Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

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Abstract

<p class="first" id="d15611188e138">Oncolytic virus (OV) therapy is an anti-cancer approach that uses viruses that preferentially infect, replicate in and kill cancer cells. Vesicular stomatitis virus (VSV, a rhabdovirus) is an OV that is currently being tested in the USA in several phase I clinical trials against different malignancies. Several factors make VSV a promising OV: lack of pre-existing human immunity against VSV, a small and easy to manipulate genome, cytoplasmic replication without risk of host cell transformation, independence of cell cycle and rapid growth to high titres in a broad range of cell lines facilitating large-scale virus production. While significant advances have been made in VSV-based OV therapy, room for improvement remains. Here we review recent studies (published in the last 5 years) that address ‘old’ and ‘new’ challenges of VSV-based OV therapy. These studies focused on improving VSV safety, oncoselectivity and oncotoxicity; breaking resistance of some cancers to VSV; preventing premature clearance of VSV; and stimulating tumour-specific immunity. Many of these approaches were based on combining VSV with other therapeutics. This review also discusses another rhabdovirus closely related to VSV, Maraba virus, which is currently being tested in Canada in phase I/II clinical trials. </p>

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VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents.

David Stojdl, Brian Lichty, Benjamin tenOever … (2003)

Ideally, an oncolytic virus will replicate preferentially in malignant cells, have the ability to treat disseminated metastases, and ultimately be cleared by the patient. Here we present evidence that the attenuated vesicular stomatitis strains, AV1 and AV2, embody all of these traits. We uncover the mechanism by which these mutants are selectively attenuated in interferon-responsive cells while remaining highly lytic in 80% of human tumor cell lines tested. AV1 and AV2 were tested in a xenograft model of human ovarian cancer and in an immune competent mouse model of metastatic colon cancer. While highly attenuated for growth in normal mice, both AV1 and AV2 effected complete and durable cures in the majority of treated animals when delivered systemically.

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Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy

Hasan Rehman, Ann Silk, Michael P. Kane … (2016)

With the recent regulatory approval of Talimogene laherparepvec (T-VEC) for the treatment of advanced of melanoma in the United States, Europe and Australia, oncolytic virus immunotherapy has earned its place in the clinic. However, the adoption of T-VEC by the U.S. oncology community has been slow, and so far has been largely limited to specialized cancer centers. Limiting factors include the intratumoral route of administration, which is unfamiliar to medical oncologists, biosafety concerns related to the use of a live virus in the clinic, and the explosion of other therapeutic strategies now available for the treatment of advanced melanoma. Herein, we review the development of T-VEC, and suggest how it fits into the in the current clinical treatment paradigm, and provide pearls for drug preparation, administration, and monitoring of response to therapy.