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Immunotherapy

Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo

Abstract

Adoptive T-cell therapy with gene-modified T cells expressing a tumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and has shown success in the treatment of B-cell malignancies and solid tumors. In all reported trials, patients have received T-cell products comprising random compositions of CD4+ and CD8+ naive and memory T cells, meaning that each patient received a different therapeutic agent. This variation may have influenced the efficacy of T-cell therapy, and complicates comparison of outcomes between different patients and across trials. We analyzed CD19 CAR-expressing effector T cells derived from different subsets (CD4+/CD8+ naive, central memory, effector memory). T cells derived from each of the subsets were efficiently transduced and expanded, but showed clear differences in effector function and proliferation in vitro and in vivo. Combining the most potent CD4+ and CD8+ CAR-expressing subsets, resulted in synergistic antitumor effects in vivo. We show that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition. These findings have important implications for the formulation of T-cell products for adoptive therapies.

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Acknowledgements

We thank Melissa Comstock (Shared Resources, FHCRC) for expertise in performing the mouse experiments. This work was supported by grants from the National Institutes of Health CA136551, CA18029 and CA114536 (SRR). DS and MH were supported by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft, SO1214/1-1, HU1668/1-1, 1-2). MH was supported by the Leukemia and Lymphoma Society (LLS, 5520-11), the German Cancer Aid (Deutsche Krebshilfe e.V., Max Eder Program 110313), and the University of Würzburg (Interdisziplinäres Zentrum für Klinische Forschung, IZKF, Z-4/109 and D-244).

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Correspondence to S R Riddell.

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MH and SRR are inventors on a patent application (PCT/US1013/055862) related to this work that has been filed by the Fred Hutchinson Cancer Research Center (FHCRC) and licensed by Juno Therapeutics. SRR is founder and shareholder of Juno Therapeutics.

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Sommermeyer, D., Hudecek, M., Kosasih, P. et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30, 492–500 (2016). https://doi.org/10.1038/leu.2015.247

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