Oncolytic Virus Immuno-Therapy: New Approach for a New Class of Immunotherapy Drugs
Curator: Larry H. Bernstein, MD, FCAP
Oncolytic viruses represent a promising novel immunotherapy strategy, which may be optimally combined with existing therapeutic modalities
Oncolytic viruses: a novel form of immunotherapy
In the majority of clinical trials performed so far, oncolytic viruses have been administered via intratumoral injection. A smaller number of studies have examined regional or intravenous delivery. Clinical experience has demonstrated a favorable toxicity and safety profile and a number of tumor responses, although overall antitumor efficacy has been limited [1]. For example, ONYX-015, a modified adenovirus, has been used in clinical trials with response rates of 0–14% following intratumoral administration [3]. In view of the short history of oncolytic virotherapy, along with recent scientific advances in methods of viral delivery and enhancing antitumor potency, these low levels of single-agent clinical responses provide encouragement for the future.
An increasingly powerful body of evidence supports the ability of the immune system to modify the immunogenicity and behavior of tumors [4]. A host of tumor-associated antigens (TAA) have been characterized [5] and in a single tumor, tumor-infiltrating lymphocytes directed towards multiple TAAs can be identified [6]. Despite these antigenic differences, the antitumor immune response is commonly ineffectual. Tumors can subvert antitumor immunity, generating an immunosuppressive tumor microenvironment by a multitude of mechanisms. These include the induction of Treg cells, secretion of soluble immunosuppressive mediators including nitric oxide, IL-10 and TGF-β and recruitment of myeloid suppressor cells [4]. Matzinger’s ‘danger’ hypothesis proposes that the prime role of the immune system is to respond to cellular or tissue distress as opposed to nonself per se [7]. Several danger signals have been identified, including RNA, DNA, IFN-α, heat-shock proteins, uric acid and hyaluron, providing a mechanistic basis for this hypothesis [8]. On this basis, tumor-associated danger signals are critical to the generation of effective antitumor immunity. In addition to their ability to disrupt immune responses, tumors commonly lack such signals and successful tumor immunotherapy will probably to depend upon their provision. Oncolytic virotherapy represents a potent approach to cancer immunotherapy, combining the enhanced release of TAA via tumor cell death, in the context of danger signals (FIGURE 1).
The role of the innate immune response to cancer is double-edged. Chronic inflammatory changes can promote tumor progression via proliferative and proangiogenic signals [9], while by contrast, the infiltration of activated innate inflammatory cells can mediate tumor regression in vivo [10]. Manipulation of the immune environment within a tumor is a potentially critical strategy towards successful tumor immunotherapy [11].
Oncolytic viruses represent prime candidates to enhance the immunogenicity of the tumor microenvironment. As detailed below, oncolytic virotherapy may be immunomodulatory via tumor cell death, production of endogenous danger signals, the release of tumor-derived cytokines and direct effects upon cells of the innate immune system. Evidence from preclinical models suggests that an early influx of immune cells, including macrophages and natural killer (NK) cells, occurs in response to tumor viral therapy [12–14]. These changes within the tumor hold the potential to alter the pre-existing immunosuppressive microenvironment, in favor of the generation of therapeutic immune responses. Dendritic cells (DC), the prime antigen-presenting cells and a component of the innate immune response are critical for the subsequent generation of antigen-specific or adaptive immune responses. However, as discussed later, the outcome of the innate response is finely balanced between promotion of tumor clearance and viral clearance limiting efficacy.
Virally induced cell death would be expected to enhance the availability of TAA for uptake by DC. Indeed, viral infection of tumors has been reported to enhance the phagocytosis of tumor-derived material [15,16]. The relationship between the mode of cell death and tumor immunogenicity has, however, been controversial; the immunogenicity of tumors has been reported not to be affected by whether tumor cells are alive, apoptotic or necrotic [17]. Even if the mode of cell death is not an immunogenic determinant, the release of intrinsic cell factors, including heat-shock protein [18], uric acid [19] and bradykinin [20], can be identified as danger signals by DC. Oncolytic viral infection may mediate production of these factors. For example, tumor cell infection by a modified oncolytic adenovirus increases intracellular uric acid levels, activating DC [19].
