Oncolytic Viruses in Cancer Treatment: a Review

Clinical Review & Education

JAMA Oncology | Review Oncolytic Viruses in Cancer Treatment A Review

Sean E. Lawler, PhD; Maria-Carmela Speranza, PhD; Choi-Fong Cho, PhD; E. Antonio Chiocca, MD, PhD

Supplemental content

IMPORTANCE Oncolytic viruses (OVs) are emerging as important agents in cancer treatment. CME Quiz at Oncolytic viruses offer the attractive therapeutic combination of tumor-specific cell lysis jamanetwork.com/learning together with immune stimulation, therefore acting as potential in situ tumor vaccines. and page 867 Moreover, OVs can be engineered for optimization of tumor selectivity and enhanced immune stimulation and can be readily combined with other agents. The effectiveness of OVs has been demonstrated in many preclinical studies and recently in humans, with US Food and Drug Administration approval of the oncolytic herpesvirus talimogene laherparepvec in advanced melanoma, a major breakthrough for the field. Thus, the OV approach to cancer therapy is becoming more interesting for scientists, clinicians, and the public. The main purpose of this review is to give a basic overview of OVs in clinical development and provide a description of the current status of clinical trials.

OBSERVATIONS In 2016 approximately 40 clinical trials are recruiting patients, using a range of OVs in multiple cancer types. There are also many more trials in the planning stages. Therefore, we are now in the most active period of clinical OV studies in the history of the field. There are several OVs currently being tested with many additional engineered derivatives. In OV clinical trials, there are a number of specific areas that should be considered, including viral pharmacokinetics and pharmacodynamics, potential toxic effects, and monitoring of the patients’ immune status. Clinical development of OVs is increasingly Author Affiliations: Harvey Cushing focused on their immune stimulatory properties, which may work synergistically with Neurooncology Laboratories, immune checkpoint inhibitors and other strategies in the treatment of human cancer. Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, CONCLUSIONS AND RELEVANCE Oncolytic viruses are an active area of clinical research. The Massachusetts. ability of these agents to harness antitumor immunity appears to be key for their success. Corresponding Author: E. Antonio Combinatorial studies with immune checkpoint blockade have started and the results are Chiocca, MD, PhD, Harvey Cushing awaited with great interest. Neurooncology Laboratories, Department of Neurosurgery, Brigham and Women’s Hospital, JAMA Oncol. 2017;3(6):841-849. doi:10.1001/jamaoncol.2016.2064 Harvard Medical School, Published online July 21, 2016. 75 Francis St, Boston, MA 02115 ([email protected]).

ncolytic viruses (OVs) comprise a diverse group of bio- neered variants with tumor-selective replication. However, it has logic agents with potential as cancer therapeutics. always been appreciated that an immune component is important O Numerous clinical trials are under way or have been and may be critical for the therapeutic efficacy of this approach. completed using this approach. In 2015, in a milestone for the Indeed, OVs are now broadly considered as immunotherapy field, talimogene laherparepvec became the first OV to gain US agents for which effectiveness in patients depends on activation Food and Drug Administration (FDA) approval in the United of host antitumor immune responses.4-6 States.1 However, the use of viruses for cancer treatment is not Early clinical trials7-9 of OVs showed encouraging safety pro- new. Throughout the 20th century, case studies and small trials of files, even at high doses, with some promising responses, evidence various viruses in cancer therapy were reported.2 These investiga- of intratumoral viral replication, and immune cell infiltrates. The field tions conducted with small numbers of patients used wild-type is now gaining traction after the report of significant benefits in a and often crudely prepared viral isolates, and it was not until the large randomized phase 3 clinical trial of the engineered immunos- 1990s that the era of genetic engineering of viruses to enhance timulatory OV talimogene laherparepvec in patients with ad- their oncolytic potential began. The first reported3 genetically vanced melanoma10-12 and its subsequent approval in the United engineered OV was based on herpes simplex virus type 1 (HSV1). States and European Union. Many OVs are now under investiga- This development was rapidly followed by many studies2 illustrat- tion in advanced trials, with some encouraging data.13 Thus, after 2 ing the effectiveness of this approach using a diverse range of decades of clinical trials in humans with cancer, OVs are emerging viruses and tumor models. The main focus of the field during the as therapeutic agents in oncology. This review summarizes recent early development of OVs was to identify viruses or their engi- progress in this area and describes ongoing clinical trials.

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Figure. Generalized Overview of Mechanisms of Action of Oncolytic Viruses.

