The discovery and development of oncolytic viruses: are they the future of cancer immunotherapy?

ABSTRACT

Introduction: Despite diverse treatment modalities and novel therapies, many cancers and patients are not effectively treated. Cancer immunotherapy has recently achieved breakthrough status yet is not effective in all cancer types or patients and can generate serious adverse effects. Oncolytic viruses (OVs) are a promising new therapeutic modality that harnesses virus biology and host interactions to treat cancer. OVs, genetically engineered or natural, preferentially replicate in and kill cancer cells, sparing normal cells/tissues, and mediating anti-tumor immunity.

Areas covered: This review focuses on OVs as cancer therapeutic agents from a historical perspective, especially strategies to boost their immunotherapeutic activities. OVs offer a multifaceted platform, whose activities are modulated based on the parental virus and genetic alterations. In addition to direct viral effects, many OVs can be armed with therapeutic transgenes to also act as gene therapy vectors, and/or combined with other drugs or therapies.

Expert opinion: OVs are an amazingly versatile and malleable class of cancer therapies. They tend to target cellular and host physiology as opposed to specific genetic alterations, which potentially enables broad responsiveness. The biological complexity of OVs have hindered their translation; however, the recent approval of talimogene laherparepvec (T-Vec) has invigorated the field.

KEYWORDS:

• Cancer
• clinical trials
• immunotherapy
• immunovirotherapy
• oncolytic virus

Abbreviations

Ad, adenovirus

BiTE, bispecific T-cell engager

CAR-T, chimeric antigen receptor T cells

CPA, cyclophosphamide

CRAd, conditionally-replicative adenovirus

CTLA-4. cytotoxic T lymphocyte-associated antigen 4

GM-CSF, granulocyte-macrophage colony-stimulating factor

HDAC, histone deacetylase

HSV, herpes simplex virus

ICD, immunogenic cell death

ICI, immune checkpoint inhibitor

IFN, interferon

IL, interleukin

MV, measles virus

MYXV, myxoma virus

NDV, Newcastle disease virus

NK, natural killer

o, oncolytic

OV, oncolytic virus

PAMP, pathogen-associated molecular pattern

PD-1, programmed cell death protein 1

PD-L1, programmed cell death-ligand 1

PPR, pattern recognition receptor

TAA, tumor-associated antigen

TK, thymidine kinase

TIL, tumor infiltrating lymphocytes

TME, tumor microenvironment

TMZ, temozolomide

T-Vec. talimogene laherparepvec

VSV, vesicular stomatitis virus

VV, vaccinia virus

Article highlights

• Oncolytic viruses (OVs) selectively replicate in and kill cancer cells, but not normal tissue, and induce anti-tumor immunity.

• Several approaches have been used to generate OVs, such as deleting viral genes not necessary in cancer cells, targeting unique cancer-cell surface receptors, or regulating essential viral gene expression with tumor-specific promoters.

• Oncolytic herpes simplex virus T-Vec is the first OV approved in the US and Europe.

• OVs armed with immunomodulatory transgenes such as cytokines, chemokines, immune checkpoint inhibitors (ICI), co-stimulatory checkpoint agonists, bispecific T-cell engagers (BiTE), and tumor-associated antigens (TAA) provide a gene therapy platform to target the tumor microenvironment and enhance immunovirotherapy.

• Combining OVs with immunomodulatory pharmacological agents such as ICIs, chemotherapy, radiotherapy, and histone deacetylase (HDAC) inhibitors can improve efficacy.

• Multiple OVs are in clinical trials for a broad range of cancers, including those expressing therapeutic transgenes and in combination with ICIs and chemotherapeutics.

This box summarizes key points contained in the article.

Declaration of interest

S. Rabkin is a co-inventor on patents relating to oHSV, owned and managed by Georgetown University and Massachusetts General Hospital, that were licensed to Amgen and ActiVec Inc, for which royalties have been received, and has received honoraria from Replimune Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One Peer Reviewer declares affiliation with the oncolytic virotherapy company, OncoMyx. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported in part by a grant from NIH (R01 CA160762) and the Thomas A. Pappas Chair in Neuroscience.