한빛사논문
Won Suk Lee 1,2,6, Seung Joon Lee 1,2,6, Hye Jin Lee 1,2,6, Hannah Yang 1,2, Eun-Jin Go 1,2, Enkhtaivan Gansukh 3, Ki-Hoon Song 3, Xiao Xiang 4, Dong Guk Park 3,5, Tommy Alain 4, Hong Jae Chon 1,2,* & Chan Kim 1,2,*
1Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea.
2Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea.
3Virocure Inc., Seoul, Republic of Korea.
4Department of Biochemistry, Microbiology, and Immunology, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
5Department of Surgery, School of Medicine, Dankook University, Cheonan, Republic of Korea.
6These authors contributed equally: Won Suk Lee, Seung Joon Lee, Hye Jin Lee.
*Corresponding authors: correspondence to Hong Jae Chon or Chan Kim
Abstract
The route of oncolytic virotherapy is pivotal for immunotherapeutic efficacy in advanced cancers. In this preclinical study, an oncolytic reovirus (RC402) is orally administered to induce antitumor immunity. Oral reovirus treatment shows no gross toxicities and effectively suppresses multifocal tumor lesions. Orally administered reovirus interacts with the host immune system in the Peyer’s patch of the terminal ileum, increases IgA+ antibody-secreting cells in the lamina propria through MAdCAM-1+ blood vessels, and reshapes the gut microbiome. Oral reovirus promotes antigen presentation, type I/II interferons, and T cell activation within distant tumors, but does not reach or directly infect tumor cells beyond the gastrointestinal tract. In contrast to intratumoral reovirus injection, the presence of the gut microbiome, Batf3+ dendritic cells, type I interferons, and CD8+ T cells are indispensable for orally administered reovirus-induced antitumor immunity. Oral reovirus treatment is most effective when combined with αPD-1(L1) and/or αCTLA-4, leading to complete colon tumor regression and protective immune memory. Collectively, oral reovirus virotherapy is a feasible and effective immunotherapeutic strategy in preclinical studies.
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