CD4 cells

(Helper) NK cells CD8 cells (Cytotoxic)

(Cytotoxic)

Virus Dendritic cells PAMPs and DAMPs

It is thought that most oncolytic viruses function through a combination of tumor cell lysis and IFN receptor stimulation of innate and adaptive Toll-like receptors immunity through presentation of Tumor cell viral and tumor antigens. JAK-STAT Cytokines and IFN DAMPs indicates damage-associated molecular patterns; IFN, interferon; MYD 88 TRIF PAMPs and DAMPs JAK-STAT, Janus kinase–signal IFN transducer and activator of NFKβ IRF3 Cytokine and IFN transcription; MYD 88, myeloid IRF7 Terminate protein receptor differentiation primary response synthesis, promote gene 88; NFKβ, nuclear factor κB; necrosis and apoptosis Cytokines T-cell receptor NK, natural killer; IFN PAMPs, pathogen-associated (limit viral molecular patterns; RF, Interferon Decrease viral replication spread) regulatory factor; and TRIF, TIR (toll/II-1 receptor)–domain-containing adapter-inducing interferon-β.

come immunosuppression in the tumor microenvironment and Mechanisms of OV Action promote antitumor immunity. The success of this approach is influ- enced by factors including pre-existing antiviral and antitumor im- A general mechanistic understanding of OV action is emerging in munity and incorporation of immune stimulatory transgenes. which therapeutic efficacy is achieved by a combination of selective tumor cell killing and establishment of antitumor immunity (Figure). Immune stimulation is caused by release of cell debris and OVs as Cancer Therapeutics viral antigens in the tumor microenvironment. Tumor selectivity in OV therapy is driven by several factors. The first of these is cellular General Properties entry via virus-specific, receptor-mediated mechanisms. A specific A wide range of viruses with diverse properties are under investi- viral entry receptor is often highly expressed on tumor cells. How- gation clinically (eTable 1 in the Supplement). Oncolytic viruses range ever, there are also efforts to improve tumor selectivity by retarget- in size and complexity from large, double-stranded DNA viruses such ing OVs to enter cells through tumor-specific receptors. as vaccinia (190 kilobase [kb])17 and HSV1 (152 kb)18 to the tiny par- Second, rapid cell division in tumor cells with high metabolic and vovirus H1 (5-kb linear, single-stranded DNA).19 Oncolytic viruses replicative activity may support increased viral replication compared cause cell lysis by various means during their life cycle, with the ex- with normal quiescent cells. In addition, tumor-driver mutations spe- ception of retrovirus, which can be rendered lytic by toxic trans- cifically increase the selectivity of virus replication in tumor cells.14,15 gene expression.20 Third, many tumor cells have deficiencies in antiviral type I inter- There are a few wild-type viruses in clinical use. These include feron signaling, therefore supporting selective virus replication.16 Vi- reovirus, a human virus with low pathogenicity21,22; coxsackievi- ralreplicationwithinthetumormicroenvironmentleadstoinnateand rus, which is structurally related to polio virus and causes several adaptive immune activation. This activation limits virus spread; how- symptoms in humans23,24; and viruses with nonhuman hosts, in- ever, the presence of virus together with cell lysis, with release of tu- cluding Newcastle disease virus (avian),25 parvovirus H1 (rat),19 and mor antigens and danger-associated molecular patterns, may over- vesicular stomatitis virus (VSV) (insects, horses, cows, and pigs).26

