Basic Study: PDF OnlyRe-examination of MAGE-A3 as a T-cell Therapeutic TargetMartin, Aaron D.; Wang, Xueyin; Sandberg, Mark L.; Negri, Kathleen R.; Wu, Ming L.; Toledo Warshaviak, Dora; Gabrelow, Grant B.; McElvain, Michele E.; Lee, Bella; Daris, Mark E.; Xu, Han; Kamb, AlexanderAuthor Information A2 Biotherapeutics Inc., Agoura Hills, CA A.D.M. and X.W. contributed equally. PA.K., H.X., M.L.S., A.D.M., and X.W.: project conceptualization, planning, and experimental design. A.D.M., X.W., M.L.S., K.R.N., M.E.M., G.B.G., and B.L.: experimental execution. X.W., A.D.M., K.R.N., M.L.S., H.X., D.T.W., and M.L.W.: data analysis. A.K., H.X., A.D.M., and X.W.: manuscript drafting. Reprints: Alexander Kamb, A2 Biotherapeutics Inc., 30301 Agoura Hills Road, Agoura Hills, CA 91301 (e-mail: [email protected]). Received September 24, 2020 Accepted October 1, 2020 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Journal of Immunotherapy: December 04, 2020 - Volume Publish Ahead of Print - Issue - doi: 10.1097/CJI.0000000000000348 Open SDC PAP Metrics 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. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.