Oncolytic Viral Therapy combined with Immunotherapy poses a possible cure for cancer Ayotola Olorunsogo Department of Biomedical Science

Oncolytic Viral Therapy combined with Immunotherapy poses a possible cure for cancer
Ayotola Olorunsogo
Department of Biomedical Science; University of Central Florida
Abstract: Oncolytic Viral Therapy is a new type of cancer therapy that can be used to fight cancer. It utilizes a mechanism that focuses on destroying tumor cells, while ignoring the normal ones. Oncolytic viruses can only replicate in infected cells, therefore leading to the death of said cells. However, to do this, the viruses must first unhinge the immuno-suppressive tumor microenvironment, making the immune system in the environment more active so that the system can create a strong and efficient response against the tumor itself. The innate and adaptive immune responses help in this, by producing an immune response against the tumor antigens and promoting immunological memory. A problem that lies with this approach is that immune system recognizes viruses as a pathogen and the resultant anti-viral response could make it difficult for the virus to fulfill its duty before its cleared out of the system. Researchers are now trying to find a balance between the anti-tumor and anti-viral immunity to maximize the benefits of oncolytic viral therapy. One method already recognized to balance this is combination therapy. Combination therapy consists of both a type of cancer therapy and an oncolytic virus in order to make what each could accomplish alone (in terms of waking up the immune system in tumors and destroying cancer cells), more efficient. An example is when anti-cytotoxic T lymphocyte-associated antigen 4 and anti-programmed cell death protein 1 immune checkpoint inhibitors are combined to double the response rate in patients with metastatic melanoma. Making the immune system more effective at sensing tumor antigens and helping in the prevention of relapse.
Most types of cancer can escape from the immune system using immuno-editing. This process contains three steps: elimination, equilibrium and escape. In the first step, elimination, the immune system recognizes the antigens expressed by tumor cells and eradicates them. In the second step, equilibrium, if any cells escape the previous step, they change their antigens to make them unrecognizable by the immune system. This is the phase where tumor cells grow until their mass increases to an extremely high volume. This leads to the third step, escape, which is the phase in which the immune system loses control of the tumor which allows the tumor to spread and become detectable by clinical devices (1). In this process, normal cancer therapies (eg. chemotherapy and radiotherapy) are inefficient as they are unable to selectively target cancer cells, thus leading to the death of normal cells and the creation of a highly toxic environment. Also, people, if using these therapies too much, can develop a resistance to their treatment (chemo-resistance), leaving only surgery as a last resort. These therapies do not produce a long-lasting effect which could lead to relapse of the cancer.
Although there are many problems that cancer poses, there is a possible solution in the works through oncolytic viral therapy. Oncolytic viral therapy utilizes oncolytic viruses to activate and arm the immune system against tumors. Viruses in general encode virokines and decoy viroreceptors to copy immune signaling in order to cause viral infection (2). The oncolytic nature of these specific viruses is an advantage as it allows them to replicate in and destroy tumor cells without harming normal cells. These viruses work by targeting cancer specific traits in RAS, TP53, RB1, PTEN, and genes encoding proteins involved in the WNT signaling pathway as well as other cancer related genes in Tumor cells (3). Which is why Tumor cells are naturally weak against viruses as they lack many of the specific components that normal cells use to respond to viral infection (like the type I IFN (interferon) pathway). Interferons are cytokines that regulate the antiviral defenses as well as expression of gene products, metabolism, apoptosis, and antigen display (4) in cells in the body and lack of these mechanisms as well as others allows the viruses to successfully replicate in tumor cells (5). In addition, progression in genetic engineering has lead to the construction of viruses lacking the thymidine kinase gene, making them only able to replicate in cells that have an up-regulation of the RAS pathway like cancer cells (6).
Proof of this lies in the fact that many viruses have already reached their clinical stages and one has even been approved by the FDA. This virus is known as Talimogene Laherparepvec or T-vec for short. It is a derivation of the herpes simplex virus which contains two viral gene deletions and is armed with the human GM-CSF gene. It has two modifications that help in the identification and destruction of cancer cells: deletion in ICP34.5 (7) and deletion in ICP47(8) which is also shown in Figure 1. The first antagonizes the activity of the RNA-dependent protein kinase PKR which is an interferon-induced gene product that usually inhibits cellular protein translation while the latter, blocks antigen presentation by inhibiting transporter involved in antigen processing proteins. In a phase II study, T-vec increased the number of tumor-specific CD8+ T cells and reduced the number of regulatory and suppressor T cells (9). It was also shown in a phase III trial, to improve the condition of melanoma (10) in patients with administration through injectable lesions in the skin and lymph nodes (11). Other Oncolytic viruses also include modified Rhabdovirus and Maraba virus which are prototype viruses. They use the lack of interferons in tumor cells to target them. Also many oncolytic viruses have also been brought about to make use of the metabolic dysfunction that is common in tumor cells. An example is pexastimogene devacirepvec (pexa-vec) which is now in a phase 3 trial for the treatment of hepatocellular carcinoma. The advantage that Pexa-vec has on cancer cells is its ability to block interferon signaling in normal cells while exploiting decreased interferon responsiveness in tumor cells. Despite the great results, tumor anti-tumor therapy’s desired result has yet to be realized (more so, when the viruses are used alone) and so new approaches are needed to further improve oncolytic viral therapy.