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Oncolytic vaccinia and measles are derived from vaccine strains.27 lation via GM-CSF as well as the use of a clinical HSV1 strain back- There are documented cases28 of wild-type measles viruses infec- bone, which may allow improved replication in patients compared tions and tumor regression. Most measles OVs are based on the at- with other oHSVs built on a laboratory HSV1 strain background. tenuated Edmonston measles vaccine strain (MVEdm), which has an excellent safety record after decades of use in humans.29 Adenovirus Each type of OV has a specific cellular entry mechanism (eTable Oncolytic adenoviruses were some of the earliest OVs to enter clini- 1intheSupplement), which can affect the efficacy.For example, po- cal trials. The history of adenovirus as an oncolytic agent has been lio virus enters cells through CD155 (the polio virus receptor), which well reviewed.57 An E1A/E1B-deleted virus (ONYX015) has been ex- is abundantly expressed in many tumor types.30 The adenovirus en- tensively tested and approved for treatment of head and neck can- try receptor, CAR (coxsackie and adenovirus receptor), is ex- cer in China under the name H101.58 An integrin-binding retar- pressed variably in tumor cells; therefore, adenovirus retargeting to getedadenovirus,Δ24RGD(DNX2401),hasbeenexaminedinclinical other cellular receptors to enhance tumor cell binding has also been trials42,59 in which the maximum tolerated dose (MTD) was not widely investigated.31 reached and some responses were observed. Trials are also under Many OVs have been engineered to improve tumor cell selectiv- way with enadenotucirev,which is built on the Ad11/3 serotype rather ity. Herpes simplex virus type 1 has strong lytic properties32 and sev- than the common Ad5 serotype, rendering it less susceptible to rapid eral variants have been constructed, often via deletion of the ICP34.5 neutralization in the bloodstream.43 neurovirulence and ICP6 (UL39) (ribonucleotide reductase) genes. ICP6 is necessary for generation of the nucleotide pool needed for vi- Vaccinia Virus ralreplicationinnormal,quiescentcells.DeletionofICP6providesrep- At the present time, JX-594 (Pexa-Vec) is being tested in multiple licativeselectivityforcellswithinactivationofthep16INK4A tumorsup- tumor types.47,48,60 Pexa-Vec is based on the Wyeth vaccinia vac- pressor,oneofthemostcommondeficitsincancer.14 Similarly,reovirus cine strain engineered to express human GM-CSF and has been has oncolytic selectivity to cells with activation of ras signaling.15 In tested in more than 300 patients. It is well tolerated and increased the case of adenovirus, replication occurs in S phase, and the wild- survival in patients with liver cancer after intravenous injection.48 type virus encodes a protein (E1A) that functions via retinoblastoma Prostvac, a prime-boost regimen targeting prostate-specific anti- signaling to promote S-phase entry.33,34 Because cancer cells typi- gen in prostate cancer, uses engineered vaccinia as a primary im- callypossessretinoblastomapathwaymutationsandenrichedS-phase munotherapy, followed by boosters using fowlpox virus. Both vec- populations, and to promote safety and prevent replication in nor- tors express prostate-specific antigen and a panel of costimulatory malcells,theE1Agene(GenBankNC_001405.1)hasbeendeletedfrom molecules: ICAM-1 (intercellular adhesion molecule 1), B7.1, and LFA3. oncolytic adenovirus. Tumor selectivity and potency may also be en- Subcutaneous injection of Prostvac initiates an antitumor immune hanced by direct intratumoral injection of high viral loads. However, response, is well tolerated, and significantly increased overall sur- the ability of some OVs, such as vaccinia virus, to spread systemically vival in phase 2 trials.49 This dual virus approach overcomes the rapid in the bloodstream may facilitate treatment of metastases, as appearance of neutralizing antibodies against vaccinia. A phase 1 demonstrated in preclinical models.17 dose-escalation trial of Prostvac in combination with ipilimumab showed no additional toxic effects and some promising responses (MTD was not reached).61 Clinical Application Measles Virus A diverse range of viruses has been investigated as potential can- Measles causes fusogenic syncytia formation and cell death.62 A cer therapeutics. The individual characteristics of OVs currently in measles virus expressing the human sodium/iodide symporter clinical trials are summarized below and outlined in Table 1. SLC5A5 (MV-NIS) is currently in a range of clinical trials63; MV-NIS allows imaging of infected cells and monitoring of treatment pro- Herpesvirus gression as well as radiovirotherapy with I 131–labeled sodium io- Oncolytic viruses derived from engineered HSV1 (oHSVs) have been dide. Clinical data have confirmed safety and demonstrated imaging tested widely in patients. A major focus of the field has now moved of virus infection and tumor regression with this approach.46 to talimogene laherparepvec, an immunostimulatory oHSV that expresses granulocyte-macrophage colony-stimulating factor Coxsackievirus (GM-CSF).55 Intratumoral injection of talimogene laherparepvec led Coxsackievirushasoncolyticpropertiesincancercelllines23 andleads to significant improvement in durable response rate (DRR) in pa- to a robust immune response.64 Wild-type coxsackievirus A21 is in tients with melanoma (16.3%) compared with controls (2.1%). Ef- clinical trials under the name Cavatak. Numerous trials are ongoing fects were most pronounced in patients with stage IIIB, IIIC, IVM1a, and are built on favorable 2015 phase 2 data in stage IIIC and stage or treatment-naive disease.10,11 Tumor regression was seen in dis- IV melanoma. One study65 reported a preliminary DRR of 21% with tant noninjected lesions, suggesting the establishment of systemic regression of distant noninjected lesions. antitumor immunity. Talimogene laherparepvec is derived from a clinical HSV1 strain (JS1) deleted for ICP34.5 and ICP47, which nor- Polio Virus mally acts to block HSV1 major histocompatibility class I antigen pre- Polio virus has demonstrated oncolytic properties in preclinical sentation on the infected cell surface resulting in immune evasion.56 studies66 andhasattractedattentionowingtoinitialresultsinbraintu- The reason for the success of this agent is likely a combination of the mors and wide media exposure. These studies were performed using choice of melanoma (an immunogenic tumor) and immunostimu- PVS-RIPO, which has been engineered to abolish the neurovirulence

