Exploiting TCR Repertoire Analysis to Select Therapeutic TCRs for Cancer Immunotherapy

Area of Science:

• Immunotherapy
• Cancer Treatment
• T Cell Receptor (TCR) Engineering

Background:

• Immunotherapy has revolutionized cancer treatment, improving survival for patients resistant to conventional therapies.
• Current strategies like immune checkpoint inhibition and adoptive cell therapy enhance T cell function against cancer.
• TCR engineering targets the entire cancer proteome, including neo-antigens, offering broader applicability than CAR engineering.

Purpose of the Study:

• To explore TCR-focused approaches as a complement to antigen-focused strategies in TCR engineering for cancer immunotherapy.
• To investigate how individual patient TCR repertoire information can guide the selection of TCRs for adoptive cell therapy.
• To discuss methods for validating TCR candidates for therapeutic use, even when the target antigen is unknown.

Main Methods:

• Analyzing TCR clonality profiles and distribution within T cell subsets.
• Utilizing bioinformatic screening against comprehensive TCR databases.
• Employing in vitro methods to prioritize TCR candidates and confirm cancer reactivity while excluding self-reactivity.

Main Results:

• TCR repertoire analysis provides a basis for selecting therapeutic TCRs for adoptive cell therapy.
• Bioinformatic screening and TCR databases aid in identifying suitable TCR candidates.
• In vitro validation confirms TCR efficacy against cancer cells and safety on healthy autologous cells.

Conclusions:

• TCR-focused strategies, leveraging patient-specific TCR repertoire data, can enhance adoptive cell therapy for cancer.
• This approach allows for the selection and validation of TCRs for therapeutic use, even without prior knowledge of the target antigen.
• Combining TCR repertoire analysis with in vitro validation offers a robust framework for developing novel cancer immunotherapies.