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Bi S, Shen J, Zhu Y, Fan L, Ju H, Liu Y. DNA scaffold-framed natural killer cell with programmed drug release for chemo-adoptive cell therapy. J Control Release 2025; 382:113679. [PMID: 40180252 DOI: 10.1016/j.jconrel.2025.113679] [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: 12/15/2024] [Revised: 03/30/2025] [Accepted: 03/31/2025] [Indexed: 04/05/2025]
Abstract
Choosing appropriate delivery system for chemotherapeutic drugs as well as arranging the time spots for adoptive cells administrations is the key to achieve efficient combined chemo-adoptive cell therapy. Tumor-homing character makes adoptive immune cells appropriate targeting delivery carriers, but they are rarely used for chemtoxic payloads considering payloads internalization during administration which impairs adoptive cells. Herein, we frame adoptive NK cells using DNA scaffold with chemotherapeutic payloads fastened exterior, and achieves time-programmed drugs release and NK cell decapsulation to minimize side effects and enhance therapeutic effect. IL-21 nanoparticles are prepared by conjugating cytokine IL-21 with a GSH cleavable linker and act as anchor points for DNA scaffold assembly. Chemotherapeutic payloads are prepared by loading DOX/verapamil drugs to PLGA nanoparticles (PLGAdrugs NPs), and connected to the exterior of DNA scaffold with a ROS cleavable linker. Porous DNA scaffold protects NK cells functions from impairing by chemotherapeutic payloads, while guarantees efficient communication of NK cells with exterior environment to keep tumor homing capability. Reactive oxygen species (ROS) in tumor microenvironment releases PLGAdrugs NPs to perform chemotherapy, which subsequently generates a reductive environment to detach DNA scaffold for NK cell and IL-21 release to achieve combined chemo-adoptive cell therapy with enhanced therapeutic efficiency.
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Affiliation(s)
- Shiyi Bi
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Jieyu Shen
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Yu Zhu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Lei Fan
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing 210023, China
| | - Huangxian Ju
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Ying Liu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, China.
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2
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Markelov V, Arabuli KV, Gaponenko I, Sergeev V, Shakirova A, Lepik KV, Kulagin AD, Zyuzin MV. Scalable and ultrafast CAR-T cell production using microfluidics. LAB ON A CHIP 2025; 25:3005-3015. [PMID: 40396473 DOI: 10.1039/d5lc00139k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy has recently gained recognition as a transformative treatment of cancer, particularly of hematological malignancies. However, CAR-T manufacturing remains a major bottleneck of this treatment modality; in standard cases, it takes up to two weeks, resulting in a phenotypic shift toward terminally differentiated T-cells and a significant depletion of T-cells with naive-like phenotype (Tnlp), crucial for sustained clinical efficacy. Leveraging the current progress in microfluidic technologies, we develop and optimize a microfluidic device (MFD) for CAR-T cell production via an ultrafast protocol that integrates T-cell activation and lentiviral transduction in a single step within 24 hours. The MFD geometry allowed reaching a transduction rate of 27% (for MOI 3) compared to 17% and 8% transduction (MOI 3) in 48- and 6-well plates, respectively, used as controls. Notably, in the ultrafast protocol in our MFD, the amount of CD3+ Tnlp is approximately six times higher than that remaining after the standard 9 day protocol (18.07 ± 6.03% vs. 3.97 ± 2.37%). A similar pattern is noted for CD4+ and CD8+ Tnlp, with percentages of 11.07 ± 6.08% vs. 3.56 ± 3.52% and 29.2 ± 7.11% vs. 4.18 ± 1.69%, respectively, in the final CAR-T product. Our results highlight MFDs as a scalable platform to streamline CAR-T manufacturing, with the potential to improve clinical accessibility and outcomes by reducing the production time while preserving essential T-cell phenotypes.
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Affiliation(s)
- Vladislav Markelov
- RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russian Federation.
| | - Konstantin V Arabuli
- School of Physics and Engineering, ITMO University, 191002 St. Petersburg, Russia.
| | - Ivan Gaponenko
- RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russian Federation.
| | - Vladislav Sergeev
- RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russian Federation.
| | - Alena Shakirova
- RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russian Federation.
| | - Kirill V Lepik
- RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russian Federation.
| | - Alexander D Kulagin
- RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russian Federation.
| | - Mikhail V Zyuzin
- School of Physics and Engineering, ITMO University, 191002 St. Petersburg, Russia.
- Moscow Center for Advanced Studies, Kulakova str. 20, Moscow, Russia
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3
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Jain MD, Abramson JS, Ansell SM. Easy as ABC: Managing Toxicities of Antibody-Drug Conjugates, Bispecific Antibodies, and CAR T-Cell Therapies. Am Soc Clin Oncol Educ Book 2025; 45:e473916. [PMID: 40294348 DOI: 10.1200/edbk-25-473916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Antibody-drug conjugates (ADCs), bispecific antibodies that engage T cells (BsAbs), and chimeric antigen receptor (CAR) T cells are widely used standard-of-care therapies that have revolutionized the treatment of lymphoid and plasma cell malignancies. With recent regulatory approvals, these therapies are poised to also revolutionize the treatment of common solid tumors and become a part of the everyday lexicon, the ABCs, of the practicing oncologist. Drawing from experience in hematology, we review the early, late, and rare toxicities of ADCs, BsAbs, and CAR T cells and provide general principles for their management.
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4
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Zhou L, Feng Y, Hong R, Wei G, Zhang M, Chang AH, Huang H, Hu Y. Integrating genomic features for prognosis in Chinese patients with B-cell lymphoma following chimeric antigen receptor T-cell therapy. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1703-1713. [PMID: 40189492 DOI: 10.1007/s11427-024-2783-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/07/2024] [Indexed: 05/28/2025]
Abstract
Despite advancements in CAR-T therapy, over half of the lymphoma patients still face drug resistance or relapse. Seventy-nine Chinese patients with B-cell lymphoma provided 192 serum samples for circulating tumor DNA (ctDNA) detection to identify the genomic features linked to prognosis during CAR-T cell therapy. Patients in complete remission and noncomplete remission groups were analyzed, and those with >10 ctDNA gene mutations before CAR-T cell therapy had significantly worse overall survival and progression-free survival rates than those with fewer mutations. MYD88, FAT1, and BTG2 mutations were correlated with poorer OS, whereas MUC16 mutations were correlated with better OS. Patients with TP53 mutation pretreatment had significantly lower CR rates than those without TP53 mutations (33.3% vs. 68.1%, P=0.02). However, TP53 mutation pretreatment did not affect long-term patient survival. All patients with TP53 mutations 4 weeks after CAR-T cell therapy failed to achieve CR, with poorer OS (1-year OS rate: 37.5% vs. 66.4%; 2-year OS rate: 12.5% vs. 56.3%, P=0.0023). Among patients with CR, those with BCR mutations at 4 weeks post-treatment exhibited poorer OS (2-year OS rate: 40.9% vs. 76.1%, P=0.035). One week after CAR-T cell therapy, patients without CDKN2A, CBLB, APC, SPEN, KMT2D, CARD11, FOXO1, or PDGFRB mutations were more likely to achieve CR (76.6% vs. 28.6%, P<0.001) and had better OS (1-year OS rate: 81.5% vs. 38.9%, 2-year OS rate: 62.2% vs. 5%, P<0.001) and PFS (1-year PFS rate: 67.2% vs. 0%, P<0.001). This study evaluated the genomic features and screened a gene set to predict CAR-T cell therapy efficacy in B-cell lymphoma, aiding clinicians in accurately evaluating efficacy and treatment decision-making.
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Affiliation(s)
- Linghui Zhou
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China
- Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, 310000, China
| | - Youqin Feng
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China
- Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, 310000, China
| | - Ruimin Hong
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China
- Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, 310000, China
| | - Guoqing Wei
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China
- Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, 310000, China
| | - Mingming Zhang
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China
- Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, 310000, China
| | - Alex H Chang
- Shanghai YaKe Biotechnology Ltd., Shanghai, 200438, China.
- Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200000, China.
| | - He Huang
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, 310000, China.
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China.
- Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, 310000, China.
| | - Yongxian Hu
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, 310000, China.
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China.
- Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, 310000, China.
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5
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O'Shea PJ, Johnson PC, El-Jawahri A, Leblanc TW. Unmet needs and lived experience of patients receiving CAR T-cell therapy. Leuk Lymphoma 2025; 66:1010-1020. [PMID: 39838695 DOI: 10.1080/10428194.2025.2455488] [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: 09/03/2024] [Revised: 12/16/2024] [Accepted: 01/14/2025] [Indexed: 01/23/2025]
Abstract
Chimeric Antigen Receptor T-Cell (CAR-T) therapy is an effective therapy and promising frontier in the treatment of hematologic malignancies. However, this revolutionary treatment has led to new challenges for patients, caregivers, and the healthcare system. In this review article, we discuss the various difficulties patients face both in the acute and long-term period following CAR-T infusion. We highlight the various ways these difficulties are addressed, as well as further areas of research and support needed to improve patient experience. Additionally, we consider the difficulties and burdens placed on caregivers and healthcare systems, as well as barriers to accessing CAR-T therapy. Finally, we address future directions of research and intervention development to meet patient and caregiver needs and improve equitable access. We pose early integration of specialty palliative care for individuals and their caregivers undergoing CAR-T therapy as one promising strategy to help improve patient experience and meet their needs.
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Affiliation(s)
- Patrick J O'Shea
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Patrick Connor Johnson
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Areej El-Jawahri
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Thomas W Leblanc
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Durham, NC, USA
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6
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Franco-Fuquen P, Figueroa-Aguirre J, Martínez DA, Moreno-Cortes EF, Garcia-Robledo JE, Vargas-Cely F, Castro-Martínez DA, Almaini M, Castro JE. Cellular therapies in rheumatic and musculoskeletal diseases. J Transl Autoimmun 2025; 10:100264. [PMID: 39931050 PMCID: PMC11808717 DOI: 10.1016/j.jtauto.2024.100264] [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: 10/29/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 02/13/2025] Open
Abstract
A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab. A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies. This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.
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Affiliation(s)
- Pedro Franco-Fuquen
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juana Figueroa-Aguirre
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - David A. Martínez
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Eider F. Moreno-Cortes
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juan E. Garcia-Robledo
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Fabio Vargas-Cely
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | | | - Mustafa Almaini
- Rheumatology, Allergy & Clinical Immunology Division, Mafraq Hospital, United Arab Emirates
| | - Januario E. Castro
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
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7
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Liu WH, Globerson Levin A, Lask A, Horn G, Waks T, Nathansohn Levi B, Milman Krentsis I, Shoshan E, Su X, Mamonkin M, Champlin RE, Reisner Y, Bachar Lustig E. Anti-viral CD8 central memory veto cells as a new platform for CAR T cell therapy. Stem Cells Transl Med 2025; 14:szaf020. [PMID: 40448965 DOI: 10.1093/stcltm/szaf020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 04/17/2025] [Indexed: 06/02/2025] Open
Abstract
Central memory CD8 T cells exhibit marked veto activity enhancing engraftment in several mouse models of T cell-depleted bone marrow (TDBM) allografting. Graft-versus-host disease (GVHD) can be prevented by stimulation of mouse or human memory CD8 T cells against their cognate antigens under cytokine deprivation, in the early phase of culture followed by further expansion with IL21, IL15, and IL7. Thus, human anti-viral CD8 central memory veto T cells generated from CMV and EBV-positive donors are currently evaluated in a clinical trial at MD Anderson Cancer Centre (MDACC). Results in 15 patients indicate a low risk of GVHD. Considering that these cells could offer an attractive platform for CAR cell therapy, we evaluated methodologies for their effective transduction with 2 retroviral vectors. Initially, a vector directed against Her2 was tested and optimal transduction was attained at day 5 of culture. The transduced cells were expanded for an additional 7 days and exhibited marked anti-tumor reactivity ex-vivo while retaining their veto activity. Transduction with a vector directed at CD19 was effectively attained at days 4-5 allowing for substantial harvest of transduced cells at day 12 of culture. These Veto-CD19CAR central memory CD8 T cells exhibited marked anti-tumor reactivity in-vitro and in-vivo without GVHD, measured following transplantation into immune-deficient mice. These results strongly suggest that Veto-CAR T cells offer an attractive platform for CAR T cell therapy without gene editing for addressing the risk of GVHD or graft rejection.
