Despite advances in chemotherapy and surgery, patients diagnosed with peritoneal carcinomatosis, a disseminated intra-abdominal tumour, usually succumb to their disease. But there’s good news: cancer researchers in Ontario have found that an oncolytic virus may lead to a promising new therapy option for these patients.
Led by Drs. Rebecca Auer and John Bell (Ottawa Hospital Research Institute), the team used cancer cells infected ex-vivo with an oncolytic virus (Maraba expressing IL-12) delivered as a personalized cancer vaccine (MG1-IL12 infected cell vaccine). The virus infected the cancer cells and secreted the immune stimulating cytokine IL-12 (a potent stimulator of NK and T cell–mediated tumour cell killing) locally, resulting in migration of highly activated natural killer (NK) cells towards the vaccine and significant tumour regression in mice.
The findings, published in Cancer Immunology Research (March 2017), suggested the vaccine was most effective when delivered in close proximity to the tumour, which is why a model of peritoneal carcinomatosis (one of the most common and challenging sites of metastases for abdominal malignancies) was selected for the study. Patients with this disease typically have a very poor prognosis, with a median survival rate of just six to 12 months.
The results of the present study were impressive: in a model of disseminated colon cancer peritoneal carcinomatosis, the infected cell vaccine could eradicate bulky disease and lead to complete cures in more than 90 per cent of mice. However, when the vaccine did not express IL-12 – or when a non-replicating virus vaccine was used – efficacy was significantly weakened. This highlighted the importance of both aspects being present in the infected cell vaccine, as well as the value of T-cells and NK cells.
This study also highlighted the importance of viral replication in therapeutic efficacy, and the team is currently investigating what aspects of viral infection of cancer cells makes them immunogenic to exploit this further. Looking forward, the group will explore how immune escape happens in those murine models where the vaccine demonstrates efficacy but does not lead to cures in the majority of animals. The present paper resulted in a grant from the Ontario Institute of Cancer Research to undertake enabling studies on manufacturing this virus from human cancer cells with the view of translating these findings into patients with peritoneal carcinomatosis in the near future.
Study: NK-cell recruitment is necessary for eradication of peritoneal carcinomatosis with an IL12-expressing maraba virus cellular vaccine
Authors: Almohanad A. Alkayyal, Lee-Hwa Tai, Michael A. Kennedy, Christiano Tanese de Souza, Jiqing Zhang, Charles Lefebvre, Shalini Sahi, Abhirami A. Ananth, Ahmad Bakur Mahmoud, Andrew P. Makrigiannis, Greg O. Cron, Blair Macdonald, E. Celia Marginean, David F. Stojdl, John C. Bell, and Rebecca C. Auer.
Funding: This work was supported in part by a grant from the Terry Fox Research Institute.
TFRI LINKS, Summer 2017