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Table of Contents
REVIEW
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 7-19

Combination of oncolytic viruses and immune checkpoint inhibitors in glioblastoma


1 Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
2 Department of Medicine, Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Date of Web Publication1-Apr-2019

Correspondence Address:
Dr. Anne Hubben
Department of Internal Medicine, Cleveland Clinic, 9500 Euclid Avenue, Na10, Cleveland, OH 44195
USA
Dr. Kunal Desai
Department of Internal Medicine, Cleveland Clinic, 9500 Euclid Avenue, NA10, Cleveland, OH 44195
USA
Dr. Manmeet Ahluwalia
Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, S73, Cleveland, OH 44195
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_5_19

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  Abstract 

Glioblastoma is associated with poor prognosis with a mean survival of 15 months after diagnosis. The current standard of care includes surgery, radiation, and temozolomide with the use of tumor-treating fields in select patient population. The past decade has witnessed a convergence in our understanding of tumor biology and the role of the immune system in fighting cancer. The highly immunosuppressive tumor microenvironment exerted by glioblastoma cells has contributed to the lack of success of novel immunotherapies till date (including checkpoint inhibitors). Oncolytic viral-based approaches are of renewed interest given advances in tumor cell tropism, pathogenicity, and immunogenicity. More importantly, oncolytic viruses have been shown to initiate a broad immune response through various mechanisms including dual activation of the innate and adaptive arms of the host immune system. Because the initial clinical studies with monotherapy checkpoint inhibition in glioblastoma have failed to demonstrate a survival advantage, most trials in glioblastoma are testing combinations that seek to augment the immune response through mutually reinforcing approaches that can overcome the immunosuppressive milieu. Preclinical data in glioblastoma models with combined oncolytic viruses therapy and checkpoint blockade are favorable and provide rationale to initiate first-in-human trials. Even though the number of clinical trials testing this combination in glioblastoma is limited, more studies are expected in the future.

Keywords: Checkpoint inhibition, checkpoint inhibitors, glioblastoma, glioma, oncolytic viruses, programmed cell death protein 1, programmed death-ligand 1


How to cite this article:
Desai K, Hubben A, Ahluwalia M. Combination of oncolytic viruses and immune checkpoint inhibitors in glioblastoma. Glioma 2019;2:7-19

How to cite this URL:
Desai K, Hubben A, Ahluwalia M. Combination of oncolytic viruses and immune checkpoint inhibitors in glioblastoma. Glioma [serial online] 2019 [cited 2019 Sep 18];2:7-19. Available from: http://www.jglioma.com/text.asp?2019/2/1/7/255155


  Introduction Top


Central nervous system tumors include a wide range of tumors defined by histologic and genomic criteria. Gliomas comprise 80% of malignant brain tumors and are responsible for the majority of deaths.[1] The most recent World Health Organization Classification of Tumors proposed a novel approach that integrated genotypic and phenotypic characteristics.[2],[3] Glioblastoma arises from progenitor cells of astrocytic and oligodendrocytic origin and offers the poorest prognosis with a mean survival of 15 months after diagnosis.[4] Unfortunately, the standard of care for glioblastoma has not changed in over a decade.[5] Patients under the age of 70 with good clinical performance status undergo maximal safe resection followed by 6 weeks of combined fractionated external beam radiation therapy and temozolomide.[6] This is followed by adjuvant temozolomide (6–12 cycles). Therapeutic options for recurrent glioblastoma are extremely limited with median progression-free survival of 10 weeks and overall survival of 30–40 weeks.[7] Clinical trials for novel therapies have focused on the recurrent setting; however, no agents have demonstrated survival benefit over the standard of care. The aim of this review is to summarize the progress to date and future direction of oncolytic viruses (OVs) in the management of glioblastoma.


  Expanding Our Knowledge of Tumor Biology and Role of the Immune System Top


The past decade has seen a convergence in our understanding of tumor biology and the role of the immune system in fighting cancer. Numerous studies have characterized the glioblastoma tumor microenvironment (TME) and the highly immunosuppressive effects it exerts upon the immune system. At the same time, the field of immunotherapy has yielded diverse therapeutic strategies, including combination approaches that seek to synergistically augment the immune system's response to the tumor. To that end, the following major immunotherapeutic approaches are being investigated in glioblastoma in various combinations: adoptive cellular therapies, checkpoint inhibitors, cytokine therapy, OVs, and tumor-specific vaccines.

Among these, OVs offer fresh potential as recent studies demonstrate their role in promoting a broad and robust immune response. OV therapies have gained renewed attention in glioblastoma as our understanding of the immune system within the TME has grown and methods of developing replication-competent viruses have improved. There has been a fundamental shift from deploying nonreplicating viral vectors to using replication-competent vectors that exploit lytic destruction of tumor cells to activate the immune system. The number of OV platforms being tested in glioblastoma has expanded and includes over 15 types of viruses with the most advanced programs using adenovirus, herpes simplex virus (HSV), poliovirus, and retrovirus.[8] OVs are well tolerated, and local administration into a single tumor has been shown to induce regression of distant, untreated tumors via immune-mediated mechanisms.[9] This review focuses on the potential role of OVs in the management of glioblastoma including the early promise seen with the combination of OVs and checkpoint inhibitors. It is important to first appreciate the unique role of the immune system in glioblastoma.


