To improve responses in solid tumors, Pierini et al. evaluated the efficacy of engineered macrophages (CAR-M) +/- anti-PD-1 in clinically relevant, fully immunocompetent, syngeneic mouse models. Both regional (intratumoral) and systemic therapy with anti-HER2 CD3-ζ CAR-M remodeled the TME (increased DCs and myeloid cells), activated TILs (CD4+ and CD8+ T cells, NK cells), induced antigen spreading, protected against antigen-negative relapses, and depended on endogenous T cells for efficacy. CAR-M therapy with anti-PD-1 significantly reduced tumor burden and prolonged survival in mice with solid tumors with limited sensitivity to anti-PD-1 alone.
Contributed by Katherine Turner
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.
Author Info: (1) Carisma Therapeutics Inc, Philadelphia, PA, USA. (2) Carisma Therapeutics Inc, Philadelphia, PA, USA. (3) Carisma Therapeutics Inc, Philadelphia, PA, USA. (4) Carisma Therapeut
Author Info: (1) Carisma Therapeutics Inc, Philadelphia, PA, USA. (2) Carisma Therapeutics Inc, Philadelphia, PA, USA. (3) Carisma Therapeutics Inc, Philadelphia, PA, USA. (4) Carisma Therapeutics Inc, Philadelphia, PA, USA. (5) Carisma Therapeutics Inc, Philadelphia, PA, USA. (6) Carisma Therapeutics Inc, Philadelphia, PA, USA. (7) Carisma Therapeutics Inc, Philadelphia, PA, USA. (8) Carisma Therapeutics Inc, Philadelphia, PA, USA. (9) Carisma Therapeutics Inc, Philadelphia, PA, USA. (10) Carisma Therapeutics Inc, Philadelphia, PA, USA. (11) Carisma Therapeutics Inc, Philadelphia, PA, USA. (12) Carisma Therapeutics Inc, Philadelphia, PA, USA. (13) Carisma Therapeutics Inc, Philadelphia, PA, USA. (14) Carisma Therapeutics Inc, Philadelphia, PA, USA. (15) Carisma Therapeutics Inc, Philadelphia, PA, USA. (16) Carisma Therapeutics Inc, Philadelphia, PA, USA. (17) Carisma Therapeutics Inc, Philadelphia, PA, USA. (18) Carisma Therapeutics Inc, Philadelphia, PA, USA. (19) Carisma Therapeutics Inc, Philadelphia, PA, USA. (20) Carisma Therapeutics Inc, Philadelphia, PA, USA. (21) Carisma Therapeutics Inc, Philadelphia, PA, USA. (22) Carisma Therapeutics Inc, Philadelphia, PA, USA. (23) Carisma Therapeutics Inc, Philadelphia, PA, USA. (24) Center for Cellular Immunotherapies, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. (25) Center for Cellular Immunotherapies, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. (26) Carisma Therapeutics Inc, Philadelphia, PA, USA. (27) Carisma Therapeutics Inc, Philadelphia, PA, USA. (28) Carisma Therapeutics Inc, Philadelphia, PA, USA. (29) Carisma Therapeutics Inc, Philadelphia, PA, USA. (30) Carisma Therapeutics Inc, Philadelphia, PA, USA. (31) Carisma Therapeutics Inc, Philadelphia, PA, USA. michael.klichinsky@carismatx.com.
