Oncolytic viruses: perspectives on clinical development

doi:10.1016/j.coviro.2015.03.020

Current Opinion in Virology

Volume 13, August 2015, Pages 55-60

https://doi.org/10.1016/j.coviro.2015.03.020 Get rights and content

Highlights

•
Oncolytic virus (OV) clinical development is more complex than other therapeutics.
•
‘Window of opportunity’ studies should be considered in the development process.
•
A well thought out clinical development plan is an essential element of the process.
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OV infectious potential should be factored into clinical trial design and conduct.
•
OV have the potential to help overcome heretofore incurable disease.

Developing a live anti-cancer agent derived in most cases from human pathogens presents a unique set of challenges to clinical development versus those anticipated with standard chemotherapeutics and small molecules. The selection of therapeutic targets for oncolytic virus (OV) clinical development, as is true with the development of any agent for cancer therapy, requires careful consideration beyond preclinical and early clinical data, especially when multiple indications may initially appear equally promising. Further, the added complexity of the potential for infectious complications following OV therapy must be anticipated in order to efficiently and safely conduct clinical studies. As more OV enter the clinic, these issues will become increasingly important to successful OV drug development.

Introduction

Unlike non-specific DNA poisons, monoclonal antibodies or even small molecule targeted therapies Oncolytic Viruses (OV) package multiple genetic effectors into a single agent [1]. As live biological agents designed to specifically target cancer, OV present both distinct advantages as well as unique challenges to clinical development. It is important to consider, as more OV constructs transition from the lab to the clinic, the complexities of OV product development, the lessons learned from OV agents that have been studied in human trials, and understand the fundamentals of drug development relevant to this growing field.

Section snippets

Preclinical studies and Phase 0 clinical trials

Mouse models are commonly used to test for toxicity and efficacy of novel therapeutics. However, in contrast to small molecule or protein therapeutics, mouse models are likely not predictive of humans with respect to OV activity (e.g. many OVs have evolved from human pathogens and do not infect murine tissue). One class of mouse models are syngeneic (implantation of murine tumors into immunocompentent mice) or transgenic models (orthotopic tumors spontaneously develop). Syngeneic models present

Clinical development: considerations for clinical trial design

Inherent OV properties as well as design elements engineered into OV constructs (e.g. inherent tropism for specific tissues, tumor selective replication, or transgene expression targeting a limited subset of tumor types) will of course influence the initial direction of clinical development. For instance, ColoAd1 was the product of a bioselection process to identify OV characteristics optimal for use in colon cancer, thereby driving development toward colorectal carcinoma [8] while the

Anticipation of adverse event profiles and risk mitigation

Despite the engineering of cancer specific promoters into viral constructs, expression in off-target cells can be observed and impact toxicity profiles of vectors in clinical development. Expected adverse events (AE) in first-in-human trials may be anticipated by examining the natural tropism and disease that is associated with the parent virus impacting initial trial design, target tumor, and patient selection.

For instance, wild type herpes simplex virus (HSV) can infrequently cause viral

Product handling at clinical trial sites

Especially important for the clinical development of OV is consideration of the natural history and infectious potential of the parent virus. Despite any attenuation gained by genetic engineering of the construct, until clearly established in the clinic, risk assessment will revolve around the parent virus. The impression of the risk of virus exposure to the health care providers or the community will be conservatively scrutinized by health care teams and local regulatory authorities regardless

Conclusion

In conclusion, on the eve of the first approval of an OV for cancer, there is much promise for the field to contribute significantly to progress in addressing a heretofore incurable disease. However, it is clear that developing a live biologic agent derived in most cases from human pathogens presents a much more complex set of challenges to clinical development versus that anticipated when embarking on a similar endeavor with other therapeutics such as small molecules (Table 2). To this end,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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Thus, the use of OTs can potentially help reduce the toxicity of adoptive T-cell therapy both by controlling CAR activity with the light of different wavelengths (depending on the location of the tumor), and precise localization of the cytotoxic effect by light-stimulated targeted infiltration of tumor-specific CAR-T cells. The oncolytic potential of viruses has been known for quite a while, however, its application for cancer therapy has been hampered by a lack of knowledge of virus biology and immune pathways (Burke et al., 2015). Most oncolytic viruses show selective replication in tumor cells and affect several key steps in the cancer–immunity cycle (Eissa et al., 2018).
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Furthermore, a phase I mechanism of action study showed that virus activity was detected in intravenously and intratumourally treated patients, and tumour infiltration by CD8+ cells was considered to be linked to an immunostimulatory effect of ColoAd1 [54]. By observation of a shift in the tumour microenvironment (e.g. T cell number and activation status) before and after treatment with oncolytic viruses and checkpoint inhibitors, combination strategies might be further optimised [55]. Several randomised trials with oncolytic virus therapy have reported considerable response rates suggesting potential clinical utility [48,56].
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View all citing articles on Scopus

View full text

Oncolytic viruses: perspectives on clinical development

Highlights

Introduction

Section snippets

Preclinical studies and Phase 0 clinical trials

Clinical development: considerations for clinical trial design

Anticipation of adverse event profiles and risk mitigation

Product handling at clinical trial sites

Conclusion

References and recommended reading

Mol Ther

Vet Immunol Immunopathol

Cell Host Microbe

N Engl J Med

Nat Rev Cancer

Oncolytic virotherapy

Nat Biotechnol

Multiple isoforms of CD46 (membrane cofactor protein) serve as receptors for measles virus

Proc Natl Acad Sci U S A

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

J Clin Invest

Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients

Sci Transl Med

Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans

Nature