Delving into the Latest Updates on GM-CSF CART19 cell (Mayo Clinic) with Synapse

Overview

Basic Info

Drug Type

CAR-T

Synonyms-

Target

CD19 x GM-CSF

Action

inhibitors

Mechanism

CD19 inhibitors(B-lymphocyte antigen CD19 inhibitors), GM-CSF inhibitors(Macrophage colony stimulating factor 2 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Mayo Clinic

Active Organization

Mayo Clinic

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Ahmed, Omar ; Mwangi, Raphael ; Tapper, Erin E ; Sakemura, Reona ; Manriquez Roman, Claudia ; Scott, Nancy S ; Kay, Neil E ; Horvei, Paulina ; Siegler, Elizabeth L ; Parikh, Sameer A ; Schick, Kendall J ; Adada, Mohamad ; Chappell, Dale ; Can, Ismail ; Hefazi, Mehrdad ; Cox, Michelle J ; Kenderian, Saad S ; Durrant, Cameron ; Kankeu Fonkoua, Lionel Aurelien ; Ruff, Michael W ; Sinha, Sutapa ; Bezerra, Evandro

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-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. 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-CSF^KO 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.

100 Deals associated with GM-CSF CART19 cell (Mayo Clinic)

Login to view more data