Related Experiment Video
Updated: Nov 27, 2025
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Re-examination of MAGE-A3 as a T-cell Therapeutic Target
Aaron D Martin1, Xueyin Wang, Mark L Sandberg
1A2 Biotherapeutics Inc., Agoura Hills, CA.
Abstract:
In 2013, an innovative MAGE-A3-directed cancer therapeutic of great potential value was terminated in the clinic because of neurotoxicity. The safety problems were hypothesized to originate from off-target T-cell receptor activity against a closely related MAGE-A12 peptide. A combination of published and new data led us to test this hypothesis with current technology. Our results call into question MAGE-A12 as the source of the neurotoxicity. Rather, the data imply that an alternative related peptide from EPS8L2 may be responsible. Given the qualities of MAGE-A3 as an onco-testis antigen widely expressed in tumors and largely absent from normal adult tissues, these findings suggest that MAGE-A3 may deserve further consideration as a cancer target. As a step in this direction, the authors isolated 2 MAGE-A3 peptide-major histocompatibility complex-directed chimeric antigen receptors, 1 targeting the same peptide as the clinical T-cell receptor. Both chimeric antigen receptors have improved selectivity over the EPS8L2 peptide that represents a significant risk for MAGE-A3-targeted therapeutics, showing that there may be other options for MAGE-A3 cell therapy.
Insights
Neurotoxicity in a MAGE-A3 cancer therapeutic was not caused by MAGE-A12. New findings suggest an EPS8L2 peptide may be responsible, opening avenues for safer MAGE-A3 cancer therapies.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- A MAGE-A3 cancer therapeutic was halted due to neurotoxicity.
- The toxicity was hypothesized to stem from T-cell receptor cross-reactivity with MAGE-A12 peptides.
Purpose of the Study:
- To investigate the cause of neurotoxicity associated with MAGE-A3 cancer therapeutics.
- To identify the specific peptide responsible for off-target effects.
Main Methods:
- Re-evaluation of existing and new data using current technological approaches.
- Isolation and characterization of MAGE-A3 peptide-major histocompatibility complex-directed chimeric antigen receptors.
Main Results:
- MAGE-A12 was ruled out as the source of neurotoxicity.
- Evidence suggests an alternative peptide from EPS8L2 is the likely culprit.
- Developed chimeric antigen receptors show improved selectivity against the EPS8L2 peptide.
Conclusions:
- The MAGE-A3 antigen remains a viable target for cancer therapy.
- EPS8L2 peptide poses a risk for MAGE-A3-targeted therapeutics.
- Engineered chimeric antigen receptors offer potential for safer MAGE-A3 cell-based therapies.
