ROR1 and ROR2—novel targets for neuroblastoma

Abstract

Background: Despite advances in immunotherapeutic strategies for neuroblastoma (NBL), relapse remains a significant cause of mortality for high risk patients. The discovery of novel tumor associated antigens to improve efficacy and minimize the toxicities of immunotherapy is therefore warranted. Receptor Tyrosine Kinase-like Orphan Receptor-1 and 2 (ROR1 and ROR2) have been found to be expressed in several malignancies with limited expression in healthy tissues.

Objectives: Given their role in tumor migration and proliferation and the fact that they were originally cloned from a NBL cell line, we hypothesized that ROR1 and ROR2 could serve as potential targets for anti-ROR1 and anti-ROR2 based immunotherapies in NBL.

Methods: We characterized the mRNA and protein expression of ROR1 and ROR2 in NBL cell lines and tissue microarrays of patient samples. To explore the potential of ROR1 targeting, we performed in vitro cytotoxicity assays against NBL using NK92 cells as effector cells.

Results: Both ROR1 and ROR2 are expressed across all stages of NBL. In patients with non-MYC amplified tumors, expression of ROR1/ROR2 correlated with survival and prognosis. Moreover, in a proof-of-concept experiment, pretreatment of NBL cell line with anti-ROR1 antibody showed additive cytotoxicity with NK92 cells.

Conclusions: ROR1 and ROR2 could serve as novel targets for immunotherapy in NBL. The additive effect of anti-ROR1 antibodies with NK cells needs to be explored further to evaluate the possibility of combining anti-ROR1 antibodies with immune effectors such as NK92 cells as a potential off-the shelf immunotherapy for NBL and other ROR1 expressing malignancies.

Keywords:

• Immunotherapy
• monoclonal antibody
• neuroblastoma
• off-the-shelf
• ROR1
• ROR2

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Acknowledgments

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. We thank the Children’s Oncology Group Neuroblastoma Biology Committee and the Biopathology Center for providing the tissue microarrays. We thank Christoph Rader, PhD, Department of Immunology and Microbiology, Scripps University, Florida for reviewing the manuscript and providing guidance to H.D. We thank Javed Khan, MD, Head, Oncogenomics Section, National Cancer Institute for providing access and help with analysis of the gene expression profiling dataset.

Additional information

Funding

This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. H.D received funding from Lymphoma Research Foundation for professional development.