Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature medicine, 2018-05, Vol.24 (5), p.563-571

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Beschreibungen/Notizen

• 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-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.