期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 584, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abd3595
关键词
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资金
- National Institutes of Health [5T32CA009071-38, GM73009, AR048522]
- JHU MacMillan Pathway to Independence Program
- Lustgarten Foundation for Pancreatic Cancer Research
- Virginia and D.K. Ludwig Fund for Cancer Research
- Commonwealth Fund
- National Institutes of Health Cancer Center Support Grants [P30 CA006973, CA62924, 5 T32 GM136577]
- Burroughs Wellcome Career Award for Medical Scientists
- NIH [R37 CA230400]
- Sol Goldman Sequencing Facility at Johns Hopkins
- Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
- SITC-Amgen Cancer Immunotherapy in Hematologic Malignancies Fellowship
Immunotherapies such as CAR T cells and bispecific antibodies have been successful in treating B cell malignancies, but require more selective targeting for T cell cancers. Targeting T cell cancers through TCR antigens provides a selective approach that preserves healthy T cells, maintaining cellular immunity.
Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen-targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR beta chain generated from 1 of 30 TCR beta chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (alpha-V5) or TRBV12 (alpha-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity.
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