Chimeric antigen receptor–T cells with cytokine neutralizing capacity

Blood Advances - Tập 4 - Trang 1419-1431 - 2020
Adrian H.J. Tan1, Natasha Vinanica1, Dario Campana1
1Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Tóm tắt

AbstractInfusion of T lymphocytes expressing chimeric antigen receptors (CARs) can produce extraordinary antitumor activity in patients with leukemia, lymphoma, and myeloma. The signaling mechanisms activating T cells and provoking tumor cell killing also trigger cytokine secretion and macrophage activation, leading to cytokine release syndrome (CRS). CRS is a serious side effect of CAR–T cells, and proinflammatory interleukin-6 (IL-6) is central to its pathogenesis. To endow T cells with anti-CRS activity, we designed a nonsignaling membrane-bound IL-6 receptor (mbaIL6) constituted by a single chain variable fragment derived from an anti–IL-6 antibody linked to a transmembrane anchoring peptide. We found that mbaIL6 expressed on the surface of T cells could rapidly remove IL-6 from the culture supernatant. IL-6 removal was proportional to the number of mbaIL6+ cells, increased with T-cell proliferation, and neutralized IL-6 signaling and function. A construct encoding for mbaIL6 and an anti–CD19-41BB-CD3ζ CAR allowed simultaneous expression of both receptors. T cells with mbaIL6 and CAR neutralized macrophage-derived IL-6 while exerting powerful antitumor activity. Cytotoxicity and proliferation were identical to those of cells expressing CAR alone in vitro, and CAR–T cells were effective in xenograft models regardless of mbaIL6 expression. Levels of human IL-6 in mice, however, were greatly reduced if T cells expressed both receptors instead of CAR alone. Thus, CAR–T cells with on-board capacity to extinguish IL-6 represent a new approach to prevent CRS and suppress its severity without affecting the antitumor potential of CAR–T cells.

