TY - JOUR
T1 - Efficiently targeting neuroblastoma with the combination of anti-ROR1 CAR NK cells and N-803 in vitro and in vivo in NB xenografts
AU - Chu, Yaya
AU - Nayyar, Gaurav
AU - Tian, Meijuan
AU - Lee, Dean A.
AU - Ozkaynak, Mehmet F.
AU - Ayala-Cuesta, Jessica
AU - Klose, Kayleigh
AU - Foley, Keira
AU - Mendelowitz, Alyssa S.
AU - Luo, Wen
AU - Liao, Yanling
AU - Ayello, Janet
AU - Behbehani, Gregory K.
AU - Riddell, Stanley
AU - Cripe, Timothy P.
AU - Cairo, Mitchell S.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/6/20
Y1 - 2024/6/20
N2 - 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.
AB - 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.
KW - IL-15 superagonist
KW - MT: Regular Issue
KW - ROR1
KW - chimerical antigen receptor
KW - cytotoxicity
KW - expanded natural killer cells
KW - neuroblastoma
KW - targeted immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=85204131288&partnerID=8YFLogxK
U2 - 10.1016/j.omton.2024.200820
DO - 10.1016/j.omton.2024.200820
M3 - Article
AN - SCOPUS:85204131288
SN - 2950-3299
VL - 32
JO - Molecular Therapy Oncology
JF - Molecular Therapy Oncology
IS - 2
M1 - 200820
ER -