Journal
CANCER DISCOVERY
Volume 7, Issue 11, Pages 1238-1247Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0538
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Funding
- Alex's Lemonade Stand Foundation [P01CA094237, 1RO1CA173750]
- Howard Hughes Medical Institutes Med into Grad Initiative
- Cytometry and Cell Sorting Core at Baylor College of Medicine
- NIH [P30 AI036211, P30 CA125123, S10 RR024574]
- [T32DK060445]
- [HL092332]
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Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer. (C) 2017 AACR.
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