Progress of oncolytic virotherapy for neuroblastoma

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.