An array of cytokines provides costimulation for T-cell responses, while by contrast, tumor-derived cytokines, including TGF-β and IL-10, have immunosuppressive properties. In addition, the tumor-derived proinflammatory cytokines VEGF, TNF-α and several chemokines have been linked to promotion of tumor growth [21]. Oncolytic viral infection is likely to alter the balance of cytokines produced and the nature of the subsequent immune response. We have investigated the release of cytokines following infection of melanoma cells with reovirus, a naturally occurring double-stranded RNA virus currently in clinical trials [22]. Reovirus was found to induce secretion of IL-8, RANTES and MIP-1α/β, which play a role in the recruitment of DC, neutrophils and monocytes [23], and of IL-6, which can inhibit the immunosuppressive function of Treg cells [24]. Reovirus additionally reduced tumor secretion of the immunosuppressive cytokine IL-10. The immunogenic property of tumor-conditioned media from reovirus-infected tumor cells (filtered to remove viral particles) was confirmed by their ability to activate DC.
DC & the response to viral infection
The immune system is adept at pathogen recognition and a host of receptors specific for pathogen-associated molecular patterns, including the toll-like receptors (TLR), have been identified [25]. Innate viral recognition can center around viral nucleic acids or viral proteins [25]. DC play a critical role in the early innate immune responses, reciprocally interacting with other innate immune cells, including NK cells [26]. In this context, oncolytic viruses can influence the nature of the innate tumor response. Reovirus-infected DC, for example, enhance NK cytotoxicity towards tumor cells [27].
The effect of viruses upon DC is virus specific: measles and a vaccinia virus strain impair DC phenotype and function [28,29], an oncolytic adenovirus has a neutral effect [30], while reovirus is directly stimulatory to DC [27]. Although the immunomodulatory effects of oncolytic viruses have been investigated to a limited degree, it follows that the immune consequences of therapy with different viruses will vary widely. In addition, the genetic modification of viruses to confer oncolytic specificity may involve interference with virulence genes whose function is to modify the antiviral immune response, including type I interferon response genes [2,31]; alteration of such immunomodulatory genes will alter the consequences of the immune interactions of these modified viruses.
Oncolytic viruses & adaptive antitumor immunity
The innate immune response is thought to provide an important link to the generation of adaptive immune responses. DC are key to this link, taking up TAA, integrating danger signals and presenting antigen in an appropriate costimulatory context to the adaptive arm of the immune system. An adaptive antitumor immune response requires activation of cytotoxic CD8 T cells by DC presenting tumor antigen on MHC class I molecules. The presentation of exogenous antigen in a MHC class I context is termed ‘cross-presentation’. Critically, virally infected cells have been shown to be superior at delivering nonviral antigen for cross-presentation and cross-priming adaptive immune responses in vivo [32]. Intriguingly, recent work has defined a role for TLR-4 receptor ligands (bacterially derived lipopolysaccharide) in enhancing cross-presentation [33]; a similar effect of viral as opposed to bacterial TLR ligands has yet to be explored. Inflammatory stimuli have additionally been shown to enhance antigen processing and the generation of MHC class II complexes, required for CD4+ T-cell help in adaptive immune responses [34,35]; such inflammatory stimuli could be provided by viral tumor infection. Oncolytic virotherapy may therefore enhance immune priming via multiple effects upon DC. There is an emerging body of data from murine and human preclinical research supporting the concept that the efficacy of oncolytic virotherapy is at least partially immune mediated and that antitumor immunity can be generated.
Overall, the antiviral humoral and cellular immune responses may have contrasting consequences. Methods of enhancing viral delivery to tumors or immunomodulation provide an opportunity to alter this balance in favor of therapeutic benefit.
Clinical trials & the immune response
Although preclinical studies have provided support for the concept that the efficacy of oncolytic virotherapy may be dependent upon the host immune response, there are limited data on the immune response following virotherapy from early clinical trials.
