ROR1 CAR-T cells control tumor growth in an autochthonous genetically-engineered mouse model (GEMM) of lung cancer
Shivani Srivastava1, Sushma Yechan-Gunja1, Stanley Riddell1
1Fred Hutchinson Cancer Research Center, Seattle WA
Lung adenocarcinoma is the leading cause of cancer mortality worldwide. Immunotherapy using chimeric antigen receptor (CAR)-modified T cells has shown impressive efficacy in hematological malignancies, but CAR-T cells have been less effective in common solid tumors, which are more challenging to treat due to their immunosuppressive tumor microenvironment (TME). Previous studies of CAR-T cells in solid tumors have relied heavily on transplantable and xenograft tumor models, which lack clinically relevant TMEs. To systematically understand and overcome the obstacles that interfere with efficacy of CAR-T cells in solid tumors, we adapted a K-Ras mutated, p53-/- GEMM of lung adenocarcinoma to express the tumor-associated antigen ROR1, which is highly expressed in human lung adenocarcinomas but absent from vital adult tissues. Unlike transplantable models, this model accurately replicates initiation, progression, and development of the TME found in human lung cancer, providing a clinically relevant model for CAR-T cell therapy. We found that adoptive transfer of murine T cells modified with ROR1-CARs into mice bearing established lung tumors significantly reduced tumor growth compared to control T cells. Whereas all tumor nodules grew steadily in control mice, tumors in ROR1 CAR-T cell-treated mice either regressed or showed minimal growth in the first 6 weeks of treatment. ROR1 CAR-T cells were initially present at 5-fold higher number in the tumor relative to control T cells but eventually up-regulated activation/exhaustion markers like PD-1 and Tim3 by 10 weeks after treatment. Progressing tumors were characterized primarily by a PD-L1+ CD11b+Gr-1+ myeloid and CTLA-4+ FoxP3+ regulatory T cell infiltrate. Preliminary data indicate that combination therapy with anti-PD-L1 and anti-CTLA-4 antibodies enhance CAR-T cell mediated antitumor activity, suggesting this model will be useful for identifying combinations to translate to the clinic.
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