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Affiliation(s)
- Wei-Hsin Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
- University of Texas MD Anderson UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, United States
| | - Anat Globerson Levin
- Immunology and advanced CAR-T cell therapy laboratory, Research & Development Department, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Dotan Center for Advanced Therapies, Tel-Aviv Sourasky Medical Center and Tel Aviv University, Tel Aviv 6423906, Israel
| | - Assaf Lask
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Galit Horn
- Immunology and advanced CAR-T cell therapy laboratory, Research & Development Department, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Dotan Center for Advanced Therapies, Tel-Aviv Sourasky Medical Center and Tel Aviv University, Tel Aviv 6423906, Israel
| | - Tova Waks
- Immunology and advanced CAR-T cell therapy laboratory, Research & Development Department, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Dotan Center for Advanced Therapies, Tel-Aviv Sourasky Medical Center and Tel Aviv University, Tel Aviv 6423906, Israel
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Bar Nathansohn Levi
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Irit Milman Krentsis
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Einav Shoshan
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Xiaohua Su
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Maksim Mamonkin
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX,77030, United States
| | - Richard E Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Yair Reisner
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Esther Bachar Lustig
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
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8
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Gu J, Li J, Xu Y, Zhang G, Xie J, Jia R, Chen W, Lu Z, Chang C, Wen H, Chang LJ, Ma H, Cai Q. Preliminary exploration of PSMA CAR-T combined with GD2 CAR-T for the treatment of refractory/relapsed gliomas. J Transl Med 2025; 23:591. [PMID: 40420236 DOI: 10.1186/s12967-025-06523-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 04/21/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND This study aimed to investigate the safety and efficacy of fourth-generation combined PSMA and GD2-targeted chimeric antigen receptor (CAR)-T cells in the treatment of refractory/relapsed gliomas. METHOD This study employed a single-arm design, enrolling patients with confirmed refractory/relapsed gliomas at the Immuno-oncology Department of the Cancer Center at Clifford Hospital in Guangdong. Eligible patients received combined treatment with PSMA CAR-T and GD2 CAR-T cells via intravenous administration. The dose of reinfused CAR-T cells ranged from 1-5 × 10^6 cells/kg of body weight. RESULTS Six patients were included in the study, all of whom responded to the treatment. The overall response rate (ORR) was 50%, with three patients achieving complete response (CR) (50%) and three demonstrating stable disease (SD) (50%). The median progression-free survival (PFS) was 9.0 months (range, 1-56 months), and the median overall survival (OS) was 24.5 months (range, 13-63 months). Three patients (50%) developed cytokine release syndrome (CRS), all of which were classified as grade I CRS, and no patients experienced immune effector cell-associated neurotoxicity Syndrome (ICANS). CONCLUSION Combined PSMA CAR-T and GD2 CAR-T cell therapy demonstrated significant efficacy and good tolerability in the treatment of refractory/relapsed gliomas, without severe adverse reactions.
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Affiliation(s)
- Jinshan Gu
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Jiasheng Li
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Yang Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Ge Zhang
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Jingyi Xie
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Rui Jia
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Wei Chen
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Zhengfeng Lu
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China
| | - Chengwei Chang
- Shenzhen Geno-Immune Medical Institute, Shenzhen, Guangdong, China
| | - Haijun Wen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Lung-Ji Chang
- Shenzhen Geno-Immune Medical Institute, Shenzhen, Guangdong, China.
| | - Huajuan Ma
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China.
| | - Qichun Cai
- Immuno-oncology department of the cancer center, 21 st Floor, Building 2, Guangdong Clifford Hospital, Hongfu Road, Panyu District, Guangzhou, 511400, China.
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9
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Pinto IS, Cordeiro RA, Oliveira ASR, Serra AC, Coelho JFJ, Faneca H. Polymer-Based DNA Delivery Nanoplatforms for Chimeric Antigen Receptor T Cells Engineering. Biomacromolecules 2025. [PMID: 40421765 DOI: 10.1021/acs.biomac.5c00208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2025]
Abstract
Although chimeric antigen receptor (CAR) T cell therapy represents a groundbreaking advancement in cancer treatment, its widespread application is hindered by high costs and complex protocols associated with the current gene delivery systems used for CAR T cell production. This study introduces an innovative, cost-effective, nonviral polymeric nanosystem for ex vivo delivery of a leukemia-targeting anti-CD19 CAR gene (used as a model) to T cells. Using cationic polymers, specifically poly[(2-dimethylamino)ethyl methacrylate] (PDMAEMA) and poly(β-amino ester) (PβAE), we developed various formulations through straightforward processes. Notably, star-shaped PDMAEMA/PβAE-based polyplexes exhibit favorable physicochemical properties as gene delivery platforms and demonstrate remarkable efficiency in CAR gene delivery with minimal toxicity due to enhanced internalization and effective endosomal escape. Our best nanosystem formulation successfully generated CAR T cells that effectively target and induce leukemia cell death. Overall, this approach simplifies manufacturing and reduces costs of CAR T cell engineering, paving the way for more accessible and effective cell therapies against cancer.
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Affiliation(s)
- Inês S Pinto
- Institute for Interdisciplinary Research, Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra 3004-504, Portugal
- CNC-UC─Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal
- Institute of Interdisciplinary Research (III), University of Coimbra, Casa Costa Alemão─Polo II, Coimbra 3030-789, Portugal
| | - Rosemeyre A Cordeiro
- CNC-UC─Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal
- Institute of Interdisciplinary Research (III), University of Coimbra, Casa Costa Alemão─Polo II, Coimbra 3030-789, Portugal
| | - Andreia S R Oliveira
- Department of Chemical Engineering, University of Coimbra, Centre for Mechanical Engineering, Materials and Processes, Rua Sílvio Lima-Polo II, Coimbra 3030-790, Portugal
| | - Arménio C Serra
- Department of Chemical Engineering, University of Coimbra, Centre for Mechanical Engineering, Materials and Processes, Rua Sílvio Lima-Polo II, Coimbra 3030-790, Portugal
| | - Jorge F J Coelho
- Department of Chemical Engineering, University of Coimbra, Centre for Mechanical Engineering, Materials and Processes, Rua Sílvio Lima-Polo II, Coimbra 3030-790, Portugal
- IPN─Instituto Pedro Nunes, Associação para a Inovação e Desenvolvimento em Ciência e Tecnologia, Coimbra 3030-199, Portugal
| | - Henrique Faneca
- CNC-UC─Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal
- Institute of Interdisciplinary Research (III), University of Coimbra, Casa Costa Alemão─Polo II, Coimbra 3030-789, Portugal
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10
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Kaestner V, Haslam A, Prasad V. Characterization of bridging therapies in clinical trials leading to FDA approval of CAR-T cell therapies. Int J Cancer 2025. [PMID: 40394455 DOI: 10.1002/ijc.35473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/04/2025] [Accepted: 04/24/2025] [Indexed: 05/22/2025]
Abstract
During the time of chimeric antigen receptor T-cell (CAR-T) manufacturing, bridging therapy is often used to control disease. Because it often involves systemic treatment, the bridging therapies can induce responses and/or adverse events. We sought to assess bridging therapies used in CAR-T trials in a cross-sectional study. We reviewed FDA drug labels and peer-reviewed registration trial reports (including supplemental data) to evaluate the characteristics of bridging therapy used in trials testing CAR-T therapies. We looked at which bridging therapies were used, whether multiple therapies were combined, the response rates, and the reported adverse events associated with bridging therapy. Of the 11 studies testing CAR-T therapies, 10 reported the bridging therapies that were used in the study. Of those that reported the types of bridging therapies (n = 10), the most commonly used bridging therapy was dexamethasone (10/10, 100%), rituximab (6/10, 60%), gemcitabine (5/10, 50%), and etoposide (5/10, 50%). Of the trials, one of 11 (9%) clearly reported whether patients had responses to bridging therapy, six of 11 (55%) vaguely reported responses, and four of 11 (36%) trials did not report or mention any response information regarding bridging therapy. Although patients are often refractory to first-line therapies, which share considerable overlap with bridging therapies, these therapies may induce responses. Despite this possibility, the reporting of bridging therapy combinations and their subsequent response rates and adverse event rates are highly variable. These findings highlight the need for greater transparency in the reporting of bridging therapy to more reliably assess the efficacy of CAR-T therapies.
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Affiliation(s)
- Victoria Kaestner
- Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Alyson Haslam
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
| | - Vinay Prasad
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
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11
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Long AH, Aftandilian C, Barmettler S, Alexander S. Hypogammaglobulinemia in Children Receiving Targeted Immunotherapies for B Lineage Malignancies: Practical Guidance for Assessment and Management. Pediatr Blood Cancer 2025:e31779. [PMID: 40372257 DOI: 10.1002/pbc.31779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/21/2025] [Accepted: 04/24/2025] [Indexed: 05/16/2025]
Abstract
Hypogammaglobulinemia is a well-defined risk factor for infection. B-cell-directed immunotherapies given in addition to conventional chemotherapy are now core elements of effective therapy for children with B lymphoid malignancies. These therapies are associated with depletion of normal B cells and consequent hypogammaglobulinemia. This review summarizes the current state of knowledge regarding the mechanism, incidence, and clinical outcomes related to hypogammaglobulinemia in children with mature B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, as well as provides practical guidance for laboratory monitoring and considerations for immunoglobulin replacement therapy.
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Affiliation(s)
- Adrienne H Long
- Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Catherine Aftandilian
- Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Sara Barmettler
- Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sarah Alexander
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
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12
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Song KW, Lim M, Monje M. Complex neural-immune interactions shape glioma immunotherapy. Immunity 2025; 58:1140-1160. [PMID: 40324379 DOI: 10.1016/j.immuni.2025.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 05/07/2025]
Abstract
Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS "immune privilege," it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence immunotherapy approaches for CNS cancers. Challenges include immune-suppressive and neurotoxicity-promoting crosstalk between brain, immune, and tumor cells. Developing effective immunotherapies for cancers of the nervous system will require a deeper understanding of these neural-immune-malignant cell interactions. Here, we review progress and challenges in immunotherapy for gliomas of the brain and spinal cord in light of these unique neural-immune interactions and highlight future work needed to optimize promising immunotherapies for gliomas.
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Affiliation(s)
- Kun-Wei Song
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA
| | - Michael Lim
- Department of Neurosurgery, Stanford University, Palo Alto, CA, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA; Department of Neurosurgery, Stanford University, Palo Alto, CA, USA; Howard Hughes Medical Institute, Stanford University, Palo Alto, CA, USA.
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13
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Zang SS, Zhang R, Zhang JR, Zhang X, Li J. Progress, Applications and Prospects of CRISPR-Based Genome Editing Technology in Gene Therapy for Cancer and Sickle Cell Disease. Hum Gene Ther 2025. [PMID: 40351170 DOI: 10.1089/hum.2024.262] [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: 05/14/2025] Open
Abstract
The advent of genome-editing technologies, particularly the RNA-guided the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas) 9, which originates from prokaryotic CRISPR/Cas adaptive immune mechanisms, has revolutionized molecular biology. Renowned for its simplicity, cost-effectiveness, and capacity for multiplexed gene editing, CRISPR/Cas9 has emerged as the most versatile and widely adopted genome-editing platform. Its applications span fundamental research, biotechnology, medicine, and therapeutics. This review highlights recent advancements in CRISPR-based technologies, focusing on CRISPR/Cas9, CRISPR/Cas12a, and CRISPR/Cas12f. It emphasizes precision editing methods like base editing and prime editing, which enable targeted nucleotide changes without double-strand breaks. The specificity of these tools, including on-target accuracy and off-target risks, is critically evaluated. Additionally, recent preclinical and clinical efforts to treat diseases such as cancer and sickle cell disease using CRISPR are summarized. Finally, the challenges and future directions of CRISPR-mediated gene therapy are discussed, emphasizing its potential to integrate with other molecular approaches to address unmet medical needs.
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Affiliation(s)
- Sha-Sha Zang
- Department of Geriatric Medicine, Affiliated Hospital of Hebei University, Baoding, China
| | - Ruirui Zhang
- Department of Employee Health Care, West China Hospital, Sichuan University, Chengdu, China
| | - Jia-Run Zhang
- Putian University School of Basic Medicine, Putian, China
| | - Xi Zhang
- Department of Comprehensive Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Li
- College of Life Sciences, Hebei Agricultural University, Baoding, China
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14
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Zhang Z, Zheng J, Liang Y, Wu Q, Ding C, Ma L, Su L. Hematologic and lymphatic disorders associated with chimeric antigen receptor T-cell therapy: a pharmacovigilance analysis of the FDA adverse event reporting system (FAERS) database. BMC Cancer 2025; 25:846. [PMID: 40346502 PMCID: PMC12063233 DOI: 10.1186/s12885-025-14227-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 04/25/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND As the application of Chimeric Antigen Receptor T-cell (CAR-T) therapy in cancer treatment becomes increasingly widespread, associated hematologic and lymphatic system adverse events pose significant challenges to its clinical use. Therefore, we aim to comprehensively investigate and summarize the hematologic and lymphatic system AEs associated with CAR-T therapy. METHODS We extracted CAR-T-related adverse event reports from the FDA Adverse Event Reporting System (FAERS) database for the period from August 2017 to December 2023. Disproportionality analysis using the Reporting Odds Ratio (ROR) and Information Component (IC) was performed to identify CAR-T-associated hematologic and lymphatic system AEs. We employed LASSO regression analysis to identify hematologic and lymphatic system AEs associated with mortality. RESULTS In the FAERS database, we identified 1,600 individual case safety reports of hematologic and lymphatic system AEs related to CAR-T therapy. The median age of patients was 57 years (interquartile range [IQR] 32-67), with fatal outcomes in 15.3% of cases. We identified 25 significant adverse event signals associated with CAR-T therapy. B-cell aplasia (ROR025 = 1054.56, IC025 = 4.74), cytopenia (ROR025 = 17.27, IC025 = 3.81), hypofibrinogenemia (ROR025 = 100.18, IC025 = 2.46), anemia (ROR025 = 1.87, IC025 = 0.59), febrile bone marrow aplasia (ROR025 = 55.32, IC025 = 2.70), and pancytopenia (ROR025 = 7.18, IC025 = 1.42) were the most significant hematologic and lymphatic system AEs for tisa-cel, axi-cel, brexu-cel, liso-cel, ide-cel, and cilta-cel, respectively. Most hematologic and lymphatic system AEs occurred within 10 days post-CAR-T infusion. Hematologic and lymphatic system AEs were associated with a mortality rate of 15.3%. Our analysis revealed 15 hematologic and lymphatic system AEs closely associated with mortality in CAR-T-treated patients, including splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia. CONCLUSIONS Our study found that hematologic and lymphatic system AEs were more closely associated with anti-CD19 CAR-T and CAR-T containing CD28. Splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia were identified as hematologic and lymphatic system AEs that, while less frequently reported clinically, were highly associated with mortality.
