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c-Jun Overexpressing CAR-T Cells are Exhaustion-Resistant and Mediate Enhanced Antitumor Activity

By Rachel Christina Lynn, Evan W Weber, David Gennert, Elena Sotillo, Peng Xu, Zinaida Good, Hima Anbunathan, Robert Jones, Victor Tieu, Jeffrey Granja, Charles DeBourcy, Robbie Majzner, Ansuman Satpathy, Stephen R. Quake, Howard Chang, Crystal L Mackall

Posted 29 May 2019
bioRxiv DOI: 10.1101/653725

CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of bZIP and IRF transcription factors that have been implicated in driving exhaustion. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in five different in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.

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