  The Immune System and Glioblastoma Top


A highly immunosuppressive tumor microenvironment limits robust antitumor response in glioblastoma

Glioblastoma exerts a highly immunosuppressive milieu through various signaling networks and adaptive mechanisms that limit an antitumor response. The complexity and diversity of suppressive mechanisms deployed by the tumor have precluded any one immunotherapeutic approach from demonstrating survival benefit. To that end, most trials in glioblastoma are testing combinations that seek to augment the immune response through mutually reinforcing approaches that can overcome the immunosuppressive milieu. Constituents of the TME are contained with a modified extracellular matrix and include central nervous system cells, tumor cells, glioma stem cells, stromal cells, and immune cells. Many immune cell types are recruited to the TME and include T cells (i.e., helper CD4+, cytotoxic CD8+, and regulatory CD4+ CD25+ FoxP3+); antigen-presenting cells (APCs) including dendritic cells (DCs); bone marrow-derived macrophages; natural killer cells; myeloid-derived suppressor cells; and tumor-associated microglia and macrophages.[10]

In particular, the tumor biology of T cells has received much attention given the recent clinical success of inhibitors that target “checkpoint” proteins such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand PD-L1. Several anti-PD-1/PD-L1 therapies have been approved across solid tumors, which include atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab; ipilimumab is the only approved anti-CTLA-4 agent.[11] Primed T cells infiltrate the TME, but signaling through their T cell receptor/CD3 complex is impaired, thereby leading to an anergic state.[12] There is a relative dearth of tumor-infiltrating cells (TILs) in glioblastoma compared to “hot” tumors such as melanoma and lung cancer, and TIL activity is further suppressed through cytokines such as interleukin (IL)-10 and transforming growth factor-β.[13],[14] Higher grades of tumor and poorer prognosis are associated with lower density of CD4+ and CD8+ T cells.[15],[16] Glioma cells express lower levels of the co-stimulatory CD80/86 proteins, thereby limiting T cell activation and proliferation.[17] The antigen-presenting function is curtailed through various mechanisms such as increased recruitment of regulatory DCs, dysregulated interferon (IFN)-γ/Janus kinase/signal transducers, and activators of transcription-3 signaling and reduced major histocompatibility complex (MHC) expression on microglia.[18] Exhaustion of previously active T cells results in diminished effector function and is a major limitation in deploying T cells against tumor cells.[19]


  Oncolytic Viruses Top


Historical perspectives

Observations about the interplay of viruses and tumor regression have been reported since the turn of the 19th century. Early interest in the use of viruses for cancer treatment stemmed from observations that cancer patients with infections occasionally experienced remission of their disease. In one widely cited example, Dock[20] reported the case of a woman with “myelogenous leukemia” that went into remission after a presumed influenza infection. In another case, varicella infection in a young boy led to remission of lymphatic leukemia.[21] Interest in viral therapy to treat cancer has varied over the past 150 years, reaching its peak in the 1950s and 1960s following the advent of cell and tissue culture systems that allowed ex vivo viral propagation. Then, following a period of near abandonment by the scientific community in the 1970s and 1980s due in part to new regulatory barriers associated with utilizing wild type, virulent pathogens, which had demonstrated superior efficacy but with ethical limitations. Hepatitis B virus, Epstein–Barr virus, Egypt 101 isolate of West Nile, and wild-type, nonattenuated mumps virus were among the early pathogens investigated, but were ultimately abandoned for lack of efficacy and unacceptable safety profiles including encephalitis.[22],[23] In their place, adenoviruses, HSVs, picornavirus, the pox virus, and paramyxoviruses emerged as promising candidates.

The long history of investigation into OVs has highlighted key challenges such as premature immune-mediated virus elimination leading to diminished response and loss of efficacy when translating to first-in-human studies. The need for viruses to have greater tumor specificity to avoid premature neutralization and greater potency led to experimentation to exploit the adaptive capacity of viruses. Moore[24] developed a form of targeted manipulation by propagating viruses with known oncolytic activity in tumors to increase the replicative and destructive capacities of the virus. The most significant advancements in OV therapeutics came with the widespread adoption of recombinant DNA technology in the 1990s. Martuza et al.[25] developed attenuated HSV-1 mutants that were shown to be oncolytic with selective replication in dividing cells from human glioma xenografts.

