Open AccessRe-examination of MAGE-A3 as a T-cell Therapeutic Target
Author(s) -
Aaron D. Martin,
Xueyin Wang,
Mark L. Sandberg,
Kathleen R Negri,
Mei Wu,
Dora Toledo Warshaviak,
Grant B. Gabrelow,
Michele McElvain,
Bella Lee,
Mark Daris,
Xu Han,
Alexander Kamb
Publication year - 2020
Publication title -
journal of immunotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.805
H-Index - 92
eISSN - 1537-4513
pISSN - 1524-9557
DOI - 10.1097/cji.0000000000000348
Subject(s) - chimeric antigen receptor , peptide , antigen , receptor , major histocompatibility complex , neurotoxicity , cancer research , biology , cancer , immunology , computational biology , medicine , immunotherapy , biochemistry , toxicity
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.