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Affiliation(s)
- Zhenpo Zhang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Jingping Zheng
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Yankun Liang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Qimin Wu
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Chufeng Ding
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Lin Ma
- School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China.
- Medical Department, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, China.
| | - Ling Su
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China.
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15
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Huang Y, Gong Y, Liu X, Ruan H, Lu J, Kouros-Mehr H, Liu H, Wang H. Case Report: Bispecific CD20/CD30-targeted chimeric antigen receptor T-cell therapy for non-Hodgkin's lymphoma. Front Immunol 2025; 16:1567149. [PMID: 40406106 PMCID: PMC12096171 DOI: 10.3389/fimmu.2025.1567149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 04/14/2025] [Indexed: 05/26/2025] Open
Abstract
CD19-directed CAR T-cell therapy is a breakthrough immunotherapy for B-cell malignancies. However, CD19 loss-mediated relapsed/refractory disease continues to pose a significant challenge, highlighting the urgent need for CAR T cells targeting alternative antigens. To address this issue, we developed a CD20-directed CAR T incorporated with an additional CD30-directed binder to enhance cytotoxicity toward cancer cells. Here, we report that a patient with bulky transformed follicular lymphoma was successfully treated with CD20/CD30-directed CAR-T cells. The patient received two doses of anti-CD20/CD30-CAR-T therapy administered one month apart. Complete metabolic remission was achieved 1 month after the first infusion without evidence of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). The second dose was given as a consolidation therapy with sustained disease-free survival exceeding 12 months to date. The report underscores the promising therapeutic potential and safety profile of CD20/CD30-directed CAR T-cell therapy. Clinical Trial Registration https://www.clinicaltrials.gov, identifier NCT06756321.
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Affiliation(s)
- Yuejiao Huang
- Department of Hematology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yiming Gong
- TriArm Therapeutics (Shanghai), Shanghai, China
| | - Xiang Liu
- TriArm Therapeutics (Shanghai), Shanghai, China
| | - Huaying Ruan
- Shanghai First Song Therapeutics, Shanghai, China
| | - Jinhua Lu
- TriArm Therapeutics (Shanghai), Shanghai, China
| | | | - Hong Liu
- Department of Hematology, Affiliated Hospital of Nantong University, Nantong, China
| | - Han Wang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China
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16
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Svoboda J, Landsburg DJ, Gerson J, Nasta SD, Barta SK, Chong EA, Cook M, Frey NV, Shea J, Cervini A, Marshall A, Four M, Davis MM, Jadlowsky JK, Chew A, Pequignot E, Gonzalez V, Noll JH, Paruzzo L, Rojas-Levine J, Plesa G, Scholler J, Siegel DL, Levine BL, Porter DL, Ghassemi S, Ruella M, Rech A, Leskowitz RM, Fraietta JA, Hwang WT, Hexner E, Schuster SJ, June CH. Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure. N Engl J Med 2025; 392:1824-1835. [PMID: 40334157 DOI: 10.1056/nejmoa2408771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not have long-term remission. We designed an anti-CD19 enhanced (armored) CAR T-cell product (huCART19-IL18) that secretes interleukin-18 to enhance antitumor activity. METHODS In this study, we assessed the safety, feasibility, and preliminary efficacy of huCART19-IL18 in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy. Using a 3-day manufacturing process, we administered huCART19-IL18-positive cells in doses ranging from 3×106 to 3×108. RESULTS A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and immune effector-cell-associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed. Robust CAR T-cell expansion was detected across all dose levels. At 3 months after infusion, a complete or partial response was seen in 81% of the patients (90% confidence interval [CI], 62 to 93) and a complete response in 52% (90% CI, 33 to 71). With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI, 5.5 to not reached). CONCLUSIONS In this small study, huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments and showed promising efficacy at low cell doses in patients with lymphoma after the failure of previous anti-CD19 CAR T-cell therapy. (ClinicalTrials.gov number, NCT04684563.).
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Affiliation(s)
- Jakub Svoboda
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Daniel J Landsburg
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - James Gerson
- University of Vermont Medical Center, Burlington
| | - Sunita D Nasta
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Stefan K Barta
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Elise A Chong
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Michael Cook
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Noelle V Frey
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Joanne Shea
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Amanda Cervini
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Amy Marshall
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Megan Four
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Megan M Davis
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Julie K Jadlowsky
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Anne Chew
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Edward Pequignot
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Vanessa Gonzalez
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Julia Han Noll
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Luca Paruzzo
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Juliana Rojas-Levine
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Gabriela Plesa
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - John Scholler
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Donald L Siegel
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Bruce L Levine
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - David L Porter
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Saba Ghassemi
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Marco Ruella
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Andrew Rech
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Rachel M Leskowitz
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Joseph A Fraietta
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia
| | - Elizabeth Hexner
- Cell Therapy and Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Stephen J Schuster
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Carl H June
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia
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17
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Patel KK, Tariveranmoshabad M, Kadu S, Shobaki N, June C. From concept to cure: The evolution of CAR-T cell therapy. Mol Ther 2025; 33:2123-2140. [PMID: 40070120 DOI: 10.1016/j.ymthe.2025.03.005] [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: 01/28/2025] [Revised: 03/04/2025] [Accepted: 03/05/2025] [Indexed: 03/21/2025] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer immunotherapy in the 21st century, providing innovative solutions and life-saving therapies for previously untreatable diseases. This approach has shown remarkable success in treating various hematological malignancies and is now expanding into clinical trials for solid tumors, such as prostate cancer and glioblastoma, as well as infectious and autoimmune diseases. CAR-T cell therapy involves harvesting a patient's T cells, genetically engineering them with viral vectors to express CARs targeting specific antigens and reinfusing the modified cells into the patient. These CAR-T cells function independently of major histocompatibility complex (MHC) antigen presentation, selectively identifying and eliminating target cells. This review highlights the key milestones in CAR-T cell evolution, from its invention to its clinical applications. It outlines the historical timeline leading to the invention of CAR-T cells, discusses the major achievements that have transformed them into a breakthrough therapy, and addresses remaining challenges, including high manufacturing costs, limited accessibility, and toxicity issues such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Additionally, the review explores future directions and advances in the field, such as developing next-generation CAR-T cells aiming to maximize efficacy, minimize toxicity, and broaden therapeutic applications.
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MESH Headings
- Humans
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Immunotherapy, Adoptive/trends
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- Neoplasms/therapy
- Neoplasms/immunology
- Animals
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Affiliation(s)
- Kisha K Patel
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mito Tariveranmoshabad
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Siddhant Kadu
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nour Shobaki
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Carl June
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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18
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Liebers N, Boumendil A, Finel H, Edelmann D, Kobbe G, Baermann BN, Serroukh Y, Blaise D, Beelen DW, Solano C, Itälä-Remes M, van Meerten T, Choi G, Schmidt SAC, Kröger N, Byrne J, Tudesq JJ, Ossami Saidy A, Nunes A, Siddiqi R, Baro E, Zheng D, Kloos I, Dreger P, Sureda A, Glass B, Dietrich S. Brexucabtagene Autoleucel versus Allogeneic Hematopoietic Cell Transplantation in Relapsed and Refractory Mantle Cell Lymphoma. Blood Cancer Discov 2025; 6:182-190. [PMID: 39913291 PMCID: PMC12050943 DOI: 10.1158/2643-3230.bcd-24-0178] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 10/27/2024] [Accepted: 02/04/2025] [Indexed: 05/06/2025] Open
Abstract
SIGNIFICANCE Patients aged ≥50 years with r/r MCL had superior OS and lower nonrelapse mortality 1 year after receiving brexu-cel compared with alloHCT. However, the long-term PFS and OS are similar for both treatments. Individual risk-benefit evaluation is essential to guide optimal treatment decisions.
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Affiliation(s)
- Nora Liebers
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Duesseldorf, Germany
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Aachen Bonn Cologne Düsseldorf, Cologne, Germany
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Ariane Boumendil
- Lymphoma Working Party, European Society for Blood and Marrow Transplantation, Paris, France
| | - Hervé Finel
- Lymphoma Working Party, European Society for Blood and Marrow Transplantation, Paris, France
| | - Dominic Edelmann
- Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
| | - Guido Kobbe
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Duesseldorf, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Aachen Bonn Cologne Düsseldorf, Cologne, Germany
| | - Ben-Niklas Baermann
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Duesseldorf, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Aachen Bonn Cologne Düsseldorf, Cologne, Germany
| | - Yasmina Serroukh
- Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | | | - Carlos Solano
- Hospital Clinico Universitario-INCLIVA, University of Valencia, Valencia, Spain
| | | | - Tom van Meerten
- University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Goda Choi
- University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Susanne Anna Christine Schmidt
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Duesseldorf, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Aachen Bonn Cologne Düsseldorf, Cologne, Germany
| | | | - Jenny Byrne
- Nottingham University, Nottingham, United Kingdom
| | | | - Anna Ossami Saidy
- Department of Hematology, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Ana Nunes
- Kite, a Gilead Company, Santa Monica, California
| | | | - Elande Baro
- Kite, a Gilead Company, Santa Monica, California
| | - Dan Zheng
- Kite, a Gilead Company, Santa Monica, California
| | - Ioana Kloos
- Kite, a Gilead Company, Santa Monica, California
| | - Peter Dreger
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Lymphoma Working Party, European Society for Blood and Marrow Transplantation, Paris, France
| | - Anna Sureda
- Lymphoma Working Party, European Society for Blood and Marrow Transplantation, Paris, France
- Clinical Hematology Department, Institut Català d’Oncologia-L’Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
| | - Bertram Glass
- Lymphoma Working Party, European Society for Blood and Marrow Transplantation, Paris, France
- Department of Hematology, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Sascha Dietrich
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Duesseldorf, Germany
- Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Aachen Bonn Cologne Düsseldorf, Cologne, Germany
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
- Lymphoma Working Party, European Society for Blood and Marrow Transplantation, Paris, France
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19
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Ouyang Z, Zeng R, Wang S, Wu X, Li Y, He Y, Wang C, Xia C, Ou Q, Bao H, Yang W, Xiao L, Zhou H. Genomic signatures in plasma circulating tumor DNA reveal treatment response and prognostic insights in mantel cell lymphoma. Cancer Cell Int 2025; 25:172. [PMID: 40319323 PMCID: PMC12049778 DOI: 10.1186/s12935-025-03789-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 04/12/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin's lymphoma. The applicability of circulating tumor DNA (ctDNA) for predicting treatment response and prognosis in MCL remains underexplored. METHODS This study included 34 MCL patients receiving first-line chemoimmunotherapy. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a noninvasive biomarker for treatment response and prognosis in MCL. RESULTS Commonly mutated genes in MCL included CCND1 (93.5%), ATM (48.4%), KMT2D (25.8%), and TP53 (25.8%). Subgroup analysis of tissue samples showed that CDKN2A mutations (P = 0.028), along with alterations in BCR and TCR signaling (P = 0.004) and the PI3K pathway (P = 0.008), were enriched in the blastoid subtype. ATM mutations (P = 0.041) were more prevalent in MIPI-low patients, while epigenetic chromatin remodeling pathway alterations (P = 0.028) were more common in MIPI-high patients. Plasma ctDNA demonstrated high sensitivity for detecting structural variants (96.6%), followed by mutations (71.3%) and copy number variants (30.0%). 75% of patients exhibited moderate-to-high concordance in detecting genomic variants between plasma and tissue samples. Pretreatment ctDNA levels exhibited high specificity in predicting clinical efficacy but had a suboptimal sensitivity of 68.2%. Higher ctDNA levels were significantly associated with shorter progression-free survival (PFS; P = 0.002) and overall survival (OS; P = 0.009). Additional ctDNA-based genetic features associated with shorter PFS included TP53 (P = 0.002), TRAF2 (P = 0.023), and SMARCA4 (P = 0.023) mutations, while TP53 (P = 0.006) and TERT (P = 0.031) mutations predicted shorter OS. Persistent positive ctDNA in post-treatment plasma samples indicated molecular relapse and poor prognosis, whereas undetectable ctDNA defined a subset of patients with favorable survival outcomes. CONCLUSIONS This study identified plasma ctDNA as a promising biomarker that noninvasively captures tumor-derived genetic variants associated with treatment response and survival outcomes in MCL, highlighting the clinical value of ctDNA for diagnosis, recurrence prediction, and surveillance monitoring.
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Affiliation(s)
- Zhou Ouyang
- Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, China
| | - Ruolan Zeng
- Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, China
| | - Song Wang
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, 210032, Jiangsu, China
| | - Xiaoying Wu
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, 210032, Jiangsu, China
| | - Yajun Li
- Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, China
| | - Yizi He
- Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, China
| | - Caiqin Wang
- Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, China
| | - Chen Xia
- Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, China
| | - Qiuxiang Ou
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, 210032, Jiangsu, China
| | - Hua Bao
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, 210032, Jiangsu, China
| | - Wei Yang
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, 210032, Jiangsu, China
| | - Ling Xiao
- Department of Histology and Embryology, School of Basic Medical Science, Central South University, Changsha, 410013, Hunan, China.
| | - Hui Zhou
- Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, China.
