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Optimizing oncolytic virotherapy in cancer treatment

Abstract

In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.

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Fig. 1: Considerations for OV drug development as part of the immune-oncology toolbox.
Fig. 2: Considerations for design of local and systemic combinations to enhance OV activity.
Fig. 3: Overcoming in vivo barriers to response.

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Acknowledgements

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by S. Gilbert and H. Dbouk of Cirrus Communications (New York, NY, USA), an Ashfield company, and was funded by AstraZeneca.

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K.H. and D.J.F. provided research data for the article and a substantial contribution to discussion of content, and were involved in writing and reviewing/editing of the manuscript. B.K., J.H. and J.-C.S. provided research data for the article, wrote, reviewed and edited the manuscript before submission.

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Correspondence to Kevin Harrington.

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D.J.F., B.K., J.H. and J.-C.S. are employees of and own stocks and shares in AstraZeneca. K.H. has received research funding from Oncolytics Biotech and Genelux GmbH, and honoraria from Amgen, Viralytics and Oncos Therapeutics. J.-C.S. has received consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Eli Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen and Takeda, and has been a full-time employee of AstraZeneca since September 2017.

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Glossary

Vaccinia virus

Large, double-stranded DNA virus belonging to the poxvirus family.

Neutralizing antibodies

(nAbs). Antibodies that bind to a virus and interfere with its ability to infect a cell.

Fusogenic activity

The ability of a virus to fuse directly with target cells, resulting in immunogenic cell death by activation of the adaptive and innate immune systems.

Seroconversion

The development of detectable IgG antibodies in the blood that are directed against an infectious agent.

Chimeric antigen receptor (CAR)-T cells

T cells that have been genetically engineered to express an antigen receptor that recognizes an antigen present only on the surface of malignant cells. Upon recognition and binding of CAR-T cells to antigen-specific tumour cells, the tumour cells are killed.

Extracellular matrix

A 3D network of extracellular macromolecules forming the non-cellular component of tissues that provides structural and biochemical support for surrounding cells.

Prime-boost regimens

The use of multiple vaccinations, using the same (homologous) or different (heterologous) vaccines each time, in order to develop cell-mediated immunity.

Chimeric adenovirus

A recombinant adenovirus containing a mixture of DNA from different adenoviral strains that may have different infection potency and activity to the original, ‘parental’ adenoviruses.

Loculated

Characterized by fluid-filled cavities and divisions within an organ or body cavity that are separated from the remainder of the tissue with mucous, serous or fibrous membranes.

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Harrington, K., Freeman, D.J., Kelly, B. et al. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov 18, 689–706 (2019). https://doi.org/10.1038/s41573-019-0029-0

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