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Table 1. Properties of Oncolytic Viruses in Current Oncology Clinical Trials

Virus Modification Published Clinical Studiesa Herpesvirus HSV-1716 ICP34.5 deletion Melanoma (exploratory),35 single intratumoral injection; tumor shrinkage, necrosis replication, safety; high-grade glioma (phase 1 trial),36 resection cavity injection; safety and responses reported HF10 UL56 deletion; single copy of UL52 Pancreatic cancer (phase 1),37 multiple intratumoral injections; safe with potential responses (stable disease) reported G207 ICP34.5 deletion; UL39 disruption Recurrent malignant glioma (phase 1),38 resection cavity injection plus irradiation; safety and some radiographic responses Talimogene ICP34.5 deletion; US11 deletion; human Advanced melanoma (phase 3),10 intralesional talimogene laherparepvec laherparepvec GM-CSF insertion vs subcutaneous GM-CSF; 16.3% DRR; safety established; effects most pronounced in patients with stage IIIB, IIIC, or IVM1a disease Adenovirus CG0070 E3 deletion; GM-CSF insertion Nonmuscle invasive bladder cancer (phase 1)39; viral replication suggested, minor toxicity; complete response rate 48.6% and median response duration 10.4 mo ICOVIR5 Modified DNX-2401-E2F promoter opimitized Diffuse intrinsic pontine glioma (exploratory); mesenchymal stem cell loaded virus; intra-arterial injection, safe40 VCN-0141 PH20 hyaluronidase insertion; RGD targeting None reported DNX-2401 Δ24RGDinsertion Recurrent malignant gynecologic disease (phase 1)42; intraperitoneal delivery; established safety, feasibility, and potential antitumor response; MTD not reached Enadenotucirev43 Chimeric Ad11/3 group B None reported (ColoAd1) Ad5-yCD/ Ad serotype 5; insertion of IL12; insertion None reported mutTKSR39rep- of yeast cytosine deaminase; insertion of hIL1244 TKSR39 (thymidine kinase mutant) Ad5PTD(CgA- Ad serotype 5; E1B deleted; conditional None reported E1AmiR122)45 neuroendocrine E1A expression with miR122 in UTR; PTD motif in capsid Measles Virus MV-NIS Edmonston vaccine measles strain; insertion of Drug-resistant ovarian cancer (phase 1)46; intraperitoneal delivery sodium-iodide symporter every 4 wk for 6 cycles; well tolerated; promising survival data, evidence for immune stimulation; radioactive iodine 123 uptake observed by PET/CT and associated with longer progression-free survival Vaccinia Virus PexaVec (JX594) TK deletion; GM-CSF insertion Advanced hepatocellular carcinoma (randomized phase 2)47; dose-related response; oncolytic and immunotherapeutic effects observed; treatment-refractory colorectal cancer (phase 1b)48; multiple dosing; no toxic effects and MTD not reached; 10 patients (67%) had radiographically stable disease Psostvac Expresses PSA; expresses TRICOM (3 costimulatory Castration-resistant prostate cancer (phase 1 and numerous phase 2 genes); administered with a subsequent fowlpox [reviewed in Singh et al49]); well tolerated, encouraging survival data, boost; engineered to express PSA and TRICOM combined with various agents including radiotherapy and docetaxel; (artificial gene construct) phase 3 trial completed in 2015 (results not available) Reovirus Reolysin Wild-type virus, serotype 3 Advanced cancer (phase 1)50; multiple intravenous injections; safe and well tolerated; evidence of response, particularly in patients with viral shedding Metastatic melanoma (phase 2)51; multiple intravenous injections; well tolerated; no objective responses Polio Virus PVS-RIPO52 Attenuated polio virus Sabin type 1; IRES replaced None reported with HRV2 IRES to prevent neurotoxic side effects Coxsackievirus Cavatak53 Wild -type coxsackievirus A21 None reported Vesicular Stomatitis Virus VSV-hIFNβ Insertion of IFNβ None reported Parvovirus ParvOryx19 Parvovirus H1 (wild-type) None reported Retrovirus Toca51153,54 Murine leukemia virus; insertion of yeast None reported cytosine deaminase Abbreviations: CT, computed tomography; DRR, durable response rate; RGD, arginine-glycine-aspartate; UTR, untranslated region; VSV, vesicular GM-CSF, granulocyte-macrophage colony-stimulating factor; HSV, herpes stomatitis virus. simplex virus; IFNβ, interferon β; IRES, internal ribosome entry site; a The clinical trials listed are not exhaustive but provide representative MTD, maximum tolerated dose; PET, positron emission tomography; examples of published studies or the most advanced studies published so far. PSA, prostate-specific antigen; PTD, protein transduction domain;

