Stroncek DF, Ren J, Lee DW, Tran M, Frodigh SE, Sabatino M, et al. Myeloid cell and cytokine interactions with chimeric antigen receptor-T-cell therapy: implication for future therapies. Omics analyses provide insights to CART cell therapy resistance. Resistance to CART cell therapy: lessons learned from the treatment of hematological malignancies. Sakemura R, Cox MJ, Hefazi M, Siegler EL, Kenderian SS. Chimeric antigen receptor T cells in refractory B-cell lymphomas. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Management of cytokine release syndrome: an update on emerging antigen-specific T cell engaging immunotherapies. Khadka RH, Sakemura R, Kenderian SS, Johnson AJ. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis. 2018 379:64–73.Īnagnostou T, Riaz IB, Hashmi SK, Murad MH, Kenderian SS. In conclusion, our study demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CART cells directly ameliorates CART cell early activation and enhances anti-tumor activity in preclinical models. GM-CSF KO CART19 cell had reduced BH3 interacting-domain death agonist (Bid), suggesting an interaction between GM-CSF and intrinsic apoptosis pathways. However, the interaction between GM-CSF and its upregulated receptors on CART cells was not the predominant mechanism of this activation phenotype. Activated CART19 cells significantly upregulate GM-CSF receptors. In this study, we show that antigen-specific activation of GM-CSF KO CART19 cells consistently displayed reduced early activation, enhanced proliferation, and improved anti-tumor activity in a xenograft model for relapsed B cell malignancies. In this report, we study the direct impact of GM-CSF disruption during the production of CD19-directed CART cells on their effector functions, independent of GM-CSF modulation of myeloid cells. We have previously shown that neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF) prevents these toxicities and enhances CART cell functions by inhibiting myeloid cell activation. Inhibitory myeloid cells and their cytokines play critical roles in limiting chimeric antigen receptor T (CART) cell therapy by contributing to the development of toxicities and resistance following infusion.
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