Molecular Therapy: Methods & Clinical Development (Dec 2022)

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

Journal volume & issue
Vol. 27
pp. 415 – 430

Abstract

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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.

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