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

嵌合抗原受体 慢性淋巴细胞白血病 CD19 CD8型 医学 细胞毒性T细胞 白血病 抗原 生物 癌症研究 T细胞 免疫学 免疫系统 体外 生物化学
作者
Joseph A. Fraietta,Simon F. Lacey,Elena J. Orlando,Iulian Pruteanu-Malinici,Mercy Gohil,Stefan Lundh,Alina C. Boesteanu,Yan Wang,Roddy S. O’Connor,Wei‐Ting Hwang,Edward Pequignot,David E Ambrose,Changfeng Zhang,Nicholas S. Wilcox,Felipe Bedoya,Corin L. Dorfmeier,Chen Fang,Lifeng Tian,Harit Parakandi,Minnal Gupta
出处
期刊:Nature Medicine [Nature Portfolio]
卷期号:24 (5): 563-571 被引量:1709
标识
DOI:10.1038/s41591-018-0010-1
摘要

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.
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