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20
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Yan S, Zhou M, Zhu X, Xiao Y. Neurological complications associated with chimeric antigen receptor T cell therapy. J Cereb Blood Flow Metab 2025:271678X251332492. [PMID: 40314208 PMCID: PMC12048402 DOI: 10.1177/0271678x251332492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/20/2025] [Accepted: 03/14/2025] [Indexed: 05/03/2025]
Abstract
Chimeric antigen receptor T (CAR-T) cells have made brilliant achievements in the treatment of many kinds of malignant tumors, and six kinds of CAR-T products have been approved by the Food and Drug Administration (FDA), bringing new hope for the treatment of diseases. However, the complications associated with CAR-T cell therapy should not be ignored. Neurological complications often jeopardize patients' lives, including immune effector cell-associated neurotoxicity syndrome, cerebrovascular accidents, movement and neurocognitive treatment-emergent adverse events. The current knowledge of the mechanism and treatment of these complications is still insufficient, which is a direction that needs to be solved in the future.
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Affiliation(s)
| | | | - Xiaojian Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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21
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Mamo T, Meulners L, Johnson A, Thibodeaux S, McKenna D. Apheresis collection parameters for approved CAR T-cell products need to be standardized. Transfusion 2025; 65:1021-1025. [PMID: 40191912 DOI: 10.1111/trf.18216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 05/21/2025]
Affiliation(s)
- Theodros Mamo
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Linda Meulners
- M Health Fairview University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - Andrew Johnson
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Suzanne Thibodeaux
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - David McKenna
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
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22
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Wang J, Chen Q, Shan Q, Liang T, Forde P, Zheng L. Clinical development of immuno-oncology therapeutics. Cancer Lett 2025; 617:217616. [PMID: 40054657 PMCID: PMC11930610 DOI: 10.1016/j.canlet.2025.217616] [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: 11/05/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.
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Affiliation(s)
- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qiang Shan
- Department of General Surgery, Haining People's Hospital, Haining, 314400, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Patrick Forde
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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23
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Weiss JM, Phillips TJ. SOHO State of the Art Updates and Next Questions | The Current State of CAR T-Cell Therapy and Bispecific Antibodies in Mantle Cell Lymphoma. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025; 25:304-308. [PMID: 39523133 DOI: 10.1016/j.clml.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
MCL remains incurable, and patients who relapse post BTK inhibitors have poor outcomes. BsAbs and CAR T cell therapy are novel strategies to treat patients with R/R MCL. These therapies exhibit favorable outcomes and side effect profiles in a previously dismal space. This review looks to detail the current data available for BsAbs and CAR T cell therapy in R/R MCL, and how are current treatment paradigm is shifting to incorporate these novel agents.
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Affiliation(s)
- Jonathan M Weiss
- Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
| | - Tycel J Phillips
- Department of Hematology and Hematopoietic Cell Transplantation, Division of Lymphoma, City of Hope Comprehensive Cancer Center, Duarte, CA.
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24
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Canelo-Vilaseca M, Sabbah M, Di Blasi R, Cristinelli C, Sureda A, Caillat-Zucman S, Thieblemont C. Lymphodepletion chemotherapy in chimeric antigen receptor-engineered T (CAR-T) cell therapy in lymphoma. Bone Marrow Transplant 2025; 60:559-567. [PMID: 40148484 PMCID: PMC12061774 DOI: 10.1038/s41409-025-02539-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/29/2024] [Accepted: 02/17/2025] [Indexed: 03/29/2025]
Abstract
The development of chimeric antigen receptor (CAR) T-cells, engineered from peripheral T-lymphocytes of a patient with lymphoma, in order to specifically target tumor cells, has been a revolution in adoptive cell therapy (ACT). As outlined in this review, ACT was initiated by hematopoietic cell transplantation (HSCT) and re-injection of interleukin-boosted tumor-infiltrating lymphocytes (TIL). The innovative venture of genetically modifying autologous peripheral T-cells to target them to cell-surface tumoral antigens through an antibody-derived structure (i.e. independent of major histocompatibility antigen presentation, physiologically necessary for T-cell activation), and intracytoplasmic T-cell costimulatory peptides, via a novel membrane CAR, has been an outstanding breakthrough. Here, focusing on B-cell hematological malignancies and mostly non-Hodgkin lymphoma, attention is brought to the importance of providing an optimal microenvironment for such therapeutic cells to proliferate and positively develop anti-tumoral cytotoxicity. This, perhaps paradoxically, implies a pre-infusion step of deep lymphopenia and deregulation of immunosuppressive mechanisms enhanced by tumoral cells. Fludarabine and cyclophosphamide appear to be the most efficient lymphodepletive drugs in this context, dosage being of importance, as will be illustrated by a thorough literature review.
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Affiliation(s)
- Marta Canelo-Vilaseca
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
| | - Mohamad Sabbah
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
- Université Paris Cité, Paris, France
| | - Roberta Di Blasi
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
| | - Caterina Cristinelli
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France
| | - Anna Sureda
- Clinical Hematology Department, Institut Català d'Oncologia-L'Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
| | - Sophie Caillat-Zucman
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Laboratoire d'Immunologie, Paris, France
| | - Catherine Thieblemont
- Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Paris, France.
- Université Paris Cité, Paris, France.
- Inserm U1153, Hôpital Saint Louis, Paris, France.
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25
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Mulvey A, Trueb L, Coukos G, Arber C. Novel strategies to manage CAR-T cell toxicity. Nat Rev Drug Discov 2025; 24:379-397. [PMID: 39901030 DOI: 10.1038/s41573-024-01100-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 02/05/2025]
Abstract
The immune-related adverse events associated with chimeric antigen receptor (CAR)-T cell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-T cell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on-off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloid cell-intrinsic druggable targets and cellular engineering strategies to develop safer CAR-T cells.
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Affiliation(s)
- Arthur Mulvey
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Lionel Trueb
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - George Coukos
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Caroline Arber
- Department of Oncology UNIL-CHUV, Service of Immuno-Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland.
- Departments of Oncology UNIL-CHUV and Laboratory Medicine and Pathology, Service and Central Laboratory of Hematology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
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26
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Kharfan-Dabaja MA, Mohty R, Easwar N, Johnston P, Iqbal M, Epperla N, Yared J, Ahmed N, Hamadani M, Beitinjaneh A, Narkhede M, Jagadeesh D, Ramakrishnan Geethakumari P, Dholaria B, Gergis U, Munoz J, Sandoval-Sus J, Locke FL, Fein J, Khurana A, Ayala E, Annunzio K, Rapoport AP, Lutfi F, Akhtar OS, Lekakis L, Mehta A, Oluwole OO, Logue J, Jain MD, Shore T, Durani U, Alhaj Moustafa M, McGuirk J, Lin Y, Yamshon S, Chavez JC. Chimeric antigen receptor T cell therapy in octogenarians with B cell lymphoma: a real-world US multicenter collaborative study. Bone Marrow Transplant 2025; 60:632-639. [PMID: 40025178 DOI: 10.1038/s41409-025-02541-1] [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: 11/17/2024] [Revised: 01/12/2025] [Accepted: 02/19/2025] [Indexed: 03/04/2025]
Abstract
Older patients with lymphoma are typically underrepresented in clinical trials with chimeric antigen receptor T cell (CAR T) therapy. In this multicenter, observational study we aimed to assess the safety and efficacy of standard CD19 CAR T in patients 80 years of age or older. At total of 88 patients, median age 82 (range, 80-89) years, were included. Diffuse large B cell lymphoma (DLBCL) (N = 60, 68.2%) represented the most common histology. Patients were treated mostly with axicabtagene ciloleucel (N = 41, 46.6%) followed by lisocabtagene maraleucel (N = 25, 28.4%). Cytokine release syndrome (CRS) (any grade) was seen in 68 (77.3%) and 51 (58%) developed immune effector cell-associated neurotoxicity syndrome (ICANS). Incidence of grade 3-4 CRS and ICANS were 7.4% and 31.4%, respectively. For patients with DLBCL/tFL, the 1-year NRM, relapse, PFS, and OS were 11.6%, 40.8%, 47.6%, and 61.2%, respectively. We conclude that CAR T is feasible and effective in patients 80 years or older with B cell lymphomas. These patients must be provided the opportunity to be evaluated for this curative approach.
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Affiliation(s)
- Mohamed A Kharfan-Dabaja
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA
| | | | - Neela Easwar
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
| | | | - Madiha Iqbal
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA
| | | | - Jean Yared
- Transplant and Cellular Therapy Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Nausheen Ahmed
- Hematologic Malignancies and Cellular Therapeutics, Department of Medicine, University of Kansas Cancer Center, Westwood, KS, USA
| | - Mehdi Hamadani
- BMT and Cellular Therapy Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Amer Beitinjaneh
- Division of Transplantation and Cellular Therapy, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Mayur Narkhede
- Division of Hematology/Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Praveen Ramakrishnan Geethakumari
- Section of Hematologic Malignancies and Cellular Therapy, Division of Hematology and Oncology, at Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
| | - Bhagirathbhai Dholaria
- Division of Hematology Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Usama Gergis
- Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Jose Sandoval-Sus
- Moffitt Cancer Center at Memorial Health Care system, Pembroke Pines, FL, USA
| | | | - Joshua Fein
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
| | | | - Ernesto Ayala
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA
| | - Kaitlin Annunzio
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Aaron P Rapoport
- Transplant and Cellular Therapy Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Forat Lutfi
- Hematologic Malignancies and Cellular Therapeutics, Department of Medicine, University of Kansas Cancer Center, Westwood, KS, USA
| | - Othman Salim Akhtar
- BMT and Cellular Therapy Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Lazaros Lekakis
- Division of Transplantation and Cellular Therapy, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Amitkumar Mehta
- Division of Hematology/Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Olalekan O Oluwole
- Division of Hematology Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jennifer Logue
- Moffitt Cancer Center at Memorial Health Care system, Pembroke Pines, FL, USA
| | | | - Tsiporah Shore
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
| | | | - Muhamad Alhaj Moustafa
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA
| | - Joseph McGuirk
- Hematologic Malignancies and Cellular Therapeutics, Department of Medicine, University of Kansas Cancer Center, Westwood, KS, USA
| | - Yi Lin
- Mayo Clinic, Rochester, MN, USA
| | - Samuel Yamshon
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
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27
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Azmal M, Miah MM, Prima FS, Paul JK, Haque ASNB, Ghosh A. Advances and challenges in cancer immunotherapy: Strategies for personalized treatment. Semin Oncol 2025; 52:152345. [PMID: 40305928 DOI: 10.1016/j.seminoncol.2025.152345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 05/02/2025]
Abstract
Cancer immunotherapy has transformed oncology by harnessing the immune system to specifically target cancer cells, offering reduced systemic toxicity compared to traditional therapies. This review highlights key strategies, including adoptive cell transfer (ACT), immune checkpoint inhibitors, oncolytic viral (OV) therapy, monoclonal antibodies (mAbs), and mRNA-based vaccines. ACT reinfuses enhanced immune cells like tumor-infiltrating lymphocytes (TILs) to combat refractory cancers, while checkpoint inhibitors (eg, PD-1 and CTLA-4 blockers) restore T-cell activity. OV therapy uses engineered viruses (eg, T-VEC) to selectively lyse cancer cells, and advanced mAbs improve targeting precision. mRNA vaccines introduce tumor-specific antigens to trigger robust immune responses. Despite significant progress, challenges like immune-related side effects, high costs, and immunosuppressive tumor microenvironments persist. This review underscores the need for combination strategies and precision medicine to overcome these barriers and maximize the potential of immunotherapy in personalized cancer treatment.
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Affiliation(s)
- Mahir Azmal
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Md Munna Miah
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Fatema Sultana Prima
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Jibon Kumar Paul
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Anm Shah Newaz Been Haque
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Ajit Ghosh
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh.
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28
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Sonar PV, Singh AK, Mandadi S, Sharma NK. Expanding horizons of cancer immunotherapy: hopes and hurdles. Front Oncol 2025; 15:1511560. [PMID: 40352591 PMCID: PMC12061710 DOI: 10.3389/fonc.2025.1511560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/31/2025] [Indexed: 05/14/2025] Open
Abstract
Background Tumor displays various forms of tumor heterogeneity including immune heterogeneity that allow cancer cells to survive during conventional anticancer drug interventions. Thus, there is a strong rationale for overcoming anticancer drug resistance by employing the components of immune cells. Using the immune system to target tumor cells has revolutionized treatment. Recently, significant progress has been achieved at preclinical and clinical levels to benefit cancer patients. Approach A review of literature from the past ten years across PubMed, Scopus, and Web of Science focused on immunotherapy strategies. These include immune checkpoint inhibitors (ICIs), tumor-infiltrating lymphocyte therapy, antibody-drug conjugates (ADCs), cancer vaccines, CAR T-cell therapy, and the role of the gut microbiome. Conclusion While immunotherapy outcomes have improved, particularly for tumor types such as melanoma and non-small cell lung cancer (NSCLC), challenges persist regarding predictive biomarker identification and better management. Ongoing research on modifiers of immune function like gut microbiome-derived metabolites, next-generation ADCs, and new classes of biologics is warranted. Overall, continued investigation toward optimizing synergistic immunotherapeutic combinations through strategic drug delivery systems is imperative for preclinical and clinical success in cancer patients.
