Tumor immunotherapy has made significant progress in recent years. It has improved the treatment of various tumors, but its application is limited by bottlenecks such as insufficient effective population. In order to make immunotherapy more potential, the academic community has been working hard to find a powerful helper, and oncolytic virus is the most eye-catching. Here is an article review explains the application prospects of oncolytic viruses in immunotherapy. (Nat Rev Cancer. 2018 Jul; 18(7): 419-432. doi: 10.1038/s41568-018-0009-4)



Oncolytic virus and common targeting mechanism

Oncolytic viruses are a class of viruses that can effectively infect and destroy tumor cells. Based on the characteristics of virus, oncolytic virus therapy can be used both systemically and locally, for primary lesions and metastases. When the tumor cells rupture and die under the infection of the virus, the newly generated virus particles are released, further infecting the surrounding tumor cells. Not only can it directly kill the tumor, but it also hopes to stimulate the human immune response and enhance the anti-tumor treatment effect.

Specific targeting of tumors is a major focus in research and development, with the goal of allowing oncolytic viruses to effectively target tumor cells. Interestingly, tumors are naturally suitable for attack by oncolytic viruses - when genetic variants such as RAS, TP53, RB1, and PTEN are weakened, the antiviral infection capacity of tumor cells is weakened, which gives the oncolytic virus an opportunity.

In response to these weaknesses in tumor cells, researchers have developed a variety of viruses that can effectively target tumors. For example, vesicular stomatitis virus (VSV) and Maraba virus (MG1). The engineered rhabdoviruses can specifically target tumor cells by relying on defects in the interferon signaling pathway. The first oncolytic virus approved by the US FDA for the treatment of melanoma was modified from herpes simplex virus (HSV-1). The design of these viruses is related to the immune response.

Other oncolytic viruses can additionally target metabolic abnormalities in malignant tumors. For example, pexastimogene devacirepvec (Pexa-Vec) itself has a defective thymidine kinase gene that can only be replicated in tumor cells with excess thymidine kinase activity. In addition, the B18R gene in this virus carries an advanced stop codon, making its encoded protein less susceptible to recognition and binding by interferons. These properties allow such viruses to effectively target tumor cells while minimizing the effects on normal cells.

Oncolytic virus and immunotherapy

The review authors point out that T cells must undergo four critical steps in order to trigger a successful anti-tumor response. The oncolytic virus can assist T cells in these four steps:

1. T cell priming

The initiation of the T cell response is inseparable from the recognition of specific epitopes, and this complex process is inseparable from antigen presenting cells. In tumors, the process of antigen presentation is often negatively affected. The oncolytic virus can achieve a similar "vaccine" effect, promoting the presentation and recognition of tumor-associated antigens.

Local oncolytic virus therapy can liberate antigen-presenting cells by lysing tumor cells, releasing a large number of tumor-associated antigens, and creating an immunogenic cytokine environment. This idea has been verified in many experiments. Some researchers have found that the mosaic of poliovirus and rhabdovirus can lead to the release of tumor antigens and the development of a class I interferon response. These stimuli eventually induce tumor-specific T cell population proliferation.

The researchers point out that the advantage of this method is that we do not need to have a prior knowledge of tumor-associated antigens, which is a simple and individualized vaccine development tool. However, it should also be noted that such methods may not be able to induce sufficient T cell responses. The researchers believe that the addition of tumor-associated viral vectors to oncolytic viruses may improve the effect.

2. Trafficking and infiltration

T cells in the circulation can move to the tumor site for infiltration, which plays an important role in the prognosis of patients. The use of oncolytic viruses is expected to enhance the infiltration of T cells into tumors, and there are many potential mechanisms behind them.

First, viral infections can trigger a potential class I interferon response, stimulate the production of chemokines, and recruit T cells. In animal models, whether it is adenovirus, HSV-1, vaccinia virus, or Newcastle disease virus, T cell infiltration can be effectively increased.

In addition, in clinical trials, oncolytic viruses have also been shown to increase T cell infiltration in melanoma and other advanced tumors. For brain tumors, positive results have also been observed in some studies.

Secondly, oncolytic virus can induce TNF, IL-1β and complement response, up-regulate the expression of selectin on endothelial cells, and provide a key signal for T cell infiltration.

