@article{3606061d26934163adb005a0e9b1f702,
title = "Incorporation of bacterial immunoevasins to protect cell therapies from host antibody-mediated immune rejection",
abstract = "Cellular therapies are engineered using foreign and synthetic protein sequences, such as chimeric antigen receptors (CARs). The frequently observed humoral responses to CAR T cells result in rapid clearance, especially after re-infusions. There is an unmet need to protect engineered cells from host-versus-graft rejection, particularly for the advancement of allogeneic cell therapies. Here, utilizing the immunoglobulin G (IgG) protease “IdeS,” we programmed CAR T cells to defeat humoral immune attacks. IdeS cleavage of host IgG averted Fc-dependent phagocytosis and lysis, and the residual F(ab′)2 fragments remained on the surface, providing cells with an inert shield from additional IgG deposition. “Shield” CAR T cells efficiently cleaved cytotoxic IgG, including anti-CAR antibodies, detected in patient samples and provided effective anti-tumor activity in the presence of anti-cell IgG in vivo. This technology may be useful for repeated human infusions of engineered cells, more complex engineered cells, and expanding widespread use of “off-the-shelf” allogeneic cellular therapies.",
keywords = "anti-CAR IgG, CAR T cells, cell therapies, humoral response, IdeS, immunogenicity",
author = "Leila Peraro and Bourne, {Christopher M.} and Dacek, {Megan M.} and Enver Akalin and Park, {Jae H.} and Smith, {Eric L.} and Scheinberg, {David A.}",
note = "Funding Information: MSKCC has filed for patent protection for D.A.S., M.M.D., and L.P. for work related to this paper. D.A.S. has an equity interest in, consults for, or is on the Board of Sellas Life Sciences, Pfizer, Oncopep, Actinium, Co-Immune, Eureka, Repertoire, Sapience, Iovance, and Arvinas. J.H.P. receives funding from the Conquer Cancer Foundation of ASCO, a Leukemia and Lymphoma Society Career Development Grant, the Geoffrey Beene Cancer Foundation, a National Comprehensive Cancer Center Young Investigator Award, and an American Society of Hematology Scholar Junior Faculty Award. J.H.P. has consulted and provided an advisory role for Amgen, Novartis, Kite Pharma, Incyte, Allogene, Autolus, Intellia, Artiva, AstraZeneca, Pfizer, Takeda, and Servier. E.L.S. received funding from NCI K08 CA241400-02. E.L.S. has licensed patents and royalties with BMS, as well as consulting and receiving research funding. E.L.S. has consulted for Fate Therapeutics and Chimeric Therapeutics. Funding Information: This work was supported by NIH R01 CA55349, R35 CA241894, P01 CA23766, F31 CA239511, F31 CA254331, NIH P30 CA008748, and the Tudor Fund. L.P. and D.A.S. designed the study and cowrote the manuscript. L.P. C.M.B. and M.M.D. performed experiments. E.A. provided samples and expertise for anti-HLA-based experiments. E.L.S. and J.H.P. provided samples and expertise for experiments with CAR T cell patient sera. C.M.B. M.M.D. E.A. and E.L.S. edited the manuscript. MSKCC has filed for patent protection for D.A.S. M.M.D. and L.P. for work related to this paper. D.A.S. has an equity interest in, consults for, or is on the Board of Sellas Life Sciences, Pfizer, Oncopep, Actinium, Co-Immune, Eureka, Repertoire, Sapience, Iovance, and Arvinas. J.H.P. receives funding from the Conquer Cancer Foundation of ASCO, a Leukemia and Lymphoma Society Career Development Grant, the Geoffrey Beene Cancer Foundation, a National Comprehensive Cancer Center Young Investigator Award, and an American Society of Hematology Scholar Junior Faculty Award. J.H.P. has consulted and provided an advisory role for Amgen, Novartis, Kite Pharma, Incyte, Allogene, Autolus, Intellia, Artiva, AstraZeneca, Pfizer, Takeda, and Servier. E.L.S. received funding from NCI K08 CA241400-02. E.L.S. has licensed patents and royalties with BMS, as well as consulting and receiving research funding. E.L.S. has consulted for Fate Therapeutics and Chimeric Therapeutics. Funding Information: This work was supported by NIH R01 CA55349 , R35 CA241894 , P01 CA23766 , F31 CA239511 , F31 CA254331 , NIH P30 CA008748 , and the Tudor Fund . Publisher Copyright: {\textcopyright} 2021 The American Society of Gene and Cell Therapy",
year = "2021",
doi = "10.1016/j.ymthe.2021.06.022",
language = "English (US)",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
}