Oncolytic viruses and the immune system

OVs have long been understood to work through two distinct but synergistic mechanisms, namely direct lysis of tumor cells and the provocation of systemic antitumor immunity. Details of the life cycle of lytic viruses have been previously described[26] which include attachment to the target cell, penetration into the host cell, biosynthesis of viral proteins and nucleic acid, assembly and maturation of viral particles, and, finally, lysis of the cell followed by release of viral particle. This is a complex process that can be preferentially engineered to optimize properties such as tumor cell tropism, pathogenicity, immunogenicity, and ability to encode transgenes with the OV's genome. Historically, the focus was on engineering viruses for tumor-selective replication because direct lysis of infected tumor cells was thought to be the primary means of tumor eradication. However, a more complex and elegant model of virus-induced immune stimulation is emerging. The capacity of OVs to ameliorate an immunosuppressive TME while also augmenting the immune response has led to a recent paradigm shift, whereby OVs are considered to be part of the armamentarium of immunotherapies.[27]

A multitude of mechanisms augment the immune response while ameliorating an immunosuppressive tumor microenvironment

There are a multitude of mechanisms deployed by OVs after infection of target tumor cells that boost the cancer immunity cycle and lend synergy to other immunotherapeutic approaches. Numerous studies have shown the breadth of immune cell types that OVs can activate following infection, including T cells, natural killer cells, DCs, and macrophages along with multiple pro-inflammatory cytokines.[28] Whereas a detailed discussion of all such mechanisms is beyond the scope of this review, we discuss the critical mechanisms that we believe will most help OVs realize synergies with checkpoint inhibitors in the treatment of glioblastoma. Broadly speaking, these include tumor cell tropism, induction of immunogenic cell death (ICD) to activate tumor-specific immunity, and dual activation of the innate and adaptive arms of the immune system (including enhanced activity of T cells).

Selective targeting of tumor cells is the first step in initiating an immune response

Whereas some viruses have an innate tropism for tumor cells, newer agents are being engineered using various creative strategies to optimize targeting of tumor cells over normal cells. Studies have shown that tumor cells are less effective in mounting an antiviral response than healthy cells, which activate IFN signaling to clear the virus.[29],[30] Furthermore, dysregulated oncogenic signaling in tumor cells provides a survival advantage for OVs; for example, mutations in the tumor suppressor retinoblastoma protein have been shown to contribute to more efficient replication of an early region 1A (E1A)-deleted adenovirus.[31] Given their highly proliferative state, tumor cells further provide a larger pool of nucleotides that can be directed toward the synthesis of the viral genome. The recombinant nonpathogenic polio/rhinovirus chimera (PVSRIPO) is a live, attenuated, modified Sabin type 1 poliovirus currently in early-stage trials for glioblastoma, which has been engineered to bind to the poliovirus receptor CD155, an immune checkpoint protein that is expressed on APCs and tumor cells in solid tumors.[32] PVSRIPO also uses a transgenic molecular “switch” that allows for selective targeting of tumor cells over normal cells.[33]

Another strategy to optimize viral replication once tumor cells have been selectively targeted is the use of tissue-specific promoters to regulate the expression of viral genes. This has been successfully demonstrated with the insertion of the human telomerase reverse transcriptase promoter into an E1A-expressing adenovirus.[34] Other examples include use of the protein B (B-Myb) promoter in ribonucleotide reductase-infected cell protein (ICP) 6-deleted HSV-1[35] and the prostate-specific antigen gene promoter in E1A- and E1B-deleted adenovirus.[36] Numerous other strategies to enhance tumor tropism and viral replication have been tested which include re-engineering of viral proteins required for host cell attachment and entry,[37],[38] preventing apoptosis of infected tumor cells, and deletion of viral virulence genes.[39],[40]

Immunogenic cell death stimulates tumor-specific immunity

OVs must strike a balance between provoking a strong immune response and rapid clearance of the virus by the body's antiviral immune response. OVs with greater immunogenicity are better suited to intratumoral delivery, whereas those with lower immunogenicity typically linger longer in circulation and are more amenable to intravenous delivery.[41] ICD follows selective replication in tumor cells and is characteristic of OVs' ability to provoke tumor-specific immunity.[42],[43] The mechanism by which ICD is induced is well characterized: infection by an OV generates endoplasmic reticulum stress which leads to death of the infected tumor cells. Upon death, these cells release various molecules broadly known as damage-associated molecular patterns (DAMPs) (i.e., “danger” signals to the immune system) which include extracellular adenosine triphosphate (ATP), cell surface-exposed calreticulin, high-mobility group protein B1 (HMGB1), and uric acid.[44]

Each molecule engages in specific downstream signaling that ultimately provokes a specific immune response. For example, extracellular ATP activates DCs and macrophages by binding to the P2 × 7 purinoceptor found on these cells.[45],[46] Calreticulin and HMGB1 activate DCs by binding to toll-like receptor 4 and driving the transcription of pro-inflammatory genes.[44],[47] PVSRIPO has been shown to release several molecules upon infection of melanoma and triple-negative breast cancer cells, including tumor-associated antigens (TAAs) such as melanoma-associated antigen recognized by T cell 1 and carcinoembryonic antigen; DAMPs such as HMGB1 and heat shock protein (HSP) 60/70/90; and double-stranded RNA.[33] Delta-24-RGD (DNX-2401, Tasadenoturev), an engineered adenovirus selective for Rb-mutated tumor cells, releases various DAMPs including HMGB1 and HSP90a, HSP70, and ATP following treatment-inducted ICD.[48]

