Antitumor mechanism and clinical progress of oncolytic viruses

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Antitumor mechanism and clinical progress of oncolytic viruses

The development of oncolytic viruses ( OVs ) builds on observations as far back as a century ago, when cancers spontaneously regress after naturally acquired viral infection. Initially, it was hoped to use virus-containing bodily fluids for therapy, but subsequent studies have shown that natural viral tropism poses serious limitations in clinical translation.

With this realization, the advent of genetic engineering has led to the optimization of viruses with clear selectivity for different cancers. Almost all kinds of viruses, including herpes simplex virus, adenovirus, vaccinia virus, measles virus, parvovirus, poliovirus, Maraba virus, reovirus, coxsackie virus, vesicular stomatitis virus, and Newcastle disease Viruses, all designed in this context and tested clinically on different types of tumors. It is usually necessary to mutate some key genes of virus replication, which greatly weakens the killing ability of host cells while conferring tumor selectivity to the virus.

This oncolytic activity enhances therapeutic advantage and induces immunogenicity after tumor cell death, resulting in increased infiltration of CD8+ T cells into the tumor microenvironment. This important feature of oncolytic viruses can warm up immune “cold” tumors, which presents an enticing prospect in combination with other immunotherapies.

Oncolytic virus history

In fact, there is a long history of treating cancer with live oncoviruses. Case reports since the mid-19th century that natural microbial infection in cancer patients can sometimes temporarily reduce tumor burden has aroused the curiosity of researchers, and the concept of oncolytic viruses and related research was born.

Beginning in 1949, many clinical trials have been conducted using different types of wild-type, non-attenuated viruses. Shortly thereafter, the trend in the OV field evolved towards the development of genetically modified viruses that are less pathogenic to humans, such as live attenuated vaccines. Over the past 20-30 years, this transition has continued into the era of the use of transgenic viruses for cancer treatment, including the use of viral gene knockouts and/or therapeutic transgene knock-ins.

Entering the 21st century, the OV field has gained considerable attention following positive results from many clinical trials. To date, four OV drugs have been approved globally.

Antitumor mechanism and clinical progress of oncolytic viruses

The first OV, a picornavirus called Rigvir, was approved in Latvia for the treatment of melanoma but not widely used. Second, in 2005 China approved an engineered adenovirus called H101 for the treatment of head and neck cancer. Third, in 2015, another engineered herpes simplex virus ( HSV-1 ) OV called Talimogene Laherparepvec ( T-VEC ) was approved in the US and Europe for the treatment of unresectable metastatic melanoma. Finally, in 2021, Japan approved a modified form of herpes simplex virus called DELYTACT for the treatment of brain cancers such as glioblastoma.

The “oncogenic” mechanism of OVs

The oncogeneity of OVs often depends on a variety of factors, such as through cell surface receptors ( for some OVs, but not all OVs ), cellular metabolic state, and the ability of the virus to overcome innate immune or antiviral signaling pathways within the cancer cell ( possibly applies to all OVs ).

It was earlier observed that some OVs utilize unique extracellular molecules expressed on cancer cells for entry, for example, CD46, CD155, and integrin α2β1 molecules are frequently overexpressed in a variety of tumor cells and function as measles virus, poliovirus, and AIDS, respectively. Receptor of covirus. Furthermore, the same OV may use different cell surface molecules for different types of cancer. For example, the measles virus uses CD46 on multiple myeloma cancer cells, while nectin-4 is the major viral receptor for pancreatic, colorectal, breast and colon cancers.

Cancer is a complex and heterogeneous disease with multiple genetic mutations that mediate frequent changes in various antiviral signaling pathways, creating an ideal environment for OV replication. For example, cancer-specific mutations in RAS, TP53, RB1, PTEN, EGFR, WNT, BCL-2, and other cancer-related genes often further predispose cancer cells to viral infection. In a heterogeneous tumor microenvironment, there may be more mutations yet to be identified in cancer cells and untransformed Sertoli cells that may also affect virus tropism.

Most tumor cells are characterized by a high rate of aerobic glycolysis ( Warburg effect ), which plays a crucial role in the development of an immunosuppressive tumor microenvironment. Viruses also activate glycolysis after infection of host cells, enhancing the synthesis of cellular biomolecules and viral particles, thereby amplifying the Warburg effect. Viruses use different mechanisms to enhance glycolysis as a strategy to favor viral replication.

OVs-mediated antitumor mechanism

After binding and entering tumor cells, OVs can utilize multiple lytic mechanisms to kill infected cancer cells. The exact mechanism of viral oncolysis is not fully understood and varies widely from virus to virus and even among target cancer cell types.

