March 2017, Vol. 6, No. 1
Talimogene Laherparepvec (T-VEC) as Cancer ImmunotherapyMelanoma
Dr Kaufman is the Chief Surgical Officer and Associate Director for Clinical Science at Rutgers Cancer Institute of New Jersey. He is a leading authority on tumor immunotherapy for the treatment of melanoma and has published more than 400 peer-reviewed scientific papers, books, review articles, and abstracts. He serves on many editorial boards, is a member of numerous professional societies, and has been appointed to the Board of Directors of several professional and academic organizations.
Melanoma is a cancer of melanocytes, which are found throughout the skin and mucous membranes. There were approximately 76,380 new cases of melanoma diagnosed in 2016, with an estimated 10,130 deaths attributed to the disease.1 Melanoma is an aggressive cancer that can be managed with surgery and/or radiation therapy in the early stages. However, until recently, there were few options available to treat patients who were diagnosed with metastatic disease.2 Fortunately, advances in targeted therapy and immunotherapy have revolutionized the clinical management of patients with metastatic melanoma. Immunotherapy, in particular, has been associated with a significant improvement in overall survival (OS), especially when it is used in combination approaches. Although predictive biomarkers of therapeutic response have not been validated, there are hints that patients with tumors presenting with large numbers of infiltrating lymphocytes, a more prominent interferon-gamma gene signature, high expression of the programmed death ligand 1 (PD-L1) receptor, or a high mutation burden may be more likely to respond to immunotherapy.3 Although it is still unclear why some melanomas may harbor these features, this information suggests that therapeutic strategies that promote influx of T-cells and induce interferon-gamma release, which can promote PD-L1 expression, and agents that increase mutation burden should remain a high priority in terms of clinical development and integration into therapeutic regimens.
Oncolytic viruses represent an attractive option for promoting tumor immunotherapy based on their ability to selectively target and lyse neoplastic cells, induce interferon-gamma production, and stimulate systemic host immune responses. Talimogene laherparepvec (T-VEC; Imlygic and previously known as OncovexGM-CSF) is an attenuated herpes simplex virus type 1 (HSV-1) derived from the JS1 strain that preferentially infects and kills cancer cells.4 Additionally, it has been engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF) after infection, which enhances therapeutic activity by fostering systemic antiviral and, theoretically, antitumor responses.5
In the clinic, T-VEC is delivered via intratumoral injection, and it has been shown in a phase 1 trial to be safe in patients with melanoma, breast cancer, head and neck cancer, and gastrointestinal malignancies.6 Subsequent clinical trials have further supported the clinical benefit of T-VEC, including a single-arm phase 2 trial and the randomized phase 3 OPTiM trial that both focused on treating patients with surgically unresectable malignant melanoma.7,8
Given the improvement in objective and durable response rates and progression-free survival (PFS) observed in these studies, T-VEC was approved by the US Food and Drug Administration for the treatment of advanced melanoma in October 2015. This approval of T-VEC was quickly followed by regulatory approvals in melanoma by the European Medicines Agency and Australian Therapeutic Goods Administration.8
This article will describe the translation of T-VEC from vector construction and preclinical testing, and review the pivotal clinical trial results leading to approval of this agent for use in melanoma. We will also discuss the potential for T-VEC to be used in combination therapy with other immunotherapies and more traditional therapies. Finally, the use of T-VEC alone and as part of combination therapies in nonmelanoma skin cancers and other solid tumors will be addressed.
Construction of T-VEC
Oncolytic viruses are naturally occurring or genetically modified viruses that exhibit preferential infectivity and lysis of cancer cells while exhibiting minimal effects on normal cells. A comprehensive description of present and past oncolytic viruses in preclinical and clinical development can be found elsewhere.9 T-VEC is a genetically modified form of the JS1 strain of HSV-1.4 The specific strain chosen and the modifications introduced allowed for improvement in therapeutic responses by fostering tumor–selective replication and improving host immunity.4,8
HSV-1 is a double-stranded DNA virus that encodes a 152-kb genome capable of expressing a large segment of eukaryotic DNA. The JS1 strain was initially isolated from a fever blister, and when compared with other laboratory strains, it exhibited potent oncolytic activity in human cancer cell lines.4 HSV-1 is a minor human pathogen causing recurrent fever blisters and exhibiting a latency phase in which viral particles can access peripheral neurons, although deletion of the neurovirulence genes can promote safety while increasing tumor-selective replication. Furthermore, HSV-1 is sensitive to antiviral therapy with agents such as acyclovir, valacyclovir, and penciclovir, which can be used in cases of accidental infection.