Figure 1: different modifications of Talimogegne laherparepepvec and their results.

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Oncolytic Viruses and Cancer therapies
There are four major steps that T cells must go through to acquire an efficient immune response: T cell priming, Trafficking and infiltration, Circumventing immune suppression, and Engagement of tumor cells. Step 1, T cell priming, involves using antigen presenting cells to present tumor associated antigens. Using oncolytic viruses as in situ (in normal location/ non-spreading) vaccines helps with this. By destroying tumor cells, localized oncolytic viruses can lead to the release of tumor-associated antigens while also creating a pro-immune cytokine environment that expedites antigen presenting cell function which leads to priming of tumor-specific T cell responses in draining lymph nodes. A study done by Brown et al. (12) demonstrated this principle by using a chimeric poliovirus-rhinovirus. It was shown that oncolytic virus infection caused release of tumor antigens together with pathogen-associated molecular patterns and danger-associated molecular patterns. The oncolytic virus also infected antigen presenting cells, leading to stimulation of type one interferon responses. Step 2, trafficking and infiltration, is when T cells travel to and infiltrate tumor sites. The chemokines that are acquainted with this include CXC-chemokine ligand 9 (CXCL9), CXCL10 and CXCL11 (13). The expression of these chemokines have been associated with the number of T cells that lie within the tumor and patient survival. Furthermore, mechanisms that may impair immune cell infiltration in tumors include recruitment of cells that dampen inflammatory signals (ex. Myeloid-derived suppressor cells or MDSCs) and the silencing or mutation of genes encoding chemokines and other motile cell attractants (14). Oncolytic viruses may also be used to promote intratumoral infiltration by T cells. Some examples include the clinical trials of vaccinia virus in melanoma, measles virus in cutaneous lymphoma, and adenovirus in various advanced carcinomas. Step 3, Circumventing immune suppression, is when T cells go against immunosuppressive cells and other inhibitory factors in the tumor microenvironment. Examples are tumor-associated macrophages and myeloid-derived suppressor cells, which can secrete molecules that suppress the immune system (IL-10, TGF?, indoleamine 2, 3-dioxygenase (IDO) and arginase) (15). Step 4, engagement of tumor cells is when T cells recognize, infect and lyse tumor cells. To avoid recognition, tumor cells can downregulate components of pathways involved in antigen processing and presentation (ex. Tap1, low molecular mass protein (LMP2 or PSMB9), tapsin). They can also down regulate major histocompatibility complex class one through loss of ??-microglobulin or individual MHC alleles (16). Through these steps the various functions of Oncolytic viruses have been considered as possible solutions. These functions of Oncolytic viruses are the ability to facilitate T cell recruitment, induce strong immunity against tumor and itself, increase T cell infiltration of tumors, induce inflammatory stimuli (ex. tumor necrosis factor (TNF), interleukin-1? (IL-1?), complement), be engineered to thrive on the same oncogenic signaling pathways that create an immunosuppressive environment in tumors, attract neutrophils to tumor site, counteract immune suppression by inducing potent pro-inflammatory T helper 1 (TH1) cell-polarized immune responses that alter the TME (17), replicate within and kill immunosuppressive cells, cause immunogenic tumor cell death and stimulate innate immune receptors on professional antigen-presenting cells, prime antitumor cells, improve recognition of tumor cells by the immune system through upregulation of pathways involved in antigen processing and presentation. Combine with encoded PD1 to produce an increased anti-tumor efficacy, decrease ability of tumor cells to avoid recognition by T cells by reversing anti-recognition processes, and causing the release of tumor associated antigens to broaden and amplify T cell responses.
