Orlando, Elena, Brogdon, Jennifer, Bitter, Hans, Joseph, Fraietta, Simon , Lacey, David, Ambrose, Nicholas, Wilcox, Felipe, Bedoya, Corin, Dofrmeier, Fang, Chen, Noelle, Frey, Wei-Ting, Hwang, Harit, Parakandi, Minnal, Gupta, A., Huang, Brad, Johnson, Irina, Kulikovskaya, Bruce , Levine, Li, Liu, Stefan, Lundh, Edward, Pequignot, Donald, Siegel, Yan, Wang, E.J., Wherry, Jun, Xu, Regina, Young, David, Porter, Carl, June, 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