The emerging field of oncolytic virus-based cancer immunotherapy

Abstract

Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs are multifaceted tumor killers. They directly lyse tumor cells while sparing normal cells, and indirectly potentiate antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment. However, some limitations, such as limited penetration of OVs into tumors, short persistence, and the host antiviral immune response, are impeding the broad translation of oncolytic virotherapy into the clinic. If these challenges can be overcome, combination therapies, such as OVs plus immune checkpoint blockade (ICB), chimeric antigen receptor (CAR) T cells, or CAR natural killer (NK) cells, may provide powerful therapeutic platforms in the clinic.

Keywords: CAR-NK; CAR-T; combination therapy; immunotherapy; oncolytic virotherapy; oncolytic virus.

Figure 1.. Oncolytic viruses replicate selectively in tumor cells.

Oncolytic viruses (OVs) can specifically infect dysfunctional tumor cells and replicate until the tumor cells lyse and newborn viruses are released to infect neighboring tumor cells. In healthy cells, including immune cells and non-immune cells, OVs have low or no replication due to antiviral type I interferon (IFN) signaling and other mechanisms. OVs can be cleared by immune cells, and do not damage healthy cells.

Figure 2.. Enhancement of immune responses by oncolytic viruses.

After infection with an oncolytic virus, tumor cells initiate an antiviral response by releasing antiviral cytokines (especially IFNs) that promote the maturation of antigen-presenting cells (APCs) such as dendritic cells (DCs) and that also stimulate CD8⁺ T cells and NK cells. After a tumor cell is lysed, viral progeny, DAMPs (including host cells proteins), PAMPs (viral particles), and TAAs (tumor-associated antigens) including neoantigens are released. The viral progeny infects more tumor cells. DAMPs and PAMPs stimulate the immune system by activating receptors, including TLRs. TAAs and neoantigens are taken up by APCs, activating antigen-/virus-specific CD8⁺ T cell responses, and thereby creating an immune-stimulatory environment. This change prompts tumor-supportive M2 macrophages to change to pro-inflammatory M1 phenotypes

Figure 3.. Oncolytic viruses remodel the tumor immune microenvironment from “cold” to “hot.”

OV-based cancer immunotherapy can remodel the tumor microenvironment (TME). A “cold” TME often has high infiltration of immunosuppressive cells, including Treg cells and M2-polarized macrophages (M2 macrophage) from the tumor site, a poor prognosis, and inadequate response to immunotherapy. In contrast, a “hot” TME associates with higher response rates with more activated immune cells (e.g., CD8⁺ T cells, NK cells, innate lymphoid cells (ILCs), DCs, and M1-polarized macrophages (M1 macrophages)) to immunotherapy. OV infection can enhance the infiltration and activity of immune cells, including innate and adaptive immune cells, within the TME. At the same time, these therapeutic viruses reduce populations of immunosuppressive cell types and shift immune cells toward an anti-tumor phenotype, thereby overcoming immune suppression within the TME. Activated DCs or macrophages can generate a broadened repertoire of tumor neoantigen-specific T cells whose effector function can be augmented by immune checkpoint blockade (e.g., anti-PD-1 and anti-CTLA4 antibody) in their killing of tumor cells locally and systemically. Activation of anti-tumor immunity by oncolytic virotherapy is often accompanied by the production of various pro-inflammatory cytokines, which further helps generate a “hot” TME.

Figure 4.. Oncolytic viruses as the foundation of combination therapy for cancer.

Conventional treatment strategies, such as radiotherapy, chemotherapeutic drugs, as well as small-molecule compounds and, more recently, immune checkpoint blockade and cell-based immunotherapy (CAR T/NK cell-based therapies) have been used to treat cancer. OVs provide a foundation and promising therapeutic platform for cancer treatment when combined with these conventional therapies and biologic therapies. Administration routes for delivering oncolytic viruses commonly include intratumoral injection, intravenous injection, and cell carriers.

Figure I.. Oncolytic viral backbones under clinical investigation from 2012 to 2022.

Characterization of oncolytic viruses used in clinical trials. Types of OVs reported in clinical trials from 2012 to 2022 as determined by searching ClinicalTrials.gov with the key words: Oncolytic virus, Not recruiting (N/R), Active not recruiting (A/NR), Recruiting (R), and Completed (C). Among the results, adenovirus is the most dominant viral backbone (n = 44) and HSV is second (n = 32). Vaccinia virus (VACV) (n = 16) and several other viruses are shown for comparison.

Figure I.. Administration routes for OVs in clinical trials.

Delivery routes for OVs used in clinical trials from 2012 to 2022 as documented at ClinicalTrials.gov. IT was the most dominant route (n = 69), and IV was second (n = 37).