In T-VEC, the HSV-1 genome has been modified by deletions of 2 copies of the RL1 gene, which encode a neurovirulence factor, infected cell protein 34.5 (ICP34.5; Figure). In healthy cells, ICP34.5 is required for viral proliferation through interactions with proliferating cell nuclear antigen, a protein involved in DNA replication and repair, and expression results in cellular proliferation, thereby increasing production of virions.10,11 In cancer cells, however, HSV-1 proliferation does not require ICP34.5 because the malignant cells undergo aberrant proliferation, allowing for the T-VEC to bypass the proliferating cell nuclear antigen–dependent mechanism. Thus, deletion of ICP34.5 prevents viral proliferation within healthy cells, but renders cancer cells susceptible based on unregulated increased cellular proliferation.12 This deletion of ICP34.5 makes the virus less pathogenic, limiting HSV infection of noncancerous cells, and providing for tumor-selective replication. In place of the 2 ICP34.5 gene deletions, 2 copies of the human GM-CSF genes were inserted to augment immune activation. GM-CSF is a proinflammatory cytokine that dramatically enhances antiviral and antitumor responses by recruiting dendritic cells to the site of infection, promoting antigen presentation and dendritic cell activation.13 These effects are thought to stimulate herpes-specific and tumor antigen–specific T-cell responses recruiting lymphocytes to sites of active infection.
In addition to the deletion and replacement of ICP34.5, the viral ICP47 gene has also been deleted from the HSV-1 backbone of T-VEC. ICP47, encoded by the US12 gene, limits antigen presentation by major histocompatibility complex (MHC) class I through blocking access of intracellular peptides to the transporter associated with the antigen processing protein.14 During a normal HSV infection, blocking antigen presentation with ICP47 allows the virus to evade the immune response. However, blocking antigen presentation in cancer cells would limit the antitumor immune response, so ICP47 deletion from the T-VEC vector allows for presentation of viral and tumor antigens. Another benefit of the deletion of ICP47 is that it leads to early expression of viral US11.15 In normal cells, the US11 gene product binds to eIF2α kinase, preventing phosphorylation, and subsequently inhibits expression of cellular protein kinase R, a critical regulator of cell proliferation and antiviral responses, which blocks protein translation and results in abortive apoptosis in an effort to limit viral propagation.16 This form of abortive apoptosis limits viral spread and results in a less immunogenic form of cell death. In cancer cells, however, the increase in active eIF2α kinase and the decrease in the overall active cellular protein kinase R levels result in an increase in viral protein formation and a decrease in apoptosis. This promotes viral replication within tumor cells and greatly improves the immunogenicity of T-VEC without decreasing its tumor selectivity.17
Immune and Nonimmune Mechanisms of Action of T-VEC
It is hypothesized that T-VEC exhibits antitumor effects by 2 different mechanisms. The first mechanism, generally known as the oncolytic effect, takes advantage of the ability of T-VEC to preferentially infect, replicate in, and lyse tumor cells. This is aided by the ICP34.5 deletion, which allows for selective replication in tumor cells, and by early expression of US11 caused by the ICP47 deletion, which allows for increased viral protein production.15 The newly released virions lead to continued infection of nearby tumor cells, producing a so-called “bystander effect.”
In addition to the release of new viral particles, which can act as pathogen-associated molecular patterns (PAMPs), tumor-associated neoantigens and danger-associated molecular patterns (DAMPs) are released into the tumor microenvironment following viral-mediated cell lysis. The release of PAMPs and DAMPs can initiate innate immunity. Furthermore, ICP47 deletion allows improved MHC class I antigen presentation, leading to activation of systemic adaptive immunity, a process that is further supported by local release of GM-CSF. Although the exact mechanism of action is not completely understood, it is thought that the PAMPs, DAMPs, and cytokines lead to the recruitment and activation of antigen-presenting cells, particularly dendritic cells. These cells then activate cytotoxic CD8+ T-cells against viral and tumor-associated antigens. The ongoing attack of tumor cells results in the release of additional soluble antigens, leading to cross-presentation and epitope spreading, ultimately causing an immune-mediated rejection of tumor cells, which could expand to mediate antitumor rejection at uninjected sites of tumor growth.18,19 In addition, the initial immune response to the virus can induce local interferon-gamma production and an influx of reactive lymphocytes, thus promoting the transition of lymphocyte-poor (or “cold”) tumors into lymphocyte-rich (or “hot”) tumors. Interferon production may also stimulate immune responses by increasing expression of MHC class I and tumor antigens and promoting a Th1-type immune response. In contrast, interferon may also increase local PD-L1 expression, which can limit tumor-specific T-cells, but this may provide a strong rationale for combining T-VEC with PD-1/PD-L1 inhibitors, as discussed later in this article.
