@article{ab142b19e1dd46ec98ea7dc999515de1,
title = "A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors",
abstract = "Background: The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection. Methods: We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors. Findings: We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhibiting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic antibodies that activate the CD16 Fc receptor. Conclusions: Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors. Funding: Funded by Fate Therapeutics and NIH (R01CA238039).",
keywords = "MICA/B, NK cell, Pre-clinical research, antigen heterogeneity, cell therapy, chimeric antigen receptor, iPSC, pan tumor antigen, solid tumor, stress ligand, tumor immune evasion",
author = "John Goulding and Yeh, {Wen I.} and Bryan Hancock and Robert Blum and Tianhao Xu and Yang, {Bi Huei} and Chang, {Chia Wei} and Brian Groff and Earl Avramis and Mochtar Pribadi and Yijia Pan and Chu, {Hui Yi} and Shohreh Sikaroodi and Lauren Fong and Nicholas Brookhouser and Thomas Dailey and Miguel Meza and Matthew Denholtz and Evelyn Diaz and Judy Martin and Peter Szabo and Sarah Cooley and {Ferrari de Andrade}, Lucas and Lee, {Tom T.} and Ryan Bjordahl and Wucherpfennig, {Kai W.} and Bahram Valamehr",
note = "Funding Information: We would like to acknowledge the following for their support that enabled the publication of this manuscript: Christine Chen, Antonio Fernandez-Perez, and all of process development staff for generating 3MICA/B CAR iNK cells and optimizing various aspects of the differentiation and expansion process; Fate Therapeutic{\textquoteright}s flow cytometry core for maintaining critical equipment and troubleshooting multiplexed phenotypic staining panels; and Jode Goodridge, Alex Garcia, Kyla Omilusik, and Yu Cai for critical reading of the manuscript. Research reported in this paper was funded by Fate Therapeutics and NIH (R01CA238039). Funding Information: We would like to acknowledge the following for their support that enabled the publication of this manuscript: Christine Chen, Antonio Fernandez-Perez, and all of process development staff for generating 3MICA/B CAR iNK cells and optimizing various aspects of the differentiation and expansion process; Fate Therapeutic's flow cytometry core for maintaining critical equipment and troubleshooting multiplexed phenotypic staining panels; and Jode Goodridge, Alex Garcia, Kyla Omilusik, and Yu Cai for critical reading of the manuscript. Research reported in this paper was funded by Fate Therapeutics and NIH (R01CA238039). Conceptualization, J.G. T.T.L. R.B. K.W.W. and B.V.; methodology and investigation, J.G. W.-I.Y. B.H. R.B. T.X. T.D. M.M. M.D. E.D. and J.M.; resources, J.G. W.-I.Y. B.H. R.B. B.-H.Y. B.G. E.A. M.P. Y.P. H.-Y.C. S.S. L.F. N.B. and L.A.; writing – original draft, J.G. W.-I.Y. and R.B.; writing – review & editing, J.G. R.B. K.W.W. and B.V.; visualization, J.G. W.-I.Y. B.H. T.X. and M.D.; supervision, J.G. P.S. S.C. R.B. K.W.W. and B.V.; project administration, J.G. R.B. K.W.W. and B.V.; funding acquisition, K.W.W. and B.V. J.G. W.-I.Y. B.H. and R.B. performed and reviewed statistical analysis. J.G. B.H. and R.B. had unrestricted access to all data. All authors agreed to submit the manuscript; read and approved the final draft; and take full responsibility of its content, including the accuracy of the data. J.G. W.-I.Y. B.H. R.B. T.X. B.-H.Y. C.C. B.G. E.A. M.P. Y.P. H.-Y.C. S.S. L.F. N.B. T.D. M.M. M.D. E.D. J.M. P.S. S.C. T.T.L. R.B. and B.V. are employees and shareholders at Fate Therapeutics. 3MICA/B binder sequence was licensed by Fate Therapeutics from Dana-Farber Cancer Institute. K.W.W. serves on the scientific advisory board of T-Scan Therapeutics, SQZ Biotech, and Nextechinvest and receives sponsored research funding from Novartis. K.W.W. is a co-founder of Immunitas, a biotech company. These activities are not related to the research reported in this publication. We support inclusive, diverse, and equitable conduct of research. Funding Information: J.G., W.-I.Y., B.H., R.B., T.X., B.-H.Y., C.C., B.G., E.A., M.P., Y.P., H.-Y.C., S.S., L.F., N.B., T.D., M.M., M.D., E.D., J.M., P.S., S.C., T.T.L., R.B., and B.V. are employees and shareholders at Fate Therapeutics. 3MICA/B binder sequence was licensed by Fate Therapeutics from Dana-Farber Cancer Institute. K.W.W. serves on the scientific advisory board of T-Scan Therapeutics, SQZ Biotech, and Nextechinvest and receives sponsored research funding from Novartis. K.W.W. is a co-founder of Immunitas, a biotech company. These activities are not related to the research reported in this publication. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = jul,
day = "14",
doi = "10.1016/j.medj.2023.04.004",
language = "English",
volume = "4",
pages = "457--477.e8",
journal = "Med",
issn = "2666-6359",
publisher = "Cell Press",
number = "7",
}