Virus-Based Immuno-Oncology Models

Abstract

Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses' mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations.

Keywords: cancer; humanized mice; immune-oncology; immunotherapeutic; oncolytic virus; tumor microenvironment; tumor-associated macrophages; vaccinia virus.

Figure 1

Molecular mechanisms of CTLA-4 and PD-1 inhibitory T-cell activation. Reprinted from “Blockade of CTLA-4 or PD-1 Signaling in Tumor Immunotherapy”, by BioRender.com (2022) (accessed on 6 March 2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 6 March 2022).

Figure 2

Outline of the stages of cancer and immune system interaction and tumor phenotypes classified by immunogenicity within the tumor microenvironment at the cellular level. Adapted from “Cancer Immunoediting” and “Cold vs. Hot tumors”, by BioRender.com (2022) (accessed on 28 March 2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2022).

Figure 3

Immune enhancement mechanisms explored utilizing OVs strategies. OVs may generate increased immunologic response by direct cell lysis with antigen release and local inflammation as well as artificially generate pro inflammatory molecules by transgene expression. Adapted from “Properties of Oncolytic Viruses”, by BioRender.com (2022) (accessed on 28 March 2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2022).

Figure 4

Targeted OV delivery to cancer cells. This illustration highlights a non-exhaustive list of the delivery platforms that have been reported in the literature to protect OVs from neutralizing antibodies as well as enhance targeted delivery by external or internal stimuli. Many are carriers but also facilitators and may be either organic or inorganic in nature. Adapted from “Nanoparticle-Mediated Targeted Drug Delivery to Cancer Stem Cells”, by BioRender.com (2022) (accessed on 28 March 2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2022).