NYMC Faculty Publications

Combinatorial Immunotherapy With Anti-ROR1 CAR NK Cells and an IL-21 Secreting Oncolytic Virus Against Neuroblastoma

Author Type(s)

Faculty, Resident/Fellow

DOI

10.1016/j.omton.2024.200927

Journal Title

Molecular Therapy Oncology

Document Type

Article

Publication Date

3-20-2025

Department

Pediatrics

Keywords

CAR, chimeric antigen receptor, IL-21, interleukin-21, natural killer cells, neuroblastoma, oncolytic herpes simplex virus, ROR1

Disciplines

Medicine and Health Sciences

Abstract

Children with recurrent/metastatic neuroblastoma (NB) have a dismal survival (<25%). Novel therapies are desperately needed. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed on NB. C021 is a selective oncolytic herpes simplex virus modified to overexpress human interleukin-21 (hIL-21), a cytokine that enhances natural killer (NK) cell cytotoxicity. In the current study, we successfully engineered ex-vivo-expanded NK cells to express a chimeric antigen receptor (CAR) against ROR1 using mRNA electroporation and investigated the efficacy of anti-ROR1-CAR-NK cells combined with C021 in targeting ROR1+ NB. We found that C021-infected NB cells secreted hIL-21 in vitro and in vivo. Compared to the non-cytokine-secreting parental virus C134, C021 significantly enhanced the in vitro cytotoxicity (p < 0.05) of anti-ROR1-CAR-NK cells with increased interferon (IFN)-γ (p < 0.05), granzyme B (p < 0.05), and perforin (p < 0.05) secretion against NB cells. Furthermore, the combination of C021 and anti-ROR1-CAR-NK cells significantly extended the survival of human NB xenografted NSG mice compared to controls (mock NK, ROR1-CAR-NK, C134, C021, C134+ROR1-CAR-NK, and C021+mock NK). Our results suggest that cytokine-secreting oncolytic virus in combination with CAR-NK cells is a novel, effective immunotherapeutic approach for high-risk NB.

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