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Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models
Stefano Pierini1, Rashid Gabbasov1, Maria Cecilia Oliveira-Nunes1
1Carisma Therapeutics Inc, Philadelphia, PA, USA.
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.
Insights
Engineered CAR macrophages (CAR-M) show promise in remodeling tumors and boosting immune responses. Combining CAR-M with checkpoint inhibitors enhances anti-tumor immunity and improves outcomes in preclinical models.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Human CAR macrophages (CAR-M) were previously developed for immunodeficient models.
- Tumor microenvironment (TME) modulation and T cell immunity are crucial for solid tumor treatment.
Purpose of the Study:
- Evaluate CAR-M in immunocompetent syngeneic models.
- Assess CAR-M's ability to remodel TME, induce T cell immunity, and sensitize tumors to PD1/PDL1 blockade.
Main Methods:
- Development of clinically relevant syngeneic models.
- In vivo administration of anti-HER2 CAR-M.
- Combination therapy with CAR-M and anti-PD1 (aPD1).
Main Results:
- Anti-HER2 CAR-M reduced tumor burden, prolonged survival, and remodeled TME.
- CAR-M increased intratumoral T cell and NK cell infiltration, inducing antigen spreading.
- CAR-M therapy conferred protection against antigen-negative relapse, indicating long-term immunity.
- Combination of CAR-M and aPD1 synergistically improved tumor control and survival in HER2+ tumors.
Conclusions:
- CAR-M therapy effectively remodels the TME and enhances anti-tumor immunity in immunocompetent models.
- CAR-M synergizes with PD1/PDL1 checkpoint blockade, offering a strategy for non-responsive tumors.
