Oncolytic virotherapies for pediatric tumors

ABSTRACT

Introduction

Many pediatric patients with malignant tumors continue to suffer poor outcomes. The current standard of care includes maximum safe surgical resection followed by chemotherapy and radiation which may be associated with considerable long-term morbidity. The emergence of oncolytic virotherapy (OVT) may provide an alternative or adjuvant treatment for pediatric oncology patients.

Areas covered

We reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). For each virus, we discuss the mechanism of tumor-specific replication and cytotoxicity as well as key findings of preclinical and clinical studies.

Expert opinion

Substantial progress has been made in the past 10 years regarding the clinical use of OVT. From our review, OVT has favorable safety profiles compared to chemotherapy and radiation treatment. However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.

KEYWORDS:

• Adenovirus
• herpes simplex virus
• measles virus
• oncolytic virus
• pediatric tumors
• poliovirus
• reovirus
• vaccinia virus

Article highlights

• Oncolytic virotherapy (OVT) represents a promising category of potential treatments for children with malignant solid tumors.

• Preclinical trials using OVT in mouse tumor models have shown promising antitumor efficacy.

• Clinical trials using OVT in pediatric oncology patients are limited to phases 1 and 2 and have shown favorable safety profiles.

• The impact on patient outcomes of OVT in humans remains unclear given the existing data from completed clinical trials which are generally early phase.

• Major challenges remain for the clinical use of OVT:

  • ∘ Characterizing OVT immunomodulatory effects

  • ∘ Determining optimal timing for the use of OVT, including at diagnosis versus at recurrence

  • ∘ Identifying the most effective viruses for specific tumor types

  • ∘ Optimizing methods of OVT delivery to target tumor

  • ∘ Investigating the safety and efficacy of OVT alone or combined with existing treatment options

Declaration of interest

James M is a board member, equity holding member (<8%), and receives royalties from Aettis, Inc. This company holds frozen oncolytic viral stocks. Mustang Bio Tech is licensing the IP of C134 an oncolytic viral therapy. J Markert is blinded to the conditions of licensing and any potential receipts he could be awarded for the C134 clinical trials. J Markert is a 25% shareholder for Treovir, Inc. LLC, a privately held Small Business Innovation Research LLC developing G207 oncolytic viral therapy now in clinical trial for pediatric patients. He does not have a pediatric practice personally. J Markert, along with UAB, hold IP in In8bio, a privately held corporation developing gamma-delta T cells for anti-glioma therapy. Merck has agreed to provide industry grant support by providing Keytruda (pembrolizumab) and funding for a pending clinical trial of M032 oncolytic virotherapy. J Markert receives the occasional invitation to present findings to other academic medical institutions (e.g. UT Southwestern, MD Anderson, Memorial Sloan Kettering, Vanderbilt) for which he may receive honoraria. J Markert received structured buyout payments from Amgen, Inc., a publicly traded company which holds a patent for oncolytic virotherapy (for the sale of Catherex, Inc. which no longer exists.) Final payment was received in March/April 2021. J Markert served as external consultant and received compensation for work completed in 2020 as well as travel reimbursement from Imugene Limited. 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This publication was supported in part by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R25NS079188 (DEO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also completed while DEO was a Cornwall Clinical Scholar supported by the University of Alabama at Birmingham. JMM is the principal investigator for NIH grants R01CA222903 and R01CA217179. He is also a co-investigator for NIH grant R01FD05379–01.