abstract

Oncolytic viruses (OVs) are an emerging class of cancer therapeutics that offer the benefits of selective replication in tumour cells, delivery of multiple eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumour immunity, and a tolerable safety profile that largely does not overlap with that of other cancer therapeutics. To date, four OVs and one non-oncolytic virus have been approved for the treatment of cancer globally although talimogene laherparepvec (T-VEC) remains the only widely approved therapy. T-VEC is indicated for the treatment of patients with recurrent melanoma after initial surgery and was initially approved in 2015. An expanding body of data on the clinical experience of patients receiving T-VEC is now becoming available as are data from clinical trials of various other OVs in a range of other cancers. Despite increasing research interest, a better understanding of the underlying biology and pharmacology of OVs is needed to enable the full therapeutic potential of these agents in patients with cancer. In this Review, we summarize the available data and provide guidance on optimizing the use of OVs in clinical practice, with a focus on the clinical experience with T-VEC. We describe data on selected novel OVs that are currently in clinical development, either as monotherapies or as part of combination regimens. We also discuss some of the preclinical, clinical and regulatory hurdles that have thus far limited the development of OVs.

Key points

• Talimogene laherparepvec (T-VEC) for patients with melanoma is the first widely approved oncolytic virus, and real-world data from the past 7 years have optimized the role of T-VEC, including identifying patients who are most likely to derive benefit.
• Research involving T-VEC has since been expanded to clinical trials involving patients with other cancers, earlier administration including in the neoadjuvant setting and combination with other therapeutic agents.
• Three other oncolytic viruses have been approved in one or a few countries; one non-oncolytic virus was FDA approved for non-muscle invasive bladder cancer in December 2022 and other oncolytic viruses are in clinical development for a variety of cancer indications.
• Novel oncolytic viruses typically have a tolerable safety profile and several have encouraging levels of activity in early phase clinical studies; nonetheless, challenges remain in optimizing appropriate clinical end points, regulatory pathways and clinical logistics.

Introduction

Oncolytic viruses (OVs) are a promising emerging class of anticancer immunotherapies that exploit the innate ability of certain replication-competent viruses to infect and preferentially lyse tumour cells while leaving non-neoplastic cells intact. OVs can be selected from native viral species on the basis of their innate ability to induce immunogenic cell death (ICD) in cancer cells, although they can also be genetically engineered to enhance tumour selectivity, promote replication competence, limit pathogenicity and increase immunogenicity¹. Engineered viruses can be manipulated by the deletion or modification of viral genes or, in viruses with larger genomes, eukaryotic transgenes can be included as an additional ‘payload’ usually for the purpose of increasing the extent of tumour cell death or promoting antitumour immunity. Both DNA and RNA viruses capable of oncolytic activity in mammalian cells are available, although most clinical studies have used DNA viruses because their molecular biology and life cycle are currently better understood². The generally larger genomes of DNA viruses have the additional advantage of facilitating recombinant gene expression. Further information on the molecular basis of OV development is published elsewhere³.

Talimogene laherparepvec (T-VEC) is an engineered oncolytic herpes simplex virus type 1 (HSV1) designed for preferential replication in tumour cells and induction of antitumour immune responses. Intratumoural injection of T-VEC was evaluated in a prospective randomized trial that met the primary end point of improved durable response rate (DRR, with a durable response defined as an objective response based on modified World Health Organization (WHO) criteria, lasting ≥6 months) in patients with accessible and unresectable melanomas⁴. In addition to DRR, T-VEC also demonstrated improvements in objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), leading to full FDA approval in 2015. T-VEC has since also been approved for use in Europe, Australia and Israel.

Since its initial approval, T-VEC has been tested in numerous other clinical trials, including in combination with other therapies for patients with melanoma and as a monotherapy in patients with a variety of other cancers, and in real-world (or clinical practice) studies from both single and multiple institutions⁵. These studies have provided new insights into how best to integrate T-VEC into the expanding clinical landscape of therapeutic agents available for patients with melanoma. The clinical experience with T-VEC has also highlighted some of the challenges associated with the development of OVs and their clinical use as intratumoural agents. Intratumoural immunotherapy is currently in the early stages of clinical development and although T-VEC is the only FDA-approved OV, in December 2022 the FDA approved a non-oncolytic adenovirus encoding IFNα-2b for the treatment of bacillus Calmette–Guerin (BCG)-unresponsive, non-muscle invasive bladder cancer (NMIBC); and three other OVs have been approved globally (although one was discontinued in 2019; Table 1), suggesting that clinicians should seek to familiarize themselves with T-VEC and other emerging OV technologies.Table 1 Currently approved oncolytic and non-oncolytic viruses worldwide

In this Review, we provide an overview of what we have learned from the clinical experience with T-VEC and define how best to include this OV in the clinical management of patients with melanoma. We also describe some of the preclinical, clinical and regulatory challenges associated with other OVs and intratumoural agents currently in development for the treatment of various advanced-stage cancers. A better understanding of how to optimize the clinical integration of T-VEC and an awareness of other promising emerging agents is expected to enhance the clinical management of patients with melanoma and perhaps also of those with other cancers.

Conclusions

OVs offer immense promise as anticancer therapies. Based on supporting data from clinical trials and real-world clinical studies with T-VEC, the selection of patients has become more focused and T-VEC provides an additional therapeutic option for selected patients with melanoma. Owing to the acceptable safety profile and a mechanism of action that largely does not overlap with that of other therapeutic modalities, T-VEC is being evaluated in combination with other anticancer treatment strategies, with promising early phase clinical data available. A number of other promising OVs are in clinical development, and ongoing research in this area includes identifying novel OV delivery methods such as intravenous administration. Considerable preclinical, clinical and regulatory challenges continue to impair OV development, which is further complicated by issues relating to the storage and administration of a live virus and the need for intratumoural injections. Renewed efforts to better understand the biology and immunology of OVs are leading to new OV strategies and the identification of potential predictive biomarkers. Furthermore, ongoing discussions between regulatory agencies, scientists, clinicians, industry representatives and professional societies are leading to better patient selection and study designs that should enable the full potential of OVs to be realized for patients with cancer.