Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.
Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.
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DOI：
10.1038/s41591-018-0010-1
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发表时间：
2018-05
期刊：
影响因子：
82.9
通讯作者：
Melenhorst JJ
中科院分区：
文献类型：
--
作者：
Fraietta JA;Lacey SF;Orlando EJ;Pruteanu-Malinici I;Gohil M;Lundh S;Boesteanu AC;Wang Y;O'Connor RS;Hwang WT;Pequignot E;Ambrose DE;Zhang C;Wilcox N;Bedoya F;Dorfmeier C;Chen F;Tian L;Parakandi H;Gupta M;Young RM;Johnson FB;Kulikovskaya I;Liu L;Xu J;Kassim SH;Davis MM;Levine BL;Frey NV;Siegel DL;Huang AC;Wherry EJ;Bitter H;Brogdon JL;Porter DL;June CH;Melenhorst JJ
对自身抗原的耐受性阻止了免疫系统对癌症的消除。我们使用合成的嵌合抗原受体（汽车）来克服慢性淋巴细胞白血病（CLL）患者的免疫耐受并介导肿瘤排斥反应。在一个受试者子集中诱导缓解，但大多数没有反应。尚未探索对患者来源的CAR T细胞进行全面评估以确定治疗成功和失败的机制。我们进行了基因组，表型和功能评价，以确定反应的决定因素。转录组学分析显示，来自完全应答的CLL患者的CAR T细胞富含记忆相关基因，包括IL-6/STAT 3特征，而来自无应答者的T细胞上调参与效应分化，糖酵解，耗竭和凋亡的程序。持续缓解与CAR T细胞产生前CD 27 + CD 45 R 0-CD 8 + T细胞频率升高相关，并且这些淋巴细胞具有记忆样特征。来自患者的高功能CAR T细胞产生STAT 3相关细胞因子，血清IL-6与CAR T细胞扩增相关。IL-6/STAT 3阻断减少CAR T细胞增殖。此外，表达高水平IL-6受体的CD 27 +PD-1CD 8 + CAR T细胞的机制相关群体预测治疗反应并负责肿瘤控制。这些发现揭示了CAR T细胞生物学的新特征，并强调了使用反应的预处理生物标志物来推进免疫疗法的潜力。
Tolerance to self-antigens prevents the elimination of cancer by the immune system. 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-1CD8+ 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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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
3.7
作者：
Jena B;Maiti S;Huls H;Singh H;Lee DA;Champlin RE;Cooper LJ
通讯作者：
Cooper LJ
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
20.3
作者：
Fraietta, Joseph A.;Beckwith, Kyle A.;Maus, Marcela V.
通讯作者：
Maus, Marcela V.
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John