期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 10, 期 12, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2022-005934
关键词
Cell Engineering; Cytotoxicity; Immunologic; Hematologic Neoplasms; Receptors; Chimeric Antigen; Immunotherapy; Adoptive
资金
- National Institute of Allergy and Infectious Diseases
- National Cancer Institute [R37 AI34495]
- Children's Cancer Research Fund [P01 CA065493, R01 CA208398]
- Randy Shaver Cancer Research and Community Fund
- Masonic Cancer Center, University of Minnesota
Current FDA-approved CAR-T cell therapies for B-cell malignancies are effective but can increase morbidity and mortality. This study compared the performances of regulatable and constitutively active CAR-T cells, and found that regulatable CAR-T cells have the potential for improved efficacy and reduced toxicity.
Current Food and Drug Administration (FDA)-approved CD19-specific chimeric antigen receptor (CAR) T-cell therapies for B-cell malignancies are constitutively active and while efficacious, can cause morbidity and mortality. Their toxicities might be reduced if CAR T-cell activity was regulatable rather than constitutive. To test this, we compared the efficacies and morbidities of constitutively active (conventional) and regulatable (switchable) CAR (sCAR) T-cells specific for human CD19 (huCD19) in an immune-competent huCD19(+) transgenic mouse model.Conventional CAR (CAR19) and sCAR T-cells were generated by retrovirally transducing C57BL/6 (B6) congenic T-cells with constructs encoding antibody-derived single chain Fv (sFv) fragments specific for huCD19 or a peptide neoepitope (PNE), respectively. Transduced T-cells were adoptively transferred into huCD19 transgenic hemizygous (huCD19(Tg/0)) B6 mice; healthy B-cells in these mice expressed huCD19(Tg). Prior to transfer, recipients were treated with a lymphodepleting dose of cyclophosphamide to enhance T-cell engraftment. In tumor therapy experiments, CAR19 or sCAR T-cells were adoptively transferred into huCD19(Tg/0) mice bearing a syngeneic B-cell lymphoma engineered to express huCD19. To regulate sCAR T cell function, a switch protein was generated that contained the sCAR-specific PNE genetically fused to an anti-huCD19 Fab fragment. Recipients of sCAR T-cells were injected with the switch to link sCAR effector with huCD19(+) target cells. Mice were monitored for survival, tumor burden (where appropriate), morbidity (as measured by weight loss and clinical scores), and peripheral blood lymphocyte frequency.CAR19 and sCAR T-cells functioned comparably regarding in vivo expansion and B-cell depletion. However, sCAR T-cells were better tolerated as evidenced by the recipients' enhanced survival, reduced weight loss, and improved clinical scores. Discontinuing switch administration allowed healthy B-cell frequencies to return to pretreatment levels.In our mouse model, sCAR T-cells killed huCD19(+) healthy and malignant B-cells and were better tolerated than CAR19 cells. Our data suggest sCAR might be clinically superior to the current FDA-approved therapies for B-cell lymphomas due to the reduced acute and chronic morbidities and mortality, lower incidence and severity of side effects, and B-cell reconstitution on cessation of switch administration.
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