Oncolytic Adenovirus: Prospects for Cancer Immunotherapy

Abstract

Immunotherapy has moved to the forefront of modern oncologic treatment in the past few decades. Various forms of immunotherapy currently are emerging, including oncolytic viruses. In this therapy, viruses are engineered to selectively propagate in tumor cells and reduce toxicity for non-neoplastic tissues. Adenovirus is one of the most frequently employed oncolytic viruses because of its capacity in tumor cell lysis and immune response stimulation. Upregulation of immunostimulatory signals induced by oncolytic adenoviruses (OAds) might significantly remove local immune suppression and amplify antitumor immune responses. Existing genetic engineering technology allows us to design OAds with increasingly better tumor tropism, selectivity, and antitumor efficacy. Several promising strategies to modify the genome of OAds have been applied: capsid modifications, small deletions in the pivotal viral genes, insertion of tumor-specific promoters, and addition of immunostimulatory transgenes. OAds armed with tumor-associated antigen (TAA) transgenes as cancer vaccines provide additional therapeutic strategies to trigger tumor-specific immunity. Furthermore, the combination of OAds and immune checkpoint inhibitors (ICIs) increases clinical benefit as evidence shown in completed and ongoing clinical trials, especially in the combination of OAds with antiprogrammed death 1/programed death ligand 1 (PD-1/PD-L1) therapy. Despite remarkable antitumor potency, oncolytic adenovirus immunotherapy is confronted with tough challenges such as antiviral immune response and obstruction of tumor microenvironment (TME). In this review, we focus on genomic modification strategies of oncolytic adenoviruses and applications of OAds in cancer immunotherapy.

Keywords: cancer vaccine; genomic modification; immune checkpoint inhibitor; immunotherapy; oncolytic adenovirus.

FIGURE 1

Mechanism of oncolytic adenoviruses (OAds) in cancer immunotherapy. OAds selectively enter into malignant cells while being cleaned up by normal cells. Subsequent viral replication leads to tumor cell lysis and release of virus- and tumor-specific antigens. These antigens are picked up by dendritic cells (DCs) and presented to T cells, which initiate local antitumor immune activation. Activated T cells migrate into the tumor tissues, where T-cell attracting chemokines recruit more immune cells, facilitating tumor immune infiltration and enhancement of immunotherapy efficacy. Furthermore, infection by OAds can also induce inflammation that contributes to immune infiltration.

FIGURE 2

Tumor selectivity of oncolytic adenoviruses with E1A gene 24-base pair deletion (Ad-D24s) and oncolytic adenoviruses without genomic modification (wild-type Ads). (A) Wild-type Ads infect normal cells. E1A protein of adenovirus interferes with Rb protein by binding it, leading to E2F release and accumulation. Free E2F allows the normal cells to enter into S phase of the cell cycle, which results in viral replication and oncolysis. (B) Wild-type Ads infect tumor cells. Due to the defective Rb pathway, the accumulation of free E2F allows tumor cells to constantly enter in S-phase. Wild-type Ads can replicate in the tumor cells and lyse them. (C) Ad-D24s infect normal cells but there is no viral replication and oncolysis. Mutated E1A protein cannot bind to Rb protein; therefore, E2F is still inactivated by Rb protein. The normal cells are unable to enter into S phase. (D) Tumor cells constantly enter in S-phase because of the defective Rb pathway; Ad-D24s can also lyse the tumor cells while generating viral progeny.