Studies of intratumoral administration have provided direct evidence of a cellular immunological response. In a Phase I trial of a second-generation oncolytic HSV expressing GM–CSF injected into subcutaneous metastases from a variety of tumor types, post-treatment biopsies revealed an extensive immune cell infiltrate [54]. Additionally, suggestive of an immune-mediated antitumor effect, was the observation of inflammation in uninjected tumor deposits in four of 30 treated patients. Similarly, in a study of intratumoral administration of a recombinant vaccinia–GM–CSF virus in patients with melanoma deposits, treated lesions were shown to have a dense immune cell infiltrate. The generation of antitumor immunity was implied by the regression of noninjected regional dermal metastases in association with an immune infiltrate in four of seven treated patients [55]. A Phase I study of injection of JX-594, a targeted poxvirus armed with GM–CSF, into primary and metastatic liver tumors has recently been reported with encouraging evidence of activity, with a partial response in three and stable disease in six of ten evaluable patients by Response Evaluation Criteria in Solid Tumors (RECIST) [56]. Consistent with a possible antitumor immune response was the durability of tumor responses. Notably, there was evidence of functional response in noninjected tumors in three of seven evaluable patients by Choi criteria for reduction in Hounsfield units (n = 2) and by reduced 18F-fluorodeoxyglucose (18FDG)-PET signal (n = 1). There was evidence of viral dissemination to noninjected tumor tissue. The responses in injected and noninjected tumor tissue could therefore have been mediated by direct viral oncolysis, antiviral immune responses towards virally infected cells or antitumor immune responses established in the injected lesions.
Oncolytic viruses have been combined with tumor vaccines in an attempt to exploit viral danger signals. Vaccinia virus–melanoma cell lysate vaccines were used in an adjuvant Phase III study of 700 patients following melanoma resection, with no improvement in recurrence or overall survival [57]. A series of clinical studies has been performed by Schirrmacher et al. using a live autologous tumor vaccine infected by NDV irradiated to render tumor cells nonviable [58]. A significant proportion of patients developed antitumor immune responses as assessed by a delayed-type hypersensitivity response to skin prick tests. Phase II studies have been performed in glioblastoma multiforme, melanoma, breast and colorectal cancer with improvements in overall survival by 20–36% at 2–5-year follow-up compared with historical controls. These studies suggest that oncolytic viruses can break immunological tumor tolerance, although Phase III studies are needed to confirm these findings.
Combination therapy may be the optimal context in which to exploit the immunotherapeutic potential of oncolytic viruses. A rationale exists for combination with existing immunotherapy strategies, along with conventional therapy.
Adoptive cellular therapy & viral delivery
The use of cell carriers to chaperone viral particles to the tumor is a promising innovation [51]. Cells of the immune system have proven particularly adept, including cytokine-activated killer cells [52] and T lymphocytes [36]. Adoptive cellular therapy has met with some clinical success, but has been limited by the trafficking to and survival of T cells in the tumor microenvironment [62]. In a mouse model, the combination of oncolytic virus delivery with antigen-specific adoptive T-cell therapy has been shown to improve upon either treatment modality alone [63]. Although yet to be tested in clinical trials, these findings are of significant translational potential.
Immunotherapy combinations
Immunotherapy approaches may be logically combined with virotherapy to enhance antitumor responses.
The host immune response will probably be critical to the efficacy of oncolytic virotherapy, although it is a fine balance between rapid viral elimination and innate and adaptive responses, which may mediate tumor regression. The rational design of combination therapy, modulating the immunological outcome, may hold the key to fulfilling the potential of these novel agents. Clinical trials should be designed to include specific assessment of immune responses to both tumor and viral antigens, and recognize the immunotherapeutic potential of virotherapy in terms of clinical end points and patient selection.