Third, the oncolytic virus is expected to target specific cancer-causing signaling pathways through transformation. The WNT-β-catenin pathway has an immunosuppressive effect and inhibits the antiviral response of cells. Through transformation, many oncolytic viruses can be activated by the β-catenin signaling pathway, promoting tumor-specific viral replication and anti-tumor effects.

Fourth, oncolytic viruses can encode T cell chemotactic agents, and it is expected that T cells will be directly recruited without fear of chemokine expression defects in the tumor environment.

The investigators pointed out that oncolytic viruses can also help overcome structural barriers and further help T cell infiltration. For example, it can attract neutrophils to release inflammatory mediators in the tumor microenvironment and proteases with cytotoxic and extracellular matrix (ECM) degradation properties.

3. Circumventing immune suppression

Even if T cells succeed in infiltration in the oncolytic, it still does not mean that they can effectively attack the tumor. The researchers point out that after entering the tumor, T cells still need to overcome the immunosuppressive molecules in the environment, such as IL-10, TGF β, and IDO.

In this regard, oncolytic viruses are expected to induce pro-inflammatory T helper 1 and thereby alter the inhibitory tumor microenvironment. In addition, it is also expected to kill immunosuppressive cells directly.

Among them, the most interesting point may be that the oncolytic virus can turn "cold tumor" into "hot tumor". In one study, the researchers first removed tumors from patients with triple-negative breast cancer and implanted secondary tumors in situ. It was subsequently discovered that the use of oncolytic viruses allowed T cells to respond to tumor antigens and prevent tumor recurrence. The use of immunological checkpoint inhibitors can further enhance the therapeutic effect. Other preclinical trials have also demonstrated the potential of combination of oncolytic viruses with immunological checkpoint inhibitors.

In clinical trials, this potential has once again been verified. Both PD-1 inhibitors and CTLA4 inhibitors, in combination with talimogene laherparepvec, increased the number of CD8 and CD4-positive T cells in patients, suggesting a systemic immune effect.

Although the trial is still in Phase I, the overall response rate for advanced melanoma is 62% and the complete response rate is 33%. In addition, patients with low immune cell infiltration also achieved good results, indicating that under the action of oncolytic viruses, "cold tumors" responded to immunological checkpoint inhibitors. This study, published in The Cell, has attracted widespread attention.

In addition to changing the tumor from "cold" to "hot", some existing studies are also attempting to deliver immunological checkpoint inhibitors with oncolytic viruses. This approach requires the inclusion of immunological checkpoint inhibitors in oncolytic viruses to avoid the toxicity of combination therapies. In addition, the specificity of the oncolytic virus to tumor cells can more specifically release the drug at the right place. At present, two studies have been initially tried. However, this idea still has many problems to be solved in terms of technology and mechanism.

4. Engagement of tumor cells

The final step in successful immunotherapy is the recognition, binding, and attack of tumor cells by T cells. To evade T cell recognition, tumor cells down-regulate pathways involved in antigen presentation and MHC class I. The oncolytic virus is expected to reverse to some extent. For example, reovirus can increase the expression of MHC class I and/or class II MHC on tumor cells and antigen presenting cells. Tumor cells infected with HSV can promote the maturation of dendritic cells and the expression of MHC class II.

The researchers point out that the oncolytic virus is expected to promote the binding of T cells to tumor cells in a completely new way. Currently, there is a class of molecules called bispecific T cell binder (BiTE) that binds to molecules such as CD3 that activate T cells and bind to antigenic targets on the surface of tumor cells. Such innovative therapies have achieved positive results in the treatment of hematological tumors, but their use in solid tumors may be limited by the tumor microenvironment and/or off-target side effects. The oncolytic virus encoding BiTE is expected to address these bottlenecks.

In an earlier study, a BiTE that directly binds EPHA2 and CD3 was integrated into an oncolytic virus, releasing BiTE at tumor cells and also killing tumor cells that were not infected with the virus. In another study, BiTE combined with EpCAM and CD3 also activated T cells in tissue biopsy samples.

The future of oncolytic virus therapy

The review concludes with two potential developments for oncolytic viruses. One is to combine with T cell therapy to assist T cells in the proliferation, movement and efficacy of local tumor microenvironment. The second is to further develop its potential by developing a better oncolytic virus through further understanding of the immune mechanism.

The development of oncolytic viruses is full of opportunities. It should be combined with existing therapies. With the continuous clarification of the anti-tumor mechanism of the immune system, oncolytic viruses are expected to provide an important boost for immunotherapy.


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