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In a recent edition of Science Translational Medicine, we identified an enhanced therapeutic activity when talimogene laherparepvec (T-VEC) was combined with MEK inhibition in murine melanoma tumor models. MEK inhibition increased viral replication independent of mutation status. Combination therapy increased PD-1/PD-L1 expression and PD-1 blockade further enhanced tumor regression. Further clinical development of this strategy for treating melanomas warranted.

Successful immunotherapy for melanoma depends on the recruitment of effector CD8+ T cells to the tumor microenvironment. Factors contributing to T cell regulation in melanoma have recently been recognized, including the stimulator of interferon genes (STING). Agents that can activate STING or enhance T cell infiltration into established tumors have become an important focus for further clinical development. Talimogene laherparepvec (T-VEC) is an oncolytic herpes simplex virus, type 1 (HSV-1) encoding granulocyte-macrophage colony stimulating factor (GM-CSF) and is approved for the treatment of melanoma and has shown therapeutic activity in murine tumors known to express high levels of STING. The mechanism of action for T-VEC has not been fully elucidated but is thought to include induction of immunogenic cell death (ICD) and activation of host anti-tumor immunity. Thus, we sought to investigate how T-VEC mediates anti-tumor activity in a melanoma model. To determine if T-VEC induced ICD we established the relative sensitivity of a panel of melanoma cell lines to T-VEC oncolysis. Following T-VEC infection in vitro, melanoma cell lines released of HMGB1, ATP, and translocated ecto-calreticulin. To identify potential mediators of this effect, we found that melanoma cell sensitivity to T-VEC was inversely related to STING expression. CRISPR/Cas9-STING knockout was also associated with increased T-VEC cell killing. In the D4M3A melanoma, which has low expression of STING and is resistant to PD-1 blockade therapy, T-VEC was able to induce therapeutic responses in both injected and non-injected tumors and demonstrated recruitment of viral- and tumor-antigen specific CD8+ T cells, and induction of a pro-inflammatory gene signature at both injected and non-injected tumors. These data suggest that T-VEC induces ICD in-vitro and promotes tumor immunity and can induce therapeutic responses in anti-PD-1-refractory, low STING expressing melanoma.

Oncolytic virotherapy is emerging as a promising approach for the treatment of several neoplasms. The term "oncolytic viruses" is generally employed to indicate naturally occurring or genetically engineered attenuated viral particles that cause the demise of malignant cells while sparing their non-transformed counterparts. From a conceptual standpoint, oncolytic viruses differ from so-called "oncotropic viruses" in that only the former are able to kill cancer cells, even though both display a preferential tropism for malignant tissues. Of note, such a specificity can originate at several different steps of the viral cycle, including the entry of virions (transductional specificity) as well as their intracellular survival and replication (post-transcriptional and transcriptional specificity). During the past two decades, a large array of replication-competent and replication-incompetent oncolytic viruses has been developed and engineered to express gene products that would specifically promote the death of infected (cancer) cells. However, contrarily to long-standing beliefs, the antineoplastic activity of oncolytic viruses is not a mere consequence of the cytopathic effect, i.e., the lethal outcome of an intense, productive viral infection, but rather involves the elicitation of an antitumor immune response. In line with this notion, oncolytic viruses genetically modified to drive the local production of immunostimulatory cytokines exert more robust therapeutic effects than their non-engineered counterparts. Moreover, the efficacy of oncolytic virotherapy is significantly improved by some extent of initial immunosuppression (facilitating viral replication and spread) followed by the administration of immunostimulatory molecules (boosting antitumor immune responses). In this Trial Watch, we will discuss the results of recent clinical trials that have evaluated/are evaluating the safety and antineoplastic potential of oncolytic virotherapy.

Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p

Oncolytic viruses are natural or genetically modified viral species that selectively infect and kill neoplastic cells. Such an innate or exogenously conferred specificity has generated considerable interest around the possibility to employ oncolytic viruses as highly targeted agents that would mediate cancer cell-autonomous anticancer effects. Accumulating evidence, however, suggests that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect, but strongly relies on the induction of an endogenous immune response against transformed cells. In line with this notion, superior anticancer effects are being observed when oncolytic viruses are engineered to express (or co-administered with) immunostimulatory molecules. Although multiple studies have shown that oncolytic viruses are well tolerated by cancer patients, the full-blown therapeutic potential of oncolytic virotherapy, especially when implemented in the absence of immunostimulatory interventions, remains unclear. Here, we cover the latest advances in this active area of translational investigation, summarizing high-impact studies that have been published during the last 12 months and discussing clinical trials that have been initiated in the same period to assess the therapeutic potential of oncolytic virotherapy in oncological indications.

The holy grail of anticancer therapy is to selectively eradicate malignant cells while sparing their normal counterparts. Tremendous progresses have been made in this sense during the past decade, as demonstrated by the development and subsequent integration into the clinical routine of ever more effective and safe therapeutic agents.1 Among these, chemical inhibitors of oncogenic drivers such as vemurafenib (an inhibitor of mutated BRAF currently employed for the treatment of melanoma),2,3 and highly specific monoclonal antibodies such as trastuzumab (an ERBB2-targeting antibody nowadays used for the treatment of several ERBB2+ solid tumors including breast carcinoma)4-6 have contributed to significantly decrease the side effects associated with antineoplastic regimens and, simultaneously, to increase their therapeutic potential.1 Thus, the introduction of targeted anticancer agents has considerably improved the life expectancy of (at least some subsets of) cancer patients. In most cases, however, the therapeutic benefits of this approach are paradoxically limited by its own specificity. Indeed, only a few tumor types, when not a single one, can be successfully treated with a highly specific chemo- or immunotherapy, owing to the restricted expression pattern of the drug target.7,8 Moreover, cancer cells can adapt quite rapidly to a very specific selective pressure, such as that posed by targeted anticancer agents, by downregulating one (or a few) protein(s), a mechanism that also intervenes in the escape of tumor cells from immunosurveillance.9 Conversely, traditional chemotherapeutics—which are generally employed as a first-line treatment against a variety of tumors—exert antineoplastic effects by targeting functions that are preferentially, but not exclusively, present in tumor cells. As a consequence, these cytotoxic chemicals are frequently associated with mild to moderate adverse reactions in a consistent proportion of patients. The identification of agents that preferentially kill cancer cells remains therefore subject of intense investigation. The notion that viruses may constitute specific antineoplastic agents is not particularly novel, but oncolytic virotherapy has emerged only recently as an actual therapeutic alternative.10 A large panel of viruses has been tested and genetically engineered in this sense, including (but not limited to) the herpes simplex virus (HSV), the Newcastle disease virus and several distinct adenoviruses.11 Oncolytic viruses mediate antineoplastic effects by preferentially infecting and killing cancer cells while simultaneously activating a tumor-specific immune response.10,11 Early attempts to exploit viruses as antineoplastic agents were not especially promising, as naturally occurring viral strains exhibit a limited selectivity for malignant cells and often result in disseminated infections as they spread to neighbor, non-malignant tissues. The advent of recombinant DNA technology allowed for the genetic engineering of viral strains with improved specificity and immunostimulatory potential.12 HSV was among the first viruses to be characterized and developed for oncolytic virotherapy, owing to the facts that it was genetically well characterized, exhibits an elevated lytic potential and is relatively safe for use in humans. More than ten years ago, Kucharczuk et al. developed a genetically engineered variant of HSV-1, HSV-1716, which is unable to replicate in normal post-mitotic cells owing to the deletion of RL1 (coding for the neurovirulence factor ICP34.5).13 A few years later, BioVex Limited, now part of Amgen, developed a second-generation HSV-1 variant that lacks not only RL1 but also the gene coding for ICP47, another neurovirulence factor that primarily functions to inhibit antigen presentation by infected cells.14 The virus was also engineered to drive the secretion of the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF),14 mainly intended at recruiting immune cells at the site of infection.15 On March 19th, 2013, Amgen announced encouraging results of a Phase III clinical trial testing the antineoplastic activity of this recombinant virus, talimogene laherparepvec, in melanoma patients. In previous Phase I and II clinical trials, the biweekly intratumoral administration of talimogene laherparepvec (formerly known as OncoVEXGM-CSF) to patients with various solid tumors, including unresectable melanoma, was well tolerated.16,17 At the injection site, tumor cell necrosis coupled to a local inflammatory reaction involving the expression of GM-CSF and the recruitment of various immune cells was documented.16 In addition, the administration of talimogene laherparepvec to melanoma patients was associated with an overall response rate, according to the Response Evaluation Criteria In Solid Tumors (RECIST), of 26%,17 prompting the initiation of several Phase III clinical studies, including OPTiM (OncoVEXGM-CSF Pivotal Trial in Melanoma, www.clinicaltrial.gov NCT00769704).18 This global, randomized, open-label Phase III trial enrolled more than 400 patients bearing unresectable Stage IIIB, IIIC or IV melanoma to evaluate the safety and therapeutic profile of intratumoral talimogene laherparepvec, as compared with subcutaneous GM-CSF. In a recent press release, Amgen's investigators reported a significant difference in the durable response rate, defined as the rate of complete or partial response lasting continuously for at least six months, between the talimogene laherparepvec and the control arm (16% vs. 2%). Fatigue, chills and fever were the most prominent adverse events. Of note, overall survival data are not yet available, but are expected for the end of 2013. These results suggest that oncolytic virotherapy may soon become an actual therapeutic option for the clinical management of melanoma. This said, there are several aspects that remain to be clarified for understanding whether oncolytic viruses may also be employed one day to treat other, less immunosensitive tumors. Several studies indicate indeed that the therapeutic effects of oncolytic viruses depend, at least in part, from the elicitation of tumor-specific immune responses.12 In this sense, melanoma (together with renal cell carcinoma) surely constitutes a relatively privileged setting. Further studies will have therefore to elucidate whether oncolytic virotherapy is sufficient to trigger a therapeutic immune response against all types of solid tumors or whether—most likely—combinatorial regimens involving one or several immunostimulatory agents will be required to fully exploit the antineoplastic potential of oncolytic viruses.