Oncolytic Viruses and Their Application to Cancer Immunotherapy
E. Antonio Chiocca1 and Samuel D. Rabkin2
Cancer Immunol Res April 2014 2; 295http://dx.doi.org:/10.1158/2326-6066.CIR-14-0015
Oncolytic viruses (OV) selectively replicate and kill cancer cells and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer selective or can be genetically engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines and can be armed with immunomodulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV–tumor/host interaction are important in delineating the effectiveness of therapy: (i) innate immune responses and the degree of inflammation induced; (ii) types of virus-induced cell death; (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture; and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers [MHC, costimulatory, and natural killer (NK) receptors], and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing granulocyte macrophage colony-stimulating factor (GM-CSF), have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between antivirus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs. Cancer Immunol Res; 2(4); 295–300. ©2014 AACR.
Oncolytic virus (OV) therapy is based on selective replication of viruses in cancer cells and their subsequent spread within a tumor without causing damage to normal tissue (1, 2). It represents a unique class of cancer therapeutics with distinct mechanisms of action. The activity of OVs is very much a reflection of the underlying biology of the viruses from which they are derived and the host–virus interactions that have evolved in the battle between pathogenesis and immunity. This provides a diverse set of activities that can be harnessed and manipulated. Typically, OVs fall into two classes: (i) viruses that naturally replicate preferentially in cancer cells and are nonpathogenic in humans often due to elevated sensitivity to innate antiviral signaling or dependence on oncogenic signaling pathways. These include autonomous parvoviruses, myxoma virus (MYXV; poxvirus), Newcastle disease virus (NDV; paramyxovirus), reovirus, and Seneca valley virus (SVV; picornavirus); and (ii) viruses that are genetically manipulated for use as vaccine vectors, including measles virus (MV; paramyxovirus), poliovirus (PV; picornavirus), and vaccinia virus (VV; poxvirus), and/or those genetically engineered with mutations/deletions in genes required for replication in normal but not in cancer cells including adenovirus (Ad), herpes simplex virus (HSV), VV, and vesicular stomatitis virus (VSV; rhabdovirus; refs. 1,3). Genetic engineering has facilitated the rapid expansion of OVs in the past two decades, enabling a broad range of potentially pathogenic viruses to be manipulated for safety and targeting (3). Many of the hallmarks of cancer described by Hanahan and Weinberg (4) provide a permissive environment for OVs; they include sustained proliferation, resisting cell death, evading growth suppressors, genome instability, DNA damage stress, and avoiding immune destruction. In addition, insertion of foreign sequences can endow further selectivity for cancer cells and safety, as well as altering virus tropism through targeting of translation with internal ribosome entry sites (IRES) or microRNAs (PV and VSV), transcription with cell-specific promoter/enhancers (Ad, HSV), or transduction with altered virus receptors (HSV, Ad, MV, and VSV; refs.1, 3). These strategies are also being used to target replication-deficient viral vectors for gene therapy applications in cancer immunotherapy.
OVs have many features that make them advantageous and distinct from current therapeutic modalities: (i) there is a low probability for the generation of resistance (not seen so far), as OVs often target multiple oncogenic pathways and use multiple means for cytotoxicity; (ii) they replicate in a tumor-selective fashion and are relatively nonpathogenic and, in fact, only minimal systemic toxicity has been detected; (iii) virus dose in the tumor increases with time due to in situ virus amplification, as opposed to classical drug pharmacokinetics that decrease with time; and (iv) safety features can be built in, such as drug and immune sensitivity. These features should result in a very high therapeutic index. An important issue for OV therapy is delivery. Although systemic intravenous administration is simpler than intratumoral injection and can target multiple tumors, it has drawbacks, including nonimmune human serum, anti-OV antibodies that preexist for human viruses or can be induced by multiple administrations, lack of extravasation into tumors, and sequestration in the liver (1). Cell carriers [i.e., mesenchymal stromal cells, myeloid-derived suppressor cells (MDSC), neural stem cells, T cells, cytokine-induced killer cells, or irradiated tumor cells] can shield virus from neutralization and facilitate virus delivery to the tumor (5). The effectiveness will vary depending upon the cell phenotype, permissiveness to virus infection, tumor-homing ability, and transfer of infectious virus to tumor cells. To block virus neutralization and extend vascular circulation, viruses can also be coated in nanoparticles (i.e., PEGylation; ref. 1).
