Journal
CANCER RESEARCH
Volume 71, Issue 10, Pages 3516-3527Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-3843
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Funding
- Cancer Center Core Grant [CA16672, PO1 CA100265, RO1 CA124782, RO1 CA120956, RO1 CA141303, R33 CA116127]
- Alex Lemonade Stand Foundation
- Burroughs Wellcome Fund
- Cancer Prevention Research Institute of Texas
- Gillson Longenbaugh Foundation
- Harry T. Mangurian Jr, Foundation
- Institute of Personalized Cancer Therapy
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- Miller Foundation
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- William Lawrence and Blanche Hughes Children's Foundation
- Mr. and Mrs. Joe H. Scales
- DOD [PR064229]
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Improving the therapeutic efficacy of T cells expressing a chimeric antigen receptor (CAR) represents an important goal in efforts to control B-cell malignancies. Recently an intrinsic strategy has been developed to modify the CAR itself to improve T-cell signaling. Here we report a second extrinsic approach based on altering the culture milieu to numerically expand CAR(+) T cells with a desired phenotype, for the addition of interleukin (IL)-21 to tissue culture improves CAR-dependent T-cell effector functions. We used electrotransfer of Sleeping Beauty system to introduce a CAR transposon and selectively propagate CAR(+) T cells on CD19(+) artificial antigen-presenting cells (aAPC). When IL-21 was present, there was preferential numeric expansion of CD19-specific T cells which lysed and produced IFN-gamma in response to CD19. Populations of these numerically expanded CAR(+) T cells displayed an early memory surface phenotype characterized as CD62L(+)CD28(+) and a transcriptional profile of naive T cells. In contrast, T cells propagated with only exogenous IL-2 tended to result in an overgrowth of CD19-specific CD4(+) T cells. Furthermore, adoptive transfer of CAR(+) T cells cultured with IL-21 exhibited improved control of CD19(+) B-cell malignancy in mice. To provide coordinated signaling to propagate CAR(+) T cells, we developed a novel mutein of IL-21 bound to the cell surface of aAPC that replaced the need for soluble IL-21. Our findings show that IL-21 can provide an extrinsic reprogramming signal to generate desired CAR(+) T cells for effective immunotherapy. Cancer Res; 71(10); 3516-27. (C) 2011 AACR.
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