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

By J. Fraietta, S. Lacey, Elena J Orlando, Iulian Pruteanu-Malinici, M. Gohil, Stefan Lundh, A. Boesteanu, Yan Wang, Roddy S. O’Connor, Wei-Ting Hwang and 27 more. Nature Medicine, 2018

1,538 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/efc0187e48d42bcb84b435c47968c3a5c3c258ea

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Citations in the corpus

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, methodology): “This suggests that more effective CART-BCMA products may be derived from subjects with a less differentiated, more naive and/or stem cell memory– like T cell compartment, as previously observed in a CLL trial at our center using CD19-directed CAR T cells (18).”
Smart nanoparticles for cancer therapy (2023, background): “330 There are also practical problems related to the large-scale production of therapeutic living cells.”
CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment (2019, methodology): “Blocking glycolysis is another approach that could be used in solid tumor-targeting CAR T cells to push formation of memory T cells during activation and transduction, particularly given (119) evidence that the initial differentiation status of a patient’s apheresed T cells may significantly affect ”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Indeed, tumor-specific CD8 T cells display hallmarks of T cell exhaustion and dysfunction in mouse models (24, 25) and human cancers including, but not limited to, melanoma (26–30), chronic myeloid leukemia (24), ovarian cancer (31), non–small cell carcinoma (32, 33), Hodgkin lymphoma (34), and chro”
Anti‐BCMA CAR T‐Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma (2019, neutral): “Stringent complete response 0 5 (63) 3 (38) 4 (36) 0 12 (40) 12 (36)”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “For example, disease-related dysfunctions of T cells 217 , such as those described in patients with CLL 218,219 or solid tumours 220 , can result in unsuccessful manufacturing or inferior products that lead to poor response rates in patients.”