In recent years, oncolytic viruses (OVs) have emerged as a powerful, targeted immunotherapy with the identification of new viral vectors as well as genetically engineered viral payloads. Owing to these advances, impressive success has been demonstrated in the treatment of metastatic melanoma; however, OVs continue to be underutilized in oncotherapy. Oncolytic viral therapy (OVT) capitalizes on the unregulated cellular control that promotes malignant transformation for viral replication and lysis of tumor cells while concurrently activating the immune system that was otherwise silenced by the tumor microenvironment. The activation of the immune system is critical to developing long-term priming and memory targeted against malignant cells. Through concerns for immunocompromised patient’s safety, OVs are engineered to have weak defense against the immune system and can not replicate in non-transformed cells. This attenuation consequently contributes to a dramatic increase in antiviral response against OVs that result in its eventual clearance. Therefore, the balance between the immune anti-viral response and the immune anti-tumor response is critical to finding the perfect equilibrium and the best opportunity for OV to fight cancer. The authors will outline some of the critical players involved in this balance as well as some advances to further expand the therapeutic window of OVT.
The tumor microenvironment is a key component driving tumor response to therapy. One of the major players that modulates this environment is the tumor-associated macrophages (TAM). TAMs are predominantly immunosuppressive (M2) in phenotype and their presence is associated with a significant resistance to chemotherapy and radiotherapy. TAMs can also induce tumor angiogenesis under conditions of hypoxia, and can enhance tumor cell invasion, motility, and intravasation, and can infiltrate and account for up to 80% percent of the tumor bulk [Citation1,Citation2]. TAMs by function and genetic signature appear to recapitulate the role of macrophages in tissue development and repair leading to the suppression of immune response to the tissue damage caused by invading tissues [Citation3,Citation4]. Given the critical role of TAMs in fostering tumor growth and progression, methods to ablate macrophages have demonstrated clinical efficacy; however, this also leads to systemic toxicity [Citation5].
One unanticipated effect of OVT is the repolarization of TAM to the proinflammatory M1 phenotype [Citation6,Citation7], effectively reactivating the immune system and altering the tumor microenvironment from immunologically ‘cold to warm’. Thus, TAMs upon M1 conversion play a crucial role in OVT through their ability to wake up the immune system and modify the tumor microenvironment following repolarization and hence drive tumor clearance. Following an M1 repolarization, TAMs also function to hinder further cycles of OV infection through their ability to promote clearance of the invading OV. This demonstrates the fine balance and need to finely tune and combine multiple strategies in order to maximize therapeutic potential.
Genetic engineering coupled with improved understanding of the synergistic effects of combinational strategies have allowed for further expansion of the therapeutic window of OVs without increased morbidity. These advances have shifted the role of OV from simply lysis of malignant cells to a strategy of inflaming treated tumors and the microenvironment, recruitment of immune cells, and priming anti-tumor immune responses. One combination treatment strategy that appears to cooperate with OVs is that of checkpoint inhibitor therapies. This combination may allow for a therapeutic window to patients who otherwise would not have a benefit from monotherapy. In clinical trials, Talimogene laherparepvec has been tested in combination with ipilimumab a CTLA-4 inhibitor and pembrolizumab a PD-1 inhibitor in a phase II study for advanced melanoma. Patients were given ipilimumab alone or in combination with talimogene laherparepvec. The objective response rate in the combination group was more than double that of the ipilimumab group (39% vs 18%, respectively) [Citation8]. Additionally, patients receiving combination treatment had improved responses in non-injected, visceral lesions, with 52% having a decrease in visceral lesion size from baseline compared to 23% of patients in the ipilimumab group. Beyond symptoms associated with viral infection, combination therapy did not result in increased toxicity compared to ipilimumab alone. Furthermore, other studies assessing the combination of pembrolizumab with talimogene laherparepvec found increased CD8 + T cell infiltration with combination therapy and found that patients with low CD8 + T-cell infiltration at baseline had a response to the combination, suggesting that talimogene laherparepvec may also be able to change the adaptive components rendering immunologically ‘cold’ tumors ‘hot’. Arming viruses with a payload to enhance effector cell function has also been exploited. For example, a recent study uncovered that an IL-12-armed HSV synergized with immune checkpoint blocking antibodies (anti-PD1 and anti-CTLA-4) to increase macrophage and T-cell influx, resulting in increased tumor rejection. In contrast, depletion or inhibition of infiltrating macrophages and/or T-cells reversed the enhanced therapeutic efficacy of the combination of IL-12 expressing oHSV and immune checkpoint blockade [Citation9].
Systemic administration of checkpoint inhibitors has also been associated with cases of severe toxicity [Citation10,Citation11], and several investigators have created OVs encoding checkpoint inhibitors or T-cell activators as a payload for targeted delivery. For example, viruses encoding PDL-1 inhibitors, CTLA-4 inhibitors, PD-1 inhibitors, immune activators such as CD40L, 4-1BBL, PTEN have been created to overcome the potential toxicities associated with the systemic immunotherapy [Citation12–Citation16]. Together these findings suggest the combination of OVs with checkpoint inhibitors may overcome some of the current obstacles to immune checkpoint therapy and offer additional modalities to expand the therapeutic window.
1. Conclusion
The impressive combination of preclinical and clinical results with their FDA approval represents a milestone in the evolution of oncolytic virus immunotherapy. These studies demonstrate that OV may help to normalize the tumor microenvironment, promote a more uniform response to oncotherapy, and promote a broader therapeutic window by altering the microenvironment from immunologically ‘cold to hot’. No less important, these studies demonstrate that combination therapy with OVT does not increase toxicity even when patients become severely immunocompromised in the case of traditional chemotherapy and radiation. At the moment, further refinement of OV combinations and optimization of viral payloads will continue to represent future challenges for promoting widespread utilization of OVT in patients.
2. Expert opinion
Although the utilization of new agents has led to significant improvements in patient outcomes, limiting treatment resistance remains a significant challenge. Over the past several decades, oncolytic viral therapy has demonstrated to be a promising and effective therapy against several malignancies. While OVs continue to face patient safety concerns, with new generation OV the risk of significant morbidity and mortality remain low. Preclinical and clinical studies with OV demonstrate that they function to help normalize the tumor microenvironment in some cases being able to change pretreatment immunogenically ‘cold’ tumors into ‘hot’. In the short term, further studies of OV with conventional therapies and new developments including checkpoint inhibitors and CAR T-cells should continue; however, with further improvement in the OV technology with improved viral payloads effective single OV therapy providing long-term protection and immunity with limited systemic morbidity is possible. While several approaches to reduce viral rejection including the use of copper chelators, TNFalpha blocking antibodies and virus loaded mesenchymal stem cells are under investigation, the results of their translation in patients will establish the utility of this approach.
Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.
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References
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