Talimogene laherparepvec (T-VEC) previously also known as OncoVEX^GM-CSF is a modified herpes simplex virus type 1-derived oncolytic immunotherapy that has been approved for use as intralesional therapy in melanoma [15, 23]. It is currently being developed for use in multiple solid tumors.

This oncolytic virus is derived from HSV-1. Given that HSV-1 is well characterized and its biology is well known, it serves as a suitable vector. Its large non-integrating double stranded DNA genome can be easily manipulated to insert large genetic inserts. The structure of T-VEC (Fig. 24.2) shows deletion of two HSV genes: ICP34.5 and ICP47. ICP34.5 confers neurovirulence to HSV-1. Thus, deletion of ICP34.5 provides selective cancer cell replication, and its replacement with two copies of the GM-CSF gene enhances local production of GM-CSF. GM-CSF is responsible for maturation and recruitment of dendritic cells and macrophages within the tumor, and these in turn allow for tumor antigen presentation leading to T-cell-mediated cytotoxic effect. Deletion of ICP47 causes an early activation of the US11 promoter which enhances viral replication and facilitates antigen presentation leading to better antitumor immune response [3, 15, 24].

Similar to other oncolytic viruses, T-VEC has been proposed to have both local and systemic effects (Fig. 24.3). Through mechanisms outlined above, T-VEC selectively replicates in tumor cells resulting in oncolysis. This in turn releases more progeny viruses and the cycle repeats itself. In conjunction with production of immunomodulatory cytokine GM-CSF, release of tumor-specific antigens induces recruitment and maturation of dendritic cells. Tumor cell antigen presentation to T cells occurs leading to activation and expansion of CD8⁺ T cells eliciting a systemic immune response [15].

A maximum injectable volume is determined based on the tumor dimension (Table). The volume of T-VEC administered varies by the lesion size: 0.1 ml for tumors up to 0.5 cm in longest dimension, 0.5 ml for tumors ranging from 0.5 to 1.5 cm, 1 ml for tumors ranging from 1.5 to 2.5 cm, 2 ml for tumors ranging from 2.5 to 5 cm, and 4 ml for tumors greater than 5 cm in longest dimension. The maximum volume per visit is 4 ml, and the volume to be administered is based on volume calculations for the tumor using its longest dimension. When multiple lesions are present, it is recommended that the largest lesions receive priority first followed by any lesions and then symptomatic lesions. Prior to injecting T-VEC, the area to be injected must be cleaned with alcohol swab and allowed to air-dry. If the lesion is not superficially palpable, then ultrasound guidance should be used for deeper subcutaneous tumors. Usually a single insertion site for the needle with T-VEC is recommended, but multiple sites may be necessary for larger tumors. Premedications and local anesthetics are usually not necessary prior to administration unless there is prior history of pain at the injection site. After treatment, holding pressure for 30 s at the site of injection is recommended. This should be covered with gauze and occlusive dressing and should remain covered for 1 week after each treatment. All materials in contact with the treatment site should be disposed of using universal precautions.

T-VEC is handled as a biosafety level 1 agent, which implies that it does not consistently harm normal healthy humans. It is prepared in a sterile biosafety cabinet. It is available in two different types of vials: the yellow-green vial with a concentration of 10⁶ PFU/ml and the blue vial with a concentration of 10⁸ PFU/ml. These are stored at −70°C or colder and thawed at room temperature until it converts to liquid form for use. Once thawed, the vials can be refrigerated for 12 h (10⁶ PFU/ml concentration) to 48 h (10⁸ PFU/ml concentration). Once thawed, the vials cannot be refrozen. Protective personal equipment with universal precautions must be followed while handling T-VEC. In case of accidental exposure, area should be cleaned with water for 15 min. In the event of a spill, 10% bleach solution should be used with absorbent materials to clean the surface [25].

A murine A20 tumor model was studied. HSV-1 viral strains with and without GM-CSF gene expression were injected into single side tumors in a bilateral flank system. HSV-1 viral strains both with and without GM-CSF expression resulted in tumor regression; however, only GM-CSF expressing HSV-1 resulted in tumor regression on the contralateral side. Cytotoxic T cells primed to parental A20 cells were seen only with treatment with HSV-1 with GM-CSF expression suggesting long-term antitumor immune response generated by this strain. This laid the foundation of further genetic modification of HSV-1 and the generation of T-VEC [3, 26].

Therapies such as T-VEC are considered ideal for melanoma treatment because (1) the presence of in-transit metastases denotes spread of melanoma cells to dermal lymphatics at the same time making surgical resection difficult and (2) metastases from melanoma preferentially spread to the skin making it optimal for targeting through intralesional therapies [24]. Therefore, much of the advancements in T-VEC therapy have been in melanoma. In keeping in line of intralesional therapies, agents such as BCG, GM-CSF, IL-2, PV-10, and IFN-alpha have been used and demonstrated responses in injected and noninjected lesions but in less than half of patients treated. Cutaneous toxicity and lack of systemic benefit have limited their use for treatment [24].

