Tuning T cell receptor sensitivity through catch bond engineering.

Area of Science:

• Immunology
• Biophysics
• Oncology

Background:

• Adoptive cell therapy using engineered T cell receptors (TCRs) shows promise for cancer treatment.
• Tumor-reactive TCRs often have weak responses to target ligands (peptide-major histocompatibility complexes, pMHCs).
• Affinity maturation of TCRs can increase efficacy but may cause harmful off-target reactions and organ immunopathology.

Purpose of the Study:

• To develop an alternative strategy for isolating TCR mutants with high activation signals and low-affinity pMHC binding.
• To engineer TCRs that utilize catch bonds for enhanced T cell therapy.
• To improve the safety and efficacy of TCR-T cell therapy by minimizing cross-reactivity.

Main Methods:

• Isolation of TCR mutants exhibiting high activation signals and low-affinity pMHC binding via catch bond acquisition.
• Engineering analogs of a MAGE-A3-specific TCR.
• Comparison of engineered TCRs with a high-affinity, clinically tested TCR.

Main Results:

• Engineered TCR analogs maintained physiological affinities and showed enhanced target killing potency against MAGE-A3.
• The engineered TCRs demonstrated undetectable cross-reactivity.
• A high-affinity, clinically tested TCR showed lethal cross-reactivity with a cardiac antigen.

Conclusions:

• Catch bond engineering is a biophysically based strategy to enhance TCR sensitivity for T cell therapy.
• This approach can improve target killing potency while reducing the potential for adverse cross-reactivity.
• Catch bond engineering offers a safer alternative for developing TCR-T cell therapies.