IBCN 2022: Oncolytic Virotherapy

(UroToday.com) Dr. Ramon Alemany provided an overview of the development of oncolytic virotherapy (OV) to kick off the session. He introduced the mechanism of action of oncolytic viruses, acting through a dual pathway both to cause direct oncolysis via selective replication within tumor cells, as well as inducing immunogenic cell death by releasing microbial and tumor antigens.

Compared to anti-tumor bacterial agents, oncolytic viruses are smaller, intracellular, receptor-targeted, and selective replicate within tumor cells via molecular mechanisms. There are several classes of oncolytic viruses, broadly separated into DNA viruses and RNA viruses. While DNA viruses can provide the viral backbone upon which genetic engineering may be performed, these viruses are also larger and may not penetrate the tumor cells as well as RNA viruses. RNA viruses also replicate more rapidly compared to DNA viruses.

For many oncolytic viruses, selective replication happens via a silenced IFN pathway in the tumor cells. To combat immune surveillance, cancer cells often dampen their own IFN response, thus making it possible for oncolytic viruses to opportunistically infect the tumor cells. One of the major challenges in OV therapy is the requirement for systemic deliver in most cases, and the anti-viral immunity present in most humans, thus neutralizing the virus prior to its oncolytic functions being carried out. In previous experiments using the T-VEC virus, it was found that although there was an attenuated abscopal effect on distant cutaneous sites, visceral metastases were more difficult to be treated through a systemic immunogenic response. 

Dr. Alemany then highlighted several strategies used to improve the efficacy of OVs. These include using and iRGD capsid modification to improve tumor targeting, decrease viral clearance by using albumin-binding domain, using selective E2F promoters in adenoviruses the enhance tumor selective replication, and also strategies to incorporate the expression of hyaluronidases within the viral backbone in order to enhance viral penetration of stromal tissue present in the tumor microenvironment. In addition, a novel strategy of combining OV with bispecific T cell engagers targeting virally expressed proteins in a stepwise fashion has also been conjectured to provide benefit.

In summary, Dr. Alemany hypothesized that oncolytic viruses may be synergistically used with immune checkpoint blockade, adoptive transfer of antitumor T cells and other immunotherapy strategies. However, OVs need to be improved on many aspects including systemic tumor targeting, intratumoral spread, and immunodominance.