Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) shows promise for solid cancers but is limited by TIL accessibility and function.
• Identifying tumor-specific T cell receptors (TCRs) is crucial for enhancing engineered T cell therapies.

Purpose of the Study:

• To develop an efficient platform for identifying tumor-specific TCR genes from diagnostic tumor biopsies.
• To enable the use of engineered T cell therapy across a broader range of cancers.

Main Methods:

• A genetic screening approach was employed to detect antigen-reactive TCRs with high sensitivity and specificity.
• High-complexity TCR libraries were screened against multiplexed antigen libraries to identify HLA class I and II restricted TCRs.
• The platform was tested on melanoma and microsatellite-stable colorectal carcinoma samples.

Main Results:

• The platform efficiently identifies tumor-specific TCR genes, even from non-viable frozen core-needle biopsies.
• Both HLA class I and II restricted TCRs were successfully identified.
• Neoantigen-specific TCRs were identified from melanoma and low tumor mutational burden colorectal carcinoma samples.

Conclusions:

• The developed platform demonstrates pan-cancer potential for identifying TCRs for engineered T cell therapy.
• This technology can overcome limitations in TIL accessibility and function, broadening the application of adoptive cell therapy.
• The platform's ability to screen diverse TCR libraries against multiplexed antigens offers a sensitive and specific method for TCR discovery.