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Affiliation(s)
- Priyanka Vijay Sonar
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India
| | - Anuj Kumar Singh
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India
- Ichnos Glenmark Innovation, Glenmark Pharmaceuticals Limited, Navi Mumbai, Maharashtra, India
| | - Sravan Mandadi
- Ichnos Glenmark Innovation, Glenmark Pharmaceuticals Limited, Navi Mumbai, Maharashtra, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India
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29
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Gazeau N, Beauvais D, Tilmont R, Srour M, Ferrant E, Safar V, Fouillet L, Flandrin-Gresta P, Gower N, Chauvet P, Duployez N, Podvin B, Demaret J, Huet S, Sujobert P, Ghesquières H, Damaj G, Bachy E, Morschhauser F, Yakoub-Agha I, Heiblig M, Sesques P. Myeloid neoplasms after CD19-directed CAR T cells therapy in long-term B-cell lymphoma responders, a rising risk over time? Leukemia 2025:10.1038/s41375-025-02605-7. [PMID: 40275069 DOI: 10.1038/s41375-025-02605-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/09/2025] [Accepted: 04/02/2025] [Indexed: 04/26/2025]
Abstract
Therapy-related myeloid neoplasms (t-MN), including myelodysplastic neoplasms (t-MDS) and acute myeloid leukemia (t-AML), have emerged as significant late complications after CAR T cell therapy. We retrospectively analyzed 539 patients with B cell lymphoma treated with CD19 directed CAR T cell therapy across four French centers. Cumulative incidences of t-MN was estimated with relapse or death treated as competing risk. Univariate and propensity score matching (PSM) analyses were conducted to assess risk factors with age and the number of prior treatments as covariates. After a median follow-up of 25 months, the cumulative incidence of t-MN was 4.5% at 2 years. T-MN occurred predominantly as t-MDS (62%) and t-AML (38%) with high cytogenetic risk. Median overall survival after t-MN diagnosis was 4.5 months. In univariate analysis, older age (p < 0.01), higher MCV (p < 0.01), and higher ICANS grade (p = 0.04) were associated with increased risk of t-MN. After PSM, MCV and ICANS grade remained significant risk factors. CAR T cell products with CD28 co-stimulatory domains trended towards higher t-MN risk (p = 0.09). NGS analysis showed that 85.7% of t-MN had pre-existing mutations, most commonly TP53. This study highlights t-MN as a severe late complication of CAR T cell therapy. MCV and ICANS grade were identified as key risk factors.
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Affiliation(s)
- Nicolas Gazeau
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France.
| | - David Beauvais
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Rémi Tilmont
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Micha Srour
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Emmanuelle Ferrant
- Hematology Department, Hospices Civils de Lyon, Pierre Bénite, Lyon, France
| | - Violaine Safar
- Hematology Department, Hospices Civils de Lyon, Pierre Bénite, Lyon, France
| | - Ludovic Fouillet
- Hematology Department, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France
| | | | - Nicolas Gower
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Paul Chauvet
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France
- CHU de Lille, Université de Lille, Inserm UMR1277, CNRS UMR9020-CANTHER, Lille, France
| | - Nicolas Duployez
- Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Benjamin Podvin
- Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Julie Demaret
- Biology and Pathology Center, Laboratory of Immunology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Sarah Huet
- Laboratory of Hematology, Centre Hospitalier Universitaire Lyon-Sud, Hospices Civils de Lyon, Pierre-Benite, France
| | - Pierre Sujobert
- Laboratory of Hematology, Centre Hospitalier Universitaire Lyon-Sud, Hospices Civils de Lyon, Pierre-Benite, France
| | - Hervé Ghesquières
- Hematology Department, Hospices Civils de Lyon, Pierre Bénite, Lyon, France
| | - Gandhi Damaj
- Hematology Department, Centre Hospitalier Universitaire de Caen, Caen, France
| | - Emmanuel Bachy
- Hematology Department, Hospices Civils de Lyon, Pierre Bénite, Lyon, France
| | - Franck Morschhauser
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Ibrahim Yakoub-Agha
- Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France
- CHU de Lille, Université de Lille, INSERM U1286, Infinite, 59000, Lille, France
| | - Maël Heiblig
- Hematology Department, Hospices Civils de Lyon, Pierre Bénite, Lyon, France
| | - Pierre Sesques
- Hematology Department, Hospices Civils de Lyon, Pierre Bénite, Lyon, France
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30
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Esmaeilzadeh A, Hadiloo K, Yaghoubi S, Makoui MH, Mostanadi P. State of the art in CAR-based therapy: In vivo CAR production as a revolution in cell-based cancer treatment. Cell Oncol (Dordr) 2025:10.1007/s13402-025-01056-7. [PMID: 40261561 DOI: 10.1007/s13402-025-01056-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 03/19/2025] [Indexed: 04/24/2025] Open
Abstract
Chimeric antigen receptor (CAR) therapy has successfully treated relapsed/refractory hematological cancers. This strategy can effectively target tumor cells. However, despite positive outcomes in clinical applications, challenges remain to overcome. These hurdles pertain to the production of the drugs, solid tumor resistance, and side effects related to the treatment. Some cases have been missed during the drug preparation due to manufacturing issues, prolonged production times, and high costs. These challenges mainly arise from the in vitro manufacturing process, so reevaluating this process could minimize the number of missed patients. The immune cells are traditionally collected and sent to the laboratory; after several steps, the cells are modified to express the CAR gene before being injected back into the patient's body. During the in vivo method, the CAR gene is introduced to the immune cells inside the body. This allows for treatment to begin sooner, avoiding potential failures in drug preparation and the associated high costs. In this review, we will elaborate on the production and treatment process using in vivo CAR, examine the benefits and challenges of this approach, and ultimately present the available solutions for incorporating this treatment into clinical practice.
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Affiliation(s)
- Abdolreza Esmaeilzadeh
- Pficell R&D Canadian Institution & Corporation, Profound Future Focused Innovative Cell and Gene Therapy, Pficell Canadian Institution and Corporation, Ontario, Canada.
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Kaveh Hadiloo
- Pficell R&D Canadian Institution & Corporation, Profound Future Focused Innovative Cell and Gene Therapy, Pficell Canadian Institution and Corporation, Ontario, Canada
- Department of Surgery, Velayat Clinical Research Development Unit, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan, Iran
| | - Sara Yaghoubi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan, Iran
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Parsa Mostanadi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan, Iran
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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31
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Reidy M, Khan M, Mills EA, Wu Q, Garton J, Draayer DE, Zahoor I, Giri S, Axtell RC, Mao-Draayer Y. New Frontiers in Multiple Sclerosis Treatment: From Targeting Costimulatory Molecules to Bispecific Antibodies. Int J Mol Sci 2025; 26:3880. [PMID: 40332536 PMCID: PMC12028294 DOI: 10.3390/ijms26083880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/13/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The therapeutic landscape for MS has evolved significantly since the 1990s, with the development of more than 20 different disease-modifying therapies (DMTs). These therapies effectively manage relapses and inflammation, but most have failed to meaningfully prevent disease progression. While classically understood as a T cell-mediated condition, the most effective DMTs in slowing progression also target B cells. Novel classes of MS therapies in development, including anti-CD40L monoclonal antibodies, CD19 chimeric antigen receptor (CAR) T cells, and Bruton's tyrosine kinase (BTK) inhibitors show greater capacity to target and eliminate B cells in the brain/CNS, as well as impacting T-cell and innate immune compartments. These approaches may help tackle the disease at its immunopathological core, addressing both peripheral and central immune responses that drive MS progression. Another emerging therapeutic strategy is to use bispecific antibodies, which have the potential for dual-targeting various disease aspects such as immune activation and neurodegeneration. As such, the next generation of MS therapies may be the first to reduce both inflammatory demyelination and disease progression in a clinically meaningful way. Their ability to target specific immune cell populations while minimizing broad immune suppression could also lead to better safety profiles. Here, we explore the biological rationale, advantages, limitations, and clinical progress of these emerging immunotherapies for relapsing-remitting and progressive forms of MS.
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Affiliation(s)
- Megan Reidy
- Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (M.R.); (M.K.); (J.G.); (D.E.D.); (R.C.A.)
| | - Meerah Khan
- Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (M.R.); (M.K.); (J.G.); (D.E.D.); (R.C.A.)
| | - Elizabeth A. Mills
- Alzheimer’s Drug Discovery Foundation, 57 West 57th Street, Suite 904, New York, NY 10019, USA;
| | - Qi Wu
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Josh Garton
- Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (M.R.); (M.K.); (J.G.); (D.E.D.); (R.C.A.)
| | - Dean E. Draayer
- Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (M.R.); (M.K.); (J.G.); (D.E.D.); (R.C.A.)
| | - Insha Zahoor
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA; (I.Z.); (S.G.)
| | - Shailendra Giri
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA; (I.Z.); (S.G.)
| | - Robert C. Axtell
- Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (M.R.); (M.K.); (J.G.); (D.E.D.); (R.C.A.)
| | - Yang Mao-Draayer
- Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (M.R.); (M.K.); (J.G.); (D.E.D.); (R.C.A.)
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32
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Majhail NS, Cox T, Larson S, Battiwalla M, Ramakrishnan A, Shaughnessy P, Tees M, Zahradka N, Wilkes M, Pantin J. Outpatient Administration of Chimeric Antigen Receptor T-Cell Therapy Using Remote Patient Monitoring. JCO Oncol Pract 2025:OP2500062. [PMID: 40249898 DOI: 10.1200/op-25-00062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/02/2025] [Accepted: 03/13/2025] [Indexed: 04/20/2025] Open
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapies are standard of care for the treatment of several hematologic malignancies. Although patients receiving CAR-T therapies are frequently hospitalized given risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is increasing interest and evidence for the safety of their outpatient administration. We review various models of care and provide operational considerations for centers that are interested in developing outpatient CAR-T programs, with a particular emphasis on using remote patient monitoring (RPM) to facilitate outpatient care. Safe and high-quality outpatient care requires involvement of a multidisciplinary team with clinical pathways for rapid triage and evaluation for CRS and ICANS and their management and, if necessary, timely transition of patients to a higher level of acute care. RPM can facilitate scaling an outpatient program in a cost-effective manner, especially across multiple sites of care, and can reduce the time patients spend in an acute care setting. Overall minimizing hospital-based care and an outpatient approach can alleviate capacity challenges treatment centers have faced that have partly impacted access to CAR-T therapies and have the potential to positively impact patient and caregiver experience and quality of life.
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Affiliation(s)
- Navneet S Majhail
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
- Sarah Cannon Transplant and Cellular Therapy Network Program at TriStar Centennial Medical Center, Nashville, TN
| | - Tonya Cox
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
| | - Stephanie Larson
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
| | - Minoo Battiwalla
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
- Sarah Cannon Transplant and Cellular Therapy Network Program at TriStar Centennial Medical Center, Nashville, TN
| | - Aravind Ramakrishnan
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
- Sarah Cannon Transplant and Cellular Therapy Network Program at South Austin Medical Center, Austin, TX
| | - Paul Shaughnessy
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
- Sarah Cannon Transplant and Cellular Therapy Network Program at Methodist Hospital, San Antonio, TX
| | - Michael Tees
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
- Colorado Blood Cancer Institute, Denver, CO
- Sarah Cannon Transplant and Cellular Therapy Program at Presbyterian/St Luke's Medical Center, Denver, CO
| | | | | | - Jeremy Pantin
- Sarah Cannon Transplant and Cellular Therapy Network, Sarah Cannon Cancer Network, Nashville, TN
- Sarah Cannon Transplant and Cellular Therapy Network Program at TriStar Centennial Medical Center, Nashville, TN
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33
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Phanthaphol N, Somboonpatarakun C, Suwanchiwasiri K, Yuti P, Sujjitjoon J, Augsornworawat P, Baillie GS, Junking M, Yenchitsomanus PT. Enhanced cytotoxicity against cholangiocarcinoma by fifth-generation chimeric antigen receptor T cells targeting integrin αvβ6 and secreting anti-PD-L1 scFv. J Transl Med 2025; 23:451. [PMID: 40241132 PMCID: PMC12004729 DOI: 10.1186/s12967-025-06453-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a fatal bile duct cancer with high resistance and recurrence rates, with only one fifth of patients eligible for surgical treatment. The disease resists standard chemotherapy and often relapses. Chimeric antigen receptor (CAR) T cell therapy has shown promise for hematological malignancies but faces challenges in solid tumors due to resistance mechanisms like PD-L1 expression, which tumors use to evade the immune system. To address this challenge, we developed fifth-generation CAR T cells targeting integrin αvβ6 that also secrete anti-PD-L1 single-chain variable fragment (scFv) to target both tumor cells and the PD-1/PD-L1 pathway. We examined integrin αvβ6 and PD-L1 expression in CCA cell lines and engineered T cells to express either fourth-generation CAR T cells targeting integrin αvβ6 (A20 CAR4 T cells) or fifth-generation CAR T cells with anti-PD-L1 scFv secretion (A20 CAR5 T cells). In vitro, A20 CAR5 T cells exhibited less exhaustion and superior long-term functionality compared to A20 CAR4 T cells. In 3D spheroid models of CCA, A20 CAR5 T cells demonstrated enhanced antitumor activity and better infiltration into the spheroid core. These findings suggest that A20 CAR5 T cells have significant potential and warrant further in vivo studies and clinical trials.
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Affiliation(s)
- Nattaporn Phanthaphol
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chalermchai Somboonpatarakun
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kwanpirom Suwanchiwasiri
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pornpimon Yuti
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Jatuporn Sujjitjoon
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Punn Augsornworawat
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - George S Baillie
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK
| | - Mutita Junking
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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34
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Dreger P, Ahmed S, Bazarbachi A, Dietrich S, Fenske TS, Ghosh N, Hermine O, Hamadani M. How we treat mantle cell lymphoma with cellular therapy in 2025: the European and American perspectives. Bone Marrow Transplant 2025:10.1038/s41409-025-02599-x. [PMID: 40229536 DOI: 10.1038/s41409-025-02599-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 04/16/2025]
Abstract
Cellular therapies have been cornerstones of the treatment of mantle cell lymphoma (MCL) for decades and have helped to improve the outcome of this formerly very unfavourable B-cell lymphoma considerably. Current established roles of cellular therapies include autologous hematopoietic cell transplantation (HCT) as part of first-line therapy, chimeric antigen receptor-engineered T-cells (CART) for relapsed/refractory MCL, and allogeneic HCT for settings in which CARTs have failed or are unavailable. Therapeutic innovations have recently entered the MCL treatment landscape and are moving upstream in treatment algorithms, challenging the existing management principles. The purpose of this paper is to give some guidance regarding how to best use cellular therapies in this increasingly complex environment. Due to differences in CART labels, available non-cellular treatment options, and philosophy between the American and the European health systems, we found it reasonable to contrast the American and European perspectives on defined standard scenarios, which are often overlapping but show discrepancies in some important aspects.