Activation of the innate immune system is a hallmark of oncolytic viruses

OVs have historically been associated with activation of the innate immune system through various mechanisms, and this avenue is a fundamental pillar of their antitumor activity. A class of immature “BATF3+” DCs that depend on two transcription factors called IFN regulatory factor 8 and basic leucine zipper transcriptional factor ATF-like 3 (BATF3) are recruited early to the TME by various chemokines.[49],[50] The required role of these BATF3+ DCs in generating antitumor response by the host cell has been validated in preclinical melanoma models with a modified vaccinia virus Ankara.[51] The binding of various viral components (i.e., DNA, RNA, DAMPs, and pathogen-associated molecular patterns) to toll-like receptors found on DCs promotes further maturation of these cells. This leads to downstream signaling through secreted cytokines to promote DC migration to local lymph nodes. The innate arm is also activated by initial recognition of viral pathogen-associated molecular patterns by pattern recognition receptors found on innate lymphoid cells[52] and by pro-inflammatory cytokines such as IL-6, IL-12, tumor necrosis factor, and others released by DCs.[53] These steps eventually build a “bridge” to the adaptive arm of the immune system by priming and activating T cells at peripheral lymphoid sites.[54]

The only approved OV today is talimogene laherparepvec (T-VEC, a modified HSV1 platform) for the treatment of melanoma. It has been shown to provoke a natural host innate immune response through release of ICD-driven molecules as well as additional immune-boosting functions through two uniquely engineered features. The first was the deletion of the ICP-47 gene which has been shown to limit antigen loading on to MHC class I molecules and thereby limiting the downstream effects of cytotoxic T cells.[39],[55] Second, the insertion of two copies of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in lieu of the ICP-47 gene enhances the immunogenicity of this virus. This cytokine has been shown to enhance DC recruitment to local sites of inflammation while boosting APC function and T cell priming.[39],[56]

Within the glioma space, several leading OV clinical candidates have demonstrated potent activation of the innate and adaptive arms. PVSRIPO produces a strong and sustained type 1 IFN-mediated innate immune response after directly infecting CD155-expressing APCs such as DCs and macrophages; this in turn generates a localized inflammatory reaction that recruits macrophages and neutrophils to the TME.[33] However, recent data suggest that this same IFN response from the host cell's innate immune system may limit the virus's efficacy by cutting short its life cycle.[57] APCs take up various antigens released by PVSRIPO-infected tumor cells and present them to cytotoxic T cells that engage in the direct lysis of cancer cells. When compared to traditional adjuvants such as polyinosinic, polycytidylic acid and lipopolysaccharides, PVSRIPO was better able to counteract immunosuppressive pressure placed on infected APCs (especially macrophages) and led to more sustained DC activation.[58] Another promising OV platform that is currently in early-stage trials, Delta-24-RGD (DNX-2401 or tasadenoturev; an engineered adenovirus selective for Rb-mutated tumor cells), has been shown to increase the infiltration of various innate immune cells in preclinical mouse models.[59] Whereas the role of OVs in activating the innate arm has been historically established, recent studies suggest that OVs play a broader immunologic role by also activating the adaptive care as described below.

Activation of the adaptive arm of the immune system

Our understanding of OVs' role in mobilizing the adaptive arm of the immune response is rapidly growing, providing rationale for combination therapy with other immunotherapeutic approaches, especially checkpoint inhibitors where early data are the most promising. In addition to provoking robust antitumor response from the innate arm, OVs can potentiate other immunotherapies' effects on the adaptive immune response (including T cells). In fact, OVs have been shown to mobilize T cells and their effector functions through a variety of mechanisms that will be addressed here. The role of DCs in presenting processed antigens to CD4+ and CD8+ T cells through MHC II and I, respectively, has been well established.[60] This step leads to further priming and activation of T cells in peripheral lymph nodes that drain tumor cells followed by migration and infiltration of these activated T cells to the TME in response to various cytokines.[61] The previously mentioned BATF3+ DCs are capable of priming and activating virus- and tumor-specific cytotoxic CD8+ T cells.[62] CD8+ T cells also target MHC I-expressing tumor cells that present TAAs.[41] HSV-1 platforms such as T-VEC have been engineered through deletion of the ICP47 gene to prevent virus-driven inhibition of antigen presentation;[40] this ameliorates MHC I downregulation that is used by tumor cells to evade immunosurveillance. The following section provides details on various strategies through which OVs have been engineered to promote an antitumor T cell response.

Oncolytic viruses further enhance activation and infiltration of T cells

Tumor cell lysis and the subsequent release of TAAs and other factors drive antigen spreading through enhanced cross-presentation to T cells. Preclinical studies in murine models of lung adenocarcinoma have shown that PD1 blockade during an oncolytic adenovirus infection led to a broader T cell response due to an enhanced “neoantigenome.”[63] Several OV models have successfully demonstrated the execution of all the following three signaling steps required to activate T cells: antigen presentation via MHC I or II; presence of co-stimulatory molecules such as CD80 and CD86; and release of inflammatory cytokines such as IL-1, IL-12, and IFN-α/β.[64],[65] This suggests the importance of incorporating potent immunogenicity into OV design in order to provoke a robust T cell response.