Virus infection and pathogenicity have been major drivers in the evolution of the human immune system, and vaccination against viruses is the quintessential exploitation of adaptive immunity. A major goal of OV-mediated immunotherapy is to activate and redirect functional innate and adaptive immune responses toward the tumor. Interactions between innate and adaptive immune cells and signaling factors (i.e., cytokines and chemokines), often involved in virus infections, play a large role in antitumor immunity or lack thereof, as well as successful immunotherapies (Fig. 1). Virus infection induces an inflammatory response leading to adaptive antivirus immunity. Thus, the immune system was seen initially as a negative factor in OV therapy for limiting virus infection/delivery because of preexisting or therapy-induced immunity, virus replication because of innate antiviral responses, and virus spread because of the infiltration of innate immune cells (6). In addition, most early studies were performed in human xenograft tumor models in immunodeficient mice lacking adaptive immune responses because some viruses were species selective or replicated better in human cells, and because there was availability of a broad diversity of human cancer cell lines. With the use of syngeneic tumor models in immunocompetent mice, it became clear that the consequences of the immune system were complex, but that the induction of antitumor immunity was feasible and efficacious (6). In particular, many OVs act asin situ vaccines, inducing robust, long lasting, and specific adaptive antitumor responses, often CD8+ T cell–mediated (7, 8). Interestingly, adaptive antiviral immunity can enhance antitumor immunity for HSV, but not for VSV (8, 9).
Figure 1.
Cartoon of OV-mediated effects in tumor. First phase, OV delivered intratumorally or systemically, infects tumor cells (can be blocked by humoral defense systems; antibodies). After infection, OV replicates (can be blocked by innate responses; i.e., IFN-α/β), kills cells often by ICD, and spreads throughout the tumor (can be blocked by innate immune cells, i.e., NK cells and macrophages), eliciting an inflammatory response. When an armed OV is used, the immunomodulatory transgene is expressed (transgene product). Second phase, ICD and inflammation recruit DCs to the tumor, where they take up TAAs and induce an adaptive immune response (T and B cells), which targets the tumor (can be blocked by Tregs and MDSCs). Innate cells such as NK cells also have antitumor activities. Antitumor immune responses can be further enhanced by transgene products. CPA, cyclophosphamide.
http://cancerimmunolres.aacrjournals.org/content/2/4/295/F1.medium.gif
The inflammatory cascade and immunogenic cell death (ICD) induced by OV infection of tumors makes OVs particularly powerful inducers of antitumor immunity (8, 10). Among the many different types of cell death, some are immunogenic and characterized by the release of danger-associated molecular patterns (DAMP), such as calreticulin, high-mobility group protein B1 (HMGB1), and ATP, along with tumor-associated antigens (TAA; ref. 10). Multiple forms of ICD have been observed after OV (Ad, VV, HSV, MV, and coxsackievirus) infection of cancer cells, and there is a suggestion that ICD occurs in patients after treatment with oncolytic Ad and temozolomide (11). However, much remains to be learned about the mechanisms of OV-mediated cell death and how it can be exploited to enhance immunogenicity. Inflammation, typically chronic, can also promote tumorigenesis and inhibit T-cell antitumor activity (12). Restraining antiviral immune responses and minimizing pathology, while promoting antitumor immune responses, is a complex and poorly understood balancing act that will dictate OV therapy outcomes. In some cases, where minimal OV replication occurs in mouse tumors (i.e., HSV) or no replication is required (i.e., reovirus; ref. 13), antitumor efficacy is principally due to OV-induced immune responses. Understanding, harnessing, modulating, and/or enhancing OV-mediated immune responses for effective antitumor immunity are major areas in current research that intersect with other immunotherapeutic strategies.