Preclinical Studies of T-VEC
In preclinical studies, the JS1 strain exhibited superior tumor cell killing compared with the 17+ and Bl strains of HSV-1, especially against melanoma, colorectal, breast, and pancreatic cancer lines.4 T-VEC was also shown to have infectivity kinetics similar to that of wild-type HSV-1 in 3T6 cells, which usually do not support growth of ICP34.5 mutants of HSV-1. The deletion of ICP47 was shown to prevent the downregulation of MHC class I expression following infection of MBA-MB-231 breast adenocarcinoma cells.4 T-VEC was able to reduce tumor volumes in mice bearing colon adenocarcinoma (HT-29), FaDu carcinoma, or glioma (U87MG).4 Thus, these initial results from mouse experiments suggested that T-VEC exhibits oncolytic effects in various tumor models and increases antigen presentation by MHC upregulation. The systemic effects of T-VEC were studied using A20 lymphoma tumors in Balb/c mice, which were challenged with tumors on both flanks. In these contralateral mouse model experiments, injecting JS1/ICP34.5¯/ICP47¯ without GM-CSF into the tumor was not able to treat contralateral tumors significantly, while injecting JS1/ICP34.5¯/ICP47¯ vectors encoding murine GM-CSF significantly reduced tumor volume of both injected and uninjected contralateral tumors.4 These experiments supported the final T-VEC configuration and suggested that systemic immunity was GM-CSF–dependent.
Preclinical studies also evaluated how circulating HSV-1–specific antibody titers affect treatment. Whereas initial analysis revealed that all mice develop antiviral titers, there was no significant correlation between titer levels and therapeutic responses following intratumoral infection, a conclusion later supported in clinical trials. Other studies investigated the safety profile of a murine-adapted T-VEC in mice, in which a better profile was seen when compared with the wild-type 17+ HSV-1 strain.4 The median lethal dose of wild-type HSV-1 was shown to be less than 10 plaque-forming units (PFU), whereas doses of up to 105 PFU of murine-adapted T-VEC were well tolerated in Balb/c mice.4 Furthermore, T-VEC infection was shown to selectively propagate in murine cancer cell lines as determined by GM-CSF production compared with healthy rat cerebellar granular cells.5 These in vitro results have also been verified with xenograft models for glioma and colorectal cancer, demonstrating that T-VEC preferentially lyses human cancer cells.4 Collectively, these preclinical results showed that the JS1/ICP34.5¯/ICP47¯ vector encoding GM-CSF was a safe and therapeutically active oncolytic agent. Based on these results, T-VEC was moved into clinical trials in 2003.
Clinical Trials of T-VEC in Melanoma
A phase 1 dose-escalation study conducted by Hu and colleagues determined that T-VEC was safe to use and generally tolerable with injection-site reactions and fever as the main side effects.6 Although no partial responses (PRs) or complete responses (CRs) were observed, there was evidence of flattening of some lesions and stable disease in a few patients. Furthermore, the investigators used serology, viral protein immunostaining, and GM-CSF mRNA levels to confirm biologic activity following local tumor injection. The study demonstrated that the virus was localized to tumor cells and did not replicate within other stromal cells. Local viral replication was reported to be associated with inflammation and necrosis, and inflammation was also reported in uninjected tumors in a minority of cases. The trial also validated a multidosing regimen in which 106 PFU, given as a seroconverting dose, followed 3 weeks later by 108 PFU for subsequent injections, given every 2 weeks thereafter, was a well-tolerated regimen that would be the basis for future studies.6
Senzer and colleagues conducted a single-arm phase 2 study of T-VEC in patients with stage IIIC-IV melanoma who had injectable lesions not amenable to curative surgery.7 Patients were treated with a standard regimen of T-VEC as defined in the phase 1 study and could continue treatment until maximum response, significant toxicity, or confirmed disease progression. Patients who remained clinically asymptomatic but developed disease progression were allowed to continue treatment. The investigators reported an overall response rate, including CRs and PRs, of 26%, with responses seen in both injected and distant lesions. The responses that were seen were durable, with 92% being maintained for 7 to 31 months. Another 20% of patients had stable disease for greater than 3 months. OS was 58% at 1 year and 52% at 2 years.7
To better understand the mechanism of local and distant control seen in this phase 2 trial, peripheral blood and tumor tissue samples were collected from select participants. These samples were analyzed to assess the number and antigen specificity of effector T-cells, regulatory CD4+FoxP3+ T-cells, suppressor CD8+ T-cells, and myeloid-derived suppressive cells.20 In this analysis, an increase in the local and systemic antigen-specific T-cell response against melanoma-associated antigen recognized by T-cells and a decrease in regulatory CD4+FoxP3+ T-cells, suppressor CD8+ T-cells, and myeloid-derived suppressive cells were noted. The greatest quantitative changes were seen in injected tumors, whereas similar changes, albeit at lower levels, were observed in uninjected lesions. These studies supported the safety and potential efficacy of T-VEC in advanced melanoma and suggested that immune responses against the cancer were associated with clinical responses. Based on these outcomes, the first randomized phase 3 trial of an oncolytic virus for cancer was conducted.
