Oncolytic virus in the frontier of tumor immunotherapy

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Oncolytic virus in the frontier of tumor immunotherapy

Oncolytic virus in the frontier of tumor immunotherapy.

Preface

The development of the oncolytic virus ( OV ) is based on observations as early as a century ago.

At that time, after a naturally-acquired virus infection, the cancer would naturally subside. Initially, people hoped to use virus-containing body fluids for treatment, but subsequent studies have shown that natural virus tropism has caused severe limitations in clinical transformation.

With this understanding, the emergence of genetic engineering has promoted the optimization of viruses, and they have a clear selectivity for different cancers.

Almost all types of viruses, including herpes simplex virus, adenovirus, vaccinia virus, measles virus, parvovirus, polio virus, Malaba virus, reovirus, Coxsackie virus, vesicular stomatitis virus and Newcastle disease Viruses have been designed in this context, and different types of tumors have been tested clinically.

It is usually necessary to mutate some key genes for virus replication, which not only confers tumor selectivity on the virus, but also greatly weakens the ability to kill host cells.

This oncolytic activity enhances the therapeutic advantage and induces immunogenicity after tumor cell death, which increases the infiltration of CD8+ T cells into the tumor microenvironment.

This important feature of oncolytic viruses can heat up immune “cold” tumors, and its combination with other immunotherapies presents an attractive prospect.

Oncolytic virus development history

In fact, the use of live oncoviruses to treat cancer has a long history. Since the mid-nineteenth century, there have been case reports showing that natural microbial infections of cancer patients can sometimes temporarily reduce the burden of tumors, which aroused the curiosity of researchers, and then the concept of oncolytic viruses and related studies were born.

Since 1949, people have conducted many clinical trials using different types of wild-type non-attenuated viruses.

Soon thereafter, the trend in the OV field evolved into the development of genetically modified viruses that are less pathogenic to humans, such as live attenuated vaccines. In the past 20-30 years, this transition has continued to the era of using genetically modified viruses for cancer treatment, including the use of viral gene knockout and/or therapeutic transgene knock-in.

In the 21st century, after the positive results of many clinical trials, the OV field has gained considerable attention. So far, four OV drugs have been approved globally.

Oncolytic virus in the frontier of tumor immunotherapy

The first OV is a picornavirus called Rigvir, which is approved in Latvia for the treatment of melanoma, but it has not been widely used.

Secondly, in 2005, China approved an engineered adenovirus called H101 for the treatment of head and neck cancer.

Third, in 2015, the United States and Europe approved another engineered herpes simplex virus ( HSV-1 ) OV called Talimogene Laherparepvec ( T-VEC ) for the treatment of unresectable metastatic melanoma.

Finally, in 2021, Japan approved a modified herpes simplex virus called DELYTACT for the treatment of brain cancers such as glioblastoma.

The “tumorophilia” mechanism of OVs

The tumorigenicity of OV usually depends on a variety of factors, such as cell surface receptors ( for some OVs, but not all OVs ), cell metabolism status, and the ability of the virus to overcome innate immunity or antiviral signaling pathways in cancer cells ( possibly Applies to all OV ).

Early observations have been made that some OVs use unique extracellular molecules expressed on cancer cells to enter.

For example, CD46, CD155 and integrin α2β1 molecules are often overexpressed in a variety of tumor cells, and can be used as measles virus, polio virus and AIDS, respectively.

Ko virus receptor. In addition, 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 main viral receptor for pancreatic, colorectal, breast, and colon cancers.

Cancer is a complex heterogeneous disease with multiple gene mutations that mediate frequent changes in various antiviral signal 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 make cancer cells more susceptible to viral infections.

In the heterogeneous tumor microenvironment, there may be more mutations in cancer cells and untransformed supporting cells that have yet to be identified, and these mutations may also affect the tropism of the virus.

Most tumor cells are characterized by a high rate of aerobic glycolysis ( Warburg effect ), which plays a vital role in the development of immunosuppressive tumor microenvironment.

After the virus infects host cells, it also activates glycolysis, enhances the synthesis of cell biomolecules and virus particles, thereby amplifying the Warburg effect. Viruses use different mechanisms to enhance glycolysis as a strategy that facilitates virus replication.

