@article{742f18fb7c9842b7947b37691afbbe39,
title = "Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction",
abstract = "Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-offunction screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. SIGNIFICANCE: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigenindependent resistance to CAR therapy.",
author = "Nathan Singh and Lee, {Yong Gu} and Olga Shestova and Pranali Ravikumar and Hayer, {Katharina E.} and Hong, {Seok Jae} and Lu, {Xueqing Maggie} and Raymone Pajarillo and Sangya Agarwal and Shunichiro Kuramitsu and Orlando, {Elena J.} and Mueller, {Karen Thudium} and Good, {Charly R.} and Berger, {Shelley L.} and Ophir Shalem and Weitzman, {Matthew D.} and Frey, {Noelle V.} and Maude, {Shannon L.} and Grupp, {Stephan A.} and June, {Carl H.} and Saar Gill and Marco Ruella",
note = "Funding Information: N. Singh holds patents related to CAR T-cell therapy at the University of Pennsylvania. E.J. Orlando is an investigator at Novartis and has ownership interest (including patents) in the same. K.T. Mueller is a clinical pharmacologist at Novartis Pharmaceuticals. S.L. Berger has received honoraria from the speakers bureaus of University of North Carolina and LMU Munich. S.L. Maude is a consultant for Novartis Pharmaceuticals and Kite Pharma and reports receiving commercial research support from Novartis Pharmaceuticals. S.A. Grupp is a SAB/consultant for Novartis, a consultant for CBMG and TCR2, a CAB for Cellectis, and a SAB for Adaptimmune and reports receiving commercial research grants from Novartis and Servier. C.H. June has ownership interest (including patents) in Tmunity and Novartis. S. Gill reports receiving a commercial research grant from Novartis. M. Ruella is an advisory board member for AbClon and a consultant for NanoString, reports receiving a commercial research grant from AbClon, has received honoraria from the speakers bureau of NanoString, and has ownership interest in patents in the CAR T field. No potential conflicts of interest were disclosed by the other authors. Funding Information: The authors thank A. Hoshino, A. Green, and I. Maillard for valuable discussions and intellectual input, S. Lacey, F. Chen, and N. Kengle for technical assistance with cytokine quantification assays, and J. Schug for informative discussions about guide library sequencing. One of the chimeric antigen receptors used in this study was obtained under a material transfer agreement from Dr. Dario Campana, Dr. Chihaya Imai, and St. Jude Children?s Research Hospital (33) and was subsequently modified by cloning into a lentiviral vector and expressed with a eukaryotic promoter (34). The research was supported by the Society of Immunotherapy for Cancer Holbrook Kohrt Immunotherapy Translational Fellowship (N. Singh), Breakthrough Bike Challenge Buz Cooper Scholarship (N. Singh), NCI K08CA194256 (S. Gill), American Society of Hematology Scholar Award, NCI 1K99CA212302, and R00CA212302 (M. Ruella), Mark Foundation ASPIRE award (M. Ruella), University of Pennsylvania-Novartis Alliance (S. Gill and C.H. June), and NCI 1P01CA214278 and R01CA226983 (C.H. June). Funding Information: The authors thank A. Hoshino, A. Green, and I. Maillard for valuable discussions and intellectual input, S. Lacey, F. Chen, and N. Kengle for technical assistance with cytokine quantification assays, and J. Schug for informative discussions about guide library sequencing. One of the chimeric antigen receptors used in this study was obtained under a material transfer agreement from Dr. Dario Campana, Dr. Chihaya Imai, and St. Jude Children{\textquoteright}s Research Hospital (33) and was subsequently modified by cloning into a lentiviral vector and expressed with a eukaryotic promoter (34). The research was supported by the Society of Immunotherapy for Cancer Holbrook Kohrt Immunotherapy Translational Fellowship (N. Singh), Break-through Bike Challenge Buz Cooper Scholarship (N. Singh), NCI K08CA194256 (S. Gill), American Society of Hematology Scholar Award, NCI 1K99CA212302, and R00CA212302 (M. Ruella), Mark Foundation ASPIRE award (M. Ruella), University of Pennsylvania-Novartis Alliance (S. Gill and C.H. June), and NCI 1P01CA214278 and R01CA226983 (C.H. June). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = apr,
doi = "10.1158/2159-8290.CD-19-0813",
language = "English",
volume = "10",
pages = "552--567",
journal = "Cancer discovery",
issn = "2159-8274",
number = "4",
}