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ofthenativevirus.PVS-RIPOisacytotoxicandimmunostimulatoryvi- nations, safety remains a concern. Despite engineering for tumor cell rus with preliminary reports of durable radiographic and clinical re- specificity, there is the possibility of off-target effects, and genetic sponsesinglioblastoma.67 Basedonrecentphase1data,PVS-RIPOwas manipulation may result in unexpected toxic effects. Other con- designated as a breakthrough therapy in recurrent glioblastoma.68 cerns include virus mutation, evolution, and recombination; cytotoxic gene products; and viral transmissibility. Oncolytic HSVs have Retrovirus retained their native thymidine kinase gene, which facilitates virus Retroviruses are potentially useful agents because they readily in- replication and is also the target of the antiviral drug ganciclovir. The fect mitotic cells and rapidly spread, although without necessarily retention of thymidine kinase allows the possibility of controlling in- causing cell lysis.20 Toca511 is based on murine leukemia virus en- fection and is seen as an important advantage in terms of safety.Po- gineered to express the yeast enzyme cytosine deaminase, which tential safety concerns are reflected in clinical trial criteria, which do converts 5-fluorocytosine to the toxic metabolite 5-fluorouracil. In not allow inclusion of immunocompromised patients or those with studies53,54 of mice with implanted gliomas, Toca511 therapy re- active viral infections. sulted in long-term survival and systemic antitumor immunity mediated by memory T cells. Toca511 is currently in a phase 2/3 clinical Toxic and Adverse Effects trial for malignant glioma and has shown promising interim results.69 Local delivery of OVs is generally well tolerated. The most common adverse effects reported are mild flulike symptoms, which may be Reovirus more severe after systemic administration, and local reaction at the Reovirus usually produces mild symptoms in humans and can read- injection site. These reactions can be reduced by acetaminophen ily enter human cells and activate innate and adaptive immune administration before treatment.73 systems.21,22 Oncolytic reovirus is marketed as Reolysin and has been examined in clinical trials alone and in combinations in a range of Dose cancers.70 Reolysin was given orphan drug status for the treat- In contrast to results in conventional drug clinical trials, many OVs ment of malignant glioma by the FDA in 2015. do not reach an MTD owing to the concentration of virus stock that is possible to achieve or very high tolerance for the virus. Maximum Parvovirus H1 tolerated dose may need to be re-established for trials using novel Parvovirus H1 causes tumor-selective cell killing that is thought to therapeutic combinations. result from a combination of toxic effects of the viral gene product NS1 as well as lytic viral replication.19 A trial of wild-type parvovirus Viral Pharmacokinetics, Pharmacodynamics, H1 (ParvOryx) in recurrent glioblastoma has been completed and this and Biomarkers agent is currently in trials for metastatic pancreatic cancer. Effectiveness of OV therapy is monitored by standard approaches, including imaging and tumor-specific biomarkers. In addition, viral Vesicular Stomatitis Virus pharmacokinetics and pharmacodynamics (shedding, viremia, rep- Vesicular stomatitis virus selectivity is dependent on deficient in- lication, genomes, and viral load) are frequently included in OV trials. terferon signaling.26,71 An engineered VSV variant overexpressing These approaches allow inpatient tracking of viral fate in patients. interferon β is currently in a clinical trial for liver cancer. It is thought Additional viral pharmacokinetic and pharmacodynamic variables that interferon β may act synergistically with VSV by protecting nor- include analysis of intratumoral viral replication and immune infil- mal cells from infection and causing tumor cell–specific destruc- trates by immunohistochemistry and circulating immune cell sta- tion and antitumor immune responses. tus. In multi-institutional trials, it may be optimal to use centralized testing to ensure reproducibility. Newcastle Disease Virus Wild-type Newcastle disease virus has oncolytic effects in a variety Resistance Mechanisms of tumor types through syncytia formation and apoptosis.25 Early One of the most fascinating features of OV therapy is the battle be- clinical trials showed promise and safety72; however, to our knowl- tween the virus and the host, which is vital in determining the thera- edge, no trials involving this virus are presently recruiting patients. peutic outcome. The major resistance mechanisms in OV therapy re- sultfromtotheabilityofthehosttorapidlyshutdownviralreplication. Host antiviral mechanisms include the presence of neutralizing antibodies and the rapid mobilization of innate immune cells in response Considerations for OV Clinical Trials to OVs. Cells recruited after OV treatment include neutrophils, natu- With the emergence of increasing numbers of OVs and combinato- ral killer cells, macrophages, and microglia in the brain.74,75 Innate im- rial studies in the clinical trial arena, it is worth considering issues in- munity is a major resistance mechanism, which can restrict the abil- volved in clinical trial design and execution. Areas evolving as the ity of the virus to replicate and spread within tumors. The existence field develops are delivery, viral pharmacokinetics and pharmaco- oftheseinnateimmuneresistancemechanismshasledtotheideathat dynamics, and biomarkers. inhibition of immune responses early in treatment may be benefi- cial, and immunosuppressants such as cyclophosphamide promote Safety viral replication.76 However, this approach should be treated with Although mortality has been reported occasionally, published trial caution for safety reasons and also to ensure that the ultimate anti- data have not shown significant general safety issues. However, as tumor response is not blocked. Studies77 have shown that vascular OVs with greater potency are developed and used in novel combi- endothelial growth factor also plays an important, although virus-

