NYMC Faculty Publications
Novel Cytokine-Antibody Fusion Protein, N-820, to Enhance the Functions of Ex Vivo Expanded Natural Killer Cells Against Burkitt Lymphoma
DOI
10.1136/jitc-2020-001238
Journal Title
Journal for Immunotherapy of Cancer
First Page
e001238
Document Type
Article
Publication Date
10-2020
Department
Pediatrics
Second Department
Health Behavior and Community Health
Keywords
Animals, Burkitt Lymphoma, Cytokines, Female, Humans, Immunotherapy, Killer Cells, Natural, Mice, Mice, Inbred NOD, Prognosis
Disciplines
Medicine and Health Sciences
Abstract
Background: The prognosis of patients with relapsed or progressive B cell (CD20+) non-Hodgkin's lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemoradiotherapy resistance. Novel therapeutic strategies are urgently needed. N-820 is a fusion protein of N-803 (formerly known as ALT-803) to four single-chains of rituximab. This agent has tri-specific binding activity to CD20 and enhanced antibody-dependent cell-mediated cytotoxicity.
Methods: We investigated the anti-tumor combinatorial effects of N-820 with ex vivo expanded peripheral blood natural killer (exPBNK) cells against rituximab-sensitive and rituximab-resistant CD20+ BL in vitro using cytoxicity assays and in vivo using human BL xenografted NOD/SCID/IL2rγnull (NSG) mice. We also investigated the cytokines/chemokines/growth factors released using ELISA and multiplex assay. Gene expression changes were examined using real-time PCR arrays.
Results: N-820 significantly enhanced the expression of NK activating receptors (p<0.001) and the proliferation of exPBNK cells with enhanced Ki67 expression and Stat5 phosphorylation (p<0.001). N-820 significantly enhanced the secretion of cytokines, chemokines, and growth factors including GM-CSF, RANTES, MIP-1B (p<0.001) from exPBNK cells as compared with the combination of rituximab+N-803. Importantly, N-820 significantly enhanced in vitro cytotoxicity (p<0.001) of exPBNK with enhanced granzyme B and IFN-γ release (p<0.001) against BL. Gene expression profiles in exPBNK stimulated by N-820+Raji-2R showed enhanced transcription of CXCL9, CXCL1, CSF2, CSF3, GZMB, and IFNG. Moreover, N-820 combined with exPBNK significantly inhibited rituximab-resistant BL growth (p<0.05) and extended the survival (p<0.05) of BL xenografted NSG mice.
Conclusions: Our results provide the rationale for the development of a clinical trial of N-820 alone or in combination with endogenous or ex vivo expanded NK cells in patients with CD20+ B-NHL failing prior rituximab containing chemoimmunotherapy regimens.
Recommended Citation
Chu, Y., Nayyar, G., Kham Su, N., Rosenblum, J. M., Soon-Shiong, P., Lee, J., Safrit, J. T., Barth, M., Lee, D., & Cairo, M. S. (2020). Novel Cytokine-Antibody Fusion Protein, N-820, to Enhance the Functions of Ex Vivo Expanded Natural Killer Cells Against Burkitt Lymphoma. Journal for Immunotherapy of Cancer, 8 (2), e001238. https://doi.org/10.1136/jitc-2020-001238