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Affiliation(s)
- Peter Dreger
- Department Medicine V, University of Heidelberg, Heidelberg, Germany.
| | - Sairah Ahmed
- Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ali Bazarbachi
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
| | - Sascha Dietrich
- University Hospital Düsseldorf, Department of Hematology, Oncology and Clinical Immunology, Düsseldorf, Germany
| | - Timothy S Fenske
- Sarah Cannon Transplant and Cellular Therapy Program, Methodist Hospital, San Antonio, TX, USA
| | - Nilanjan Ghosh
- Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC, USA
| | - Olivier Hermine
- Department of Adult Hematology, Necker Hospital, Université de Paris-Cité, Assistance Publique des Hôpitaux de Paris, Imagine Institute, INSERM U1183, Paris, France
| | - Mehdi Hamadani
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
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35
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Zhao L, Yan F, Tang D, Li W, An N, Ren C, Wang Y, Xu K, Zhao K. The transition between M1 and M2 macrophage phenotypes is associated with the disease status following CD19 CAR-T therapy for B cell lymphoma/leukemia. Cell Death Dis 2025; 16:275. [PMID: 40216772 PMCID: PMC11992075 DOI: 10.1038/s41419-025-07610-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/19/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025]
Abstract
Although anti-CD19 chimeric antigen receptor (CAR-T) cells demonstrate high response rates in relapsed/refractory B-cell lymphomas, a considerable proportion of patients eventually encounter disease progression or relapse. The short-term and long-term outcomes of CAR-T treatment are intricately linked to the tumor microenvironment (TME), wherein macrophages with polarized characteristics can exhibit either anti-tumorigenic or pro-tumorigenic roles. Despite evidence implicating the crucial involvement of macrophages in CAR-T cell-treated lymphoma, their dynamic distribution and immune function related to lymphoma progression remain poorly understood. Immunocompetent mice were utilized to establish syngeneic A20 lymphoma/leukemia models. The distribution and polarization of macrophages were detected using immunohistochemistry (IHC) and flow cytometry techniques. We observed that CD19 CAR-T therapy exhibited significant efficacy in protecting mice against lymphoma, leading to increased infiltration of macrophages into the tumor tissue. Notably, during remission stages, M1-like macrophages (CD11b+F4/80+C206-CD80+) were predominant, whereas in relapsed mice, there was a shift towards M2-like phenotypes (CD11b+F4/80+C206+CD80+). The transition from remissive to relapsed status was accompanied by a reduction in the M1/M2 ratio and a decrease in pro-inflammatory cytokines. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed differential expression levels of CD206 and CD163 between remissive and relapsed mice, while signaling pathways involving PI3K and STAT3 may contribute to the skewing towards M2 polarization. In summary, our findings highlight the dynamic transformation of macrophage polarization during different stages of lymphoma progression and underscore its potential implications for immunotherapeutic interventions.
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Affiliation(s)
- Li Zhao
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fen Yan
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Donghai Tang
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wenwen Li
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Na An
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chunxiao Ren
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ying Wang
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kailin Xu
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Kai Zhao
- Department of hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Blood diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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36
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Lee MJ, Cichocki F, Miller JS. Chimeric antigen receptor therapies: Development, design, and implementation. J Allergy Clin Immunol 2025:S0091-6749(25)00386-0. [PMID: 40220909 DOI: 10.1016/j.jaci.2025.04.005] [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: 12/11/2024] [Revised: 03/06/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025]
Abstract
Chimeric antigen receptor (CAR) T and natural killer (NK) cell therapies represent a promising strategy for the treatment of cancers and other chronic diseases. Engineered CAR constructs endow immune cells with the ability to target desired antigens with high specificity, allowing for directed responses to antigen-expressing cells. CAR T and NK cells have shown marked success in the treatment of hematologic malignancies, although there remains a large population of patients with disease that fails to respond to CAR therapies, and their efficacy in solid tumors is still limited. In this review, we provide a broad overview of the development, design, and implementation of CAR therapies from bench to bedside. We discuss the building blocks of CAR constructs and how these can be manipulated to optimize CAR functionality, review the possible sources of T and NK cells for CAR therapies, and examine the limitations of both CAR T and CAR NK cells. Finally, we discuss recent breakthroughs in the CAR field and consider how these advances may affect the success of CAR therapies in the years to come.
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Affiliation(s)
- Madeline J Lee
- Department of Medicine, University of Minnesota, Minneapolis, Minn
| | - Frank Cichocki
- Department of Medicine, University of Minnesota, Minneapolis, Minn
| | - Jeffrey S Miller
- Department of Medicine, University of Minnesota, Minneapolis, Minn.
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37
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Stewart CM, Siegler EL, Kenderian SS. The road ahead for chimeric antigen receptor T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf047. [PMID: 40209174 DOI: 10.1093/jimmun/vkaf047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/25/2025] [Indexed: 04/12/2025]
Abstract
Chimeric antigen receptor T (CART) cell therapy is an innovative form of immunotherapy that has shown remarkable and long-term responses in patients with B-cell malignancies. Over the years, the field has made significant progress in our understanding of the successes and challenges associated with CART cell therapy. In this review, we provide an overview of the current state of CART cell therapy in the clinic. We detail current challenges including patient access, CART-associated toxicity, tumor heterogeneity, CART cell trafficking, the tumor microenvironment, and different CART cell fates. With each challenge, we review lessons learned, potential solutions and outline areas for future development. Finally, we discuss how the field of engineered cell therapy is moving into the treatment of solid tumors and other diseases beyond cancer.
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Affiliation(s)
- Carli M Stewart
- T Cell Engineering, Mayo Clinic, Rochester, MN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Elizabeth L Siegler
- T Cell Engineering, Mayo Clinic, Rochester, MN, United States
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Saad S Kenderian
- T Cell Engineering, Mayo Clinic, Rochester, MN, United States
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
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38
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Roex G, Gordon KS, Lion E, Birnbaum ME, Anguille S. Expanding the CAR toolbox with high throughput screening strategies for CAR domain exploration: a comprehensive review. J Immunother Cancer 2025; 13:e010658. [PMID: 40210240 PMCID: PMC11987143 DOI: 10.1136/jitc-2024-010658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/06/2025] [Indexed: 04/12/2025] Open
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy has been highly successful in the treatment of B-cell hematological malignancies. CARs are modular synthetic molecules that can redirect immune cells towards target cells with antibody-like specificity. Despite their modularity, CARs used in the clinic are currently composed of a limited set of domains, mostly derived from IgG, CD8α, 4-1BB, CD28 and CD3ζ. The current low throughput CAR screening workflows are labor-intensive and time-consuming, and lie at the basis of the limited toolbox of CAR building blocks available. High throughput screening methods facilitate simultaneous investigation of hundreds of thousands of CAR domain combinations, allowing discovery of novel domains and increasing our understanding of how they behave in the context of a CAR. Here we review the growing body of reports that employ these high throughput screening and computational methods to advance CAR design. We summarize and highlight the important differences between the different studies and discuss their limitations and future considerations for further improvements. In conclusion, while still in its infancy, high throughput screening of CARs has the capacity to vastly expand the CAR domain toolbox and improve our understanding of CAR design. This knowledge could be foundational for translating CAR therapy beyond hematological malignancies and push the frontiers in personalized medicine.
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Affiliation(s)
- Gils Roex
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium
| | - Khloe S Gordon
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
| | - Eva Lion
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium
- Center for Cell Therapy and Regenerative Medicine, University Hospital Antwerp, Edegem, Belgium
| | - Michael E Birnbaum
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
- Ragon Institute of Mass General MIT and Harvard, Cambridge, Massachusetts, USA
| | - Sébastien Anguille
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium
- Center for Cell Therapy and Regenerative Medicine, University Hospital Antwerp, Edegem, Belgium
- Division of Hematology, University Hospital Antwerp, Edegem, Belgium
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Shahid S, Prockop SE, Flynn GC, Mauguen A, White CO, Bieler J, McAvoy D, Hosszu K, Cancio MI, Jakubowski AA, Scaradavou A, Boelens JJ, Sauter CS, Perales MA, Giralt SA, Taylor C, Chaudhari J, Wang X, Rivière I, Sadelain M, Brentjens RJ, Kernan NA, O'Reilly RJ, Curran KJ. Allogeneic off-the-shelf CAR T-cell therapy for relapsed or refractory B-cell malignancies. Blood Adv 2025; 9:1644-1657. [PMID: 39908482 PMCID: PMC11995077 DOI: 10.1182/bloodadvances.2024015157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/10/2024] [Accepted: 12/31/2024] [Indexed: 02/07/2025] Open
Abstract
ABSTRACT Despite clinical benefit with the use of chimeric antigen receptor (CAR) T cells, the need to manufacture patient-specific products limits its clinical utility. To overcome this barrier, we developed an allogeneic "off-the-shelf" CAR T-cell product using Epstein-Barr virus (EBV)-specific T cells (EBV-VSTs) genetically modified with a CD19-specific CAR (19-28z). Patients with relapsed/refractory (R/R) B-cell malignancies were stratified into 3 treatment cohorts: cohort 1 (n = 8; disease recurrence after allogeneic or autologous hematopoietic cell transplantation [HCT]), cohort 2 (n = 6; consolidative therapy after autologous HCT), or cohort 3 (n = 2; consolidative therapy after allogeneic HCT). The primary objective of this trial was to determine the safety of multiple CAR EBV-VST infusions. Most patients (n = 12/16) received multiple doses (overall median, 2.5 [range, 1-3]) with 3 × 106 T cells per kg determined to be the optimal dose enabling multiple treatments per manufactured cell line. Severe cytokine release syndrome or neurotoxicity did not occur after infusion, and no dose-limiting toxicity was observed in the trial. Median follow-up was 48 months (range, 4-135) with 4 deaths due to disease progression. Overall survival of all patients was 81% at 12 months and 75% at 36 months. Postinfusion expansion and persistence were limited, and CAR EBV-VSTs demonstrated a unique T-cell phenotype compared with autologous 19-28z CAR T cells. Our study demonstrates the feasibility and safety of an allogeneic "off-the-shelf" CAR EBV-VST product with favorable outcomes for patients with CD19+ R/R B-cell malignancies. This trial was registered at www.ClinicalTrials.gov as #NCT01430390.
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Affiliation(s)
- Sanam Shahid
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Susan E. Prockop
- Department of Hematopoietic Stem Cell Transplant, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
| | - Georgia C. Flynn
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Audrey Mauguen
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Charlie O. White
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jennifer Bieler
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Devin McAvoy
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Kinga Hosszu
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Maria I. Cancio
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ann A. Jakubowski
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Jaap Jan Boelens
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Craig S. Sauter
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | | | - Sergio A. Giralt
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Clare Taylor
- Department of Pharmacology, Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jagrutiben Chaudhari
- Department of Pharmacology, Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Xiuyan Wang
- Department of Pharmacology, Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Isabelle Rivière
- Department of Pharmacology, Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michel Sadelain
- Department of Pharmacology, Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Renier J. Brentjens
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Nancy A. Kernan
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Richard J. O'Reilly
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Kevin J. Curran
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
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Morgan HT, Derman BA, Ma H, Kumar SK. Changing lanes: extending CAR T-cell therapy to high-risk plasma cell dyscrasias. Front Immunol 2025; 16:1558275. [PMID: 40264764 PMCID: PMC12011880 DOI: 10.3389/fimmu.2025.1558275] [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: 01/10/2025] [Accepted: 03/10/2025] [Indexed: 04/24/2025] Open
Abstract
Chimeric antigen receptor (CAR) cellular therapies have advanced outcomes in challenging hematologic malignancies like leukemia, lymphoma, and multiple myeloma. Plasma cell-directed CAR T-cell therapies have been particularly beneficial in multiple myeloma, suggesting that these agents may have a role in other challenging plasma cell disorders such as systemic AL amyloidosis and plasma cell leukemia. AL amyloidosis is a monoclonal plasma cell disorder resulting in the deposition of protein fibrils that compromise end-organ function. Delays in diagnosis can result in end-organ dysfunction and organ failure, making designing and completing treatment difficult. Plasma cell leukemia (PCL) is a rare and highly challenging malignancy with dismal survival outcomes despite aggressive therapy. Both diagnoses are currently treated with regimens borrowed from myeloma: a combination of novel agents and chemotherapy induction, then autologous stem cell transplantation (ASCT), with the current practice trending towards consolidation and maintenance. Unfortunately, only 20% of AL amyloidosis patients are transplant-eligible at diagnosis. Those transplant-ineligible (TIE) patients are treated with combination induction chemotherapy, which may be limited by worsening disease-related end-organ dysfunction. Plasma cell leukemia patients are still very likely to relapse after this intensive and prolonged therapy. Despite the promise of a shorter course of therapy, CAR T-cell therapies directed against plasma cells have not been rigorously investigated in patients with AL amyloidosis or PCL; most trials of MM have excluded these patients. Herein, we describe current treatment paradigms for AL amyloidosis and PCL and review the evidence for CAR T-cell therapies in these challenging plasma cell disorders. Further investigation into CAR T-cell therapies for plasma cell disorders other than multiple myeloma is warranted.