On 2015, October 27th, the US Food and Drug Administration (FDA) has officially approved talimogene laherparepvec (T-VEC, also known as OncoVEXGM-CSF) for use in melanoma patients with injectable but non-resectable lesions in the skin and lymph nodes. T-VEC (which is commercialized by Amgen, Inc. under the name of Imlygic®) becomes therefore the first oncolytic virus approved for cancer therapy in the US.

Oncolytic viruses are natural or genetically modified viral species that selectively infect and kill neoplastic cells. Such an innate or exogenously conferred specificity has generated considerable interest around the possibility to employ oncolytic viruses as highly targeted agents that would mediate cancer cell-autonomous anticancer effects. Accumulating evidence, however, suggests that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect, but strongly relies on the induction of an endogenous immune response against transformed cells. In line with this notion, superior anticancer effects are being observed when oncolytic viruses are engineered to express (or co-administered with) immunostimulatory molecules. Although multiple studies have shown that oncolytic viruses are well tolerated by cancer patients, the full-blown therapeutic potential of oncolytic virotherapy, especially when implemented in the absence of immunostimulatory interventions, remains unclear. Here, we cover the latest advances in this active area of translational investigation, summarizing high-impact studies that have been published during the last 12 months and discussing clinical trials that have been initiated in the same period to assess the therapeutic potential of oncolytic virotherapy in oncological indications.