Tài liệu tham khảo

Rosenberg, 2015, Adoptive cell transfer as personalized immunotherapy for human cancer, Science, 348, 62, 10.1126/science.aaa4967 June, 2018, Chimeric antigen receptor therapy, N Engl J Med, 379, 64, 10.1056/NEJMra1706169 Maude, 2014, Chimeric antigen receptor T cells for sustained remissions in leukemia, N Engl J Med, 371, 1507, 10.1056/NEJMoa1407222 Davila, 2014, Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia, Sci Transl Med, 6, 224ra25, 10.1126/scitranslmed.3008226 Lee, 2015, T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial, Lancet, 385, 517, 10.1016/S0140-6736(14)61403-3 Turtle, 2016, CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients, J Clin Invest, 126, 2123, 10.1172/JCI85309 Kochenderfer, 2015, Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor, J Clin Oncol, 33, 540, 10.1200/JCO.2014.56.2025 Turtle, 2016, Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells, Sci Transl Med, 8, 355ra116, 10.1126/scitranslmed.aaf8621 Gardner, 2017, Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults, Blood, 129, 3322, 10.1182/blood-2017-02-769208 Neelapu, 2017, Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma, N Engl J Med, 377, 2531, 10.1056/NEJMoa1707447 Maude, 2018, Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia, N Engl J Med, 378, 439, 10.1056/NEJMoa1709866 Schuster, 2019, Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma, N Engl J Med, 380, 45, 10.1056/NEJMoa1804980 Raje, 2019, Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma, N Engl J Med, 380, 1726, 10.1056/NEJMoa1817226 Lee, 2014, Current concepts in the diagnosis and management of cytokine release syndrome [published corrections appear in Blood. 2015;126(8):1048 and Blood. 2016;128(11):1533], Blood, 124, 188, 10.1182/blood-2014-05-552729 Maude, 2014, Managing cytokine release syndrome associated with novel T cell-engaging therapies, Cancer J, 20, 119, 10.1097/PPO.0000000000000035 Park, 2016, CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date, Blood, 127, 3312, 10.1182/blood-2016-02-629063 Brudno, 2016, Toxicities of chimeric antigen receptor T cells: recognition and management, Blood, 127, 3321, 10.1182/blood-2016-04-703751 Karschnia, 2019, Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells, Blood, 133, 2212, 10.1182/blood-2018-12-893396 Grupp, 2013, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, N Engl J Med, 368, 1509, 10.1056/NEJMoa1215134 Mueller, 2018, Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia, Clin Cancer Res, 24, 6175, 10.1158/1078-0432.CCR-18-0758 Manabe, 1994, Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia, Blood, 83, 1731, 10.1182/blood.V83.7.1731.1731 Imai, 2004, Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia, Leukemia, 18, 676, 10.1038/sj.leu.2403302 Szymczak-Workman, 2012, Design and construction of 2A peptide-linked multicistronic vectors, Cold Spring Harb Protoc, 2012, 199, 10.1101/pdb.ip067876 Kudo, 2014, T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing, Cancer Res, 74, 93, 10.1158/0008-5472.CAN-13-1365 Taga, 1987, Receptors for B cell stimulatory factor 2. Quantitation, specificity, distribution, and regulation of their expression, J Exp Med, 166, 967, 10.1084/jem.166.4.967 Onozaki, 1989, Synergistic regulatory effects of interleukin 6 and interleukin 1 on the growth and differentiation of human and mouse myeloid leukemic cell lines, Cancer Res, 49, 3602 Zhong, 1994, Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6, Science, 264, 95, 10.1126/science.8140422 Bock, 1993, Characterization of a new IL-6-dependent human B-lymphoma cell line in long term culture, Cytokine, 5, 480, 10.1016/1043-4666(93)90039-8 Lemmink, 2001, Identification of LIL-STAT in monocytic leukemia cells and monocytes after stimulation with interleukin-6 or interferon gamma, Blood, 98, 3849, 10.1182/blood.V98.13.3849 Long, 2015, 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors, Nat Med, 21, 581, 10.1038/nm.3838 Sanceau, 1991, IL-6 and IL-6 receptor modulation by IFN-gamma and tumor necrosis factor-alpha in human monocytic cell line (THP-1). Priming effect of IFN-gamma, J Immunol, 147, 2630, 10.4049/jimmunol.147.8.2630 Slifka, 2000, Activated and memory CD8+ T cells can be distinguished by their cytokine profiles and phenotypic markers, J Immunol, 164, 208, 10.4049/jimmunol.164.1.208 Hay, 2017, Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy, Blood, 130, 2295, 10.1182/blood-2017-06-793141 Fry, 2018, CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy, Nat Med, 24, 20, 10.1038/nm.4441 Santomasso, 2018, Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia, Cancer Discov, 8, 958, 10.1158/2159-8290.CD-17-1319 Gardner, 2019, Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy, Blood, 134, 2149, 10.1182/blood.2019001463 Hay, 2018, Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy, Br J Haematol, 183, 364, 10.1111/bjh.15644 Nellan, 2018, Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques, Blood, 132, 662, 10.1182/blood-2018-05-846428 Ghorashian, 2019, Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR, Nat Med, 25, 1408, 10.1038/s41591-019-0549-5 Ying, 2019, A safe and potent anti-CD19 CAR T cell therapy, Nat Med, 25, 947, 10.1038/s41591-019-0421-7 Tanaka, 2014, The biology and medical implications of interleukin-6, Cancer Immunol Res, 2, 288, 10.1158/2326-6066.CIR-14-0022 Spencer, 2019, Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses, J Exp Med, 216, 1986, 10.1084/jem.20190344 Giavridis, 2018, CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade, Nat Med, 24, 731, 10.1038/s41591-018-0041-7 Norelli, 2018, Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells, Nat Med, 24, 739, 10.1038/s41591-018-0036-4 Hunter, 2015, IL-6 as a keystone cytokine in health and disease [published correction appears in Nat Immunol. 2017;18(11):1271], Nat Immunol, 16, 448, 10.1038/ni.3153 McInnes, 2017, Pathogenetic insights from the treatment of rheumatoid arthritis, Lancet, 389, 2328, 10.1016/S0140-6736(17)31472-1 Chen, 2009, Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease, Blood, 114, 891, 10.1182/blood-2009-01-197178 Tawara, 2011, Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation, Clin Cancer Res, 17, 77, 10.1158/1078-0432.CCR-10-1198 Roddy, 2016, Tocilizumab for steroid refractory acute graft-versus-host disease, Leuk Lymphoma, 57, 81, 10.3109/10428194.2015.1045896
Thông tin
Thông tin xuất bản

Blood Advances

Tập 4

1419-1431

Thông tin tác giả