TY - JOUR
T1 - Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma
AU - Chu, Yaya
AU - Tian, Meijuan
AU - Saini, Uksha
AU - Ayala-Cuesta, Jessica
AU - Klose, Kayleigh
AU - Mendelowitz, Alyssa S.
AU - Foley, Keira
AU - Ozkaynak, Mehmet F.
AU - Luo, Wen
AU - Cripe, Timothy P.
AU - Lee, Dean A.
AU - Cassady, Kevin A.
AU - Cairo, Mitchell S.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2025/3/20
Y1 - 2025/3/20
N2 - 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.
AB - 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.
KW - CAR
KW - IL-21
KW - ROR1
KW - chimeric antigen receptor
KW - interleukin-21
KW - natural killer cells
KW - neuroblastoma
KW - oncolytic herpes simplex virus
UR - http://www.scopus.com/inward/record.url?scp=85214803517&partnerID=8YFLogxK
U2 - 10.1016/j.omton.2024.200927
DO - 10.1016/j.omton.2024.200927
M3 - Article
AN - SCOPUS:85214803517
SN - 2950-3299
VL - 33
JO - Molecular Therapy Oncology
JF - Molecular Therapy Oncology
IS - 1
M1 - 200927
ER -