Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade.

Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the Kras ^LSL-G12D/+ ;p53 ^f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.
Competing Interests: Declaration of Interests S.S. and S.R.R. are inventors on a patent (“Immunogenic chemotherapy markedly enhances the efficacy of ROR1 CAR T cells in lung adenocarcinoma”; PCT/US2018/049812) filed by Fred Hutchinson Cancer Research Center and licensed by Lyell Immunopharma. S.S. holds equity and has served as a consultant for Lyell Immunopharma. D.G.M. has received research funding from Kite Pharma, Juno Therapeutics, and Celgene, and has served on advisory boards for Kite Pharma, Gilead, Genentech, Novartis, and Eureka Therapeutics. S.R.R. was a founder, has served as an advisor, and has patents licensed to Juno Therapeutics; is a founder of and holds equity in Lyell Immunopharma; and has served on the advisory boards for Adaptive Biotechnologies and Nohla. C.R. is named inventor on US Patent 9,758,586 claiming anti-ROR1 monoclonal antibodies R11 and R12 and is on the advisory board of NBE-Therapeutics. No potential conflicts of interest were disclosed by the other authors.
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