SARS-CoV-2 RBD protein enhances the oncolytic activity of the vesicular stomatitis virus

Oncolytic virotherapy is an emerging treatment modality which uses replication competent viruses to destroy cancers. Advances in the past two years include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, new strategies to maximize the immunotherapeutic potential of oncolytic virotherapy, and clinical confirmation of a critical viremic thereshold for vascular delivery and intratumoral virus replication. The primary clinical milestone was completion of accrual in a phase III trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Challenges for the field are to select ‘winners’ from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders of magnitude higher yields compared to established vaccine manufacturing processes.

Key Points Oncolytic viruses mediate anti-tumour responses through a dual mechanism involving viral oncolysis of cancer cells and induction of host anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements, release of danger signals and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been utilized as oncolytic vectors in preclinical studies, which have demonstrated therapeutic activity against several types of cancer. Oncolytic viruses can be genetically modified to decrease pathogenicity, increase lytic potential and enhance immunogenicity, improving the risk–benefit ratio for clinical development. The approval of a modified adenovirus, H101, in China and the pending approval of a modified herpes simplex virus type 1 (HSV-1) encoding granulocyte–macrophage colony stimulating factor (GM-CSF), termed talimogene laherparepvec (T-VEC), by the US Food and Drug Administration (FDA) in the United States is likely to promote further drug development within this new class of cancer therapeutics. Oncolytic viruses face unique challenges in drug development, including the need for optimal clinical trial designs and response assessment that capture therapeutic responses, different regulatory and commercialization pathways, the need for live culture scale-up procedures, and novel biosafety concerns related to viral persistence in patients and transmission to household contacts and health-care providers. Supplementary information The online version of this article (doi:10.1038/nrd4663) contains supplementary material, which is available to authorized users.

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.