Another important strategy to amplify T cell activity is through insertion of therapeutic genes into a chosen OV's genome. Once expressed in infected tumor cells, these foreign genes carry out a variety of functions, including directly and indirectly boosting T cell response within the TME. A common strategy is to integrate genes that express cytokines that recruit, prime, activate, and expand the T cell population. Several cytokines including GM-CSF, IL-2, tumor necrosis factor, and IL-12 have been engineered into a variety of OV platforms and have demonstrated activity in preclinical animal models across tumor types[66],[67] and in clinical trials (most notably, GM-CSF in T-VEC).[68] Another strategy to amplify T cell activity is to boost the populations of DCs within the TME by integrating genes that encode TAAs.[69] Several groups have engineered genes that encode co-stimulatory proteins such as CD80, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 3 that activate T cells.[70],[71],[72] Increased expression of these co-stimulatory molecules complements the other two steps involved in T cell activation (namely antigen presentation and secretion of pro-inflammatory cytokines), both of which are also carried out by the OV.

The most promising clinical OV candidates have demonstrated a favorable impact on T cell activity. PVSRIPO was shown in vitro in several tumor types to enhance the populations of T cells that engage in the direct lysis of cancer cells through enhanced APC activity.[33] Preliminary immune analysis from a Phase 1 trial of PSVRIPO in glioma suggested a reduction in immunosuppressive regulatory T cell counts with recovered T effector cell counts.[32] The authors suggested, however, that these favorable shifts may be offset by the use of lymphodepleting chemotherapy. DNX-2401 has shown a TH1 cell-mediated response in preclinical studies and in a subsequent Phase 1 trial with recurrent glioma patients.[48] Interestingly, patients in this trial demonstrated an immune response after a single intratumoral injection of the OV. Analysis of resected tumor tissue showed infiltration of T cells with widespread necrosis. The expression of PD-1 was not significantly altered by DNX-2401 therapy, but the expression of T cell immunoglobulin and mucin domain 3 (TIM-3) (another T cell inhibitory protein) was reduced. Increased expression of PD-1 and TIM-3 is a marker of exhausted T cells.[73] Given the downregulation of TIM-3, the authors suggest that a potential role of DNX-2401 in reversing T cell exhaustion may provide synergies with checkpoint inhibitors. The growing preclinical and clinical data suggest that OVs augment T cell activation and infiltration into the glioblastoma TME and provide strong rationale for combination therapy with the current class of checkpoint inhibitors.


  Clinical Trials of Oncolytic Viruses in Glioma Top


Several OVs have demonstrated safety and efficacy in preclinical and early-phase clinical trials in glioma and are reviewed elsewhere.[27],[28],[74] Here, we briefly review those that successfully transitioned to clinical trials as monotherapy for glioma and focus on the OV candidates under investigation in combination therapy.

Herpes simplex virus

Three oncolytic HSV-1 strains (HSV1716, G207, and G47delta) have completed Phase 1 trials in glioma patients. Each of these viruses was attenuated by the deletion of ICP34.5, which confers neurovirulence. HSV1716 (Seprehvir) was tested in two small Phase 1 clinical trials of intratumoral inoculation of malignant glioma with good demonstrated tolerability[75] and detectable immunological response;[76] however, median overall survival was not significantly impacted. G207 is derived from wild-type HSV-1 strain F, attenuated by a deletion in both copies of ICP34.5 and inactivation of ICP6 by insertion of the  Escherichia More Details coli LacZ gene in UL39.[77] G207 was tested in Phase 1 trials[78],[79],[80] and found to have tolerable safety profiles without significant adverse events or the development of encephalitis. G47 delta added another deletion of ICP47 to G207 and is currently in Phase 1 and 2 trials.[81],[82]

Adenovirus

ONYX-015 is an oncolytic adenovirus that was evaluated in a Phase 1 clinical trial of 24 patients with malignant gliomas; while no severe adverse events were reported, antitumor effect was not demonstrated and median survival was only 6.2 months.[83] h101, a related E1B gene-deleted adenovirus similar to ONYX-015, was approved in China in 2005 for the treatment of head-and-neck or esophageal squamous cell carcinoma but has not been studied in glioma.[84] DNX-2401, a tumor-selective, replication-competent oncolytic adenovirus, is under investigation in ongoing clinical trials. The insertion of an RDG-4c peptide motif into the adenoviral fiber of DNX-2401 enables the virus to bind to integrins avB3 or avB5, which are enriched on tumor cells. A Phase 1 dose-escalation biologic end-point clinical trial of DNX-2401 in 37 patients with recurrent malignant glioma was recently published.[48] Per protocol, one group (n = 25) received a single intratumoral injection of DNX-2401 into recurrent tumor to evaluate safety and response across eight dose levels. A second group (n = 12) underwent intratumoral injection through an implanted catheter followed 14 days later by en bloc resection of posttreatment specimens to investigate the mechanism of action. No dose-limiting toxicities were observed, and tumor reduction was demonstrated in 72% of Group A with a median overall survival of 9.5 months regardless of dose. Analysis of surgical specimens from the second group showed evidence of viral replication within the tumor and demonstrated the ability of DNX-2401 to lyse glioma cells. Histopathological examination of immune markers in posttreatment specimens showed tumor infiltration by CD8+ and T-bet+ cells and downregulation of TIM-3, suggesting that DNX-2401 may be capable of increasing immune cell infiltrates in glioma and altering checkpoint protein expression.[48] Results are currently pending for a Phase 1/2 trial (NCT01582516) in recurrent glioblastoma of DNX-2401 administered by convection-enhanced delivery. Two ongoing trials are investigating DNX-2401 in combination therapy. A Phase 1 trial (NCT01956734) of DNX-2401 intratumoral injection followed by up to two cycles of temozolomide completed enrollment in March 2017 with results pending. TARGET-1 is a Phase 1b (NCT02197169) multicentric trial of DNX-2401 alone or in combination with IFN-γ for recurrent glioblastoma or gliosarcoma.

