CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows success in hematological cancers but limited efficacy in solid tumors.
• Solid tumor treatment challenges include identifying suitable antigens, immune evasion, and poor T cell infiltration.
• Targeting tumor vasculature presents an alternative strategy to overcome these limitations.

Purpose of the Study:

• To engineer T cells to target the tumor vasculature via chimeric antigen receptors (CARs) specific for CLEC14A.
• To evaluate the safety and efficacy of CLEC14A-specific CAR T cells in preclinical cancer models.

Main Methods:

• Generated CARs from CLEC14A-specific antibodies and expressed them in T cells.
• Conducted in vitro studies to assess T cell proliferation, cytokine release (IFN-γ), and cytotoxicity.
• Administered CAR T cells to mice with established solid tumors (Rip-Tag2, mPDAC, Lewis lung carcinoma) to evaluate in vivo efficacy and toxicity.

Main Results:

• Engineered T cells proliferated, released IFN-γ, and killed target cells in vitro.
• CAR T cell infusion in healthy mice showed no toxicity.
• Treated mice exhibited significant inhibition of tumor growth across three different cancer models.
• Reduced tumor burden correlated with decreased CLEC14A expression and vascular density in tumors.

Conclusions:

• Targeting tumor vasculature using CLEC14A-specific CAR T cells is a safe and effective strategy for solid tumors.
• This approach demonstrates potential as a widely applicable cancer therapy by targeting tumor neovasculature.