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Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T cell dysfunction

Nathan Singh, Yong Gu Lee, Olga Shestova, Pranali Ravikumar, Katharina E Hayer, Seok Jae Hong, Xueqing Maggie Lu, Raymone Pajarillo, Sangya Agarwal, Shunichiro Kuramitsu, Elena J. Orlando, Karen Thudium Mueller, Charly R. Good, Shelley L. Berger, Ophir Shalem, Matthew D Weitzman, Noelle V. Frey, Shannon L. Maude, Stephan A. Grupp, Carl H. June, Saar Gill and Marco Ruella
Nathan Singh
University of Pennsylvania
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  • For correspondence: nathan.singh@wustl.edu
Yong Gu Lee
University of Pennsylvania
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Olga Shestova
University of Pennsylvania
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Pranali Ravikumar
Center for cellular Immunotherapies, University of Pennsylvania
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Katharina E Hayer
Biomedical and Health Informatics, Children's Hospital of Philadelphia
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Seok Jae Hong
University of Pennsylvania
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Xueqing Maggie Lu
University of Pennsylvania
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Raymone Pajarillo
Center for Cellular Immunotherapies (CCI), University of Pennsylvania
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Sangya Agarwal
Center for cellular immunotherapies, University of Pennsylvania
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Shunichiro Kuramitsu
Center for Cellular Immunotherapies, University of Pennsylvania
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Elena J. Orlando
Novartis
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Karen Thudium Mueller
PK Sciences, Novartis Institutes for BioMedical Research
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Charly R. Good
University of Pennsylvania
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Shelley L. Berger
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Ophir Shalem
Children's Hospital of Philadelphia
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Matthew D Weitzman
Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia
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Noelle V. Frey
University of Pennsylvania
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Shannon L. Maude
Division of Oncology, Children's Hospital of Philadelphia
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Stephan A. Grupp
Division of Oncology, Children's Hospital of Philadelphia
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Carl H. June
Parker Institute for Cancer Immunotherapy, University of Pennsylvania
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Saar Gill
Division of Hematology-Oncology and Center for Cellular Immunotherapies, University of Pennsylvania
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Marco Ruella
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania
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DOI: 10.1158/2159-8290.CD-19-0813
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Abstract

Primary resistance to CD19-directed chimeric antigen receptor T cell therapy (CART19) occurs in 10-20% of patients with acute lymphoblastic leukemia (ALL), however the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function 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 which 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.

  • Received July 12, 2019.
  • Revision received November 27, 2019.
  • Accepted January 10, 2020.
  • Copyright ©2020, American Association for Cancer Research.

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Published OnlineFirst January 30, 2020
doi: 10.1158/2159-8290.CD-19-0813

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Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T cell dysfunction
Nathan Singh, Yong Gu Lee, Olga Shestova, Pranali Ravikumar, Katharina E Hayer, Seok Jae Hong, Xueqing Maggie Lu, Raymone Pajarillo, Sangya Agarwal, Shunichiro Kuramitsu, Elena J. Orlando, Karen Thudium Mueller, Charly R. Good, Shelley L. Berger, Ophir Shalem, Matthew D Weitzman, Noelle V. Frey, Shannon L. Maude, Stephan A. Grupp, Carl H. June, Saar Gill and Marco Ruella
Cancer Discov January 30 2020 DOI: 10.1158/2159-8290.CD-19-0813

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Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T cell dysfunction
Nathan Singh, Yong Gu Lee, Olga Shestova, Pranali Ravikumar, Katharina E Hayer, Seok Jae Hong, Xueqing Maggie Lu, Raymone Pajarillo, Sangya Agarwal, Shunichiro Kuramitsu, Elena J. Orlando, Karen Thudium Mueller, Charly R. Good, Shelley L. Berger, Ophir Shalem, Matthew D Weitzman, Noelle V. Frey, Shannon L. Maude, Stephan A. Grupp, Carl H. June, Saar Gill and Marco Ruella
Cancer Discov January 30 2020 DOI: 10.1158/2159-8290.CD-19-0813
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