OVs-mediated anti-tumor mechanism

In conjunction with hand after the tumor cells, OVs can use a variety of mechanisms to kill cancer cells lysed infected.

The exact mechanism of viral oncolysis is not fully understood, and there are great differences between different viruses, even between different target cancer cell types.

OV is generally believed to mediate anti-tumor activity through multiple mechanisms:

(1) Direct lysis of tumor cells :

The virus replicates in large amounts 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 remote effects :

The lysis of tumor cells leads to a large release of tumor-associated antigens (TAA), which in turn recruits more immune cells such as dendritic cells (DC) to infiltrate the tumor and activate anti-tumor immunity The response functions as an “in situ vaccine”. Oncolytic viruses can also use “in situ vaccines” to promote the regression of remote uninfected metastases through cross-presentation, resulting in “remote effects.”

(3) Induction of innate immunity :

There are receptors (such as Toll-like receptors) in or on the cell, which can recognize the nucleic acid or protein of the virus, 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 an adaptive immune response :

After the virus lyses the tumor cells, the released tumor-specific antigens are presented by the DC, and the DC cells recruit and activate CD8+ and CD4+ T cells, thereby inducing antigen-specific T cell killing.

(5) Destroy 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 ) can directly infect and destroy tumor blood vessels in the body through intravenous administration, 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 break the existing anatomical structure of the tumor microenvironment, but also break the tumor suppressive tumor microenvironment, creating good microenvironmental conditions for other immunotherapies.

Combination therapy of OVs

The efficacy of OV as a monotherapy is still limited. With the increasing understanding of the inherent intratumoral and inter-tumor heterogeneity of most solid cancers, people gradually realize that the best therapeutic effect of OV may require a more reasonable combination.

Emerging data indicate that OVs interact with a variety of cellular processes during their life cycle. Drugs that have been approved by the FDA to regulate these cellular processes may release the true therapeutic potential of OVs.

OV combined with chemotherapy

Temozolomide ( Temozolomide is, TMZ ) is an alkylating agent, it is considered the treatment of various solid tumors ( including melanoma and glioma ) an effective anticancer drugs.

TMZ shows better anti-tumor effects in killing glioblastoma, lung cancer, melanoma and breast cancer through oncolytic herpes simplex virus, adenovirus, Newcastle disease virus and myxoma virus.

In the glioblastoma stem cell ( GSC ) model, the combined effect of oHSV G47Δ and TMZ caused strong DNA damage.

The activated ATM relocates to the HSV DNA replication zone, which may enhance the replication of oHSV and make it unable to participate in the repair of TMZ-induced DNA damage.

G47Δ and TMZ synergistically kill GSC in vitro, prolong the survival period of GSC-derived intracranial tumor mice, and achieve long-term remission in 50% of mice.

OV combined with targeted therapy

During the process of infection, replication, and release from cancer cells, oncolytic viruses interact with specific genes, proteins, or tissue environment of cancer, which may promote tumor growth and survival.

This makes it possible for OVs to act synergistically with targeted therapy, which prevents tumor growth by interfering with specific molecules required for carcinogenesis and tumor growth.

Sorafenib is a targeted anticancer drug and a tyrosine kinase inhibitor that inhibits a variety of 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 the treatment of 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 hormone growth.

An early study showed that estrogen β-estradiol increased the replication of oncolytic HSV-1 NV1066 in estrogen receptor-positive ( ER+ ) human breast cancer. Estrogen enhanced the oncolytic effect of NV1066.

When the MOI was 0.1 and 0.5, the cell killing rate was 95% and 97%, respectively, and when estrogen was not used, it was 53% and 87%, respectively.

The enhanced viral oncolytic effect is related to the increase of cell proliferation by estrogen and the decrease of ER+ breast cancer cell apoptosis.

So far, there have not been too many reports on the combination of OV with approved hormone therapy drugs.

More efforts are needed to understand the role of OVs in hormone-related signaling pathways in order to seek a theoretical basis for the combination of viral therapy and hormone therapy.

