J Cancer 2022; 13(6):1933-1944. doi:10.7150/jca.69338 This issue

Research Paper

ONP-302 Nanoparticles Inhibit Tumor Growth By Altering Tumor-Associated Macrophages And Cancer-Associated Fibroblasts

Laxminarasimha Donthireddy1, Prashanthi Vonteddu2, Tushar Murthy3, Taekyoung Kwak1, Rukiye-Nazan Eraslan4, Joseph R. Podojil3,5, Adam Elhofy3, Michael T. Boyne II3,5, John J. Puisis3, Filippo Veglia1,6, Surya S. Singh7, Farokh Dotiwala2, Luis J. Montaner1,2, Dmitry I. Gabrilovich1,8✉

1. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
2. Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA.
3. Research & Development, Cour Pharmaceuticals Development Company, Northbrook, IL, USA.
4. Invivotek, Genesis Drug Discovery and Development (GD3), Hamilton, NJ, USA.
5. Department of Microbiology and Immunology, Northwestern University, Chicago, IL, USA.
6. Current affiliation: H. Lee Moffitt Cancer Center, Tampa, FL.
7. Department of Biochemistry, Osmania University, Hyderabad, India.
8. Current affiliation: ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, 20878, USA.

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Citation:
Donthireddy L, Vonteddu P, Murthy T, Kwak T, Eraslan RN, Podojil JR, Elhofy A, Boyne MT II, Puisis JJ, Veglia F, Singh SS, Dotiwala F, Montaner LJ, Gabrilovich DI. ONP-302 Nanoparticles Inhibit Tumor Growth By Altering Tumor-Associated Macrophages And Cancer-Associated Fibroblasts. J Cancer 2022; 13(6):1933-1944. doi:10.7150/jca.69338. Available from https://www.jcancer.org/v13p1933.htm

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Abstract

Graphic abstract

In this study, we evaluated the ability of negatively charged bio-degradable nanoparticles, ONP- 302, to inhibit tumor growth. Therapeutic treatment with ONP-302 in vivo resulted in a marked delay in tumor growth in three different syngeneic tumor models in immunocompetent mice. ONP- 302 efficacy persisted with depletion of CD8+ T cells in immunocompetent mice and also was effective in immune deficient mice. Examination of ONP-302 effects on components of the tumor microenvironment (TME) were explored. ONP-302 treatment caused a gene expression shift in TAMs toward the pro-inflammatory M1 type and substantially inhibited the expression of genes associated with the pro-tumorigenic function of CAFs. ONP-302 also induced apoptosis in CAFs in the TME. Together, these data support further development of ONP-302 as a novel first-in- class anti-cancer therapeutic that can be used as a single-agent as well as in combination therapies for the treatment of solid tumors due to its ability to modulate the TME.

Keywords: MDSC, Tumor Microenvironment, Nanoparticles, Tumor Associated Macrophages (TAMs), Cancer Associated Fibroblasts (CAFs), PMN-MDSC, M-MDSC.