients and skewed toward effector memory T cells with markedly reduced naive T cells. We found higher regulatory T (Treg)-cell/conventional T (Tcon)-cell ratios early after HCT and increased PD-1 expression on memory T cells. Within the haplo-HCT, patients who did not develop chronic GVHD (cGVHD) had higher PD-1 expression on central and effector memory CD4+ Treg cells at 1 month after transplant. These findings suggest an immunologic milieu that promotes immune tolerance in haplo-HCT patients. NK cells were decreased early after haplo-HCT with preferential expansion of immature CD56brightCD16- NK cells compared with matched donor transplants. One month after transplant, mass cytometry revealed enrichment of immature NK-cell metaclusters with high NKG2A, low CD57, and low killer-cell immunoglobulin-like receptor expression after haplo-HCT, which partially recovered 3 months post-HCT. At 2 months, immature NK cells from both groups were functionally impaired, but interleukin-15 priming corrected these defects in vitro. Increased immature/mature NK-cell ratios were associated with cytomegalovirus reactivation and increased incidence of cGVHD after haplo-HCT. These homeostatic imbalances in T- and NK-cell reconstitution after haplo-HCT reveal opportunities for early immune-based interventions to optimize clinical outcomes.
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Affiliation(s)
- Benedetta Rambaldi
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
- Clinical and Experimental Sciences Department, Bone Marrow Transplant Unit, ASST Spedali Civili, University of Pavia, Brescia, Italy
| | - Haesook T Kim
- Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA; and
| | - Carol Reynolds
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Sharmila Chamling Rai
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Yohei Arihara
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Tomohiro Kubo
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Leutz Buon
- Department of BioInformatics and Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Mahasweta Gooptu
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - John Koreth
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Corey Cutler
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Sarah Nikiforow
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Vincent T Ho
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Edwin P Alyea
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Joseph H Antin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Robert J Soiffer
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Jerome Ritz
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Rizwan Romee
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
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50
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Yu Q, Wang H, Zhang L, Wei W. Advances in the treatment of graft-versus-host disease with immunomodulatory cells. Int Immunopharmacol 2021; 92:107349. [PMID: 33486323 DOI: 10.1016/j.intimp.2020.107349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/14/2020] [Accepted: 12/24/2020] [Indexed: 12/19/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely used to treat hematological malignancies and genetic diseases. Graft-versus-host disease (GVHD) induced by donor immune system is the most common complication, contributing to severe morbidity and mortality after allo-HSCT. Currently, in terms of the prevention and treatment of GVHD, the major first-line therapeutic drugs are corticosteroids. However, most patients with systemic corticosteroid treatment are prone to steroid-refractory and poor prognosis. The use of several immune cells including Tregs, Bregs and mesenchymal stromal cells (MSCs) as an alternative on prevention or therapy of GVHD has been demonstrated to be beneficial. However, there are still many defects to a certain degree. Based on immune cells, it is promising to develop new and better approaches to improve GVHD. In this article, we will review the current advance of immune cells (Tregs, Bregs, MSCs) with negative regulation in the treatment of GVHD and present emerging strategies for the prevention and treatment of GVHD by other immune regulatory cells and chimeric antigen receptor (CAR) Tregs. In addition, these new therapeutic options need to be further evaluated in well-designed prospective multicenter trials to determine the optimal treatment for GVHD patients and improve their prognosis.
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Affiliation(s)
- Qianqian Yu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China
| | - Han Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China
| | - Lingling Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China.
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