Therapeutic high affinity T cell receptor targeting a KRAS^G12D cancer neoantigen

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Somatic mutations in KRAS drive cancer pathogenesis.
• Neoantigens from these mutations are promising targets for cancer immunotherapy.
• KRAS is the most frequently mutated oncogene in human cancers.

Purpose of the Study:

• To identify and develop an affinity-enhanced T cell receptor (TCR) targeting a KRAS G12D neoantigen.
• To investigate the molecular mechanisms underlying TCR specificity for mutant KRAS peptides.
• To create a bispecific molecule for potential cancer immunotherapy.

Main Methods:

• Engineering of a T cell receptor (TCR) with enhanced affinity for KRAS G12D peptide presented by HLA-A*11:01.
• Structural analysis using crystal structures.
• Thermodynamic analysis and molecular dynamics simulations to understand TCR-peptide interactions.
• Fusion of the enhanced TCR with a humanized anti-CD3 scFv.

Main Results:

• An affinity-enhanced TCR was developed, showing over one million-fold increased affinity for KRAS G12D over wild-type KRAS.
• TCR specificity was driven by differences in indirect electrostatic interactions, not just direct binding.
• The bispecific molecule selectively killed cancer cells expressing KRAS G12D.

Conclusions:

• Revealed a molecular mechanism for TCR selectivity against cancer neoantigens.
• Developed a soluble bispecific molecule with therapeutic potential against KRAS G12D-driven cancers.
• Demonstrated the feasibility of targeting common shared neoantigens in cancer immunotherapy.