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Solid cancer-directed CAR T cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1
Yan Luo1,2, Martha E Gadd1, Yaqing Qie1
1Regenerative Immunotherapy and CAR-T Translational Research Program, Mayo Clinic, Jacksonville, FL, USA.
Abstract:
Chimeric antigen receptor (CAR) T cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T cell therapies against solid tumors.
Insights
A novel chimeric antigen receptor (CAR) T-cell therapy targeting PD-L1 shows promise for solid tumors. This therapy, MC9999, effectively targets both tumor cells and immunosuppressive cells, demonstrating broad applicability in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy faces challenges in solid tumors due to antigen scarcity and immunosuppressive tumor microenvironments (TME).
- Programmed death ligand 1 (PD-L1) is a key immune-evasive target upregulated by tumor and immunosuppressive cells within the TME.
- PD-L1 represents a universal target for overcoming immune suppression in various solid malignancies.
Purpose of the Study:
- To develop and evaluate a novel PD-L1-targeted CAR T-cell therapy (MC9999) for solid tumors.
- To assess the efficacy of MC9999 CAR T-cells against tumor cells and immunosuppressive cells within the TME.
- To validate the potential of MC9999 as a therapeutic strategy for diverse solid cancers.
Main Methods:
- Development of a humanized anti-PD-L1 monoclonal antibody for CAR construction.
- Engineering of MC9999 CAR T-cells designed for dual targeting of tumor and immunosuppressive cells.
- In vivo testing of MC9999 CAR T-cells in preclinical models of breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM).
- Assessment of MC9999 CAR T-cell cytotoxicity against various immunosuppressive cells (microglia, M2 macrophages) and patient-derived tumor-associated macrophages.
Main Results:
- MC9999 CAR T-cells demonstrated consistent antigen-specific antitumor effects across multiple solid tumor models.
- Intravenous administration of MC9999 CAR T-cells led to the eradication of intracranial GBM tumors, indicating blood-brain barrier penetration.
- MC9999 CAR T-cells exhibited potent cytolytic activity against immunosuppressive cells, including microglia and M2 macrophages.
- Cytotoxicity was confirmed against primary tumor-associated macrophages isolated from GBM tumors.
- Validation of the dual-targeting concept using CAR T-cells derived from cancer patients.
Conclusions:
- MC9999 CAR T-cell therapy is a promising approach for targeting PD-L1 in solid tumors.
- The dual-targeting capability of MC9999 effectively addresses both tumor cells and the immunosuppressive TME.
- MC9999 provides a strong foundation for developing next-generation CAR T-cell therapies for challenging solid cancers.
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