How to identify the friends and enemies of oncolytic viruses and maximize their anti-cancer efficacy?

People's interest in using viruses to treat cancer can be traced back to the early 20th century, when scientists observed the phenomenon of tumor regression under natural viral infection. However, the feasibility of this method was limited at the time due to the pathogenicity and related toxicity of the virus.

In recent years, the advancement of genetic engineering technology has enhanced the safety and efficacy of oncolytic viruses (OVs), prompting people to take an interest in oncolytic virus therapy (OVT).

In 2015, Talimogene laherparepvec (T-VEC) was approved by the FDA as an oncolytic virus for the treatment of malignant melanoma.

Currently, many different OVs are being evaluated in clinical trials, including adenovirus (AdV), herpes simplex virus (HSV), poxvirus, Newcastle disease virus, measles virus, and reovirus, which have been shown to have tumor specificity, relatively non-toxic, and can induce strong anti-tumor immunity.

face challenges

Oncolytic virus is an emerging targeted anti-cancer therapy that aims to selectively infect, replicate, and lyse tumor cells without causing harm to normal healthy tissues.

In addition to its direct oncolytic activity, OV also demonstrates dual potential as an immunotherapy agent. The presence of viral infection and subsequent immunogenic tumor cell death trigger innate and adaptive immune responses, which mediate further tumor destruction.

The activation of the host immune system is a key link in OV mediated tumor destruction. However, antiviral immune response can inherently limit OV infection and transmission, thereby reducing treatment efficacy and overall effectiveness. The host's immune system can act as both a barrier and a promoter, sometimes playing a dual role depending on the specific stage of viral infection.

Therefore, the key challenge facing oncolytic virus therapy is: how to manipulate the host immune system for our use? Specifically, how to minimize antiviral response and virus clearance while promoting tumor destruction mediated by anti-tumor immune response!

Virus mediated tumor cell death

OV mediates tumor cell death through direct and indirect mechanisms, acting as a direct cytotoxic agent and therapeutic cancer vaccine.

These mechanisms are associated with many immunogenic forms of OV that tend to induce tumor cell death, including immunogenic cell apoptosis, necrosis, pyroptosis, and autophagy, which promote the activation of anti-tumor immune responses.

The characteristics of immunogenic cell death (ICD) are cell surface exposure to calreticulin and heat shock proteins, as well as the release of immunostimulatory molecules such as ATP, uric acid, and high mobility group 1. Unlike normal cell apoptosis (non immunogenic), ICD can induce anti-tumor immune response through activation of dendritic cells (DCs). In addition, the ICD of tumor cells also releases tumor associated antigens (TAA), activating antigen-specific anti-tumor immune responses.

OV mediates the destruction of tumor cells through two main mechanisms: (1) direct lysis and infection of tumor cells; (2) Inducing host anti-tumor immune response (Image source: Frontiers)

Natural antigen-presenting cells

Antigen presenting cells (APCs), such as DCs, are key mediators of innate and adaptive immunity, promoting immune response by releasing cytokines and activating T cells.

APCs are recruited to sites of infection and inflammation, such as the site of immunogenic tumor cell death. DCs capture viruses and tumor antigens released during oncolysis and present them to T cells, initiating antigen-specific adaptive immune responses that mediate targeted destruction of residual and recurrent tumor cells.

Tumor/virus induced cytokines

The tumor microenvironment (TME) typically exhibits a deep state of immune suppression. Tumors overexpress cytokines such as interleukin-10 and transforming growth factor - β (TGF - β), which suppress the natural anti-tumor immune response. Tumor derived cytokines and chemokines also include tumor necrosis factor alpha (TNF - α) and vascular endothelial growth factor, which promote growth and angiogenesis.

