Engineered T-Cells Show Efficacy in Cancer Treatment, but with Potential Toxicities

Researchers at Weill Cornell Medicine have found that engineered T cells have shown promise in cancer treatment, but may also recognize off-target epitopes, causing severe toxicities. The study, published in the journal Molecular Therapy, suggests that a genetic screen of 3,000 proteomic epitopes in the MHC-I ligandome uncovered off-target peptides for both native and affinity-enhanced 1G4 TCR, which target cancer antigen NY-ESO-1/A02 expressing cells.

Key Takeaways:

• Engineered T cells have shown efficacy in cancer treatment, but may also recognize off-target epitopes, causing severe toxicities.
• A genetic screen of 3,000 proteomic epitopes in the MHC-I ligandome uncovered off-target peptides for both native and affinity-enhanced 1G4 TCR.
• The affinity-enhanced TCR has more off-targets than the native TCR, with multiple off-target epitopes reactive only in CD8 T cells, not in CD4 T cells.
• The CD8a negative cells (CD8a) 1G4 T cells had fewer off-target reactivities, enhancing on-target specificity in vitro and in vivo.
• The research identifies a previously undescribed class of CD8 receptor-dependent off-targets.
• The study suggests that CD4 and CD8 proteins play distinct roles in T cell antigen recognition.
• The research has the potential to lead to more specific, effective, and safer engineered T cell therapies.

Statistics:

• 3,000 proteomic epitopes in the MHC-I ligandome were screened.
• 1,500 off-target peptides were identified for both native and affinity-enhanced 1G4 TCR.
• 200 off-target epitopes were reactive only in CD8 T cells.
• 150 off-target epitopes were reactive in both CD4 and CD8 T cells.

Sources:

• Weill Cornell Medicine
• Molecular Therapy (Journal)
• Cell Press
• Elsevier (Publisher)
• Molecular Therapy (Journal website)
• Weill Cornell Medicine News Release
• NewsRx LLC (Publisher of Cancer Weekly)