Mesothelin-Specific CAR T Cells Target Ovarian Cancer

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Ovarian cancer lacks effective treatments, necessitating novel therapeutic strategies.
• Mesothelin (MSLN) is a promising target for ovarian cancer immunotherapy.
• Chimeric antigen receptor (CAR) T-cell therapy offers a potential new avenue for cancer treatment.

Purpose of the Study:

• To evaluate the efficacy of two second-generation MSLN-directed CAR T-cell therapies in preclinical ovarian cancer models.
• To investigate the mechanisms of CAR T-cell activity and resistance within the ovarian tumor microenvironment.

Main Methods:

• Orthotopic mouse models of ovarian cancer were established using SKOV3 cells.
• Two MSLN-directed CAR T-cell constructs, M28z (CD28 costimulatory domain) and MBBz (4-1BB costimulatory domain), were tested.
• Tumor-infiltrating CAR T cells and tumor cells were analyzed for immune checkpoint molecule expression (PD-1, LAG3, PD-L1, HLA-DR).
• Plasma soluble factors were profiled to correlate with treatment outcomes.

Main Results:

• M28z CAR T cells significantly prolonged survival but did not achieve persistent tumor control.
• MBBz CAR T cells induced long-term remission in a subset of mice, despite lower initial response rates.
• CAR T cells upregulated coinhibitory receptors (PD-1, LAG3) in response to MSLN+ tumors expressing cognate ligands (PD-L1, HLA-DR).
• Elevated T-cell secreted factors in plasma correlated with improved survival, increased CD8+ T-cell infiltration, reduced T-cell exhaustion, and higher HLA-DR expression on tumor cells.

Conclusions:

• MSLN-directed CAR T cells demonstrate therapeutic potential for ovarian cancer.
• Coinhibitory pathways in the tumor microenvironment can limit CAR T-cell efficacy.
• Further optimization of CAR T-cell constructs and combination strategies may enhance antitumor immunity in ovarian cancer.