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Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia

Orlando, Elena and Brogdon, Jennifer and Bitter, Hans and Joseph, Fraietta and Simon , Lacey and David, Ambrose and Nicholas, Wilcox and Felipe, Bedoya and Corin, Dofrmeier and Fang, Chen and Noelle, Frey and Wei-Ting, Hwang and Harit, Parakandi and Minnal, Gupta and A., Huang and Brad, Johnson and Irina, Kulikovskaya and Bruce , Levine and Li, Liu and Stefan, Lundh and Edward, Pequignot and Donald, Siegel and Yan, Wang and E.J., Wherry and Jun, Xu and Regina, Young and David, Porter and Carl, June and Jan, Melenhorst and Pruteanu-Malinici, Iulian (2018) Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nature Medicine, 24 (5). pp. 563-571. ISSN 1546170X

Abstract

Tolerance to self-antigens prevents the elimination of cancer by the immune system 1,2 . We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO-CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1-CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.

Item Type: Article
Date Deposited: 05 Jun 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/35850

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