Efficiently targeting neuroblastoma with the combination of anti-ROR1 CAR NK cells and N-803 in vitro and in vivo in NB xenografts

Yaya Chu; Gaurav Nayyar; Meijuan Tian; Dean A Lee; Mehmet F Ozkaynak; Jessica Ayala-Cuesta; Kayleigh Klose; Keira Foley; Alyssa S Mendelowitz; Wen Luo; Yanling Liao; Janet Ayello; Gregory K Behbehani; Stanley Riddell; Tim Cripe; Mitchell S Cairo

doi:10.1016/j.omton.2024.200820

Efficiently targeting neuroblastoma with the combination of anti-ROR1 CAR NK cells and N-803 in vitro and in vivo in NB xenografts

Mol Ther Oncol. 2024 May 24;32(2):200820. doi: 10.1016/j.omton.2024.200820. eCollection 2024 Jun 20.

Authors

Yaya Chu¹, Gaurav Nayyar¹, Meijuan Tian¹, Dean A Lee², Mehmet F Ozkaynak¹, Jessica Ayala-Cuesta¹, Kayleigh Klose¹, Keira Foley¹, Alyssa S Mendelowitz¹, Wen Luo¹, Yanling Liao¹, Janet Ayello¹, Gregory K Behbehani³, Stanley Riddell⁴, Tim Cripe², Mitchell S Cairo^{1

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Affiliations

¹ Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA.
² Department of Pediatric Hem/Onc/BMT, Nationwide Children's Hospital, Columbus, OH 43205, USA.
³ Department of Internal Medicine, Division of Hematology, the Ohio State University; Columbus, OH 43210, USA.
⁴ Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵ Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
⁶ Department of Microbiology, Immunology and Pathology, New York Medical College, Valhalla, NY 10595, USA.
⁷ Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.

Abstract

The prognosis for children with recurrent and/or refractory neuroblastoma (NB) is dismal. The receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is highly expressed on the surface of NB cells, provides a potential target for novel immunotherapeutics. Anti-ROR1 chimeric antigen receptor engineered ex vivo expanded peripheral blood natural killer (anti-ROR1 CAR exPBNK) cells represent this approach. N-803 is an IL-15 superagonist with enhanced biological activity. In this study, we investigated the in vitro and in vivo anti-tumor effects of anti-ROR1 CAR exPBNK cells with or without N-803 against ROR1⁺ NB models. Compared to mock exPBNK cells, anti-ROR1 CAR exPBNK cells had significantly enhanced cytotoxicity against ROR1⁺ NB cells, and N-803 further increased cytotoxicity. High-dimensional analysis revealed that N-803 enhanced Stat5 phosphorylation and Ki67 levels in both exPBNK and anti-ROR1 CAR exPBNK cells with or without NB cells. In vivo, anti-ROR1 CAR exPBNK plus N-803 significantly (p < 0.05) enhanced survival in human ROR1⁺ NB xenografted NSG mice compared to anti-ROR1 CAR exPBNK alone. Our results provide the rationale for further development of anti-ROR1 CAR exPBNK cells plus N-803 as a novel combination immunotherapeutic for patients with recurrent and/or refractory ROR1⁺ NB.

Keywords: IL-15 superagonist; MT: Regular Issue; ROR1; chimerical antigen receptor; cytotoxicity; expanded natural killer cells; neuroblastoma; targeted immunotherapy.