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Omics strategies to uncover the mechanisms of resistance in CART cell therapy. Strategies involve studying (A) the tumor itself, (B) the TME, or (C) the T cells themselves. These studies are performed before and/or after infusion of CART cells. Studies specific to T cells include TCRB sequencing, lentiviral integration sites, and phenotype. DNA and RNA sequencing as well as gene regulation are studied. Classification models can also be created or used. Created with BioRender.com. CART: chimeric antigen receptor T cell; TME: tumor microenvironment; TCRB: T cell receptor beta; DNA: deoxyribonucleic acid; RNA: ribonucleic acid.
Source publication
Chimeric antigen receptor T (CART) cell therapy has revolutionized the treatment of relapsed/refractory B cell malignancies in recent years. Despite high initial response rates, durable response rates are low, and CART cell efficacy in solid tumors is very modest. Additionally, the overall success of CART cell therapy is limited by toxicities such...
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Citations
... Despite the remarkable activity of CD19-directed chimeric antigen receptor T cell (CART19) therapy in treating B-cell hematologic malignancies [1,2], limitations include 1) the development of potential life-threatening complications such as neurotoxicity (NT) and cytokine release syndrome (CRS) [3,4] and 2) lack of durable response [5][6][7][8]. Emerging literature suggests that inhibitory myeloid cells and their cytokines play an important role in inducing CART cell toxicities and contribute to CART inhibition [9][10][11][12]. Specifically, and of relevance to the work presented in this manuscript, granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in the development of NT and CRS after CART19 therapy based on correlative studies from pivotal clinical trials [5,13]. ...
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. 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. 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. In this study, we show that antigen-specific activation of GM-CSFKO CART19 cells consistently displayed reduced early activation, enhanced proliferation, and improved anti-tumor activity in a xenograft model for relapsed B cell malignancies. Activated CART19 cells significantly upregulate GM-CSF receptors. However, the interaction between GM-CSF and its upregulated receptors on CART cells was not the predominant mechanism of this activation phenotype. GM-CSFKO CART19 cell had reduced BH3 interacting-domain death agonist (Bid), suggesting an interaction between GM-CSF and intrinsic apoptosis pathways. 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.
