Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma

Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma

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 interleuk...

Full description

Saved in:
Bibliographic Details
Main Authors: Yaya Chu, Meijuan Tian, Uksha Saini, Jessica Ayala-Cuesta, Kayleigh Klose, Alyssa S. Mendelowitz, Keira Foley, Mehmet F. Ozkaynak, Wen Luo, Timothy P. Cripe, Dean A. Lee, Kevin A. Cassady, Mitchell S. Cairo
Format: Article
Language:English
Published: Elsevier 2025-03-01
Series:Molecular Therapy: Oncology
Subjects:
neuroblastoma
chimeric antigen receptor
CAR
ROR1
natural killer cells
oncolytic herpes simplex virus
Online Access:http://www.sciencedirect.com/science/article/pii/S2950329924001693
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2950-3299

Similar Items