Combining Oncolytic Viruses With Cancer Immunotherapy: Establishing a New Generation of Cancer Treatment

Abstract

The recent successes of tumor immunotherapy approaches, such as immune checkpoint blockade (ICB) and chimeric antigen receptor T cell (CAR-T) therapy, have revolutionized cancer treatment, improving efficacy and extending treatment to a larger proportion of cancer patients. However, due to high heterogeneity of cancer, poor tumor cell targeting, and the immunosuppressive status of the tumor microenvironment (TME), combinatorial agents are required to obtain more effective and consistent therapeutic responses in a wide range of cancers. Oncolytic viruses (OVs) are able to selectively replicate in and destroy tumor cells and subsequently induce systematic anti-tumor immune responses. Thus, they are ideal for combining with cancer immunotherapy. In this review, we discuss the current understanding of OVs, as well as the latest preclinical and clinical progress of combining OVs with cancer immunotherapies, including ICB, CART therapy, bispecific T cell engagers (BiTEs), and cancer vaccines. Moreover, we consider future directions for applying OVs to personalized cancer immunotherapies, which could potentially launch a new generation of cancer treatments.

Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors

“…There are several ways to enhance the tumor selectivity of OVs. Because tumor cells activate various oncogenic signaling pathways during carcinogenesis, engineering viruses that depend on these oncogenic pathways can remarkably increase their tumor selectivity without affecting normal tissues [ 4 , 8 , 25 ]. For example, the oncolytic vaccinia virus, pexastimogene devacirepvec (Pexa-Vec), was engineered to inactivate its own thymidine kinase (TK) gene for tumor selectivity.…”

“…After viral infection, OVs continue self-replication until the cell bursts. (2) OVs can recruit and activate tumor-infiltrating immune cells by releasing a large amount of tumor antigens and secreting cytokines [ 2 , 8 , 22 ]. When an OV directly breaks tumor cells, viral antigens, tumor antigens, and damage-associated molecular patterns are massively released from dying tumor cells.…”

“…Moreover, these innate immune cells uptake viral and tumor antigens and present them for T cell activation. Finally, activated T cells proliferate and accumulate within the TME and exert their effector functions against cancer cells [ 2 , 8 , 24 , 25 , 26 , 27 ]. In particular, this T cell-mediated adaptive immunity plays a critical role in durable cancer control after oncolytic virotherapy and enables effective control of tumor cells at distant sites beyond the locoregional site of OV injection [ 2 , 24 ].…”

“…Some viruses such as myxoma virus or reovirus have inherent selectivity to tumor cells, while being nonpathogenic in healthy human cells [ 7 ]. On the other hand, other OVs, including adenovirus, herpes simplex virus type-1 (HSV-1), and vesicular stomatitis virus (VSV), have been genetically engineered to function as vectors to boost anti-tumor immune responses [ 8 ]. The anti-tumor efficacies of these OVs have been evaluated in many preclinical and clinical studies as monotherapy and combination therapy [ 2 , 5 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

“…Immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4); programmed cell death 1 (PD-1); and PD-1’s main ligand PD-L1, have been introduced for the treatment of more than a dozen types of cancers [ 18 , 19 , 20 ]. However, only 20–30% of patients respond to ICI monotherapy, while others show intrinsic resistance to ICI treatment due to a non-inflamed cold tumor microenvironment (TME) [ 8 , 21 , 22 ]. These non-inflamed cold tumors are also described as “immune deserts” because they are poorly immunogenic and have very few anti-tumor immune effector cells within the TME [ 5 , 23 , 24 ].…”