Many viruses express immune evasion genes that enable them to establish infections and spread within their host (14). Mutations in these genes (i.e., HSV Us11, VV E3L, MYXV M156R, Ad VAI, and reovirus σ2/σ3, inhibitors of PKR; HSV ICP0, VV N2, NDV V, and MV V, inhibitors of IRF3; HSV ICP0, MYXV M13L, MV V, PV 3C, and VSV M, inhibitors of NF-κB; VV B8R and MYXV MT-7, inhibitors of IFN-γ; HSV ICP47 and AdE3-19K, inhibitors of MHC class I presentation; MV gp, inhibitor of T cells; and MYXV M128L and MV H, inhibitors of CD46) are likely to enhance the induction of immunity and possibly cross-presentation of TAAs. Such mutations should improve the safety of OVs by making them more visible to the immune system, as well as increasing antitumor immune responses. Conversely, they may diminish virus replication and spread. An additional problem not as easily addressed is OV infection of immune cells, especially dendritic cells (DC), that interferes with their function (15, 16).
Although adaptive immunity seems to provide and, in fact, represent even the major mode of anticancer action for OVs, it is also evident that an initial host response against an administered OV could destroy it along with the infected cells before the OV has a chance to replicate and induce cytotoxicity of a magnitude that is sufficient to set up an effective vaccination response (17). Location and site of OV administration is an important determinant of the characteristics of these initial host responses against the OV. For instance, intravenous or intra-arterial administration of OVs, such as recombinant HSV1, leads to its rapid recognition and elimination by the circulating complement and antibodies of the humoral defense system (18, 19). This has also been shown for VV (20), NDV (21), MV (22), and Ad (23, 24). Intratumoral administration can also lead to complement- and antibody-mediated destruction of the OV. In addition, intracellular and microenvironmental antiviral defense responses in infected tumor cells can also greatly limit the magnitude of OV replication (25–31). Finally, innate immune cells can rapidly respond to an administered OV, further limiting its survival and that of OV-infected tumor cells (32–35). In all these models, circumvention of such responses using pharmacologic agents, such as histone deacetylase (HDAC) inhibitors or immunomodulating drugs, or genes that block antiviral defense mechanisms, has led to improved OV replication and tumor cytotoxicity (reviewed in ref. 36). When pharmacologic agents are used, the interference of antiviral responses can be applied in a transient fashion usually right before or at the time of OV administration. This should lead to an initial burst of OV replication leading to tumor cell lysis. As the pharmacologic effects against host innate immunity wane, a large debris field of OVs and tumor antigens could be more promptly recognized by the antiviral host response, leading to a secondary long-term vaccination effect responsible for effective tumor immunity (Fig. 1). However, quantification of responses to OV therapy is a sorely needed area of investigation. For instance, the number of OV-replicative rounds, the tumor cell-OV burst size, the number of OV-replicative tumor foci, and the temporal kinetics of innate response suppression that are needed for an efficient lytic and vaccination effect are still undetermined. In fact, current applications of innate immunity modulation with OV administration remain to be determined in an empirical manner.
Enhancing OV Immunotherapy
Many OVs can accommodate gene insertions and thus can be “armed” with therapeutic transgenes, combining local gene delivery with oncolytic activity (42). Local expression in the tumor obviates toxicity arising from systemic administration of potent immune modulators. GM-CSF, based on its effects in cytokine-transduced cancer cell vaccines (i.e., clinically approved Sipuleucel-T), has been incorporated into a number of OVs [HSV T-Vec, VV JX-594, Ad Ad5/3-D24-GMCSF (43), and CG0070 (44)] that have entered clinical trials (8). GM-CSF–expressing OVs demonstrated only moderate activity in preclinical studies (45, 46), while JX-594 was not compared with a VV lacking GM-CSF (47). Other therapeutic transgenes include interleukin (IL)-2 (NDV, HSV, and parvovirus), IL-12 (Ad and HSV), IL-15 (VSV), IL-18 (HSV), IFN-α/β (Ad, VSV, and VV), soluble CD80 (Ad and HSV), 4-1BB (VV), CD40L (Ad, and no effect with VSV), Flt3L (Ad and HSV), CCL3 (Ad), CCL5 (Ad and VV), and combinations thereof (2). In addition to transgenes that enhance adaptive immune responses, cytokines/chemokines directed at the tumor microenvironment can alter the immune cell balance toward productive therapeutic immunity (Fig. 1). IL-12, a potent antitumor cytokine with antiangiogenic activities, when expressed from oncolytic HSV, reduced neovasculature and tumor regulatory T cells (Treg) and induced T cell–mediated immunity in an immunocompetent cancer stem cell model (48). Expression of a CXCR4 antagonist from oncolytic VV reduced tumor vasculature and accumulation of bone marrow–derived epithelial and myeloid cells and induced antitumor humoral responses (49).