Anti-Tumor mechanisms of Oncolytic Virus Therapy
Due to the IFN pathway not working correctly in cancer cells, Oncolytic viruses can easily infect the cells and destroy them. But the purpose of the therapy is not only to kill the cells. It must also activate the silenced immune system, allowing for a long-lasting immunity from the cancer. When Oncolytic viruses infect tumor cells, an inflammatory reaction occurs because viruses can induce immunogenic cell death (a specific form of apoptosis in which the destruction of cancerous cells can generate an anti-tumor response using the recruitment and activation of dendritic cells and the resultant stimulation of certain T-lymphocytes. Immunogenic cell death releases dangerous metabolites called damage-associated molecular patterns. There are three damage-associated molecular patterns and they are calreticulin, ATP (adenosine triphosphate), and HMGB1 (High-mobility group box 1 protein) (18). Antigen presenting cells in the tumor environment recognize the metabolites and generate an immune response as shown in figure 2. Additionally, when oncolytic viruses kill cancer cells, tumor associated antigens are released into the microenvironment, generating an immune response and breaking down the immune-editing process. According to Bell’s group, tumor cell infection with oncolytic virus produces an inflammatory site, causing the release of cytokines that activate the immune system. In this, the activation of the immune system against the oncolytic virus, creates an anti-tumor immunological memory with long term benefits that help prevent relapse.
Anti-Viral Mechanisms of Oncolytic Virus Therapy
Once the virus targets and infects the tumor cells, the immune system detects the infection and activates both innate and adaptive immunity to attack the foreign antigens present in both the virus and the cancer cells using T cells. Because of this, it is necessary that oncolytic viruses can replicate quickly to induce the maximum anti-tumor effect. A possible solution to this is to block the antibody response of the immune system to the virus which gives the virus extra time to take effect and eradicate tumor cells through the immune system’s T cell response. It has been shown in a Syrian hamster model that anti-viral immunity can be bypassed by repeatedly administering adenovirus locally, improving the efficiency of anti-cancer therapy) (19). If the virus is injected within the tumor, humoral immunity (immunity coming from body fluids) has no effect on the clearance of the virus which means cytotoxic T cells and innate immunity play an important role. When the immune system responds to the virus present in the tumor cells, many types of immune cells are attracted to the site including innate cells (ex. NK cells) and adaptive cells (ex. CTL). These cells lead to the eradication of tumor cells which augments the direct lysis of tumor cells by viral infection. This can be enhanced by fitting viruses with immune modulatory proteins (ex. Cytokines) which aid in the attraction of immune cells to the tumor site (20).
Innate Immune Cells and Anti-Viral Therapy
Macrophages are the first line of defense in the immune system as they recognize pathogens in a non-specific way, creating an immune response. This is a threat to Oncolytic viruses because when the viruses are administered to the host, they are taken up by these macrophages and large amounts end up in the spleen and liver (21,22). Research has found some strategies to solve this problem. One such strategy is chemically modifying the viral coat proteins, so the macrophages do not recognize the virus, allowing it to travel to the tumor site. To complete this, some have used polyethylene glycol. It is a hydrophilic, non-immunogenic, uncharged compound that can interact with biological material to limit or avoid protein-protein interactions (23). Eto et al, utilized polyethylene glycol to coat the adenovirus surface which made it unidentifiable my macrophages. Another way to avoid virus detection by macrophages is to precondition the macrophage before viral administration (24-26). This is because the macrophages identify the antigens using scavenger receptors which can be saturated, making them inhibited. The final way to get past viral detection by macrophages, is to deplete the macrophages before the virus is administered (27). The most efficient way is to use clodronate liposomes so that when a macrophage phagocytoses one, cell death is triggered within it. This method has a good side and a bad side as it can work to deliver the virus to the tumor site as well as reducing the anti-tumor efficacy.
It is very important that the tumor environment is transformed from cold to warm so that the immune system can be active. Tumor-associated macrophages are a key part of this process as macrophages can polarize into pro-inflammatory cells (M1 classical activation) that sustain the TH1 response or into anti-inflammatory, tissue repairing cells (M2 alternative activation) that sustain the TH2 response and create an immunosuppressive environment. Tumor-associated macrophages are mainly like M2 and create cytokines (ex TGF-? and IL-10) to make the microenvironment non-reactive against tumor antigens. However, TAMs can change their phenotype depending what the microenvironment is like (28). Oncolytic virus therapy can transform the M2 function, activating the immune response against tumor cells. Which is why it is essential to not destroy the macrophages and instead to reprogram them to become strong weapons. Tam et al. proves that Tumor-associated macrophages can help the death by oncolytic virus of attenuated measles and mumps in vitro (29). This shows that viral administration can transform the tumor microenvironment making it a site of inflammation. An example of this is Tumor-associated macrophages (as plastic cells) changing their phenotype from M2-like to M1-like to upregulate their anti-tumor properties. In vivo allows the release of many tumor antigens into the tumor microenvironment using a therapeutic virus with a lytic effect. An example of this is when macrophages and dendritic cells exploit anti-tumoral functions. This confirms that using macrophages as antigen presenting cells to carry viruses into the tumor is a strategy that shows promise in improving the efficacy of oncolytic virus therapy.

