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

Authors

Kajal Chaudhry, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Ashley Geiger, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Ehsan Dowlati, Department of Neurosurgery, Georgetown University Medical Center, Washington, DC, USA.
Haili Lang, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Danielle K. Sohai, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Eugene I. Hwang, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Christopher A. Lazarski, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Eric Yvon, GW Cancer Center, George Washington University, Washington, DC, USA.
Matthias Holdhoff, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Richard Jones, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Barbara Savoldo, Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA.
Conrad Russell Cruz, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Catherine M. Bollard, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.

Document Type

Journal Article

Publication Date

12-8-2022

Journal

Molecular therapy. Methods & clinical development

Volume

27

DOI

10.1016/j.omtm.2022.10.010

Keywords

B7H3 CAR; CAR-NK cells; GBM; NK cells; TGF-β; cord blood

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 . 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 . 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.

APA Citation

Chaudhry, Kajal; Geiger, Ashley; Dowlati, Ehsan; Lang, Haili; Sohai, Danielle K.; Hwang, Eugene I.; Lazarski, Christopher A.; Yvon, Eric; Holdhoff, Matthias; Jones, Richard; Savoldo, Barbara; Cruz, Conrad Russell; and Bollard, Catherine M., "Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β" (2022). GW Authored Works. Paper 2128.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/2128

Department

Medicine