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Nat Med. 2018 May;24(5):563-571. doi: 10.1038/s41591-018-0010-1. Epub 2018 Apr 30.

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

Author information

1
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.
3
Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.
4
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
5
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
6
Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA.
7
Division of Transfusion Medicine and Therapeutic Pathology, University of Pennsylvania, Philadelphia, PA, USA.
8
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
9
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu.
10
Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu.
11
Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu.

Abstract

Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. 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.

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