Editors' ChoiceCancer

CAR T cells engage in anticancer martial arts

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Science Translational Medicine  18 Jan 2017:
Vol. 9, Issue 373, eaal4996
DOI: 10.1126/scitranslmed.aal4996

Abstract

A clever redesign of the chimeric antigen receptor T cell concept turns a cancer-mediated immunosuppressive cytokine into a growth signal.

In martial arts such as judo, fighters turn their opponents’ force against them, thus doubling their own strength. In the sparring between T cells and cancer, the immune attack by T cells is often weakened upon exposure to immunosuppressive signals produced by the cancer. These signals include inhibitory cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), or tumor growth factor beta (TGF-β), which can be produced by cellular or stromal components of the tumor microenvironment.

Mohammed and colleagues retooled chimeric antigen receptor (CAR) T cells to sidestep and even benefit from the production of immunosuppressive cytokines by cancer. The authors used a model system consisting of a pancreatic cancer cell line that produces IL-4 and targeted it with CAR T cells directed against prostate stem cell antigen (PSCA), a cell-surface protein that is highly expressed on most pancreatic cancer cells but not on normal cells. They first confirmed the observation that CAR T cells exposed to IL-4 had markedly diminished proliferative capacity compared with CAR T cells exposed to the classic stimulatory cytokine IL-2. They then produced a new protein construct incorporating the extracellular domain of the inhibitory IL-4 receptor fused to the intracellular domain of the stimulatory IL-7 receptor to produce an inverted cytokine receptor (ICR), reasoning that because these receptors belong to the common gamma chain family and share a requirement for heterodimerization with the common gamma chain, the chimeric cytokine receptor would be functional in T cells. This hypothesis was correct, and T cells expressing the ICR exhibited increased rather than decreased proliferation upon exposure to IL-4. The authors then coexpressed anti-PSCA CAR and the ICR in T cells and showed enhanced T cell functions such as proliferation and markedly increased killing of pancreatic cancer xenografts in vivo, compared with the appropriate controls.

There was an additional potential benefit of this “switch” receptor approach, one that was not clearly articulated by the authors but that could represent an important advance. Because the ICR-expressing T cells require both an IL-4 signal and a PSCA signal to proliferate and survive in vivo, we would expect that normal tissues that do not produce IL-4 would not be attacked by adoptively transferred CAR T cells even if they express small amounts of PSCA. This strategy could render CAR T cells more effective as well as safer.

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