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Affiliation(s)
- Heather T. Morgan
- Clinical Development, Oricell Therapeutics, Roseland, NJ, United States
| | - Benjamin A. Derman
- Section of Hematology/Oncology, University of Chicago, Chicago, IL, United States
| | - Hong Ma
- Clinical Development, Oricell Therapeutics, Roseland, NJ, United States
| | - Shaji K. Kumar
- Department of Hematology, Mayo Clinic, Rochester, MN, United States
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41
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Yu W, Li P, Zhou L, Yang M, Ye S, Zhu D, Huang J, Yao X, Zhang Y, Li L, Zhao J, Zhu K, Li J, Zheng C, Lan L, Wan H, Yao Y, Zhang H, Zhou D, Jin J, Liang A. A phase 1 trial of prizloncabtagene autoleucel, a CD19/CD20 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. Blood 2025; 145:1526-1535. [PMID: 39813680 DOI: 10.1182/blood.2024026401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/09/2024] [Accepted: 12/09/2024] [Indexed: 01/18/2025] Open
Abstract
ABSTRACT Prizloncabtagene autoleucel (prizlon-cel), a novel bispecific chimeric antigen receptor T cell, targets and eliminates CD19/CD20-positive tumor cells. This phase 1, open-label study investigated the safety and efficacy of prizlon-cel in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Patients with CD19 and/or CD20-positive R/R B-NHL received a 3-day lymphodepletion (cyclophosphamide: 300 mg/m2 per day; fludarabine: 30 mg/m2 per day) followed by an IV dose of prizlon-cel. The primary end points were dose-limiting toxicity (DLT) and incidence and severity of treatment-emergent adverse events (TEAEs). Secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of the 48 patients infused prizlon-cel, 44 had large B-cell lymphoma (LBCL). No patient experienced DLT. Cytokine release syndrome occurred in 93.8% of the patients, with only 1 case of grade 3. Immune effector cell-associated neurotoxicity syndrome occurred in 6.3% of patients, with no grade 3 or higher events. The most common grade 3 or higher TEAEs were neutropenia (83.3%) and leukopenia (50%). The ORR and complete response (CR) rates in all patients were 91.5% and 85.1%, respectively, and in LBCL patients, ORR was 90.7% with 86.0% CR. With median follow-up of 30.0 months, median DOR, PFS, and OS were all not reached. Kaplan-Meier estimate of 2-year DOR, PFS, and OS rates were 66.0%, 62.6%, and 76.5%, respectively. Prizlon-cel had a favorable safety profile and a high and durable response in patients with R/R B-NHL, suggesting a promising treatment option for patients with R/R B-NHL. These trials were registered at www.clinicaltrials.gov as #NCT04317885, #NCT04655677, #NCT04696432, and #NCT04693676.
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Affiliation(s)
- Wenjuan Yu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ping Li
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
| | - Lili Zhou
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
| | - Min Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shiguang Ye
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
| | - Dan Zhu
- Shanghai AbelZeta Ltd, Shanghai, China
| | | | - Xin Yao
- Shanghai AbelZeta Ltd, Shanghai, China
| | - Yan Zhang
- Department of Hematology, Peking Union Medical College Hospital, Beijing, China
| | - Lanfang Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jing Zhao
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Kevin Zhu
- University of Maryland School of Medicine, Baltimore, MD
| | - Jing Li
- Shanghai AbelZeta Ltd, Shanghai, China
| | | | | | - Hui Wan
- Shanghai AbelZeta Ltd, Shanghai, China
| | | | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Daobin Zhou
- Department of Hematology, Peking Union Medical College Hospital, Beijing, China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Aibin Liang
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China
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Bindal P, Trottier CA, Elavalakanar P, Dodge LE, Kim S, Logan E, Ma S, Liegel J, Arnason J, Alonso CD. Early versus late infectious complications following chimeric antigen receptor-modified T-cell therapy. Leuk Lymphoma 2025; 66:702-712. [PMID: 39704413 DOI: 10.1080/10428194.2024.2439513] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/28/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024]
Abstract
Despite increasing utilization of CAR T-cell therapy, data are lacking regarding long term follow up and risk of infectious complications after the early period following CAR T-cell infusion. In this study, we sought to compare epidemiology and risk factors for early (≤ 3 months) and late (3 months to 1 year) infections. Data were retrospectively collected at six time points: pre-CAR T, day of infusion, and at 3, 6, 9, and 12 months post CAR-T infusion for all consecutive adult patients treated at our institution. In this cohort, the cumulative incidence of any infection was 73.2% in the first year. Bridging therapy, CRS, neurotoxicity and steroid use were identified as contributing risk factors for early bacterial infections. After 3 months, community acquired respiratory infections were common. We characterize bacterial, viral and fungal pathogens based on time elapsed after CAR T-cell infusion.
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Affiliation(s)
- P Bindal
- Division of Oncology, Department of Medicine, University of Massachusetts, Worcester, Massachusetts, USA
| | - C A Trottier
- Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA
| | - P Elavalakanar
- Division of Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - L E Dodge
- Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - S Kim
- Division of Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - E Logan
- Division of Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - S Ma
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - J Liegel
- Division of Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - J Arnason
- Division of Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - C D Alonso
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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43
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Marshalek JP, Qing X, Tomassetti S. CD19 Expression in B-Cell Lymphomas and Clinical Considerations in the Evolving Landscape of CD19-Targeted Therapy. World J Oncol 2025; 16:235-238. [PMID: 40162108 PMCID: PMC11954608 DOI: 10.14740/wjon2534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/12/2025] [Indexed: 04/02/2025] Open
Affiliation(s)
- Joseph P. Marshalek
- Division of Hematology and Medical Oncology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Xin Qing
- Department of Pathology, Harbor-UCLA Medical Center, CA 90502, USA
| | - Sarah Tomassetti
- Division of Hematology and Medical Oncology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USA
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Mousavi S, Khazaee-Nasirabadi MH, Seyedmehdi MS, Bazi A, Mirzaee Khalilabadi R. Natural killer cells: a new promising source for developing chimeric antigen receptor anti-cancer cells in hematological malignancies. Leuk Lymphoma 2025; 66:594-616. [PMID: 39656564 DOI: 10.1080/10428194.2024.2438802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 11/18/2024] [Accepted: 12/01/2024] [Indexed: 12/17/2024]
Abstract
In recent times, the application of CAR-T cell treatment has significantly progressed, showing auspicious treatment outcomes in hematologic malignancies. However, along with these advances, certain limitations and challenges hurdle the widespread utilization of this technology. Recently, CAR-NK cells have gained attention in cancer treatment, as this approach has an important advantage over CART therapy (i.e. no need for HLA matching) for targeting foreign cells. This review aims to explore the benefits of CAR NK cell therapy, and generation strategies, as well as the challenges and limitations hindering the application of CAR NK cells in experimental studies and trials on hematologic malignancies.
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Affiliation(s)
- Shahrzad Mousavi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Maryam Sadat Seyedmehdi
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Technology, Shahid Beheshti University, Tehran, Islamic Republic of Iran
| | - Ali Bazi
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Faculty of Allied Medical Sciences, Zabol University of Medical Sciences, Zabol, Iran
| | - Roohollah Mirzaee Khalilabadi
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
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Wang Y, Ding L, Wang Y, Li H, Wu M, Li S, Xu Q, Chen Y, Wang X. Tetrandrine alleviates macrophage activation syndrome after CAR-T cell therapy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156483. [PMID: 39947004 DOI: 10.1016/j.phymed.2025.156483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/22/2025] [Accepted: 02/06/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND Cytokine release syndrome (CRS) and secondary hemophagocytic lymphohistiocytosis (sHLH) are severe and potentially life-threatening complications after chimeric antigen receptor T (CAR-T) cell therapy, driven by excessive cytokine release from macrophages. The traditional Chinese herbal remedy d-tetrandrine (tetrandrine) exhibits anti-inflammatory properties in various diseases; however, its efficacy in mitigating CRS and sHLH remains underexplored. METHODS To establish an in vitro CRS model, supernatants from co-cultures of CAR-T and Raji cells were used to stimulate mTHP-1 macrophages. To model CRS and lymphoma in vivo, CAR-T and Raji cells were infused into the tail vein of NCG mice. An sHLH model was established in C57BL/6 J mice through intraperitoneal administration of Poly I:C and LPS. RESULTS Results demonstrated that tetrandrine markedly reduced the secretion of IL-6 and IL-1β from macrophages, alone with IL-2, TNF-α, GM-CSF, IL-8, and IFN-γ from CAR-T cells, while preserving the cytotoxic functions exhibited by CAR-T cells. In mouse models, tetrandrine treatment effectively decreased the concentrations of mouse IL-6 and human IFN-γ in mice serum, while maintaining the therapeutic efficacy exhibited by CAR-T cells. Mechanistically, tetrandrine enhances autophagy through the restraint of the AKT/mTOR signaling pathway, which is dysregulated in macrophages during CRS. Notably, lysosomal injury observed in macrophages during CRS was ameliorated by tetrandrine, which restored lysosomal pH and increased lysosome numbers, thereby positively influencing autophagy. In the sHLH model, tetrandrine treatment extended survival and alleviated pathological features, highlighting its protective role in mitigating the adverse effects of CRS and sHLH. CONCLUSION This study identified tetrandrine as a promising therapeutic candidate for attenuating macrophage activation associated with CAR-T cell therapy and LPS/Poly I:C-induced stimulation. These findings underscore the potential of tetrandrine to mitigate toxicities after CAR-T cell therapy while ensuring its therapeutic efficacy.
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Affiliation(s)
- Youming Wang
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Li Ding
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Yingxiang Wang
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Hui Li
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Miaomiao Wu
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Sujun Li
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Qianwen Xu
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Yuanli Chen
- Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, 230001, China
| | - Xingbing Wang
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, 230001, China.
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Lalu MM, Igweokpala S, Kekre N, Jeffers MS, Montroy J, Ghiasi M, Hay K, McComb S, Weeratna R, Atkins H, Hutton B, Yahya A, Masurekar A, Giguere P, Sabri E, Sobh M, Fergusson DA. Identifying Modifiers of CAR T-Cell Therapeutic Efficacy and Safety: A Systematic Review and Individual Patient Data Meta-Analysis. Transfus Med Rev 2025; 39:150897. [PMID: 40280037 DOI: 10.1016/j.tmrv.2025.150897] [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: 05/22/2024] [Revised: 03/26/2025] [Accepted: 04/01/2025] [Indexed: 04/29/2025]
Abstract
CAR T-cell therapy is effective in relapsed/refractory hematologic malignancies, but its use has been tempered by heterogeneity in response and safety outcomes. We performed individual patient data meta-analysis (IPDMA) of CAR T-cell therapy in patients with hematologic malignancies to explore whether patient-level factors modify therapeutic efficacy/safety. We searched MEDLINE, Embase, and Cochrane CENTRAL for relevant trials. IPD was collected and pooled from each included trial, and prevalence of outcomes among strata of potential modifiers was explored. Our primary outcome was complete response, and the secondary outcomes were cytokine release syndrome (CRS), and immune effector cell associated neurotoxicity syndrome (ICANS). We identified 89 trials comprising 2,331 patients for the IPDMA. Complete response proportion ranged from 25% to 75% depending on cancer type. Decreased complete response was seen in those that received bridging therapy compared to those that did not (34% vs 58%, RR:0.55, 95% CI:0.30-0.98), as well as with autologous cell sources compared to allogeneic sources (53% vs 67%, RR:0.61, 95% CI:0.43-0.87). Compared to CAR T-cell therapies targeting CD19 alone, therapies that combine CD19 targeting with additional targets such as CD20, CD22, CD30, CD33, LeY, NKG2D, or BCMA were associated with higher complete response rates (72% vs 58%, RR:1.69, 95% CI:1.15-2.50). Autologous cell sources demonstrated increased risk of ICANS relative to allogeneic sources (24% vs 3%, RR:10.48, 95% CI:1.87-58.57). Safety and efficacy of CAR T-cell therapy within specific cancer types was also affected by modifiers including bridging therapy, CAR T-cell source, CAR T-cell target, sex, age, number of cell infusions, co-stimulatory domain, and dose.
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Affiliation(s)
- Manoj M Lalu
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
| | | | - Natasha Kekre
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Transplantation and Cell Therapy Program, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Matthew S Jeffers
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Joshua Montroy
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Maryam Ghiasi
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Kevin Hay
- Department of Medicine, University of British Columbia, Vancouver, Ontario, Canada
| | - Scott McComb
- National Research Council of Canada, Ottawa, Ontario, Canada
| | - Risini Weeratna
- National Research Council of Canada, Ottawa, Ontario, Canada
| | - Harold Atkins
- Transplantation and Cell Therapy Program, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Brian Hutton
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Ayel Yahya
- Division of Medicine, Department of Hematology, University of Ottawa, Ottawa, Ontario, Canada
| | - Ashish Masurekar
- Division of Medicine, Department of Hematology, University of Ottawa, Ottawa, Ontario, Canada
| | - Philippe Giguere
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Transplantation and Cell Therapy Program, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Elham Sabri
- Ottawa Methods Centre, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Mohamad Sobh
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Dean A Fergusson
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.
