Tuning T cell receptor sensitivity through catch bond engineering
Xiang Zhao1, Elizabeth M Kolawole2, Waipan Chan3
1Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abstract:
Adoptive cell therapy using engineered T cell receptors (TCRs) is a promising approach for targeting cancer antigens, but tumor-reactive TCRs are often weakly responsive to their target ligands, peptide-major histocompatibility complexes (pMHCs). Affinity-matured TCRs can enhance the efficacy of TCR-T cell therapy but can also cross-react with off-target antigens, resulting in organ immunopathology. We developed an alternative strategy to isolate TCR mutants that exhibited high activation signals coupled with low-affinity pMHC binding through the acquisition of catch bonds. Engineered analogs of a tumor antigen MAGE-A3-specific TCR maintained physiological affinities while exhibiting enhanced target killing potency and undetectable cross-reactivity, compared with a high-affinity clinically tested TCR that exhibited lethal cross-reactivity with a cardiac antigen. Catch bond engineering is a biophysically based strategy to tune high-sensitivity TCRs for T cell therapy with reduced potential for adverse cross-reactivity.
Insights
Engineered T cell receptors (TCRs) can be improved for cancer therapy by using catch bonds. This strategy enhances tumor cell killing while reducing dangerous off-target reactions, improving TCR-T cell therapy safety.
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.
