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

被引：1177

作者：

Fraietta, Joseph A. ^{[1
,2
,3
]}

Lacey, Simon F. ^{[1
,2
,3
,8
]}

Orlando, Elena J. ^{[4
,8
]}

Pruteanu-Malinici, Iulian ^{[4
]}

Gohil, Mercy ^{[2
]}

Lundh, Stefan ^{[2
]}

Boesteanu, Alina C. ^{[2
]}

Wang, Yan ^{[2
]}

O'Connor, Roddy S. ^{[2
]}

Hwang, Wei-Ting ^{[5
]}

Pequignot, Edward ^{[2
]}

Ambrose, David E. ^{[2
]}

Zhang, Changfeng ^{[2
]}

Wilcox, Nicholas ^{[2
]}

Bedoya, Felipe ^{[2
]}

Dorfmeier, Corin ^{[2
]}

Chen, Fang ^{[2
]}

Tian, Lifeng ^{[2
]}

Parakandi, Harit ^{[2
]}

Gupta, Minnal ^{[2
]}

Young, Regina M. ^{[2
]}

Johnson, F. Brad ^{[1
]}

Kulikovskaya, Irina ^{[2
]}

Liu, Li ^{[2
]}

Xu, Jun ^{[2
]}

Kassim, Sadik H. ^{[4
]}

Davis, Megan M. ^{[1
,2
]}

Levine, Bruce L. ^{[2
]}

Frey, Noelle V. ^{[2
,6
]}

Siegel, Donald L. ^{[2
,7
]}

Huang, Alexander C. ^{[3
,8
]}

Wherry, E. John ^{[3
,8
]}

Bitter, Hans

Brogdon, Jennifer L. ^{[4
]}

Porter, David L. ^{[1
,6
]}

June, Carl H. ^{[1
,2
,3
]}

Melenhorst, J. Joseph ^{[1
,2
,3
]}

机构：

[1] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[2] Univ Penn, Ctr Cellular Immunotherapies, Philadelphia, PA 19104 USA

[3] Univ Penn, Parker Inst Canc Immunotherapy, Philadelphia, PA 19104 USA

[4] Novartis Inst BioMed Res, Cambridge, MA USA

[5] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Internal Med, Div Hematol Oncol, Philadelphia, PA 19104 USA

[7] Univ Penn, Div Transfus Med & Therapeut Pathol, Philadelphia, PA 19104 USA

[8] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 05期

关键词：

TELOMERASE ACTIVITY; EXPRESSION ANALYSIS; EFFECTOR FUNCTION; B-CELL; IDENTIFICATION; EXHAUSTION; EFFICACY; SUBSETS; GENE; PD-1;

D O I：

10.1038/s41591-018-0010-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：563 / +

页数：12

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