Reovirus

Pelareorep (REOLYSIN®) is a double-stranded RNA virus that is naturally oncoselective for tumors with upregulated Ras pathways through interaction with the protein kinase R pathway.[85] Pelareorep was investigated in a Phase 1 dose-escalation study with 12 recurrent glioma patients to determine the safety of a single intratumoral injection. The median survival was 21 weeks, and the maximum tolerated dose was not reached.[86] A subsequent multicentric Phase 1 trial was the first to demonstrate the safety of continuous infusion as a novel delivery technique.[87] A group from Mayo Clinic is currently studying wild-type reovirus in combination with GM-CSF (sargramostim) to enhance the immune response in a Phase 1 trial (NCT 02444546) in a pediatric population with high-grade relapsed or refractory brain tumors.

Paramyxovirus

Newcastle disease virus (NDV) is an avian pathogen member of the Paramyxoviridae family of negative-stranded RNA viruses known to cause only mild symptoms in humans. NDV was demonstrated to replicate in and lyse tumor cells as early as the 1950s and has been the subject of several studies in animal tumor models with encouraging results in human neuroblastoma.[88] Two strains of NDV have been investigated in glioma: MTH-68/H, a live-attenuated strain, and NDV-HUJ, a lentogenic (avirulent) strain. A Phase 1/2 trial of lentogenic NDV-HUJ in patients with glioblastoma (n = 14) was the first to examine the systemic administration of OVs in this population. Maximum tolerable dose was not achieved, and NDV-HUJ was detected in various body fluids and tumor tissues. One patient achieved a complete response.[89] Another member of the paramyxoviridae family is measles virus. The Edmonston vaccine strain of measles virus has high oncoselectivity and has been modified to express human carcinoembyronic antigen. The resulting OV, MV-carcinoembyronic antigen, was efficacious and safe in animal models and is currently being studied in a Phase 1 trial (NCT00390299) for the treatment of recurrent glioblastoma.

Parvovirus

One recently published Phase 1/2a trial of H-1PV (ParvOryx) is important to mention because it provided a detailed description of the tumor immune response to OV therapy in glioma patients.[90] H-1PV was administered via intratumoral or intravenous injection followed by tumor resection and re-administration of virus around the resection cavity. H-1PV was safe and well tolerated. The authors demonstrated that the virus could cross the blood–brain barrier (BBB) in both directions; spread widely through the tumor; induce dose-dependent antibody formation; and increase the infiltration of T cells, microglia, and macrophages within tumors with low numbers of infiltrated regulatory T cells.

Poliovirus

PVSRIPO is a recombinant, live-attenuated, nonpathogenic OVs containing the oral Sabin type 1 poliovirus in which the internal ribosomal entry site is replaced with the internal ribosomal entry site from human rhinovirus type 2, with potential antineoplastic activity. PVSRIPO was designated a breakthrough therapy by the Food and Drug Administration in June 2016 based on the strength of a Phase 1 dose-escalation study (n = 61, 7 doses; NCT01491893) in recurrent glioblastoma. Overall survival for patients who received PVSRIPO was 21% at 24 and 36 months and was judged to be superior to that of historical standards. Whereas, there were no instances of neurovirulent toxicity; one patient who was administered dose level 5 experienced Grade 4 intracranial hemorrhage upon removal of the catheter used to deliver the therapy. This adverse event was determined not to be related to PVSRIPO treatment based on subsequent histological evaluation.

Retrovirus

Toca 511 (vocimagene amiretrorepvec) is an amphotropic gammaretrovirus-based retroviral replicating vector containing a codon-optimized, heat-stabilized yeast cytosine deaminase (CD) transgene. Toca 511 was designed to spread through cancer cells and stably deliver the CD gene whose protein product converts courses of the prodrug Toca FC (an investigational extended-release version of flucytosine; 5-fluorocytosine, 5-FC) into 5-fluorouracil. Flucytosine is an oral antifungal drug that crosses the BBB and is approved to treat patients with fungal infections of the central nervous system. Use of Toca 511 and 5-FC in combination with radiation resulted in longer survival compared to that of Toca 511 and 5-FC alone in an immune-deficient glioma mouse model, suggesting the additive effect of 5-fluorouracil with radiation.[91],[92] In the United States, patients with recurrent high-grade glioma have been treated across three Phase 1 ascending dose studies of Toca 511 and Toca FC combination treatment. In addition, a long-term follow-up study is ongoing for patients that have previously been treated with Toca 511 (to evaluate for delayed adverse events) in accordance with regulatory requirements for gene transfer studies.

