T-cell receptors identified by a personalized antigen-agnostic screening approach target shared neoantigen KRAS Q61H

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptive cell therapy (ACT) using T-cell receptors (TCRs) shows promise for advanced solid cancers.
• Current TCR selection requires known target antigens, limiting treatment accessibility.
• Developing antigen-agnostic methods is crucial for expanding ACT applications.

Purpose of the Study:

• To develop and validate a method for identifying tumor-specific T-cell clonotypes without prior antigen knowledge.
• To advance TCR-engineered T-cell manufacturing for patients with aggressive solid cancers.
• To explore potential therapeutic targets for KRAS-mutated non-small cell lung cancer (NSCLC).

Main Methods:

• Comparing TCRβ-chain repertoires of tumor-infiltrating lymphocytes (TILs) and adjacent tissue-resident lymphocytes.
• Utilizing tumor-to-nontumor frequency ratios and scRNA-Seq for clonotype selection.
• Engineering TCR-T cells and screening for reactivity against autologous tumors and cancer cell lines.

Main Results:

• Identified tumor-specific clonotypes in six of seven NSCLC patients.
• Demonstrated reactivity of predicted clonotypes against autologous tumors in three patients.
• Engineered TCR-T cells recognized autologous tumors and HLA-matched NSCLC cell lines.
• Discovered three TCRs recognizing KRAS Q61H-mutated peptide presented by HLA-A*01:01, found in tumor relapse and cell-free DNA.

Conclusions:

• The developed method enables antigen-agnostic identification of tumor-specific TCRs for ACT.
• This approach can broaden patient eligibility for TCR-T cell therapy.
• The identified TCRs targeting KRAS Q61H present a potential therapeutic strategy for HLA-A*01:01 positive NSCLC patients.