The prospective, international, randomized phase 3 OPTiM trial was established for patients with unresected stage IIIB-IV melanoma with accessible lesions that were not thought to be surgically resectable.8 This was an open-label study comparing intralesional T-VEC (initial dose of 106 PFU followed 3 weeks later by 108 PFU every 2 weeks until CR, toxicity, or confirmed disease progression) with subcutaneous recombinant GM-CSF (125 mcg/m2 daily for 2 weeks each month and followed until maximum response, toxicity, or confirmed disease progression). The trial was designed to demonstrate an improvement in durable response rate, which was defined as an objective response by modified World Health Organization criteria, initiating within 1 year of starting treatment and lasting ≥6 months. This end point was selected to demonstrate response and to include a time element, which was considered important since the immunotherapy mechanism suspected for T-VEC could result in clinical progression prior to regression and clinical benefit may be missed without incorporating an appropriate time element into the primary end point. The study met its primary end point, demonstrating an improved durable response rate (16.3% vs 2.1%) and overall response rate (26.4% vs 5.7%) in patients treated with T-VEC.8 The median OS was 23.3 months in the T-VEC arm versus 18.9 months in the GM-CSF arm (P = .05). The improved durable response rate and OS were particularly prominent in patients with stage IIIB-IVM1a disease and those who had not received prior therapy of any type.8 These findings led to the approval of T-VEC in the United States and Australia for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. In Europe, T-VEC was approved for the treatment of stage III and IVM1a melanoma based on the improvement in OS and response rates in this subset of patients.8
The approval of T-VEC has led to several additional studies aimed at better defining the role of T-VEC in the treatment of patients with melanoma. A subset analysis of the OPTiM trial suggested that injected lesions had a 64% objective response rate compared with 34% for uninjected cutaneous or subcutaneous lesions and 15% for uninjected visceral disease.21 The higher responses observed in injected lesions suggest a variety of strategies to improve the therapeutic effectiveness of T-VEC. One possibility is to consider injecting melanoma tumors earlier in the course of the disease, such as in high-risk stage II or III patients. To evaluate this approach, a phase 2, multi-institutional, randomized study comparing neoadjuvant T-VEC followed by surgery versus surgery alone in patients with resectable stage IIIB-IVM1a melanoma is in progress (NCT02211131). The primary end point of this study is 2-year recurrence-free survival. The trial will also assess the rate of pathologic CR (pCR) after treatment with T-VEC and determine whether treatment results in an increase in negative-margin resections. Other end points include safety, rate of local control, metastasis-free survival, and OS.
Another strategy for improving the response rate of visceral lesions is to directly inject them with T-VEC. The safety and feasibility of this approach are being tested in another clinical trial in which patients with hepatic tumors will be injected with T-VEC through interventional radiology techniques (NCT02509507).
In addition to optimizing therapeutic approach, several studies are underway to evaluate T-VEC pharmacodynamics and immune responses. A phase 2, multicenter study assessing the biodistribution and shedding of T-VEC in patients with stage IIIB¯IVM1c melanoma has completed accrual (NCT02014441). This study aims to determine the proportion of patients who have detectable T-VEC DNA in the blood and urine after administration, as well as the kinetics of viral clearance after treatment. A related phase 4 postmarketing trial is being conducted to assess herpes infection rates after treatment (NCT02910557).
A single-arm phase 2 trial assessing the correlation between initial intratumoral CD8+ T-cell density and objective response rate in patients with stage IIIB-IVM1c also recently completed accrual (NCT02366195). Immune infiltration has previously been described as having prognostic value and could be used to predict efficacy of traditional cytotoxic chemotherapy, targeted therapy, and other immunotherapies,22 and the outcome of this study may shed light on the predictive nature of the tumor microenvironment in response to T-VEC.
Clinical Use and Adverse Events
T-VEC is a live, replicating virus and thus requires special precautions for storage and drug preparation as well as for clinical administration in the ambulatory oncology clinic. These precautions are comparable to other live agents used in cancer therapy, such as bacillus Calmette-Guérin for bladder cancer. T-VEC is available in 2 doses, a 106-PFU dose for initial treatment and a 108-PFU dose for all subsequent injections. The vials are generally stored at –70°C or colder and are thawed at room temperature until T-VEC converts to liquid form, after which it can be refrigerated for 12 to 48 hours depending on the concentration. Once thawed, it should not be refrozen or exposed to light during storage or thawing.
T-VEC is best prepared by drawing the appropriate volume of liquid from the vials into a syringe under a sterile biosafety cabinet. Clinicians and staff should use universal precautions while handling T-VEC, including gloves, a protective gown, and face protection. In case of a spill, small volumes of T-VEC can be cleaned with a 10% bleach solution.23,24 At our center, we dedicate 1 room for T-VEC injections and have patients undergo a brief physical examination with lesion measurement to allow drug volume to be determined. Then, we bring patients back to the same room for injection. The room is terminally cleaned once treatment is complete.