Viral infection stimulates the release of cytokines (IL-1, IL-6, IL-12, IL-18, IFN - γ, and TNF - α) and chemokines (RANTES, MIP-1 α/β), altering the balance of pro-inflammatory and anti-inflammatory factors in TME. In addition to their direct antiviral and immunomodulatory activities, these compounds also mediate the recruitment of immune cells with additional effector functions. Viral infection and the resulting local inflammation enhance the effector function of infiltrating immune cells, counteract tumor induced immune suppression, and promote the production of anti-tumor immunity.

Enemy | Immunological disorders

Viral infection and oncolytic effects naturally activate innate and adaptive immune responses, which help to kill tumor cells. However, the host's immune response to viral infection can also reduce the overall efficacy of OVT.

The activation of different components and the affinity and duration of oncolytic activity during host immune response seem to be related to the overall efficacy of OVT.

Immune disorders associated with oncolytic virus therapy (Image source: Frontiers)

The transmission of OV at tumor sites is hindered by neutralizing antibodies, complement proteins, and isolation in organs such as the liver and spleen;

2. Antiviral response, such as type I interferon (IFN) signaling limiting viral replication within tumor cells;

3. Cells from the innate immune system, such as neutrophils, macrophages, and natural killer (NK) cells, may prematurely terminate viral infection by destroying tumor cells infected with OV;

4. Tumor induced immune suppression, such as enrichment of immunosuppressive cytokines, accumulation of regulatory T cells, overexpression of checkpoint regulators, hinders the production and effector function of antigen-specific anti-tumor immune responses.

innate immunity

The infection of the virus triggers the production of antiviral proteins, enrichment of cytokines, and recruitment of immune cells to the site of infection. Type I IFN is an antiviral protein that reprograms gene expression in infected and uninfected cells to directly inhibit viral replication. IFN also induces cell cycle arrest and apoptosis, upregulates major histocompatibility complex (MHC) expression, stimulates B cell secretion of antibodies, and promotes the development and proliferation of memory T cells.

APCs and other innate immune cells first respond to viral infections. In addition to releasing antiviral cytokines, these cells also have mechanisms that can promote the anti-tumor efficacy of OVT.

Among them, neutrophils respond to pathogens by secreting reactive oxygen species and proteases, inducing necrotic cell death and local inflammation. In an ectopic mouse model of colon cancer, the accumulation of neutrophils within the tumor in response to OV infection promotes the destruction of the tumor vascular system and widespread apoptosis of tumor cells.

NK cells have also been shown to be key effectors of OV induced anti-tumor immune response. They specifically target cells lacking MHC molecules or displaying virus induced cell stress markers (such as MIC-A/B), and induce cell death by releasing granzyme and perforase, while activating apoptosis inducing receptors.

It can be seen that the relationship between the immune system and OV agonists/antagonists is not static, but develops with the stages of infection and tumor destruction.

Adaptive immunity

When a virus or TAA is presented to cells of the adaptive immune system, antigen-specific cells and humoral immunity are activated.

cellular immunity

The main anti-tumor effector cells of the adaptive immune system are CD8+CTLs (cytotoxic T cells), which have been shown to be a key mediator of OV induced anti-tumor immunity. They can recognize specific antigens and induce cell death by releasing perforin and granzyme.

In the context of OVT, CT * targeting viral antigens appears, followed by TAA specific CTLs. APC also activates CD4+T helper cells, which release pro-inflammatory cytokines and assist in CTL killing function, which is crucial in the development of anti-tumor immunity.

humoral immunity

Exposure of the body to viral particles triggers humoral immune responses, activating B cells to secrete antibodies. These neutralizing or modulating antibodies inhibit viral function and promote clearance of viral infections.

Response | Strategy

Strategy 1: Reduce early virus clearance

In order to achieve therapeutic effects, OV must last for a sufficient period of time and induce sufficient oncolytic activity to stimulate the development of long-lasting adaptive anti-tumor immunity.

