Journal
MOLECULAR THERAPY
Volume 25, Issue 1, Pages 249-258Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2016.10.016
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Funding
- NIH-NCI [P01 CA094237, P50 CA126752, P50 CA186784]
- Adrienne Helis Malvin Medical Research Foundation
- Mentored Research Scholars Grant in Applied and Clinical Research from American Cancer Society [MRSG-14-197-01-LIB]
- Elsa U. Pardee Foundation
- Ruth L. Kirschstein National Research Service Award from the NIH [F32 CA189423]
- Dan L. Duncan Chair
- Fayez Sarofim Chair
- Flow Cytometry and Cell and Vector Production shared resources in the Dan L. Duncan Comprehensive Cancer Center support grant [P30 CA125123]
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The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function. Thus, to protect our cells from the immunosuppressive cytokine IL-4, we generated an inverted cytokine receptor in which the IL-4 receptor exodomain was fused to the IL-7 receptor endodomain (4/7ICR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL-4 and instead promote T cell proliferation. We now demonstrate the suppressed activity of CAR T cells in tumor-milieu conditions and the ability of CAR/ICR T cells to thrive in an IL-4-rich microenvironment, resulting in enhanced antitumor activity. Importantly, CAR/ICR T cells remained both antigen and cytokine dependent. These findings support the benefit of combining the 4/7 ICR with CAR-PSCA to treat pancreatic cancer, a PSCA-expressing tumor characterized by a dense immunosuppressive environment rich in IL-4.
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