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dependent, role in OV action. In the case of oHSV, vascular endothe- There is presently a clear opportunity to investigate the im- lial growth factor can limit efficacy, potentially because of recruit- pact of combining immunostimulatory OVs with immune check- ment of myeloid cells into the tumor microenvironment. Conversely, point blockade in cancers, effectively accelerating the antitumor im- vascular endothelial growth factor sensitizes tumor vasculature to mune response while removing the barriers that may otherwise vaccinia and VSV via a novel mechanism.78 impair T-cell–mediated tumor killing. Indeed, talimogene laherparepvec is now in a clinical trial in combination with ipilimumab. Cur- Delivery rently, pembrolizumab (anti-PD1) and ipilimumab are being tested Therapeutic delivery of OVs is dependent on virus and tumor type. in combination with talimogene laherparepvec, Cavatak, and Reo- Most often, OVs are injected directly into the tumor site. For ex- lysin (eTable 2 in the Supplement). These combinations may allow ample, tumors of the brain are treated using local delivery by mul- greater response rates in immune-sensitive tumors, such as mela- tiple injections at a single time point (during surgery). Other, more noma, and may render checkpoint inhibitor–resistant tumors more accessible tumors can be treated with multiple doses and multiple sensitive to treatment. The number of potential combinations of im- injection sites over time. The experience with talimogene laherpar- mune therapies is enormous, and an important question is whether epvec provides an indication that OV administration at a single tu- preclinical studies can accurately predict which of these combina- mor site can lead to regression of distant tumors, implying that the tions will be the most efficacious in humans.84 Overall, further work induction of local antitumor immunity can have systemic effects. In- is required to evaluate the possible direct effects of each type of OV travenous injection is also commonly used and allows systemic ad- on immune checkpoint mechanisms and determine the best ministration to multiple tumor sites. Cellular carriers may also be combinations for future trials. used, which may protect the virus from recognition by the host The creation of novel OVs expressing checkpoint inhibitory an- immune system before reaching the tumor.79 tibody molecules is under way in many laboratories. This development would allow in situ expression, avoiding adverse effects from Ongoing OV Trials systemic delivery of the antibody,and increase the local immune re- A search of clinicaltrials.gov performed April 1, 2016, listed approxi- sponse against the tumor cells. An engineered oncolytic adenovi- mately 40 clinical trials currently recruiting patients for treatment rus Delta-24,RGDOX (DNAtrix Inc) has been shown85 to enhance with OVs (summarized in Table 2; full list in eTable 2 in the Supple- antitumor immune responses through expression of OX40L, an ment). There is representation from multiple countries across 4 con- immune checkpoint costimulatory ligand. tinents, with most trials being conducted in the United States. These trials have been almost exclusively performed in adults, with stud- Other OVs in Development ies in young adults and pediatric patients just beginning.73 Most trials Many laboratories are developing improved OVs at the preclinical are early-phase, dose-finding, and exploratory studies, although in- level. In addition to immune stimulation, efforts are being made to creasing numbers of late-phase trials are anticipated. Trials increas- improve virus potency and tumor targeting. For example, in the past ingly incorporate viral pharmacokinetics and pharmacodynamics, few years, seed sequences of differentially expressed microRNAs and a consistent feature is monitoring of the immune response to have been incorporated into OVs to increase tumor cell selectivity.86 virus and tumor. Few viruses in the present trials express human This strategy can be adapted to different viruses and may provide a transgenes. Based on encouraging preclinical data, numerous com- safer and more efficient way to increase virus efficacy by reducing bination studies are under way using small molecules and chemo- collateral damage to healthy cells. At present, one clinical trial on therapy.As described below,most trials involve combination therapy adenovirus Ad5PTD (CgA-E1AmiR122)45 uses miR-122 to control E1A with immune checkpoint blockade. expression to ensure tumor selective replication. It is also recognized that improved tumor cell lysis may be necessary for therapeutic efficacy. It is thought that this improvement Immune Therapy OV Combinations can serve the dual role of shrinking tumors and provoking greater antitumor immune responses via release of tumor antigens and dan- Recently, cancer immunotherapies have gathered an unprec- ger signals. A wide range of next-generation OVs are in preclinical edented level of interest owing to newly FDA-approved immuno- development with improved lytic properties. For example, logic treatments based on targeting immune checkpoint inhibition rQNestin34.5 was developed for use in brain tumors in which ICP34.5 pathways that can relieve T-cell exhaustion in the tumor expression (deleted in other oHSVs) is restored under transcrip- microenvironment.80,81 Ligands that activate checkpoint path- tional control of the nestin promoter to drive expression selec- ways and cause T-cellexhaustion are often expressed by tumor cells tively in glioma stem cells.87 Other combinations have also been or within the tumor microenvironment. These ligands include PD-1, reported,88 including histone deacetylase inhibition, which PD-L1, PD-L2, and many others. Multiple blocking antibodies against promotes oncolytic herpesvirus replication in animal models. these molecules are now in clinical trials and have shown low toxic effects and durable responses in clinical studies82 in various solid tumors. In addition, combinations of multiple checkpoint inhibitors ap- Conclusions pear to improve outcomes in melanoma compared with single checkpoint inhibitors. Phase 3 studies in advanced melanoma show83 that Recent clinical trials have shown great promise for immune thera- patients treated with the combination of ipilimumab (anti-CTLA4) pies in cancer treatment. However, the ability of tumor cells to evade and nivolumab (anti-PD1) have an 11.5-month median survival the immune system remains a major challenge. After years of devel- compared with 2.5 months for ipilimumab alone. opment and study, OVs are showing promise as immunotherapeutic

