@article{59f97af604a544eda35fbf0838accd87,
title = "Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia",
abstract = "Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1+ CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.",
keywords = "CART cell exhaustion, chimeric antigen receptor T cells, chronic lymphocytic leukemia, extracellular vesicles, microenvironment",
author = "Cox, {Michelle J.} and Lucien-Matteoni Fabrice and Reona Sakemura and Boysen, {Justin C.} and Yohan Kim and Paulina Horvei and {Manriquez Roman}, Claudia and Hansen, {Michael J.} and Tapper, {Erin E.} and Siegler, {Elizabeth L.} and Cynthia Forsman and Crotts, {Sydney B.} and Schick, {Kendall J.} and Mehrdad Hefazi and Ruff, {Michael W.} and Ismail Can and Mohamad Adada and Evandro Bezerra and {Kankeu Fonkoua}, {Lionel Aurelien} and Nevala, {Wendy K.} and Braggio, {Esteban D} and Wei Ding and Parikh, {Sameer A.} and Kay, {Neil Elliot} and Saad Kenderian",
note = "Funding Information: This work was supported through grants from the Mayo Clinic Center for Biomedical Discovery (to F.L., N.E.K., and S.S.K.), K12CA090628 (to S.S.K.), the Mayo Clinic K2R Career Development Program (to S.S.K.), the National Comprehensive Cancer Network (to S.S.K.), the Mayo Clinic Center for Individualized Medicine (to S.S.K.), the Foundation Predolin (to S.S.K.), and by the Exact Foundation (to S.S.K.). F.L. is funded by a postdoctoral fellowship from the Fonds de Recherche du Qu{\'e}bec - Sant{\'e} (FRQS). This work was supported in part by the Henry J. Predolin Foundation (to Biobank ). Funding Information: S.S.K. is an inventor on patents in the field of CAR immunotherapy that are licensed to Novartis (through an agreement between the Mayo Clinic, the University of Pennsylvania, and Novartis). M.J.C., R.S., and S.S.K. are inventors on patents in the field of CAR immunotherapy that are licensed to Humanigen (through the Mayo Clinic). S.S.K. is an inventor on patents in the field of CAR immunotherapy that are licensed to Mettaforge (through the Mayo Clinic). S.S.K. receives research funding from Kite, Gilead, Juno, Celgene, Novartis, Humanigen, MorphoSys, Tolero, Sunesis, Leahlabs, and Lentigen. M.J.C., F.L., N.E.K., and S.S.K. are inventors on patents related to this work. N.E.K. receives research funding from Acerta Pharma, BMS, Pharmacyclics, MEI Pharma, and Sunesis. N.E.K. has participated in Advisory Board meetings of Cytomx Therapy, Janssen, Juno Therapeutics, AstraZeneca, and Oncotracker, and on the DSMC for Agios and Cytomx Therapeutics. S.A.P. receives research funding from Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, AbbVie, and Ascentage Pharma. S.A.P. has participated in Advisory Board meetings of Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie (he was not personally compensated for his participation).",
year = "2021",
doi = "10.1016/j.ymthe.2020.12.033",
language = "English (US)",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
}