Pharmacologic control of CAR-T cell function using dasatinib

Blood Advances - Tập 3 Số 5 - Trang 711-717 - 2019
Evan W. Weber1, Rachel C. Lynn1, Elena Sotillo1, John Lattin1, Peng Xu1, Crystal L. Mackall2,3,1
1Stanford Cancer Institute
2Department of Medicine, Stanford University School of Medicine, Stanford, CA
3‡Department of Pediatrics and

Tóm tắt

Key Points Dasatinib potently and reversibly suppresses CAR-T cell cytotoxicity, cytokine secretion, and proliferation. Dasatinib could be repurposed as a safety switch to mitigate CAR-mediated toxicity in patients.

Từ khóa


Tài liệu tham khảo

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

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

Lee, 2014, Current concepts in the diagnosis and management of cytokine release syndrome [published correction appears in Blood. 2015;126(8):1048], Blood, 124, 188, 10.1182/blood-2014-05-552729

Brudno, 2016, Toxicities of chimeric antigen receptor T cells: recognition and management, Blood, 127, 3321, 10.1182/blood-2016-04-703751

Neelapu, 2018, Chimeric antigen receptor T-cell therapy - assessment and management of toxicities, Nat Rev Clin Oncol, 15, 47, 10.1038/nrclinonc.2017.148

Hoyos, 2010, Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety, Leukemia, 24, 1160, 10.1038/leu.2010.75

Gargett, 2014, The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells, Front Pharmacol, 5, 235, 10.3389/fphar.2014.00235

Diaconu, 2017, Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells, Mol Ther, 25, 580, 10.1016/j.ymthe.2017.01.011

Schade, 2008, Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation, Blood, 111, 1366, 10.1182/blood-2007-04-084814

Blake, 2008, The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro, Clin Immunol, 127, 330, 10.1016/j.clim.2008.02.006

Weichsel, 2008, Profound inhibition of antigen-specific T-cell effector functions by dasatinib, Clin Cancer Res, 14, 2484, 10.1158/1078-0432.CCR-07-4393

Lee, 2010, Lck is a key target of imatinib and dasatinib in T-cell activation, Leukemia, 24, 896, 10.1038/leu.2010.11

Davenport, 2018, Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity, Proc Natl Acad Sci USA, 115, E2068, 10.1073/pnas.1716266115

Salter, 2018, Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function, Sci Signal, 11, eaat6753, 10.1126/scisignal.aat6753

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

Barrett, 2011, Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling, Blood, 118, e112, 10.1182/blood-2011-04-346528

Sotillo, 2015, Convergence of Acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy, Cancer Discov, 5, 1282, 10.1158/2159-8290.CD-15-1020

Gust, 2017, Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells, Cancer Discov, 7, 1404, 10.1158/2159-8290.CD-17-0698

Teachey, 2016, Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia, Cancer Discov, 6, 664, 10.1158/2159-8290.CD-16-0040

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

Singh, 2017, Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function, Cytotherapy, 19, 867, 10.1016/j.jcyt.2017.04.001

Dasatinib: dosing/administration (2018). In: Micromedex (lane.stanford.edu) [electronic version]. Ann Arbor, MI: Truven Health Analytics. http://www.micromedexsolutions.com/. Accessed 16 September 2018.

Demetri, 2009, Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors, Clin Cancer Res, 15, 6232, 10.1158/1078-0432.CCR-09-0224

Pennell, 2018, Human CD19-targeted mouse T-cells induce B-cell aplasia and toxicity in human CD19 transgenic mice, Mol Ther J Am Soc Gene Ther, 26, 1423, 10.1016/j.ymthe.2018.04.006

Porkka, 2008, Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia, Blood, 112, 1005, 10.1182/blood-2008-02-140665