| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Methods & Clinical Development, Vol 27, Iss , Pp 415-430 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2329-0501 |
| DOI: |
10.1016/j.omtm.2022.10.010 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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