The initial, first-in-human clinical study (NCT01156584) was a study of the safety and tolerability of increasing doses of Toca 511 administered intratumorally, via stereotactic, transcranial injection, followed by orally administered Toca FC.[93] This study showed that a single intratumoral administration of Toca 511 was both safe and well tolerated. Another clinical study (NCT01470794) evaluated the ascending doses of Toca 511 injected into the bed of the resection cavity in patients with recurrent high-grade glioma who are undergoing resection, followed by orally administered Toca FC.[94] The third clinical study (NCT01985256) evaluated the safety and tolerability of increasing doses of Toca 511 administered intravenously with subsequent intracranial delivery at the time of resection followed by orally administered Toca FC, in patients with recurrent high-grade glioma who are undergoing planned resection.[95] Across these studies, a total of 127 patients have been treated, and long-term follow-up for response and survival are ongoing. In this study, tumor shrinkage, in 6 out of 53 efficacy-evaluable patients (11.3%) with complete disappearance of lesions (or complete response), has been demonstrated based on independent radiology review. A subgroup of 23 patients that matched the recommended Phase 3 Toca 511 dose and entry criteria and planned dose appeared to derive the greatest benefit (five durable complete responders) with the median duration of response not reached (median follow-up of 37.4 months at December 2017 data cutoff). Clinical benefit rate of 43.5% was noted in this subgroup population.


  Oncolytic Viruses in Combination Immunotherapy Top


OVs are being investigated in a myriad of combinations with various treatment modalities in glioma including chemotherapy, targeted therapy, radiation therapy, and novel immunotherapies such as adoptive T cell therapy and checkpoint inhibitors.[41] These are summarized in [Table 1]. This list of clinical trials suggests the breadth of treatment modalities that are being considered in combination use with OVs in glioblastoma. For reasons described below, we believe that dual OV therapy and checkpoint blockade offer the greatest hope of demonstrating sustained survival benefit above the standard of care with an acceptable safety profile.
Table 1: Summary of key clinical trials that include oncolytic viruses and other treatment modalities in glioblastoma

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Oncolytic viruses make the tumor microenvironment more susceptible to checkpoint blockade

The efficacy data available for checkpoint inhibitors in glioblastoma are limited and mixed. Nivolumab failed to demonstrate survival benefit over bevacizumab (an anti-angiogenesis agent) in a Phase 3 trial (CheckMate 143 cohort 2, NCT02017717) of recurrent glioblastoma patient arm.[96] However, in that same study, nivolumab was noted to have more sustained responses with a median duration of response that was twice as long. A Phase 1 trial (NCT02313272) that studied pembrolizumab, hypofractionated stereotactic irradiation, and bevacizumab in recurrent high-grade glioma suggested a trend toward favorable survival when compared to historical controls.[97]

The combination of OVs and checkpoint inhibitors is of particular interest because of their complementary effects on the immune system and nonoverlapping toxicity profiles.[41] Combining immunostimulatory OVs with immune checkpoint blockade suggests a way to boost the antitumor immune response while removing the barriers that impair T cell-mediated tumor killing. We know that clinical responses to immune checkpoint blockade correlate with preexisting antitumor immune responses. With respect to PD-1 blockade, it was observed that tumors devoid of CD8+ T cells were unlikely to respond to PD-1 blockade.[98] Combination immunotherapy designed to attract CD8+ T cells into tumors by altering the immunosuppressive TME, therefore, offers a chance to augment the antitumor activity of PD-1 blockade therapy. As discussed in detail above, OVs recruit TILs into immune-deficient tumors, triggering the immune cascade to further increase T cell recruitment and promote immune cell activation. Viral infection also results in the reactive expression of PD-L1 and other immune checkpoint molecules, a countermeasure that inhibits T cell activation and antitumor immunity and a potential resistance mechanism to oncolysis. When applied in combination, the reactive expression of PD-L1 and other co-inhibitory molecules (e.g., CTLA-4) sensitizes tumors to immune checkpoint blockade. Once fully stimulated, CD8+ T cells can traffic to and infiltrate distant metastatic lesions.

Preclinical and clinical data for oncolytic viruses and checkpoint inhibitors in combination therapy

Preclinical and early clinical trials of combination therapy with OVs and checkpoint blockade have confirmed improved response rates, sensitization of otherwise refractory tumors, and increased levels of activated CD4+ and CD8+ T cells in both primary injected tumors and distant sites. Most of these observations are from nonglioblastoma studies but have yielded valuable insights and proof of concept for combination oncolytic immunotherapy and checkpoint blockade. A preclinical study of NDV in a B16-F10 melanoma model induced the infiltration of tumor-specific CD4+ and CD8+ T cells into both the injected tumor and distant metastases and increased tumor sensitivity to CTLA-4 blockade.[9] In a preclinical model of triple-negative breast cancer, Maraba virus sensitized otherwise refractory tumors to immune checkpoint blockade.[99] A Phase 1b trial of intratumoral T-VEC followed by standard dose ipilimumab in melanoma (n = 19) demonstrated 50% objective response rate, with 44% achieving a durable response of >6 months.[100] A larger subsequent randomized controlled trial to compare combination T-VEC and ipilimumab versus ipilimumab alone enrolled 198 patients with unresectable melanoma.[101] They demonstrated a significant improvement in response rate with combination therapy (38% in combination versus 18% ipilimumab monotherapy). T-VEC in combination treatment with pembrolizumab in a Phase 1b study of 21 patients with advanced melanoma demonstrated a 62% objective response rate and 33% complete response rate.[98] Patients who responded to combination therapy were shown to have increased CD8+ T cells, PD-L1 expression, and IFN-γ gene expression. A larger randomized Phase 1b/2 trial (NCT02263508) is ongoing to evaluate pembrolizumab with or without T-VEC.