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47
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Graham CE, Velasco R, Alarcon Tomas A, Stewart OP, Dachy G, Del Bufalo F, Doglio M, Henter JI, Ortí G, Peric Z, Roddie C, van de Donk NWCJ, Frigault MJ, Ruggeri A, Onida F, Sánchez-Ortega I, Yakoub-Agha I, Penack O. Non-ICANS neurological complications after CAR T-cell therapies: recommendations from the EBMT Practice Harmonisation and Guidelines Committee. Lancet Oncol 2025; 26:e203-e213. [PMID: 40179916 DOI: 10.1016/s1470-2045(24)00715-0] [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: 11/07/2024] [Revised: 12/03/2024] [Accepted: 12/04/2024] [Indexed: 04/05/2025]
Abstract
Neurological complications are an important concern in patients undergoing chimeric antigen receptor (CAR) T-cell therapy. Consensus guidelines inform the management of immune effector cell-associated neurotoxicity syndrome (ICANS). However, these guidelines are based on the early clinical experience with CD19 targeting CAR T cells in B-cell malignancies. In contrast, there are so far no published best practice recommendations on the current management of other non-classical neurological complications, which frequently develop after CAR T-cell infusion and cause clinically significant neurotoxicity. These non-classical neurological complications could be more prevalent because of additional CAR T-cell targets (eg, B cell maturation antigen [BCMA]), widened access, new indications in clinical development (including solid tumours in the CNS), and long-term follow-up. In this Review, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and Guidelines Committee provides recommendations on the management of CAR T-cell associated neurological complications that occur after treatment with the licensed CD19 and BCMA CAR T cells, as well as neurological toxicities that are emerging with CAR T cells in clinical trials for solid and haematological cancers. We address movement and neurocognitive toxicity, cranial nerve palsies, tumour inflammation-associated neurotoxicity, stroke, myelopathy, peripheral neuropathy, Guillain-Barré syndrome, fludarabine-associated neurotoxicity, and provide guidance on the psychological support for patients. CNS infections were excluded. The guidelines were developed based on the currently available literature and expert opinion. Recommendations are provided when possible, and areas for further research are highlighted to provide a framework to improve patient care.
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Affiliation(s)
- Charlotte E Graham
- Transplant Complications Working Party, EBMT, Paris, France; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK; Department of Haematology, King's College Hospital NHS Foundation Trust, London, UK.
| | - Roser Velasco
- Department of Neurology, Neuro-oncology Unit, Institut Català d'Oncologia - Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute, Barcelona, Spain
| | - Ana Alarcon Tomas
- Cellular Therapy & Immunobiology Working Party, EBMT, Paris, France; Hematology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Orla P Stewart
- Department of Haematology, King's College Hospital NHS Foundation Trust, London, UK
| | - Guillaume Dachy
- Hematology Service, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Francesca Del Bufalo
- Department of Hematology/Oncology, Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico, Bambino Gesù Children's Hospital, Rome, Italy
| | - Matteo Doglio
- Autoimmune Diseases Working Party, EBMT, Paris, France; Experimental Hematology Unit, Vita-Salute University, Milan, Italy; Pediatric Immuno-Hematology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Jan-Inge Henter
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Guillermo Ortí
- Department of Hematology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Zinaida Peric
- Transplant Complications Working Party, EBMT, Paris, France; Department of Haematology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Claire Roddie
- Research Department of Haematology, University College London, London, UK; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Niels W C J van de Donk
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Matthew J Frigault
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA; Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Pathology and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Annalisa Ruggeri
- Cellular Therapy & Immunobiology Working Party, EBMT, Paris, France; Practice Harmonisation and Guidelines Committee, EBMT, Paris, France; Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Onida
- Practice Harmonisation and Guidelines Committee, EBMT, Paris, France; Haematology and BMT Unit, ASST Fatebenefratelli-Sacco, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Isabel Sánchez-Ortega
- Practice Harmonisation and Guidelines Committee, EBMT, Paris, France; Executive Office, EBMT, Barcelona, Spain
| | - Ibrahim Yakoub-Agha
- Practice Harmonisation and Guidelines Committee, EBMT, Paris, France; Centre Hospitalier Universitaire de Lille, University of Lille, INSERM U1286, Lille, France
| | - Olaf Penack
- Department of Hematology, Oncology and Tumorimmunology, Charite University Hospital, Free University of Berlin and Humboldt University of Berlin, Berlin, Germany; National Center for Tumor Diseases, Berlin, Germany
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48
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Raj SS, Fei T, Fried S, Ip A, Fein JA, Leslie LA, Alarcon Tomas A, Leithner D, Peled JU, Corona M, Dahi PB, Danylesko I, Epstein-Peterson Z, Funnell T, Giralt SA, Jacoby E, Kedmi M, Landego I, Lin RJ, Parascondola A, Pascual L, Orozco N, Park JH, Palomba ML, Salles G, Saldia A, Schöder H, Sdayoor I, Shah GL, Scordo M, Shem-Tov N, Shimoni A, Slingerland J, Yerushalmi R, Nagler A, Greenbaum BD, Vickers AJ, Suh HC, Avigdor A, Perales MA, van den Brink MRM, Shouval R. An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma. Nat Med 2025; 31:1183-1194. [PMID: 40169864 PMCID: PMC12003198 DOI: 10.1038/s41591-025-03532-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/23/2025] [Indexed: 04/03/2025]
Abstract
Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60-4.91; P < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy.
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Grants
- P01 CA023766 NCI NIH HHS
- R01 CA228308 NCI NIH HHS
- R01 HL147584 NHLBI NIH HHS
- K08 CA282987 NCI NIH HHS
- UL1 TR002384 NCATS NIH HHS
- R01 CA228358 NCI NIH HHS
- K08 HL143189 NHLBI NIH HHS
- R01 HL123340 NHLBI NIH HHS
- P30 CA008748 NCI NIH HHS
- P01 AG052359 NIA NIH HHS
- The reported research was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) award number P01CA023766 and Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748). Dr. Roni Shouval reports grant support from an NIH-NCI K08CA282987, the Long Island Sound Chapter, Swim Across America, the Robert Hirschhorn Award, Comedy vs. Cancer, and the MSK Steven Greenberg Lymphoma Research.
- Dr. Sandeep S. Raj reports funding from the American Society for Transplantation and Cellular Therapy (ASTCT) New Investigator Award, the Louis V. Gerstner, Jr. Physician Scholars Award, and the Weill Cornell Medicine Clinical and Translational Science Center Grant 2UL1-TR-2384.
- Dr. Jonathan U. Peled reports funding from NHLBI NIH Award K08HL143189.
- Dr. Magdalena Corona’s work was supported by a grant from the Alfonso Martin Escudero Foundation.
- Dr. Marcel van den Brink reports funding from the National Cancer Institute (NCI; R01-CA228358, R01-CA228308, and P01-CA023766); National Heart, Lung, and Blood Institute (NHLBI; R01-HL123340 and R01-HL147584); National Institute on Aging (NIA; P01-AG052359), and Tri-Institutional Stem Cell Initiative. Additional funding was received from the Lymphoma Foundation, the Susan and Peter Solomon Family Fund, the Solomon Microbiome Nutrition and Cancer Program, Cycle for Survival, Parker Institute for Cancer Immunotherapy, Paula and Rodger Riney Multiple Myeloma Research Initiative, Starr Cancer Consortium, and Seres Therapeutics.
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Affiliation(s)
- Sandeep S Raj
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Teng Fei
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shalev Fried
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Andrew Ip
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Joshua A Fein
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Lori A Leslie
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Ana Alarcon Tomas
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Hematology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Doris Leithner
- Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan U Peled
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Magdalena Corona
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Parastoo B Dahi
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ivetta Danylesko
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Zachary Epstein-Peterson
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tyler Funnell
- Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Sergio A Giralt
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elad Jacoby
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Meirav Kedmi
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ivan Landego
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Internal Medicine, Max Rady Faculty of Health Sciences, Section of Medical Oncology and Hematology, University of Manitoba, Winnipeg, MB, Canada
| | - Richard J Lin
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Allison Parascondola
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lauren Pascual
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Natali Orozco
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Jae H Park
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - M Lia Palomba
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Gilles Salles
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amethyst Saldia
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Heiko Schöder
- Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Inbal Sdayoor
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gunjan L Shah
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Scordo
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Noga Shem-Tov
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Avichai Shimoni
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Ronit Yerushalmi
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Arnon Nagler
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Benjamin D Greenbaum
- Halvorsen Center for Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
| | - Andrew J Vickers
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hyung C Suh
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Abraham Avigdor
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Miguel-Angel Perales
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Roni Shouval
- Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
- Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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49
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Zhang Q, Dai J, Liu T, Rao W, Li D, Gu Z, Huang L, Wang J, Hou X. Targeting cardiac fibrosis with Chimeric Antigen Receptor-Engineered Cells. Mol Cell Biochem 2025; 480:2103-2116. [PMID: 39460827 DOI: 10.1007/s11010-024-05134-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 10/04/2024] [Indexed: 10/28/2024]
Abstract
Cardiac fibrosis poses a significant challenge in cardiovascular diseases due to its intricate pathogenesis, and there is currently no standardized and effective treatment approach. The fibrotic process entails the involvement of various cell types and molecular mechanisms, such as fibroblast activation and proliferation, increased collagen synthesis, and extracellular matrix rearrangement. Traditional therapies often fall short in efficacy or carry substantial side effects. However, recent studies have shown that Chimeric Antigen Receptor T (CAR-T) cells can selectively target and eliminate activated cardiac fibroblasts (CFs) in mice, leading to reduced cardiac fibrosis and improved myocardial tissue compliance. This breakthrough presents a new and promising avenue for treating cardiac fibrosis. Currently, CAR-T cell-based therapy for cardiac fibrosis is undergoing animal experimentation, indicating ample scope for enhancement. Future investigations could explore the application of CAR cell therapy in cardiac fibrosis treatment, including the potential of CAR-natural killer (CAR-NK) cells and CAR macrophages (CAR-M), offering novel insights and strategies for combating cardiac fibrosis.
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Affiliation(s)
- Qinghang Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Jinjie Dai
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Tianbao Liu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Wutian Rao
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200030, China
| | - Dan Li
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Zhengying Gu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Lin Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Jiayi Wang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Xumin Hou
- Hospital's Office, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
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50
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Yang P, Li CY, Liu SZ, Wang J, Chen YT, Zhang WL, Jing HM. Treatment outcomes of BTK inhibitors and venetoclax with or without anti-CD20 monoclonal antibody in relapsed or refractory mantle cell lymphoma. Ann Hematol 2025; 104:2361-2371. [PMID: 40278919 PMCID: PMC12052948 DOI: 10.1007/s00277-025-06379-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 04/18/2025] [Indexed: 04/26/2025]
Abstract
To characterise the effectiveness of Bruton tyrosine kinase inhibitors with venetoclax in patients with refractory or relapsed mantle cell lymphoma, with or without the addition of an anti-CD20 antibody. Progression-free and overall survival were estimated for forty-nine patients treated with Bruton tyrosine kinase inhibitors and venetoclax (200 mg, daily) or in combination with an anti-CD20 monoclonal antibody between June 2018 and February 2022 in China. The median number of treatment lines before combination therapy was three (range, 2-7). The median patient age was 62 years, with a male-to-female ratio of 3.08:1. Patients exhibited high-risk features including Ki-67 ≥ 30% (89.8%), blastoid/pleomorphic histology (36.7%), high-risk mantle cell lymphoma International Prognostic Index group (42.9%), complex karyotype (27.7%), TP53 mutations (71.4%), TP53 mutations combined with other high-risk gene mutations including KMT2D, NSD2, CCND1, NOTCH1, CDKN2A, NOTCH2 and SMARCA4 (57.1%), and progression of disease within 24 months (65.3%), with similar efficacy and prognosis to low-risk cases. Basic clinical and cytogenetic characteristics, as well as efficacy and survival, were similar between the dual and triple combination therapy groups (all p > 0.05). The optimal overall response and complete remission rates were 67.4% and 53.1%, respectively. The 3-year progression-free and overall survival rates were 37.5% and 50.8%, respectively. Eastern Cooperative Oncology Group≥2was an independent predictor of progression-free survival. Eastern Cooperative Oncology Group performance status ≥ 2, TP53 mutations combined with other high-risk gene mutationswere independent factors for poor overall survival. The most common adverse reactions were haematological and pulmonary infections. The leading cause of death was disease progression (19/22). The combination of Bruton tyrosine kinase inhibitors and venetoclax, demonstrated good efficacy in patients with refractory or relapsed mantle cell lymphoma, particularly in the early treatment. There was no efficacy or survival advantages of adding CD20 antibodies. Patients in the ultrahigh-risk group required more aggressive treatments.
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Affiliation(s)
- Ping Yang
- Department of Hematology, Peking University Third Hospital, No. 49 Huayuan N Rd Haidian District, Beijing, China
| | - Chun-Yuan Li
- Department of Hematology, Peking University Third Hospital, No. 49 Huayuan N Rd Haidian District, Beijing, China
| | - Shuo-Zi Liu
- Department of Hematology, Peking University Third Hospital, No. 49 Huayuan N Rd Haidian District, Beijing, China
| | - Jing Wang
- Department of Hematology, Peking University Third Hospital, No. 49 Huayuan N Rd Haidian District, Beijing, China
| | - Ying-Tong Chen
- Department of Hematology, Peking University Third Hospital, No. 49 Huayuan N Rd Haidian District, Beijing, China
| | - Wei-Long Zhang
- Department of Hematology, Peking University Third Hospital, No. 49 Huayuan N Rd Haidian District, Beijing, China
| | - Hong-Mei Jing
- Department of Hematology, Peking University Third Hospital, No. 49 Huayuan N Rd Haidian District, Beijing, China.
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