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

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 sub...

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Veröffentlicht in:	Nature medicine Jg. 24; H. 5; S. 563 - 571
Hauptverfasser:	Fraietta, Joseph A., Lacey, Simon F., Orlando, Elena J., Pruteanu-Malinici, Iulian, Gohil, Mercy, Lundh, Stefan, Boesteanu, Alina C., Wang, Yan, O’Connor, Roddy S., Hwang, Wei-Ting, Pequignot, Edward, Ambrose, David E., Zhang, Changfeng, Wilcox, Nicholas, Bedoya, Felipe, Dorfmeier, Corin, Chen, Fang, Tian, Lifeng, Parakandi, Harit, Gupta, Minnal, Young, Regina M., Johnson, F. Brad, Kulikovskaya, Irina, Liu, Li, Xu, Jun, Kassim, Sadik H., Davis, Megan M., Levine, Bruce L., Frey, Noelle V., Siegel, Donald L., Huang, Alexander C., Wherry, E. John, Bitter, Hans, Brogdon, Jennifer L., Porter, David L., June, Carl H., Melenhorst, J. Joseph
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.05.2018 Nature Publishing Group
Schlagworte:	631/250/2520 692/53/2423 Animals Antigen receptors, T cell Antigens Antigens, CD19 - metabolism Apoptosis Autoantigens Biomarkers Biomedical and Life Sciences Biomedicine Cancer Cancer Research Care and treatment CD19 antigen CD27 antigen CD8 antigen Cell proliferation Cell therapy Cellular therapy Chimeric antigen receptors Chronic lymphocytic leukemia Cytokines Development and progression Exhaustion Female Genomics Glycolysis Health aspects Immunological memory Immunological tolerance Immunology Immunotherapy Immunotherapy, Adoptive Infectious Diseases Interleukin 6 Interleukin 6 receptors Interleukin-6 - metabolism Letter Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - immunology Leukemia, Lymphocytic, Chronic, B-Cell - therapy Lymphatic leukemia Lymphocytes Lymphocytes T Male Memory cells Metabolic Diseases Methods Mice Molecular Medicine Neurosciences Patients PD-1 protein Physiological aspects Receptors Receptors, Chimeric Antigen - metabolism Remission Stat3 protein STAT3 Transcription Factor - metabolism T cells Transcription, Genetic Treatment Outcome Tumors
ISSN:	1078-8956, 1546-170X, 1546-170X
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Zusammenfassung:	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. An IL-6/STAT3 signature and memory CD8 T cell subset in preinfusion chimeric antigen receptor–expressing T cells associate with response in patients with high-risk chronic lymphocytic leukemia.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 J.A.F., S.F.L., F.B.J., R.M.Y., N.V.F., B.L.L., D.L.S., E.J.W, J.L.B., D.L.P., C.H.J. and J.J.M. designed the experiments and/or performed analysis. J.A.F., M.Gohil, S.L., A.C.B., Y.W, R.S.O., D.E.A., C.Z., N.W, F.B., C.D., F.C., L.T., H.P, M. Gupta, I.K., L.L., J.X., S.H.K., M.M.D. and A.C.H. performed experiments. E.J.O. and H.B. analyzed RNA-seq. data. I.P.-M. carried out the computational analyses of flow cytometric data. W-T.H. and E.P. performed statistical analyses. J.A.F., C.H.J. and J.J.M. wrote the paper, and all authors contributed to writing and providing feedback. Author contributions
ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/s41591-018-0010-1