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Pooled screening of CAR T cells identifies non-native signaling domains for next-generation immunotherapies

View ORCID ProfileDaniel B. Goodman, Camillia S. Azimi, Kendall Kearns, Kiavash Garakani, Julie Garcia, Nisarg Patel, Byungjin Hwang, David Lee, Emily Park, View ORCID ProfileChun Jimmie Ye, Alex Marson, Jeff A. Bluestone, Kole T. Roybal
doi: https://doi.org/10.1101/2021.07.11.451980
Daniel B. Goodman
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
5Gladstone UCSF Institute for Genetic Immunology, San Francisco, CA, 94107, USA
9School of Medicine, University of California, San Francisco, San Francisco, CA, USA
14Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
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  • ORCID record for Daniel B. Goodman
Camillia S. Azimi
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
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Kendall Kearns
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
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Kiavash Garakani
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
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Julie Garcia
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
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Nisarg Patel
7Department of Oral and Maxillofacial Surgery, University of California, San Francisco, San Francisco, CA, USA
8Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
9School of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Byungjin Hwang
10Institute for Human Genetics (IHG), University of California, San Francisco, San Francisco, California, USA
11Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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David Lee
10Institute for Human Genetics (IHG), University of California, San Francisco, San Francisco, California, USA
11Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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Emily Park
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
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Chun Jimmie Ye
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
4Chan Zuckerberg Biohub, San Francisco, California, 94158, USA
8Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
10Institute for Human Genetics (IHG), University of California, San Francisco, San Francisco, California, USA
11Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
12Department of Epidemiology and Biostatistics, San Francisco, San Francisco, CA 94143, USA
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  • ORCID record for Chun Jimmie Ye
Alex Marson
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, 94158, USA
4Chan Zuckerberg Biohub, San Francisco, California, 94158, USA
5Gladstone UCSF Institute for Genetic Immunology, San Francisco, CA, 94107, USA
9School of Medicine, University of California, San Francisco, San Francisco, CA, USA
10Institute for Human Genetics (IHG), University of California, San Francisco, San Francisco, California, USA
13Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA
14Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
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Jeff A. Bluestone
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
14Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
15Sonoma Biotherapeutics, South San Francisco, CA, USA
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Kole T. Roybal
1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, 94143, USA
2Parker Institute for Cancer Immunotherapy, San Francisco, California, 94143, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, 94158, USA
4Chan Zuckerberg Biohub, San Francisco, California, 94158, USA
5Gladstone UCSF Institute for Genetic Immunology, San Francisco, CA, 94107, USA
6UCSF Cell Design Institute, San Francisco, California, 94158, USA
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  • For correspondence: kole.roybal@ucsf.edu
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SUMMARY

Chimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers, but have shown limited efficacy against solid tumors. Here, we introduce ‘CAR Pooling’, a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with diverse immune costimulatory domains were assessed in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several non-native domains from the TNF receptor family exhibited enhanced proliferation (CD40) or cytotoxicity (BAFF-R and TACI) relative to clinical benchmarks, and fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic and NK-cell-like innate phenotype previously associated with positive clinical outcomes. ‘CAR Pooling’ enables efficient exploration of how CAR design affects cell activity and can be applied to optimize receptors across a range of applications and cell types.

Competing Interest Statement

K.T.R. is a cofounder, consultant, SAB member, and stockholder of Arsenal Biosciences. He was a founding scientist/consultant and stockholder in Cell Design Labs, now a Gilead Company. K.T.R. holds stock in Gilead. K.T.R. is on the SAB of Ziopharm Oncology and an Advisor to Venrock. D.B.G. is a stockholder and consultant of Arsenal Biosciences. D.B.G is a scientific advisor and stockholder of Manifold Bio, Gordian Biotechnology, and NExTNet. J.A.B is a co-founder, CEO and a Board member of Sonoma Biotherapeutics. He is a co-founder of Celsius Therapeutics; a member of the Board of Directors of Gilead and Provention Bio, and a member of the scientific advisory boards of Arcus Biosciences, Solid Biosciences, and Vir Biotechnology. J.A.B is the A.W. and Mary Margaret Clausen Distinguished Professor in Metabolism and Endocrinology in the Diabetes Center at the University of California, San Francisco. A.M. is a compensated co-founder, member of the boards of directors, and a member of the scientific advisory boards of Spotlight Therapeutics and Arsenal Biosciences. A.M. was a compensated member of the scientific advisory board at PACT Pharma and was a compensated advisor to Juno Therapeutics and Trizell. A.M. owns stock in Arsenal Biosciences, Spotlight Therapeutics, and PACT Pharma. A.M. has received fees from Merck and Vertex. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. C.J.Y. is a Scientific Advisory Board member for and holds equity in Related Sciences and ImmunAI, is a consultant for and holds equity in Maze Therapeutics, and is a consultant for TReX Bio. C.J.Y. has received research support from Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, and Genentech. K.T.R, D.B.G, C.S.A., J.A.B., and A.M. are listed as inventors on a patent application related to this work, which has been licensed.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 12, 2021.
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Pooled screening of CAR T cells identifies non-native signaling domains for next-generation immunotherapies
Daniel B. Goodman, Camillia S. Azimi, Kendall Kearns, Kiavash Garakani, Julie Garcia, Nisarg Patel, Byungjin Hwang, David Lee, Emily Park, Chun Jimmie Ye, Alex Marson, Jeff A. Bluestone, Kole T. Roybal
bioRxiv 2021.07.11.451980; doi: https://doi.org/10.1101/2021.07.11.451980
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Pooled screening of CAR T cells identifies non-native signaling domains for next-generation immunotherapies
Daniel B. Goodman, Camillia S. Azimi, Kendall Kearns, Kiavash Garakani, Julie Garcia, Nisarg Patel, Byungjin Hwang, David Lee, Emily Park, Chun Jimmie Ye, Alex Marson, Jeff A. Bluestone, Kole T. Roybal
bioRxiv 2021.07.11.451980; doi: https://doi.org/10.1101/2021.07.11.451980

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