OV is generally thought to mediate antitumor activity through multiple mechanisms:

(1) Direct lysis of tumor cells : The virus replicates in large numbers in tumor cells and lyses the cells. When the tumor cells rupture and die under the infection of the virus, the released virus particles further infect the surrounding tumor cells.

(2) In situ vaccines and distant effects : The lysis of tumor cells leads to the massive release of tumor-associated antigens (TAAs), which in turn recruits more immune cells such as dendritic cells (DCs) to infiltrate the tumor and activate anti-tumor immunity. Response, play the role of “in situ vaccine”. Oncolytic viruses can also use “in situ vaccine” to promote the regression of distant uninfected metastases through cross-presentation, resulting in “distal effects”.

(3) Induction of innate immunity : There are receptors (such as Toll-like receptors) in cells or on the surface, which can recognize nucleic acids or proteins of viruses, induce the expression of cytokines, and the expressed cytokines bind to receptors on other cells, resulting in Expression of antiviral genes and recruitment of immune cells.

(4) Stimulate adaptive immune response : After virus lyses tumor cells, the released tumor-specific antigens are presented by DCs, which recruit and activate CD8+ and CD4+ T cells, thereby inducing antigen-specific T cell killing.

(5) Destruction of tumor vasculature : Compared with other treatment methods, the characteristics of oncolytic virus destroying tumor blood vessels make it have obvious advantages in tumor treatment. Studies have shown that vesicular stomatitis oncolytic virus ( VSV ), administered intravenously, can directly infect and destroy tumor blood vessels in vivo without affecting normal blood vessels.

(6) Improve the inhibitory microenvironment : Tumors have a highly complex immunosuppressive microenvironment, which contains a large number of immunosuppressive cells such as Treg and MDSC, and immunosuppressive cytokines such as IL-10 and TGF-β. Oncolytic viruses can not only disrupt the existing anatomical structure of the tumor microenvironment, but also disrupt the tumor-suppressive tumor microenvironment, creating favorable microenvironmental conditions for other immunotherapies.

Combination therapy for OVs

The efficacy of OV as a monotherapy remains limited, and with the growing understanding of the intratumoral and intertumoral heterogeneity inherent in most solid cancers, it is increasingly recognized that optimal treatment of OV may require more rational combinations.

Emerging data suggest that OVs interact with multiple cellular processes during their life cycle, and FDA-approved drugs that modulate these cellular processes may unlock the true therapeutic potential of OVs.

OV combined with chemotherapy

Temozolomide ( Temozolomide, TMZ ), an alkylating agent, is considered an effective anticancer drug for the treatment of various solid tumors, including gliomas and melanomas .

TMZ showed better antitumor effect in killing glioblastoma, lung cancer, melanoma and breast cancer by oncolytic herpes simplex virus, adenovirus, Newcastle disease virus and myxoma virus.

In a glioblastoma stem cell ( GSC ) model, the combined effect of oHSV G47Δ and TMZ resulted in robust DNA damage.

Activated ATM relocates to the HSV DNA replication domain, potentially enhancing oHSV replication and rendering it incapable of participating in the repair of TMZ-induced DNA damage.

G47Δ and TMZ synergistically kill GSCs in vitro and prolong survival in mice with GSC-derived intracranial tumors, achieving long-term remission in 50% of mice.

OV combined with targeted therapy

Oncolytic viruses interact with cancer-specific genes, proteins, or tissue environments during infection, replication, and release from cancer cells, potentially promoting tumor growth and survival. This makes it possible for OVs to work synergistically with targeted therapy, which blocks tumor growth by interfering with specific molecules required for cancer and tumor growth.

Sorafenib, a targeted anticancer drug, is a tyrosine kinase inhibitor that inhibits multiple protein kinases, including VEGFR, PDGFR, and RAF kinases. Heo et al. demonstrated the preclinical and clinical efficacy of the sequential combination of oncolytic poxvirus JX-594 and sorafenib in hepatocellular carcinoma ( HCC ).

OV combined with hormone therapy

The goal of hormone therapy is to target hormone signaling pathways to inhibit the growth of cancer cells that require hormones for growth. An early study showed that the estrogen beta-estradiol increased the replication of oncolytic HSV-1 NV1066 in estrogen receptor-positive ( ER+ ) human breast cancer. Estrogen enhanced the oncolytic effect of NV1066, with cell killing rates of 95% and 97% at MOIs of 0.1 and 0.5, respectively, compared to 53% and 87% without estrogen, respectively.

Enhanced viral oncolysis is associated with increased cell proliferation and decreased apoptosis in ER+ breast cancer cells by estrogen. So far, there have not been many reports of OV in combination with approved hormone therapy drugs. More efforts are needed to understand the role of OVs in hormone-related signaling pathways to pursue a rationale for combining viral and hormone therapy.

