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...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329924001693 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yaya Chu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-890724d086f648c186b0f186148081c8 |
| institution | Kabale University |
| issn | 2950-3299 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-890724d086f648c186b0f186148081c82025-01-16T04:29:32ZengElsevierMolecular Therapy: Oncology2950-32992025-03-01331200927Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastomaYaya Chu0Meijuan Tian1Uksha Saini2Jessica Ayala-Cuesta3Kayleigh Klose4Alyssa S. Mendelowitz5Keira Foley6Mehmet F. Ozkaynak7Wen Luo8Timothy P. Cripe9Dean A. Lee10Kevin A. Cassady11Mitchell S. Cairo12Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USACenter for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH 43210, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USACenter for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH 43210, USACenter for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH 43210, USACenter for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH 43210, USADepartment of Pediatrics, New York Medical College, Valhalla, NY 10595, USA; Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595, USA; Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA; Department of Medicine, New York Medical College, Valhalla, NY 10595, USA; Corresponding author: Mitchell S. Cairo, Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA.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.http://www.sciencedirect.com/science/article/pii/S2950329924001693neuroblastomachimeric antigen receptorCARROR1natural killer cellsoncolytic herpes simplex virus |
| spellingShingle | 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 Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma Molecular Therapy: Oncology neuroblastoma chimeric antigen receptor CAR ROR1 natural killer cells oncolytic herpes simplex virus |
| title | Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma |
| title_full | Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma |
| title_fullStr | Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma |
| title_full_unstemmed | Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma |
| title_short | Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma |
| title_sort | combinatorial immunotherapy with anti ror1 car nk cells and an il 21 secreting oncolytic virus against neuroblastoma |
| topic | neuroblastoma chimeric antigen receptor CAR ROR1 natural killer cells oncolytic herpes simplex virus |
| url | http://www.sciencedirect.com/science/article/pii/S2950329924001693 |
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