Patients who have active herpetic lesions, are on treatment with systemic corticosteroids or antiviral medications, or have signs of immune suppression should not be treated with T-VEC. Administration of T-VEC takes place in a stepwise manner, during which a lower concentration dose (106 PFU/mL) is given first to allow seronegative patients to convert, limiting toxicity, followed 3 weeks later by subsequent doses of 108 PFU/mL given every 2 weeks until maximum response, significant adverse events, or confirmed disease progression.23,24 Lesions must be accessible for injection by direct clinical visualization or palpation, and lesions seen under ultrasound guidance may also be injected.25
On the day of each injection, all injected tumors should be measured and recorded. The amount of T-VEC that is injected is dependent on the size of the tumor, with 4 mL being the maximum volume that can be injected at any one visit.23,24 We typically use a single syringe for each lesion and begin with the largest lesions first. If any new lesions arise during the course of treatment, these take priority.24 The site of injection should be washed with alcohol or povidone-iodine solution, and injections should be given in a 4-quadrant manner to ensure equal distribution of the virus throughout the established tumor. Once the virus is delivered, the lesions should be covered with a dry gauze and adhesive dressing, and the bandage left intact for at least 4 to 5 days. Lesions may continue to be treated until CR or confirmed disease progression in the absence of significant toxicity or clinical deterioration.24 A decrease in lesion size may be preceded by eschar formation, induration, flattening of raised lesions, or softening. In some patients, biopsy can be considered to confirm response, especially when the morphology changes but pigment remains.
The most common adverse events associated with the use of T-VEC include constitutional flulike symptoms, including fatigue, chills, fever, gastrointestinal distress, and headaches.7,8,24 If these events occur, acetaminophen and/or nonsteroidal anti-inflammatory drugs can be given. Another common side effect is injection-site pain, which may be prevented or alleviated by applying ice packs, or less commonly, with pain medication.24 Less common side effects, such as cellulitis, are possible, and if suspected, patients should undergo standard workup for bacterial cellulitis and begin antibiotic treatment. Whereas disseminated herpes infection is unlikely, a high clinical suspicion should elicit testing of the blood (for suspected viremia) or cerebrospinal fluid (for encephalitis) through HSV DNA by polymerase chain reaction assay. Confirmed systemic infection should be treated with acyclovir.23,24 Overall, treatment with T-VEC is generally safe and well tolerated if appropriate precautions are taken by patients and their caregivers.26
The additional biosafety concerns associated with T-VEC use are easily managed with brief education of clinic staff, which should include physicians, nurses, and pharmacists involved in the care of patients with melanoma. HSV-1 is considered a biosafety level 1 agent and is susceptible to 10% bleach solution. Accidental exposures, which have been reported largely through needlestick injuries, should be treated by immediate antiviral oral medications. Patients should be advised to wash their hands before and after changing bandages and to avoid direct contact with immunosuppressed individuals. To date, there have been no reports of household transmission of T-VEC.
Combination Therapy with T-VEC
The favorable safety profile and ability to elicit a local T-cell and interferon-gamma response makes T-VEC an attractive agent for combination immunotherapy studies. A multi-institutional phase 1b/2 trial was initiated to assess safety and efficacy of combination therapy with the anti–CTLA-4 antibody ipilimumab, with or without T-VEC, in patients with unresected stage IIIB-IV melanoma (NCT01740297). The trial has completed accrual and the phase 1b results were recently published, showing a side effect profile with no dose-limiting toxicities in the 19 patients included in the safety analysis. There were expected grade 3/4 treatment-related adverse events observed in 26.3% of patients. An objective response rate of 50% was reported with 18-month PFS and OS rates of 50% and 67%, respectively, which compare favorably to historical controls of monotherapy with T-VEC or ipilimumab.27 The long-term results of the phase 2 randomized portion of the trial are awaited.
A similar multicenter phase 1b/3 study with an anti–PD-1 checkpoint inhibitor, pembrolizumab, is currently recruiting patients (NCT02263508). The results of the phase 1b portion of this study were presented at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), and showed a 33% rate of grade 3/4 toxicity and no grade 5 toxicity. The confirmed overall response and CR rates of 48% and 14%, respectively, were favorable.28 In the double-blind phase 3 portion of this study, all patients will receive pembrolizumab and will be randomized to T-VEC versus placebo injection with primary end points being PFS and OS. These trials provide a potentially unique mechanism of synergy, as checkpoint inhibitors have increasingly become standard therapy in melanoma.29-32
Previous studies have suggested that PD-L1 expression may be associated with higher response rates to T-cell checkpoint inhibitors in melanoma and non–small-cell lung cancer.29 Because T-VEC probably promotes PD-L1 expression, the hypothesis that T-VEC may be able to reverse resistance to PD-1 blockade will be tested in NCT02965716, a single-arm phase 2 trial proposed by SWOG. The trial will accrue patients with unresectable stage III-IV melanoma whose disease has progressed after anti–PD-1 or anti–PD-L1 therapy. Eligible subjects will receive coadministration of intralesional T-VEC and intravenous pembrolizumab every 21 days for up to 18 courses. The study end points will be durable response and objective response rates. The study is also designed to assess changes in T-cell infiltration into tumors, T-cell receptor clonality, and the mutational load of the tumors.
