Optimally engineered HLA/peptide-specific CAR-T cells outperform TCR-T cells to eradicate solid tumors.

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Tumor-specific HLA/peptides (pHLA) are promising cancer targets.
• T cell receptor (TCR)-T cells and TCR-mimetic (TCRm) antibodies as chimeric antigen receptors (CARs) are two cell-based approaches to target pHLA-expressing tumors.

Purpose of the Study:

• To compare the efficacy of TCR-T cells and CAR-T cells targeting the same pHLA.
• To inform optimal strategies for deploying these cell therapies for clinical benefit.

Main Methods:

• Utilized HLA-A2/MAGEA4_230-239 as a model pHLA.
• Assessed the in vivo antitumor efficacy, proliferation, and phenotype of TCR-T and CAR-T cells.
• Investigated the impact of coengaging 41BB or IL-2 signaling pathways on TCR-T cell durability.

Main Results:

• TCR-T cells were more sensitive to low-density pHLA but exhibited transient in vivo efficacy and tumor relapse.
• CAR-T cells with costimulatory signaling achieved complete tumor regression.
• Enhancing TCR-T cell durability via 41BB or IL-2 signaling improved in vivo tumor control.

Conclusions:

• Established differential activities between human TCR-T and CAR-T cells targeting the same pHLA.
• Demonstrated that CAR-T cells can overcome limitations of TCR-T cells for durable responses.
• Provided insights for developing optimized cell-based targeting strategies for durable clinical responses in cancer therapy.