Targeting intracellular LMP2 with costimulatory signal-armed antibody-like TCR T cells

Area of Science:

• Immunology
• Cellular Therapy
• Oncology

Background:

• Engineered T cell therapies, including CAR T cells, primarily target surface antigens.
• Intracellular antigens present a challenge for conventional CAR T cell therapy.
• TCR-like T cells offer a strategy to target intracellular antigen-derived peptides presented by HLA molecules.

Purpose of the Study:

• To develop and evaluate antibody-like TCR (abTCR) T cells for targeting intracellular antigens.
• To assess the efficacy of abTCR T cells against Epstein-Barr virus (EBV)-associated lymphoproliferative diseases (EBV-LPDs).
• To compare the performance of abTCR T cells with conventional CAR T cells targeting the same epitope.

Main Methods:

• Engineered antibody-like TCR (abTCR) T cells targeting HLA-A*02:01-restricted LMP2426 peptides (EBV latency II protein).
• Evaluation of abTCR T cell function, including CD107A expression, cytotoxicity, and IFN-γ secretion.
• Development and testing of a costimulatory signal-armed abTCR (Co-abTCR) for enhanced T cell activity.
• In vivo assessment of tumoricidal efficacy.

Main Results:

• abTCR T cells demonstrated superior efficiency compared to classic CAR T cells against target cells presenting antigens.
• Enhanced CD107A expression, cytotoxicity, and IFN-γ secretion were observed with abTCR T cells.
• Co-abTCR T cells exhibited improved proliferation and in vivo tumoricidal efficacy.

Conclusions:

• Novel TCR-like T cell therapy targeting HLA-A*02/LMP2426 developed for EBV-LPDs.
• abTCR T cells provide a promising approach for targeting intracellular antigens in cancer immunotherapy.
• This strategy offers a potential therapeutic solution for EBV-associated malignancies.