Combination therapies with other immunotherapeutic agents and traditional cancer treatments, particularly combinations of checkpoint inhibition with radiation therapy, have revealed synergy and improved outcomes.33-35 There is a potential for some viruses to act as radiosensitizers and radiation to enhance viral replication.36,37 Memorial Sloan Kettering Cancer Center is currently enrolling patients in a randomized phase 2 clinical trial assessing subjective level of response in patients treated with T-VEC with or without hypofractionated radiotherapy in solid tumors with subcutaneous or superficial lymphatic metastases not amenable to surgical resection (NCT02819843). Although optimal dose fractionation of radiation is still an open question with differing results in preclinical and clinical trials,33,38-40 using a hypofractionated regimen is certainly a reasonable approach with decreased risk for concomitant lymphopenia.41-44
T-VEC in Other Malignancies
An initial phase 1/2 study of T-VEC in stage III-IVB squamous-cell carcinoma of the head and neck was completed at 2 academic centers in the United Kingdom.45 Patients received standard-of-care chemoradiotherapy with a cisplatin-based regimen and were treated with intratumoral injection of T-VEC concurrently with cisplatin on days 1, 22, and 43, and once on day 64. Six to 10 weeks later, patients underwent a planned neck dissection. There were no delays in treatment caused by T-VEC, and dose-limiting toxicity was not observed, even at the higher dose level of 106 PFU on day 1 followed by 108 PFU for subsequent administrations. In this 17-patient study, the investigators showed an 82.3% response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) and pCR in 93% of patients at the time of neck dissection. Locoregional control was 100% and disease-specific survival was 82.4% at 29 months. They also reported that injected and uninjected tumors had higher levels of virus than the injected dose, providing evidence that viral replication had occurred.45 This initial study led to a phase 3 clinical trial in patients with previously untreated locally advanced head and neck cancer (NCT01161498). This trial was terminated before completing accrual, however, to allow for trial modification because of the changing treatment paradigm of head and neck cancer, including the prognostic consequences of HPV status.46,47
A phase 1b/3 randomized trial is assessing combined T-VEC and pembrolizumab in recurrent or metastatic squamous-cell carcinoma of the head and neck that is not amenable to curative surgery or radiotherapy (NCT02626000). In the 1b portion, 18 patients will initially receive combined therapy to assess dose-limiting toxicities; this will be followed by a 22-patient expansion cohort to further assess safety and efficacy. Based on the results of these first 40 patients, a decision will be made on whether to initiate the phase 3 portion of the study.
A phase 2 study being conducted by MD Anderson Cancer Center is currently accruing patients with recurrent breast cancer to assess the primary outcome of disease control rate (CR, PR, or stable disease) and the secondary outcome of PFS after treatment with single-agent T-VEC (NCT02658812). Patients will be eligible regardless of molecular status or presence of metastatic disease. Subjects must have discontinued radiation therapy at least 2 months prior, any chemotherapy at least 4 weeks prior, and any hormonal therapy at least 1 week prior to enrollment. The Moffitt Cancer Center began enrolling patients in February 2017 for a phase 1/2 study of combination T-VEC and neoadjuvant chemotherapy in triple-negative breast cancer (NCT02779855). The primary outcome in the phase 1 portion is to find the maximum tolerated dose and recommended phase 2 dose of T-VEC in combination with neoadjuvant paclitaxel, doxorubicin, and cyclophosphamide–based chemotherapy. The phase 2 portion has a primary end point of pCR rates in the breast and axillary nodes as well as secondary end points of recurrence-free survival and OS at 5 years.
NCT00402025 was a small phase 1 dose-escalation trial initiated in 2006 that assessed safety and early efficacy of T-VEC in patients with locally advanced, unresectable pancreatic cancer who failed or were unable to receive standard therapy. These patients were scheduled to receive at least 3 doses of T-VEC via endoscopic ultrasound-guided fine needle injection. Although the final results have yet to be published, an abstract published in conjunction with the 2012 ASCO annual meeting revealed that only 41% (7/17) received all 3 planned doses.48 The investigators found that endoscopic ultrasound-guided injection in advanced pancreatic cancer was both feasible and well tolerated. At the highest dose level of 106 PFU/mL × 1, followed by 107 PFU/mL × 2, there was a median decrease in the injected tumor diameter. Some patients also had decreased diameters of untreated tumors. The investigators concluded that in the future, studies in patients with less advanced disease would be preferable.48 An early phase 1 safety and efficacy trial is also ongoing in patients with unresectable primary and metastatic liver tumors that are not amenable to local therapy with curative intent (NCT02509507).