OV combined with immune checkpoint inhibitor

Preclinical studies have demonstrated that OV mJX-594 can sensitize ICI-resistant tumors and promote T-cell infiltration in mouse tumors, and in combination with anti-PD-1 therapy, reduces tumor growth by 70%. Similarly, another study demonstrated that combined treatment with NDV and anti-CTLA-4 doubled protection from tumor recurrence and enhanced tumor lymphocyte infiltration compared to mice treated with anti-CTLA-4 alone.

Similar results were also confirmed in human trials. During clinical trials for the treatment of stage IIB-IV melanoma, the immune response of patients receiving T-VEC and treatment with ipilimumab was studied, and the combination therapy demonstrated increased CD4+ICOS+ compared to the limited response observed with ipilimumab monotherapy T cells are associated with significantly improved treatment outcomes. The potential synergy between OVs and ICIs has made their combination in clinical trials popular, and multiple combinations are currently being evaluated.

Antitumor mechanism and clinical progress of oncolytic viruses

OV combined with cell therapy

Chimeric antigen receptor ( CAR ) T cells, which have also achieved remarkable success in hematological malignancies. However, TME has limited therapeutic efficacy in solid tumors due to the inhibition of CAR-T cell trafficking and penetration, and the current lack of excellent targets in solid tumors.

However, recent studies have utilized uniquely designed OVs to express a truncated form of CD19 on infected tumor cells, “tagging” these cells to favor tumor cell killing by CD19-CAR-T cells, which increases tumor infiltration of T cells and improved survival in mouse models of melanoma and colorectal cancer.

In addition, it has also been explored to use CAR-T cells as OV vectors to direct the virus to tumor cells. These examples suggest that OV may also provide additional benefits for CAR-T therapy.

OV in combination with bispecific antibodies

Bispecific antibody drugs have achieved preclinical and clinical success and are currently one of the hottest areas of research. Nonetheless, bispecific antibodies are still limited by toxicity, half-life, tumor site retention capacity, and inability to generate durable immune memory.

In response to this situation, an oncolytic adenovirus ( ICOVIR-15K ) was developed that was engineered to express an EGFR-targeting BiTE ( cBITE ). In co-culture assays, oncolysis resulted in T cell activation, proliferation, and enhanced cytotoxicity.

ICO15K-cBITE was shown to be tumor-selective, with intratumoral injection increasing the persistence and accumulation of tumor-infiltrating T cells in vivo compared to the parental virus, demonstrating enhanced antitumor activity in animal models.

Another example is an oncolytic virus expressing a fibroblast-activating protein ( FAP )-targeted BiTE ( fBiTE ). In this way, immune cells are redirected to tumor stromal fibroblasts to improve tumor permeability and facilitate viral spread.

Furthermore, oncolytic viruses can be easily engineered into combinations of different immunotherapies, including BiTEs, cytokines, and ICIs. CAdTrio, an adenovirus encoding IL-12, anti-PD-L1 antibody, and a specific BiTE against CD44v6, in combination with HER-2-CAR-T cells, significantly improved tumor control in a mouse animal model and survival rate.

Summary

More than three decades of extensive research and clinical trials have proven oncolytic virus therapy to be a promising modality for cancer treatment. Several aspects of OV therapy have been significantly improved, including safety, efficacy, selectivity, method of administration, and production.

Perhaps the most dramatic change in the OV field has been from its use as a direct lysing agent to its development as a multimodal agent involving cell lysis, immune stimulation, and gene therapy, which further establishes OV as a strong candidate for cancer therapy.

However, it is becoming increasingly clear that OVs as single agents may not be successful in providing complete response therapy to cancer, so a combination strategy is essential.

There are more and more combinations of OV and various therapies, especially immunotherapy, in preclinical and clinical research stages, but given the existence of multiple OV types, targeting strategies, and immune killing methods, finding this combination therapy The optimal combination of , is still a challenge.

It is believed that with the deepening of clinical research, OV will bring more possibilities and better prospects for tumor immunotherapy.

References:

1. OncolyticViruses: Newest Frontier for Cancer Immunotherapy. Cancers (Basel). 2021Nov; 13(21): 5452.

2. Pouring petrol on the flames: Using oncolytic virotherapies to enhance tumor immunogenicity. Immunology. 2021 Aug; 163(4): 389–398.

3. Combining oncolytic virus with FDA approved pharmacological agents for cancer therapy. Expert Opin Biol Ther . 2020 Sep 14;1-7.

Antitumor mechanism and clinical progress of oncolytic viruses

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Antitumor mechanism and clinical progress of oncolytic viruses