Locked and loaded: engineering and arming oncolytic adenoviruses to enhance anti-tumor immune responses

ABSTRACT

Introduction

Oncolytic adenoviruses (Ads) are promising therapeutics to enhance anti-tumor immune responses and modulate the immune-suppressive tumor microenvironment (TME). Due to their potent ability to deliver genes in vivo, oncolytic Ads have been armed with a variety of immune stimulatory payloads to boost tumor immunotherapy.

Areas covered

We describe current knowledge about engineering oncolytic Ads to insert transgene payloads, including methods to increase its genome capacity for transgene insertion. We also review several categories of immune stimulatory payloads that have been used in oncolytic Ads to combat different barriers to effective immunotherapy.

Expert opinion

We anticipate that multi-armed oncolytic Ads alone or in combination with other types of immunotherapies will greatly improve the efficacy of oncolytic virotherapy in the future by targeting several immune barriers. However, the production and testing of multiple payload-armed Ads can be complex and time-consuming due to the limitations of current tools. Given this, we should develop new tools for rapid construction of armed Ads, improve animal models or new systems to compare the efficacy of multiple payloads, and carefully monitor the immunological toxicity induced by payloads or by systemic delivery. Most importantly, we should pursue payload-arming approaches with great care to ensure safety.

KEYWORDS:

• Oncolytic adenoviruses
• combination cancer immunotherapy
• immune payloads
• barriers to cancer immunotherapy
• immune checkpoints

Article highlights

• Oncolytic adenoviruses (Ads) are highly immunogenic and potent vectors to deliver transgenes.

• Adenoviral mRNA splicing is highly complex. Intrinsic viral splicing events should be considered when determining the location of transgene insertion.

• Ad E3 and E1B genes can be partially or fully deleted to increase genome capacity, with consequences that need to be carefully evaluated.

• Transgenes can be expressed by replacing existing viral ORFs, inserting autonomous expression cassettes, using internal ribosome entry sites (IRESs), translational truncation sequences (2A peptides), and/or by the insertion of exogenous splicing elements.

• At least four tumor immunotherapy barriers need to be addressed:

  1. Insufficient immune signaling and priming

  2. Tumor cell-intrinsic immune evasion mechanisms

  3. Physical barriers to immune cell infiltration

  4. Immunosuppressive tumor microenvironments (TMEs).

• Multiple immune stimulatory payloads can be loaded into oncolytic Ads to overcome each barrier.

This box summarizes key points contained in the article.

Declaration interest

M Barry is the Chief Scientific Officer for Adze Biotechnology, he does not own stock in this company. M Barry is co-inventor of single-cycle adenovirus which has been licensed to Tetherex Pharmaceuticals, and he does not own stock in this company. 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 project was supported by the Congressionally Directed Medical Research Program (W81XWH-19-1-0756), the Mayo Graduate School of Biomedical Sciences, and the Walter & Lucille Rubin Fund in Infectious Diseases Honoring Michael Camilleri, M.D. at Mayo Clinic.