A single-arm phase 1/2 trial currently accruing participants at the University of Iowa is assessing T-VEC in combination with standard-of-care preoperative radiation therapy in patients with stage IIB-IV soft tissue sarcoma that is deemed to be unresectable with widely negative margins (NCT02453191). This trial, which will assess both safety and efficacy as measured by pCR rates, is an interesting departure from the others, as it is the only one designed to evaluate combination therapy without previous clinical data on the effectiveness of T-VEC alone in the primary tumor type.
NCT02923778 is a similar phase 2 study of preoperative T-VEC and radiation in patients with potentially resectable soft tissue sarcoma of the extremity and trunk. This study will be conducted at the Mayo Clinic and will assess not only toxicity and clinical outcome measures, but also changes in PD-L1 expression status and peripheral and tumor-infiltrating immune cells.
Given the favorable side effect profile of T-VEC in adults, a multicenter phase 1 study is set to evaluate T-VEC in pediatric patients with advanced non–central nervous system tumors that can be directly injected without difficulty (NCT02756845). Specifically, the patients will have non–central nervous system solid tumors that have no standard treatment options or have recurred after standard therapy. Patients will be assigned to 1 of 6 cohorts based on their age (0 to <2, 2 to <12, and 12 to <18 years) as well as their HSV-1 serostatus. The primary end point will be evaluation of safety based on dose-limiting toxicities, and secondary end points will include incidence of adverse events and laboratory abnormalities as well as clinical response evaluation by immune-related response criteria and RECIST.
T-VEC has been shown to be effective as a local therapy in injectable melanoma as well as a stimulator of the host immune system. An important goal of future investigation will be to confirm the exact mechanisms of antitumor activity induced by T-VEC, including confirming how tumor cells are killed and determining the role of the antiviral response in mediating improved outcomes. Although T-VEC has shown significant overall and durable response rates in melanoma, there is no clear identified biomarker that predicts response to therapy. Further study of the tumor microenvironment and other host-related factors are needed to select the patients who will be most likely to benefit. Clinical trials in several types of solid malignancies are already ongoing, and the number is only likely to rise with increased use in tumors that can be reached via advanced endoscopic or interventional methods. Furthermore, assessments of rational combinations with traditional therapies, including surgery, chemotherapy, and radiation therapy, as well as targeted therapies and other immunotherapies, are likely to continue. The favorable safety profile and immune-potentiating effects of T-VEC suggest that this oncolytic virus may be an important component of combination regimens. The completion of ongoing and future combination studies will help to define the role of T-VEC in the armamentarium against cancer.
Dr Jhawar is a resident in the Department of Radiation Oncology at Rutgers Cancer Institute of New Jersey. His interests include radiation and its effects on tumor immunity.
Dr Goyal is an Assistant Professor in the Department of Radiation Oncology at Rutgers Cancer Institute of New Jersey. His interests include radiation oncology for melanoma and other tumors.
Dr Bommareddy is a graduate student in the Rutgers School of Biomedical Sciences and is pursuing his PhD degree in the study of oncolytic herpes viruses and their role in mediating antitumor activity.
Dr Zloza is the Chief of the Section of Surgical Oncology Research at Rutgers Cancer Institute of New Jersey. His interests include the role of viral infections in suppressing tumor immunity.
- Howlader N, Noone A, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER website, April 2016. Accessed February 23, 2017.
- National Cancer Comprehensive Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Melanoma. Version 1.2017. www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. November 10, 2016. Accessed February 23, 2017.
- Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17:e542-e551.
- Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10:292-303.
- Toda M, Martuza RL, Rabkin SD. Tumor growth inhibition by intratumoral inoculation of defective herpes simplex virus vectors expressing granulocyte-macrophage colony-stimulating factor. Mol Ther. 2000;2:324-329.
- Hu JC, Coffin RS, Davis CJ, et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006;12:6737-6747.
- Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009;27:5763-5771.
- Harrington KJ, Andtbacka RH, Collichio F, et al. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase III OPTiM trial. Onco Targets Ther. 2016;9:7081-7093.
- Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642-662.
- Brown SM, MacLean AR, McKie EA, Harland J. The herpes simplex virus virulence factor ICP34.5 and the cellular protein MyD116 complex with proliferating cell nuclear antigen through the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34. J Virol. 1997;71:9442-9449.
- Harland J, Dunn P, Cameron E, et al. The herpes simplex virus (HSV) protein ICP34.5 is a virion component that forms a DNA-binding complex with proliferating cell nuclear antigen and HSV replication proteins. J Neurovirol. 2003;9:477-488.
- Rampling R, Cruickshank G, Papanastassiou V, et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther. 2000;7:859-866.
- Hamilton JA, Anderson GP. GM-CSF biology. Growth Factors. 2004;22:225-231.
- Raafat N, Sadowski-Cron C, Mengus C, et al. Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope. Int J Cancer. 2012;131:E659-E669.
