Towards Safer and More Effective CART Cell Therapy Through the Modulation of Myeloid Cytokines

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PROJECT SUMMARY Despite the impressive activity of chimeric antigen receptor (CART) T cell therapy in the treatment of B-cell malignancies, the therapy is limited by the development of cytokine release syndrome (CRS) and neurotoxicity, as well as by lower rates of durable responses. While CRS is related to extreme elevation of cytokines associated with T cell expansion, the exact etiology of neurotoxicity is unknown and no options for treatment of neurotoxicity are available. It has, however, become apparent that inhibitory myeloid cells and cytokines contribute to both CART cell toxicities and resistance. We have identified granulocyte-macrophage colony- stimulating factor (GM-CSF) as a dominant driver for CART cell toxicity and inhibition of their functions. Our robust preclinical data indicate that GM-CSF inhibition reduces monocyte activation, enhances CART cell functions and prevents the development of both CRS and neurotoxicity in a novel xenograft model for CART cell-associated toxicities. Our additional studies suggest that GM-CSF disruption in CART cells ameliorates their apoptosis, independent of its effect on myeloid cells. These findings were corroborated when we utilized GM-CSF depletion as a therapeutic strategy in patients with cytokine storm and severe Coronavirus Disease 2019, COVID-19. Based on this work, a Phase 1/2 multi-center study of GM-CSF neutralization after CART19 cell therapy was launched. Our central hypothesis is that depletion of GM-CSF results in modulation of myeloid cell behavior, amelioration of CART cell activation, reduction of CART cell associated toxicities, and enhancement of their efficacy. We will leverage our laboratory tools, novel preclinical models, and samples from this clinical trial to test our hypothesis. In Aim 1 of this project, we will examine the interactions between GM-CSF and monocytes after CART cell therapy. In Aim 2 of this project, we will study the effect of GM-CSF directly on CART cells, and Aim 3 will test how these changes affect toxicity and efficacy of CART19 cell therapy in the novel Phase 1/2 clinical trial. Completion of these Aims will identify novel insights into the toxicity and activity of CART cells and will develop a new strategy to prevent CART cell associated neurotoxicity and CRS, potentially enabling the outpatient administration of CART cell therapy.