Figure 2: illustrates what occurs during Oncolytic vaccine immunotherapy.
Adaptive Immune Cells and their role in Oncolytic Viral Therapy
Macrophages, Dendritic cells, and other Antigen presenting cells activate the adaptive immune response. Lymphocyte activation is more powerful and specific than innate immune response, making it slower. The aim of immune stimulation during Oncolytic viral therapy is to activate T lymphocytes against tumor antigens. T cells provide long term-immunity by recognizing tumor peptides. Because T cells are able to generate memory, the cancer patient will be protected from relapse. Due to this, tumor cells usually try to become unidentifiable by the immune system to avoid activation of lymphocytes. Oncolytic viral therapy recruits lymphocytes using a cytokine storm which breaks down the immune-suppressive environment. Sadly, T lymphocytes not only react against tumor cells, but they initiate a strong and rapid anti-viral response which causes the invading virus to be destroyed before it can eradicate all the tumor cells. When
T lymphocytes are activated, they express checkpoint molecules (ex. PD-1, CTLA/4). During “physiological inflammation” these proteins have the role of switching off T cells to block the abnormal inflammatory response and to and avoid a higher risk of autoimmune disease.
Cancer Therapy and Oncolytic Virus Combination Approaches in Development
As discussed before, the only current FDA approved oncolytic virus to treat cancer is T-vec which is derived from HSV-1 and is armed with the human GM-CSF gene. Despite its great results with Melanoma, is has been speculated that combining these types of viruses with other forms of cancer therapy could increase their effectiveness in treating cancer. When oncolytic viruses are used in combination with other forms of cancer therapy such as cytotoxic chemotherapy, targeted molecular agents, radiation therapy and other forms of immunotherapy (ex. Cytokines, adoptive T cell therapy and immune checkpoint inhibitors), their effectiveness has indeed been proven to increase as stated in the previous sentence (30).
Cytotoxic chemotherapy and targeted therapy kill tumor cells, resulting in the release of soluble antigens and enhancing oncolytic-virus-induced expansion of neoantigen reserve, causing the replication of ONYX-015 in cancer cells and enhancing tumor cell death (31). This is able to occur because the p53 gene is mutated in cancer cells. Figure 3 shows that a decrease in the p53 gene allows ONYX-015 to multiply in cancer cells.
In Immune checkpoint blockade is attractive as Oncolytic viruses can recruit TILs into the immunosuppressed tumors and triggers release of soluble tumor antigens, danger signals, and pro-inflammatory cytokines. Which facilitate T cell recruitment and promote immune cell activation (32).
In Adoptive T cell therapy, Oncolytic viruses can shape the local tumor microenvironment to improve T cell recruitment and effector function. They also induce necrosis and pyro ptosis of tumor cells, triggering the release of neoantigens and epitope spreading and promoting priming of neoantigen specific CD8+ T cells by BATF3+ dendritic cells, thus helping the T cells spread throughout the tumor (33).
Finally, the combination of Radiation therapy and Oncolytic virus therapy has proven results in increasing antitumor activity in various preclinical models through radiation-mediated enhancement of an oncolytic virus’s ability to destroy cancer cells= and virus-mediated sensitization of cells to radiation therapy (34).

Figure 3: shows what occurs with different types of immune molecules when foreign molecules interact with them.
Conclusions and Future Outlook on Oncolytic Viruses and other Cancer Therapies
Oncolytic viruses show a lot of promise in treating cancer, but alone they are not effective enough to destroy the tumors AND facilitate and appropriate immune response so relapse does not occur. Together with other cancer therapies however, oncolytic viruses have been proven to attain an increased anti-tumor efficacy. But challenges still await as systematic delivery and spread of Oncolytic viruses can still be improved upon. Strategies to address this are already in motion. Examples are the development of de-glycosylated vaccinia virus and lymphocytic Choriomeningitis virus to eliminate, evade, or reduce the effect of antiviral antibody responses (35,36). Through strategies like this we see that although Oncolytic viruses still have a lot of development before they can successfully achieve their desired outcome, they still stand to be a new hope for the scientists in the fight against cancer.
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