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Table 2. Selected Open Oncolytic Virus Trialsa

Secondary Virus Delivery, Combination Phase/Sponsor Tumor Type Primary Measures Measuresb Location Herpesvirus HSV-1716 Intratumoral, single agent Phase 1/ Pediatric Recurrent pediatric MTD Efficacy, United States Brain Tumor brain/AA, AO, GBM, imaging, viral Consortium GC, GS PK/PD, immune response HF10 Intratumoral, ipilimumab Phase 2/Takara Bio, Malignant melanoma Efficacy Immune United States Inc response T-VEC Intratumoral, single agent Phase 2/Amgen Melanoma Efficacy, intratumoral Safety, response Europe (unresected) CD8+ T cells measures, correlations with CD8+ Ipilimumab Intratumoral, with/without Phase 2/Amgen Melanoma Safety/tolerability, Additional Germany T-VEC (unresected) efficacy safety; additional efficacy Adenovirus VCN-01 Intravenous (single), Phase 1/VCN Advanced solid Safety/tolerability Efficacy, viral Spain with/without Biosciences, S.L. tumors PK/PD gemcitabine/abraxane DNX-2401 Intratumoral, with/without Phase 1b/DNAtrix, Recurrent brain, Efficacy (MRI imaging) Efficacy, safety, United States interferon-γ Inc. GBM, GS immune response, QoL Enadenotucirev Intravenous, pembrolizumab Phase 1/Psioxus Colorectal cancer, MTD, safety Viral PK/PD, United States Therapeutics Ltd bladder, SCCHN, antitumor salivary gland cancer activity Measles Virus MV-NIS Intraperitoneal, Phase 1/2/Mayo Recurrent ovarian MTD, safety, efficacy Tumor United States mesenchymal stem cell Clinic response, immune response, viral PK/PD Vaccinia Virus Sorafenib Intratumoral (multiple), Phase 3/SillaJen, Inc Hepatocellular Efficacy Additional United States, with/without PexaVec carcinoma efficacy, safety New Zealand Prostvac Subcutaneous vs no Phase 2/National Recurrent prostate Decreased PSA rise United States treatment Cancer Institute cancer Reovirus Reolysin Intravenous, pembrolizumab Phase 1b/Oncolytics Pancreatic Safety Efficacy, United States and chemotherapy Biotech adenocarcinoma immune response Polio Virus PVSRIPO Intracerebral Phase 1/Duke Recurrent GBM MTD Efficacy United States (convection-enhanced University Medical delivery), single agent Center Coxsackie Virus Cavatak Intratumoral, ipilimumab Phase 1/Viralytics Advanced melanoma Safety, tolerability Efficacy United States Cavatak Intratumoral, Phase 1/Viralytics Advanced melanoma Safety, tolerability United States pembrolizumab Other Viruses TOCA FC/TOCA 511 Intratumoral (single dose), Phase 2/3/Tocagen Brain, recurrent Efficacy (comparison United States single agent Inc GBM/AA with chemotherapy) Abbreviations AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; term] and EU clinical trials register). GBM, glioblastoma multiforme; GC, gliomatosis cerebri; GS, gliosarcoma; b Efficacy includes overall response rate, progression-fee survival, overall HSV, herpes simplex virus; MRI, magnetic resonance imaging; MTD, maximum survival, durable response rate, time to progression, and radiographic tolerated dose; PK/PD, pharmacokinetics/dynamics; PSA, prostate-specific response. Viral PK/PD includes replication, shedding, and replication. Immune antigen; QoL, quality of life; SCCHN, squamous cell carcinoma of the head and response includes antiviral immunity and measurement of circulating immune neck; TILS, serum cytokines, intratumoral PD1-expressing cells, neutralizing cells. antibodies. a Recruiting as of December 30, 2015 (clinicaltrials.gov [oncolytic virus as search

