Despite the global rapid increase in the number of clinical trials employing chimeric antigen receptors (CARs), no comprehensive survey of their scope, targets and design exists. In this study, we present an interactive CAR clinical trial database, spanning 64 targets deployed in T cells (CAR-T), natural killer cells (CAR-NK) or mixtures (CAR-NK/T) from over 500 clinical trials in 20 countries, encompassing >20,000 patients. By combining these data with transcriptional and proteomic data, we create a ‘targetable landscape’ for CAR cell therapies based on 13,206 proteins and RNAs across 78 tissues, 124 cell types and 20 cancer types. These data suggest a landscape of over 100 single targets and over 100,000 target pairs using logical switches for CAR cell engineering. Our analysis of the CAR cellular therapeutic landscape may aid the design of future therapies, improve target-to-patient matching, and ultimately help inform our understanding of CAR therapy’s safety and efficacy.
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We have created an indexed and searchable online site for displaying clinical CAR targets (https://carglobaltrials.com), which also features the normal (tissue group, tissue and cell type) and pathological gene expression data for those targets.
Relevant code for identification of new targets and target pairs, and for parsing the current CAR targets is available in the Supplementary Materials.
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This work was supported by STARR Cancer Consortium grants (nos. I7-A765, I9-A9-071) and funding from the Irma T. Hirschl and Monique Weill-Caulier Charitable Trusts, Bert L. and N. Kuggie Vallee Foundation, Igor Tulchinsky and the WorldQuant Foundation, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health (grant nos. P01CA214274, 1R01MH117406) and the Leukemia and Lymphoma Society (grant nos. LLS 9238-16, Mak, LLS-MCL-982, Chen-Kiang). Funding also came from the National Natural Science Foundation of China (grant nos. 81402529 and 81672994), Zhejiang Provincial Foundation for Natural Sciences (grant no. LZ15H220001), Zhejiang Provincial Medical Scientific Research Foundation of China (grant nos. 2015KYB325 and 2015PYA009), Hangzhou City Medical Scientific Research Foundation of Zhejiang Province (grant no. 2015Z04) and Hangzhou City Scientific Technology Research Foundation of Zhejiang Province (grant no. 20150733Q64) of the Hangzhou Science and Technology Development Program (grant no. 20150733Q63).
There are no specific, relevant competing interests related to this work. However, in the interest of full disclosure, C.M. is a cofounder and board member for Biotia and Onegevity Health, as well as an advisor or compensated speaker for Abbvie, Acuamark Diagnostics, ArcBio, BioRad, DNA Genotek, Genialis, Genpro, Karius, Illumina, New England Biolabs, QIAGEN, Whole Biome and Zymo Research.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
(a) The number of trials from 2017–2019 that used a given CAR compare to the percent of tissues with medium-high levels of expression of the CAR target. (b) The percentage of tissue groups with not-detected, low, medium, or high levels of target expression based on maximum expression seen within a cell type for CARs used in multiple recent trials. (c) Tissue group, (d) tissue, and (e) cell types with a given CAR target highly expressed. CARs examined are listed in (b).
Supplementary Fig. 1.
Supplementary Tables 1–3.
CAR_NBT_analysis_expression.js, CAR_NBT_analysis_location.js, CAR_NBT_analysis_logicalAndNotPairs.R, CAR_NBT_analysis_logicalAndPairs.R, CAR_NBT_analysis_meta.js, CAR_NBT_analysis_singleTargets.R
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MacKay, M., Afshinnekoo, E., Rub, J. et al. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat Biotechnol (2020). https://doi.org/10.1038/s41587-019-0329-2