Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β

Kajal Chaudhry; Ashley Geiger; Ehsan Dowlati; Haili Lang; Danielle K Sohai; Eugene I Hwang; Christopher A Lazarski; Eric Yvon; Matthias Holdhoff; Richard Jones; Barbara Savoldo; Conrad Russell Y Cruz; Catherine M Bollard

doi:10.1016/j.omtm.2022.10.010

Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β

Mol Ther Methods Clin Dev. 2022 Oct 21:27:415-430. doi: 10.1016/j.omtm.2022.10.010. eCollection 2022 Dec 8.

Authors

Affiliations

¹ Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
² Department of Neurosurgery, Georgetown University Medical Center, Washington, DC, USA.
³ GW Cancer Center, George Washington University, Washington, DC, USA.
⁴ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA.

Abstract

Cord blood (CB)-derived natural killer (NK) cells that are genetically engineered to express a chimeric antigen receptor (CAR) are an attractive off-the-shelf therapy for the treatment of cancer, demonstrating a robust safety profile in vivo. For poor prognosis brain tumors such as glioblastoma multiforme (GBM), novel therapies are urgently needed. Although CAR-T cells demonstrate efficacy in preclinical GBM models, an off-the-shelf product may exhibit unwanted side effects like graft-versus-host disease. Hence, we developed an off-the-shelf CAR-NK cell approach using a B7H3 CAR and showed that CAR-transduced NK cells have robust cytolytic activity against GBM cells in vitro. However, transforming growth factor (TGF)-β within the tumor microenvironment has devastating effects on the cytolytic activity of both unmodified and CAR-transduced NK cells. To overcome this potent immune suppression, we demonstrated that co-transducing NK cells with a B7H3 CAR and a TGF-β dominant negative receptor (DNR) preserves cytolytic function in the presence of exogenous TGF-β. This study demonstrates that a novel DNR and CAR co-expression strategy may be a promising therapeutic for recalcitrant CNS tumors like GBM.

Keywords: B7H3 CAR; CAR-NK cells; GBM; NK cells; TGF-β; cord blood.