OV combined with immune checkpoint inhibitor

Preclinical studies have proven that OV mJX-594 can sensitize ICI-resistant tumors and promote T cell infiltration in mouse tumors.

Combined with anti-PD-1 therapy, tumor growth can be reduced by 70%.

Similarly, another study demonstrated that the combined treatment of NDV and anti-CTLA-4 doubled the protection against tumor recurrence and enhanced tumor lymphocyte infiltration compared with mice treated with anti-CTLA-4 alone.

Similar results have also been confirmed in human trials. During the clinical trial for the treatment of stage IIB-IV melanoma, the immune response of patients receiving T-VEC and the treatment of ipilimumab was studied.

Compared with the limited response observed with ipilimumab monotherapy, the combined treatment demonstrated increased CD4+ICOS+ T cells are associated with significantly improved treatment outcomes.

The potential synergy of OVs and ICIs has made their combined application in clinical trials very popular, and multiple combinations are currently being evaluated.

Oncolytic virus in the frontier of tumor immunotherapy

OV combined cell therapy

Chimeric antigen receptor ( CAR ) T cells have also achieved remarkable success in hematological malignancies. However, due to TME’s inhibition of CAR-T cell transport and penetration, and the current lack of excellent targets in solid tumors, its therapeutic efficacy in solid tumors is limited.

However, recent studies have used a uniquely designed OV to express truncated form of CD19 on infected tumor cells, and “mark” these cells to facilitate the killing of tumor cells by CD19-CAR-T cells, which increases The tumor infiltration of T cells improves the survival rate of mouse melanoma and colorectal cancer models.

In addition, some people have explored the use of CAR-T cells as OV vectors to direct the virus to tumor cells. These examples show that OV can also provide additional benefits for CAR-T therapy.

OV combined bispecific antibody

Bispecific antibody drugs have achieved preclinical and clinical success and are currently one of the hottest research fields.

Nevertheless, bispecific antibodies are still limited by toxicity, half-life, tumor retention ability, and the inability to produce durable immune memory.

In response to this situation, an oncolytic adenovirus ( ICOVIR-15K ) was developed, which was designed to express BiTE ( cBITE ) that targets EGFR .

In the co-culture test, oncolysis caused T cell activation and proliferation, and enhanced cytotoxicity. ICO15K-cBITE has been proven to be tumor-selective.

Compared with the parental virus, intratumoral injection increased the persistence and accumulation of tumor-infiltrating T cells in the body, and showed enhanced anti-tumor activity in animal models.

Another example is an oncolytic virus expressing Fibroblast Activation Protein ( FAP ) targeted BiTE ( fBiTE ).

In this way, immune cells are redirected to tumor stromal fibroblasts to improve tumor permeability and help virus spread.

In addition, oncolytic viruses can easily be designed as a combination of different immunotherapies, including BiTE, cytokines, and ICIs.

CAdTrio is an adenovirus that encodes IL-12, anti-PD-L1 antibody and specific BiTE against CD44v6.

It is used in combination with HER-2-CAR-T cells to significantly improve tumor control in mouse animal models. And survival rate.

Summary

More than 30 years of extensive research and clinical trials have proven that oncolytic virus therapy is a promising cancer treatment.

Several aspects of OV therapy have been significantly improved, including safety, efficacy, selectivity, method of administration, and production.

The most significant change in the field of OV may be its application as a direct lysing agent to its development as a multimodal formulation involving cell lysis, immune stimulation and gene therapy, which further establishes OV as a powerful candidate for cancer therapy.

However, it is increasingly clear that OVs as a single agent may not be able to successfully provide a complete response to cancer, so a combination strategy is essential.

At present, more and more combinations of OV and various therapies, especially immunotherapies, appear in the preclinical and clinical research phases.

However, in view of the existence of multiple OV types, targeting strategies and immune killing methods, this combination therapy has been found The optimization of the combination is still a challenge.

It is believed that with the continuous 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 tumour 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.

Oncolytic virus in the frontier of tumor immunotherapy

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Oncolytic virus in the frontier of tumor immunotherapy

Oncolytic virus in the frontier of tumor immunotherapy

Preface

Oncolytic virus development history

The “tumorophilia” mechanism of OVs