Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models
Stefano Pierini, Rashid Gabbasov, Maria Cecília Oliveira-Nunes, Rehman Qureshi, Alison Worth, Shuo Huang, Karan Nagar, Crystal Griffin, Lurong Lian, Yumi Yashiro–Ohtani, Kayleigh C. Ross, Christopher Sloas, Michael Ball, Benjamin H. Schott, Poonam Sonawane, Linara Cornell, Daniel J. Blumenthal, Sotheavy Chhum, Nicholas G. Minutolo, Kerri Ciccaglione, Lauren Shaw, Isaac Zentner, Hyam I. Levitsky, Olga Shestova, Saar Gill, Bindu Varghese, Daniel Cushing, Sabrina Ceeraz DeLong, Sascha Abramson, Thomas Condamine, Michael Klichinsky
Abstract
We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors. Anti-PD1 monotherapy shows limited efficacy against HER2+ tumors. Here, the authors show that murine CAR macrophages (CAR-M) induce tumor microenvironment remodeling, T-cell mediated immunity and synergy with PD1 blockade, improving survival in immunocompetent female-mouse models of HER2+ solid tumors.