Like many cancer vaccine strategies, OVs expressing TAAs can be used to induce tumor-selective adaptive immune responses. The combination of TAA expression in the tumor and OV-mediated cell killing induces enhanced T-cell migration and activation compared with OV-infected tumor cells expressing the TAA (50). This can be coupled to a prime (replication-deficient Ad or oncolytic Semliki Forest virus expressing a TAA)–boost (oncolytic VSV or VV expressing the same TAA) vaccine strategy, in which the boosted secondary response to the tumor dominates the primary anti-OV response (6, 8). To expand the antigenic repertoire, cDNA libraries from normal tissue (e.g., prostate for prostate tumors) or recurrent tumors have been inserted into VSV, and induced therapeutic immunity (51). Further enhancement was obtained by expressing xenogeneic TAAs (51, 52). The ability of oncolytic VSV expressing TAAs to induce IL-17 in the context of tumor immunity has been exploited to screen tumor cDNA libraries for individual TAAs and optimal TAA combinations, limiting potentially inappropriate responses of whole-cell or cDNA vaccines (53). Developing a similar strategy in a human setting would be a major advance.
A number of immunomodulatory agents have been examined to restrain antiviral immune responses and promote OV replication and spread. Cyclophosphamide can increase OV replication and inhibit tumor growth by suppressing innate immune cell (34) and antibody responses (54), depleting Tregs, and enhancing the antitumor activity of CTLs (Fig. 1; ref.8). A challenge is to identify immunosuppressive strategies that can blunt acute innate cells from blocking virus replication and spread, while permitting sufficient inflammation and cross-priming for robust antitumor immunity. Conversely, it will be of interest to combine OV with chemotherapies that induce ICD (e.g., cyclophosphamide, oxaloplatin, or anthracyclines such as doxorubicin and mitoxantrone), increase tumor cell antigenicity (e.g., gemcitabine, cisplatin, or etoposide) or susceptibility to immune cells (e.g., HDAC inhibitors, paclitaxel, or doxorubicin), or suppress MDSCs (e.g., gemcitabine and paclitaxel) and Tregs (e.g., cyclophosphamide or sunitinib; ref. 55) in immunocompetent preclinical models.
In conclusion, the field of virotherapy is becoming mature in its knowledge of effective anticancer mechanisms in animal tumor models with OVs that are also safe in human clinical trials. It seems that there may soon be a first-in-humans OV approved for use in the United States, which will further stimulate laboratory and clinical endeavors with this therapeutic strategy.
Oncolytic viruses: a new class of immunotherapy drugs.
Oncolytic viruses represent a new class of therapeutic agents that promote anti-tumour responses through a dual mechanism of action that is dependent on selective tumour cell killing and the induction of systemic anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been developed as oncolytic agents, and the approval of the first oncolytic virus by the US Food and Drug Administration (FDA) is anticipated in the near future. This Review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describes oncolytic viruses in advanced clinical trials and discusses the unique challenges in the development of oncolytic viruses as a new class of drugs for the treatment of cancer.
Nat Rev Drug Discov. 2015 Sep;14(9):642-62. http://dx.doi.org:/10.1038/nrd4663.
Oncolytic Virus-Mediated Immunotherapy: A Combinatorial Approach for Cancer Treatment
SE Lawler, EA Chiocca JCO.2015.62.5244 http://dx.doi.org:/10.1200/JCO.2015.62.5244
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Oncolytic Viruses in Cancer Therapy @ CHI’s PreClinical Congress, June 14, 2016 Westin Boston Waterfront, Boston
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