agents.Becausetheseviruseshaveco-evolvedwithhumans,theypro- ther advances in patient outcomes. Given the increasing array of OVs vide unique ways to stimulate immune attack, which may overcome indevelopment,aswellasotherimmunestimulatoryagents,thechal- the formidable interactions of tumor cells with the immune system. lenge in the field will be to successfully identify the OVs and combi- Improved viruses, in terms of tumor selectivity and potency, and op- nations that will be the most effective for patients, particularly those timized combinations with other immune therapies may lead to fur- with tumors that are resistant to other therapies.

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ARTICLE INFORMATION malignant gliomas, in the adjuvant setting. 26. Lichty BD, Power AT, Stojdl DF, Bell JC. Accepted for Publication: April 26, 2016. Mol Ther. 2004;10(5):958-966. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med. 2004;10(5):210-216. Published Online: July 21, 2016. 9. Kemeny N, Brown K, Covey A, et al. Phase I, doi:10.1001/jamaoncol.2016.2064. open-label, dose-escalating study of a genetically 27. Kirn DH, Thorne SH. Targeted and armed engineered herpes simplex virus, NV1020, in oncolytic poxviruses: a novel multi-mechanistic Author Contributions: Dr Lawler had full access to subjects with metastatic colorectal carcinoma to therapeutic class for cancer. Nat Rev Cancer. 2009; all of the data in the study and takes responsibility the liver. Hum Gene Ther. 2006;17(12):1214-1224. 9(1):64-71. for the integrity of the data and the accuracy of the data analysis. 10. Andtbacka RH, Kaufman HL, Collichio F, et al. 28. Bluming AZ, Ziegler JL. Regression of Burkitt’s Study concept and design: Lawler, Speranza, Talimogene Laherparepvec improves durable lymphoma in association with measles infection. Chiocca. response rate in patients with advanced melanoma. Lancet. 1971;2(7715):105-106. Acquisition, analysis, or interpretation of data: J Clin Oncol. 2015;33(25):2780-2788. 29. Russell SJ, Peng KW. Measles virus for cancer Lawler, Cho, Chiocca. 11. Kaufman HL, Kim DW, DeRaffele G, Mitcham J, therapy. Curr Top Microbiol Immunol. 2009;330: Drafting of the manuscript: All authors. Coffin RS, Kim-Schulze S. Local and distant 213-241. Critical revision of the manuscript for important immunity induced by intralesional vaccination with 30. Hogle JM. Poliovirus cell entry: common intellectual content: Lawler, Cho, Chiocca. an oncolytic herpes virus encoding GM-CSF in structural themes in viral cell entry pathways. Annu Obtained funding: Chiocca. patients with stage IIIc and IV melanoma. Ann Surg Rev Microbiol. 2002;56:677-702. Administrative, technical, or material support: All Oncol. 2010;17(3):718-730. 31. Mathis JM, Stoff-Khalili MA, Curiel DT. Oncolytic authors. 12. Lawler SE, Chiocca EA. Oncolytic Study supervision: Lawler, Chiocca. adenoviruses—selective retargeting to tumor cells. virus–mediated immunotherapy: a combinatorial Oncogene. 2005;24(52):7775-7791. Conflict of Interest Disclosures: Dr Chiocca is a approach for cancer treatment. J Clin Oncol. 2015; member of the scientific advisory boards of 33(25):2812-2814. 32. Cunningham AL, Diefenbach RJ, Miranda-Saksena M, et al. The cycle of human Alcyone Lifesciences Inc, Tocagen Inc, and NanoTx, 13. Pol J, Bloy N, Obrist F, et al. Trial watch: with financial compensation, as well as StemGen herpes simplex virus infection: virus transport and oncolytic viruses for cancer therapy. immune control. J Infect Dis. 2006;194(suppl 1): and DNATrix, with no financial compensation. Oncoimmunology. 2014;3:e28694. No other disclosures are reported. S11-S18. 14. 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