- Peters C, Rabkin SD. Designing herpes viruses as oncolytics. Mol Ther Oncolytics. 2015;2:15010.
- Garcia MA, Gil J, Ventoso I, et al. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev. 2006;70:1032-1060.
- Clemens MJ. Targets and mechanisms for the regulation of translation in malignant transformation. Oncogene. 2004;23:3180-3188.
- Kohlhapp FJ, Kaufman HL. Molecular pathways: mechanism of action for talimogene laherparepvec, a new oncolytic virus immunotherapy. Clin Cancer Res. 2016;22:1048-1054.
- Kaufman HL, Ruby CE, Hughes T, Slingluff CL Jr. Current status of granulocyte-macrophage colony-stimulating factor in the immunotherapy of melanoma. J Immunother Cancer. 2014;2:11.
- Kaufman HL, Kim DW, DeRaffele G, et al. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol. 2010;17:718-730.
- Andtbacka RH, Ross M, Puzanov I, et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol. 2016;23:4169-4177.
- Ladanyi A. Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res. 2015;28:490-500.
- Imlygic (talimogene laherparepvec) Suspension for intralesional injection [prescribing information]. Thousand Oaks, CA: Amgen, Inc; October 2015.
- Rehman H, Silk AW, Kane MP, Kaufman HL. Into the clinic: talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer. 2016;4:53.
- Kaufman HL, Bines SD. OPTIM trial: a phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol. 2010;6:941-949.
- Lim F, Khalique H, Ventosa M, Baldo A. Biosafety of gene therapy vectors derived from herpes simplex virus type 1. Curr Gene Ther. 2013;13:478-491.
- Puzanov I, Milhem MM, Minor D, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol. 2016;34:2619-2626.
- Long GV, Drummer R, Ribas A, et al. Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB–IV melanoma. J Clin Oncol. 2016;34(suppl). Abstract 9568.
- Barbee MS, Ogunniyi A, Horvat TZ, Dang TO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Ann Pharmacother. 2015;49:907-937.
- Camacho LH. CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Cancer Med. 2015;4:661-672.
- Luke JJ, Ott PA. PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma. Oncotarget. 2015;6:3479-3492.
- Mashima E, Inoue A, Sakuragi Y, et al. Nivolumab in the treatment of malignant melanoma: review of the literature. Onco Targets Ther. 2015;8:2045-2051.
- Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379-5388.
- Ngiow SF, McArthur GA, Smyth MJ. Radiotherapy complements immune checkpoint blockade. Cancer Cell. 2015;27:437-438.
- Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373-377.
- Harrington KJ, Melcher A, Vassaux G, et al. Exploiting synergies between radiation and oncolytic viruses. Curr Opin Mol Ther. 2008;10:362-370.
- McEntee G, Kyula JN, Mansfield D, et al. Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling. Oncotarget. 2016;7:48517-48532.
- Seung SK, Curti BD, Crittenden M, et al. Phase 1 study of stereotactic body radiotherapy and interleukin-2—tumor and immunological responses. Sci Transl Med. 2012;4:137ra174.
- Srivastava RM, Clump DA, Ferris RL. Anti-PD-1 mAb pre-radiotherapy (RT) loading dose and fractionated RT induce better tumor-specific immunity and tumor shrinkage than sequential administration in an HPV+ head and neck cancer model. J Immunother Cancer. 2015;3(suppl 2):P314.
- Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86:343-349.
- Crocenzi T, Cottam B, Newell P, et al. A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma. J Immunother Cancer. 2016;4:45.
- Tang C, Liao Z, Gomez D, et al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys. 2014;89:1084-1091.
- Wild AT, Herman JM, Dholakia AS, et al. Lymphocyte-sparing effect of stereotactic body radiation therapy in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2016;94:571-579.
- Yovino S, Kleinberg L, Grossman SA, et al. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest. 2013;31:140-144.
- Harrington KJ, Hingorani M, Tanay MA, et al. Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin Cancer Res. 2010;16:4005-4015.
- Harrington KJ, Puzanov I, Hecht JR, et al. Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1-derived oncolytic immunotherapy. Expert Rev Anticancer Ther. 2015;15:1389-1403.
- Malhotra A, Sendilnathan A, Old MO, Wise-Draper TM. Oncolytic virotherapy for head and neck cancer: current research and future developments. Oncolytic Virother. 2015;4:83-93.
- Chang KJ, Senzer NN, Binmoeller K, et al. Phase I dose-escalation study of talimogene laherparepvec for advanced pancreatic cancer (ca). J Clin Oncol. 2012;30(suppl). Abstract e14546.
In the United States, colorectal cancer (CRC) is the fourth most common malignancy, with 134,490 new cases and 49,190 deaths estimated in 2016.1 Among these patients, 25% present with advanced disease at diagnosis, and nearly 50% will eventually develop metastatic disease.2 Survival rates for metastatic CRC (mCRC) have been improving, [ Read More ]
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