Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Cancer immunotherapies rely on T cell responses to neoantigens.
• Few predicted neoantigens are recognized by patient T cells, limiting treatment efficacy.
• Broadening neoantigen-specific T cell responses is a key therapeutic goal.

Purpose of the Study:

• To investigate if healthy donor T cells can recognize patient-specific neoantigens.
• To explore the potential of using T cells from healthy donors for cancer immunotherapy.
• To assess the efficacy of redirected T cells in recognizing and targeting cancer cells.

Main Methods:

• Prediction of human leukocyte antigen (HLA)-A*02:01-binding neoantigen epitopes from three cancer patients.
• Screening of naïve T cell repertoires from healthy blood donors for reactivity against predicted neoantigens.
• Identification and characterization of T cell receptors (TCRs) from reactive donor T cells.
• Testing the ability of TCR-redirected T cells to recognize and kill patient-derived melanoma cells.

Main Results:

• Healthy donor T cells recognized 11 out of 57 predicted neoantigen epitopes.
• Many recognized epitopes were not targeted by the patients' own tumor-infiltrating lymphocytes.
• T cells engineered with TCRs from donor T cells efficiently recognized and targeted patient melanoma cells with relevant mutations.

Conclusions:

• Naïve T cell repertoires in healthy donors are a valuable source of neoantigen-specific T cells.
• These "outsourced" immune responses can target cancer cells effectively.
• This approach provides a promising strategy for enhancing cancer immunotherapy efficacy.