However, viruses are foreign pathogens and naturally trigger host immune responses, mediating their clearance. After being introduced into the body, viral particles are enveloped by neutralizing antibodies and eliminated in a complement dependent manner. The infiltration of innate immune cells and virus antigen-specific T cells can destroy infected tumor cells, but it may also terminate OV infection before achieving therapeutic effects.

This means that transient suppression of early immune response has the potential to improve OV delivery to the tumor site, prolong viral infection, and enhance the overall efficacy of OVT.

Low dose chemotherapy or TGF - β therapy

Inhibiting the infiltration of early tumor immune cells has been shown to enhance OV replication, reduce OV clearance rate, and improve anti-tumor efficacy in several mouse models of glioma.

Immunosuppressive chemotherapy drug pretreatment

Cyclophosphamide has been shown to improve virus transmission, promote replication, and enhance oncolytic activity by eliminating antiviral antibodies and disrupting complement function.

Virus coated modified polymer

Combining polyethylene glycol with N - [2-hydroxypropyl] methacrylamide (HPMA) or lipid encapsulation can protect OV from neutralizing serum factors and prevent the production of new antiviral antibodies.

Cell carrier

OV can be hidden within cell carriers and transported to the tumor site. Mesenchymal stem cells (MSCs) and neural stem cells (NSCs) have shown promising preclinical potential as OV carriers for malignant brain tumors. MSC and NSC both have a natural tendency towards primary tumors and their metastasis, and are considered to have immune privilege.

Plus histone deacetylase inhibitor

Histone deacetylase (HDAC) inhibitors are an emerging class of anti-tumor drugs that enhance the efficacy of OVT by inhibiting the induction of IFN activated genes. HDAC inhibitors have been shown to enhance viral replication, reduce early recruitment of immune cells within tumors, and enhance the oncolytic activity of OV in various tumors.

As epigenetic modifiers of transcription, HDAC inhibitors also alter the gene expression profile of cells, which is beneficial for inducing growth arrest and apoptosis of tumor cells, antagonizing tumor angiogenesis, and enhancing tumor cell immunogenicity by increasing the expression of MIC-A/B, MHC, and co stimulatory molecules.

Strategy 2: Enhance anti-tumor immune response

During and after OV mediated tumor destruction, it is advisable to take advantage of the situationchaseStrike, by enhancing the host's anti-tumor immune response, further destroys residual or recurrent tumor cells. This can be achieved by reducing tumor induced immune suppression, enhancing tumor cell immunogenicity, or directly activating host immune response.

Armed OV

By genetically modifying OV to express inflammatory factors and promote the development of local inflammation, it can not only counteract the immunosuppressive properties of TME, but also recruit and activate effector immune cells.

Combination therapy

1. Plus chemotherapy

Compounds that induce cellular stress or DNA damage in combination, such as chemotherapy, can stimulate the expression of NK cell activating ligands and stimulate tumor ICD, thereby enhancing tumor cell immunogenicity.

2. Plus immune checkpoint inhibitors

CTLA-4 and PD-1/L1 antibodies can improve T cell function and restore anti-tumor cell immune response, but the response rate in patients is currently not high. There is evidence to suggest that OV combined with immune checkpoint inhibitors can induce relatively strong antigen-specific anti-tumor immune responses.

3. Plus CAR-T cell therapy

CAR-T cells can bind to TAA on the surface of tumor cells and induce anti-tumor immune responses, but currently have poor efficacy in solid tumors. Preclinical studies combining OV and CAR-T have shown that both therapies can independently/additionally control tumor growth.

Conclusion

In theory, the anti-tumor effect of OV can be achieved by reducing early immune response to allow OV replication, oncolysis, and spread, and then stimulating the host immune system to destroy any residual tumor cellsExcellentTransform.

Our understanding of the antiviral/anti-tumor immune response process caused by oncolytic viruses still needs to be further strengthened, and skillfully controlling each of these processes will greatly promote the development of oncolytic virus therapy. (Biological Valley)