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Affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10: strategy for selection of an

Ellen C Border1, Joseph P Sanderson2, Thomas Weissensteiner3

  • 1Protein Sciences, Adaptimmune Ltd., Abingdon, UK.

Oncoimmunology
|February 5, 2019
PubMed

Insights

Engineered T-cell receptors (TCRs) show promise for cancer immunotherapy. A novel X-scan method enhances TCR specificity, mitigating off-target toxicities for safer, more effective cancer treatments.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • T-cell receptors (TCRs) typically have low affinity for cancer antigens, limiting their anti-tumor efficacy.
  • Engineering TCRs for higher affinity is a key strategy in adoptive cancer immunotherapy.
  • Increased TCR affinity risks cross-reactivity with normal tissues, posing safety concerns.

Purpose of the Study:

  • To develop an in vitro testing strategy to mitigate off-target toxicities of engineered TCRs.
  • To identify the most specific and potent affinity-enhanced TCRs for cancer immunotherapy.
  • To assess TCR specificity using a comprehensive peptide substitution analysis.

Main Methods:

  • Developed an "X-scan" method involving systematic substitution of antigenic peptide sequences.
  • Searched the human proteome for potential cross-reactive sequences matching the TCR specificity profile.
  • Tested engineered TCRs against a panel of primary cell lines and performed biochemical assays.
  • Engineered affinity-enhanced TCRs targeting the MAGE-A10 cancer-testis antigen.

Main Results:

  • Identified several affinity-enhanced TCRs specific for MAGE-A10.
  • Two TCR candidates showed similar optimal affinities in standard assays.
  • The X-scan method successfully differentiated TCRs, identifying the most specific and potent candidate.
  • The X-scan approach revealed potential off-target reactivities not detected by conventional assays.

Conclusions:

  • The X-scan method is a valuable tool for selecting optimal TCRs for cancer immunotherapy.
  • This in vitro strategy effectively mitigates the risk of off-target toxicities in engineered TCRs.
  • The developed approach enhances the safety and efficacy of TCR-based cancer therapies.
Keywords:
MAGE-A10T-cell receptoradoptive T-cell therapycross-reactivityoff-targetpeptide scan

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