Combination therapy of oncolytic viruses and checkpoint inhibitors in glioblastoma

To date, the number of OV and checkpoint inhibitor combination trials is limited. One preclinical study using a GSC-derived orthotopic glioblastoma model employed T-VEC-expressing IL-2 in combination with checkpoint inhibitors targeting PD-1 and CTLA-4.[102] The authors report that curative response was achieved using CD4+ and CD8+ T cells and macrophages. The CAPTIVE/KEYNOTE-192 trial (NCT02798406) is underway to evaluate a single intratumoral injection of DNX-2401 via cannula (initial phase includes n = 12 in three dose cohorts) followed by intravenous pembrolizumab every 3 weeks in recurrent glioblastoma or gliosarcoma. Following the initial phase, up to 36 additional patients will receive a single dose of DNX-2401 (dose to be determined in the initial phase) followed by pembrolizumab every 3 weeks for 2 years or until disease progression.


  Future Direction Top


The number of potential combinations is large, and predicting the most efficacious combination of OV and checkpoint inhibitor is a considerable challenge. It is still early in the field of combination OV and checkpoint inhibition therapy, with initial studies being conducted in other solid tumors such as melanoma and breast cancer. The clinical data to date for OV monotherapy in glioblastoma are promising, with leading candidates (e.g., PVSRIPO and DNX-2401) demonstrating favorable survival compared to historical standards and an acceptable toxicity profile. We expect additional OV agents to demonstrate similar efficacy in a monotherapy setting, but additional head-to-head studies comparing OV monotherapy to other modalities need to be conducted to determine if OVs provide definite survival benefit based on standard of care. Like many monotherapy agents in the past, OVs will likely struggle to translate favorable immunological responses (i.e., increased antigen presentation via APCs and greater T cell trafficking to the TME) into sustained clinical benefit in glioblastoma. In fact, we remain more optimistic about combination OV therapy and checkpoint blockade yielding the most favorable outcomes than either modality alone. This is due to synergies realized through the activation of both the innate (as seen historically with OVs) and adaptive arms (as seen with checkpoint inhibitors but increasingly with OVs) of the immune system. Furthermore, both modalities have been shown to be safe in glioblastoma patients with no documented reports in clinical trials of immune-related or neurotoxic side effects attributable to OVs. Potential drawbacks to combination OV and checkpoint therapy in glioblastoma include inability to overcome multiple immunosuppressive mechanisms despite the mobilization of both arms of the immune system, additive immune-related side effects due to unleashed T cells (due to activity of both OVs and checkpoint inhibitors), and the significant financial burden that co-administration would place on the health-care system.

In the meantime, various research groups continue to improve upon OV design and delivery to target cells. Novel OVs engineered to express checkpoint inhibitory antibodies are under development to allow in situ expression in hopes of minimizing systemic toxicity and enhanced local immune response. One such OV developed from a backbone of Delta-24-RGD and engineered to express the mouse OX40 ligand to increase the recognition of TAAs by immune cells was tested in glioma. The authors report that Delta-24-RGDOX retained the oncolytic potency of the backbone virus and efficiently expressed OX40 ligand on infected cells while inducing higher anti-glioma activity in immunocompetent models.[103] Efforts are additionally focused on engineering viruses with greater potency and immunogenicity, increased tumor selectivity, and improved lytic properties.[27] A novel glioma-selective HSV-1 mutant (rQNestin34.5) was designed with restored ICP34.5 expression under transcriptional control of a synthetic nestin promoter for selective ICP34.5 expression in glioma cells.[104] Replication, cellular propagation, and cytotoxicity of rQNestin34.5 were significantly enhanced in cultured and primary human glioma cell lines compared with control virus and rQNestin34.5 treatment which doubled the life span of test animals.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Kunal Desai and Dr. Anne Hubben declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Dr. Ahluwalia has received consulting fees or honorarium from Prime Education, Prime Oncology, Elsevier, Monteris AstraZeneca, Bristol-Myers Squibb, Abbvie, CBT Pharmaceuticals, Kadmon, VBI Vaccines, Flatiron Health, Varian Medical Systems, Karyopharm Therapeutics. Dr. Ahluwalia has stock/stock options in Mimivax and Doctible. Dr. Ahluwalia has grants received or pending from Novartis, Novocure, Astrazeneca, Abbvie, BMS, Pharamacyclics, Incyte, Merck, Bayer, Mimivax, and Boston Biomedical.



 
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Introduction
Expanding Our Kn...
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Oncolytic Viruses
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