Administration of T-VEC was shown to increase local and systemic MART-1-specific CD8⁺ effector T cells, while at the same time there is decrease in both CD4⁺ Foxp3⁺ regulatory T cells and myeloid-derived suppressor cells (MDSC). Proportion of Tregs is lower in injected sites as compared to uninjected sites [3, 27].

In a Phase I trial, T-VEC was evaluated for safety, optimal dose, and schedule in 30 patients including advanced breast cancer, head and neck cancer, colorectal cancer, and melanoma with cutaneous, subcutaneous, or superficial nodal sites of disease. Out of 19 evaluable histological specimens, inflammation and necrosis were noted in 73% of biopsies from the site of injection. The necrosis stained strongly for HSV protein. Tumor specificity of T-VEC was demonstrated by no evidence of necrosis in the non-tumor cells within the tumor microenvironment. The optimum dose and schedule derived from this study were initial dose of 10⁶ PFU/ml followed by a dose of 10⁸ PFU/ml after 3 weeks and repeated every 2 weeks until clinical response, toxicity, or disease progression. Clinical activity was similar between HSV-seronegative and HSV-seropositive patients [28].

After demonstration of good biologic activity of T-VEC in the Phase I study, a Phase II study was conducted in patients with stage III and IV melanoma. Twenty-six percent of patients achieved some form of response as assessed using RECIST criteria including eight patients achieving complete response. Durable responses were seen in 92% of patients ranging from 7 months to 31 months. The survival rate at 1 year was 58% in the intention to treat population, while it was 93% in those with initial objective response [3, 29].

In a Phase Ib study [1] (NCT01740297) conducted in the USA, 19 patients received T-VEC in combination with ipilimumab. T-VEC was administered at a dose of 10⁶ PFU/ml on day 1 and second dose in 3 weeks at a dose of 10⁸ PFU/ml repeated every 2 weeks. Ipilimumab was administered at a dose of 3 mg/kg every 3 weeks for four doses starting on day 1 of week 6. The regimen was overall well tolerated, except in five patients in which ≥Grade 3 adverse events (AE) were reported. Nausea was a common Grade 3 adverse event. Other AEs reported were fever, fatigue, flu-like symptoms, dehydration, diarrhea, and vomiting. Overall response rate assessed using the immune-related response criteria (irRC) [30] was 56%, with four (33%) complete responses and five partial responses. This overall response rate is comparable to 56% that was seen with ipilimumab and nivolumab, except that 55% of participants had Grade 3/4 AEs [31]. Durable response rate (responses seen for ≥6 months) was 44%. Twelve-month progression-free survival (PFS) was 50% and overall survival (OS) 72%. Activated CD8⁺ T cells (CD3⁺, CD4⁻, HLA-DR⁺) increased 1.5-fold from baseline after treatment and correlated with response.

On similar lines a Phase Ib/III study (NCT2263508) studying the combination of T-VEC with pembrolizumab in previously untreated, unresectable stage III/IV melanoma patients is being conducted. Based on results published so far from the Phase Ib portion of the study, the confirmed overall response rate as assessed using irRC was 57.1% with CR rate of 23.8%. Participants received T-VEC at a dose of 106 PFU/ml on day 1, 108 PFU/ml on day 22 and every 2 weeks thereafter, while pembrolizumab was administered at a dose of 200 mg IV on day 36 and every 2 weeks thereafter. Grade 3/4 AEs were noted in 33% of patients, and no Grade 5 AEs were noted [32].

In another Phase I trial studying the safety of T-VEC in advanced pancreatic cancer patients, it was demonstrated that T-VEC can be administered directly to visceral lesions via endoscopic, ultrasound-guided, fine needle injection (EUS-FNI) safely. The trial was designed such that patients would receive their first dose ranging between 10⁴ PFU/ml and 10⁶ PFU/ml followed by every 2 weeks of additional two doses of T-VEC ranging 10⁷–10⁸ PFU/ml all administered endoscopically. Four cohorts were planned; however, the study was stopped prior to enrollment of cohort 4 for reasons other than safety. Two of four in cohort 3 showed tumor reductions greater than 30%. Most common AEs observed were ascites, dehydration, anemia, abdominal pain, constipation, nausea, and vomiting. Although two Grade 5 AEs were noted, these were not attributed to the study drug. Interestingly, 59% of participants discontinued the study before receiving the planned treatment [33].

T-VEC has also been studied in combination with radiotherapy and cisplatin in a Phase I/II study in patients with untreated stage III/IV squamous cell cancer of the head and neck. Participants received chemoradiotherapy 70 Gy in 35 fractions with cisplatin dosed at 100 mg/m² on days 1, 22, and 43. T-VEC was administered as an initial dose of 10⁶ PFU/ml followed by two additional doses of 10⁶ PFU/ml, 10⁷ PFU/ml, or 10⁸ PFU/ml in cohorts 1, 2, and 3, respectively. The regimen was overall well tolerated with no reported DLTs. All patients underwent neck dissection after 6–10 weeks. Response rate as assessed by RECIST was 82% (four complete responses, ten partial responses), and pathological complete response was noted in 93% of patients at the time of neck dissection. At 29 months, the disease-specific survival was 82% and relapse-free survival of 76% [34].

Other selected ongoing trials are listed in Table 24.1.