Myeloid inhibitory cells and their cytokines play an important role in limiting chimeric antigen receptor T (CART) cell therapy by contributing to the induction of toxicity and resistance. Researchers previously discovered that GM-CSF inhibition reduces the toxicities and improves CART cell functions by preventing myeloid cell activation. In the study, they investigated the direct influence of GM-CSF disruption during CD19-directed CART cell production on their effector activities, without taking into account GM-CSF modulation of myeloid cells. Study group demonstrated that antigen-specific activation of GM-CSFKO CART19 cells resulted in reduced early activation, accelerated proliferation, and enhanced anti-tumor efficacy in a xenograft model for relapsed B cell malignancies.GM-CSF receptors are significantly upregulated in activated CART19 cells. However, the interaction between GM-CSF and its upregulated receptors on CART cells was not solely responsible for this activation phenotype. CART19 cells, in which BH3 interacting-domain death agonist (Bid) was decreased, indicated an interaction between GM-CSF and intrinsic apoptosis pathways. Finally, our study demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CART cells improves anti-tumor activity and reduces early activation in preclinical models.
Source:www.nature.com/articles/s41375-022-01572-7
