Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia
Autor: | Lifeng Tian, Joseph A. Fraietta, Jun Xu, Hans Bitter, Carl H. June, Iulian Pruteanu-Malinici, Edward Pequignot, Alina C. Boesteanu, Roddy S. O’Connor, Changfeng Zhang, Noelle V. Frey, Corin L. Dorfmeier, F. Brad Johnson, Simon F. Lacey, Nicholas Wilcox, Bruce L. Levine, Sadik H. Kassim, Stefan Lundh, Harit Parakandi, E. John Wherry, Megan M. Davis, J. Joseph Melenhorst, Regina M. Young, David L. Porter, Wei-Ting Hwang, Yan Wang, Felipe Bedoya, Alexander C. Huang, David E Ambrose, Li Liu, Mercy Gohil, Jennifer Brogdon, Elena Orlando, Don L. Siegel, Fang Chen, Irina Kulikovskaya, Minnal Gupta |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male STAT3 Transcription Factor Transcription Genetic medicine.medical_treatment Chronic lymphocytic leukemia T-Lymphocytes Antigens CD19 Cell- and Tissue-Based Therapy Biology Immunotherapy Adoptive General Biochemistry Genetics and Molecular Biology CD19 Article 03 medical and health sciences Mice 0302 clinical medicine Immune system Antigen medicine Cytotoxic T cell Animals Humans Receptors Chimeric Antigen Interleukin-6 General Medicine Immunotherapy medicine.disease Leukemia Lymphocytic Chronic B-Cell Chimeric antigen receptor Leukemia 030104 developmental biology Treatment Outcome 030220 oncology & carcinogenesis Cancer research biology.protein Female |
Popis: | 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. 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. |
Databáze: | OpenAIRE |
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