期刊
JOURNAL OF IMMUNOTHERAPY
卷 37, 期 4, 页码 204-213出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0000000000000032
关键词
CAR (chimeric antigen receptor); aAPC (artificial antigen presenting cell); gene therapy; Sleeping Beauty; T cell; ex vivo propagation; manufacturing
资金
- Cancer Center Core Grant [CA16672]
- RO1 [CA124782, CA120956, CA141303]
- R33 [CA116127]
- P01 [CA148600]
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas
- CLL Global Research Foundation
- DARPA (Defense Sciences Office)
- Department of Defense
- Estate of Noelan L. Bibler
- Gillson Longenbaugh Foundation
- Harry T. Mangurian, Jr, Fund for Leukemia Immunotherapy
- Institute of Personalized Cancer Therapy
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- MDACC's Sister Institution Network Fund
- Miller Foundation
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- William Lawrence and Blanche Hughes Children's Foundation
T cells genetically modified to stably express immunoreceptors are being assessed for therapeutic potential in clinical trials. T cells expressing a chimeric antigen receptor (CAR) are endowed with a new specificity to target tumor-associated antigen (TAA) independent of major histocompatibility complex. Our approach to nonviral gene transfer in T cells uses ex vivo numeric expansion of CAR(+) T cells on irradiated artificial antigen presenting cells (aAPC) bearing the targeted TAA. The requirement for aAPC to express a desired TAA limits the human application of CARs with multiple specificities when selective expansion through coculture with feeder cells is sought. As an alternative to expressing individual TAAs on aAPC, we expressed 1 ligand that could activate CAR(+) T cells for sustained proliferation independent of specificity. We expressed a CAR ligand (designated CARL) that binds the conserved IgG4 extracellular domain of CAR and demonstrated that CARL(+) aAPC propagate CAR(+) T cells of multiple specificities. CARL avoids technical issues and costs associated with deploying clinical-grade aAPC for each TAA targeted by a given CAR. Using CARL enables 1 aAPC to numerically expand all CAR(+) T cells containing the IgG4 domain, and simplifies expansion, testing, and clinical translation of CAR(+) T cells of any specificity.
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