Preclinical studies showed that T-VEC and its murine variant OncoVEX^mGM-CSF induced strong local and also systemic antitumor responses, showing synergistic effects in combination with ICI [54, 55]. These findings laid the foundation for clinical trials evaluating T-VEC alone or in combination with other treatments.

Initial clinical experience was obtained in a first-in-human Phase I trial conducted between 2003 and 2007, which demonstrated the safety, tolerability, and preliminary antitumor activity of T-VEC in 30 patients with advanced solid tumors [56]. Building on these findings, a subsequent Phase II study in 50 patients with unresectable melanoma conducted from 2004 to 2008 (NCT00289016) confirmed clinically meaningful and durable response rates [57]. The encouraging results from these early clinical studies provided the rationale for initiating the phase III open-label, randomized OPTiM trial (NCT00769704) in 2009. This trial compared intratumoral T-VEC to subcutaneous GM-CSF in 436 patients with unresectable stage IIIB–IVM1c melanoma. The final analysis was published in 2019. With a median follow-up of 49 months, median overall survival (OS) was 23.3 months in the T-VEC group compared to 18.9 months in the GM-CSF arm (HR 0.79; 95% CI, 0.62–1.00; p = 0.0494). T-VEC showed greater efficacy with a durable response rate (DRR) of 19.0% vs. 1.4%, and an ORR of 31.5% vs. 6.4%. CR occurred in 16.9% of patients treated with T-VEC, with a median time to CR of 8.6 months and an estimated 5-year survival of 88.5% among CR patients. The strongest benefit was seen in stage IIIB (advanced regional disease) – IVM1a (metastatic disease limited to skin, subcutis, or lymph nodes; no visceral organ metastases). Immunologic analyses demonstrated systemic activity through increased CD8⁺ T cell and NK cell infiltration in non-injected tumor lesions [58].

Promising preliminary data had already supported the FDA approval of T-VEC for advanced melanoma in 2015, as well as its further evaluation in combination with other therapies.

Initiated in 2016, a phase II randomized controlled trial (RCT) (NCT02819843) investigated T-VEC with or without radiotherapy (RT) in 19 patients with cutaneous metastases from solid tumors, including melanoma and NMSC (T-VEC: n = 9; T-VEC+RT: n = 10). One patient in each arm achieved a complete remission (CR) in a non-target lesion, but no overall modified WHO responses were observed. Median PFS was 1.2 months (T-VEC) and 2.5 months (T-VEC+RT), with OS of 4.9 and 17.3 months, respectively. Treatment-related adverse events (TRAE) were consistent with prior T-VEC data (e.g., flu-like symptoms, chills, pyrexia, fatigue, and injection-site reactions), and skin-related quality of life remained poor throughout. The trial was terminated early due to slow accrual, lack of systemic responses, and the COVID-19 pandemic. The authors suggested that more effective strategies are needed to induce systemic antitumor immunity with immunoradiotherapy combinations [59].

Beginning in 2018, a phase I trial (NCT03747744) evaluated intratumoral T-VEC administration combined with CD1c⁺ (BDCA-1) and/or CD141⁺ (BDCA-3) myeloid dendritic cells (myDCs) in 13 patients with advanced, ICI-refractory melanoma. T-VEC was given on day 1, followed by myDCs on day 2, with repeated T-VEC injections every 2–3 weeks. The treatment was well tolerated, with fatigue, fever, and flu-like symptoms being the most common side effects. Two out of three patients in the highest CD1c⁺ dose cohort achieved durable complete responses (> 33 months), while in cohort 4 (patients treated with the combination of CD1c⁺ and CD141⁺myDCs) one unconfirmed partial and two mixed responses were observed. Of note, biopsies revealed strong tumor immune infiltration, suggesting that this combination may offer clinical benefit in heavily pretreated melanoma [60].

Starting in 2019, T-VEC was further evaluated in combination with ICIs. Consequently, the MASTERKEY-265 phase III trial (NCT02263508) evaluated T-VEC combined with the PD1 inhibitor pembrolizumab versus pembrolizumab alone in unresectable stage IIIB–IVM1c melanoma with injectable metastases. While the combinatorial treatment showed slightly higher response rates (ORR 48.6% vs. 41.3%; CRR 17.9% vs. 11.6%; DRR 42.2% vs. 34.1%), it did not significantly improve the primary endpoint PFS (14.3 vs. 8.5 months; HR 0.86; p = 0.13) or OS, leading to a negative final outcome. Improved PFS was seen in subgroups with lower lactate dehydrogenase (LDH) levels or smaller baseline tumor burden, suggesting that patient selection may be crucial and influence outcomes [61].

Subsequently, the open-label phase II MASTERKEY-115 trial (NCT04068181) evaluated T-VEC plus pembrolizumab in 72 patients with PD-1–refractory stage IIIB–IVM1d melanoma. Cohorts 1 and 2 included patients with unresectable disease and primary or acquired resistance, respectively, within 12 weeks of their last anti–PD-1 dose. Cohorts 3 and 4 included resected patients who relapsed < 6 or ≥ 6 months after starting adjuvant anti–PD-1. Confirmed ORRs were 0%, 6.7%, 40.0%, and 46.7% across cohorts 1–4; ORRs were 3.8%, 6.7%, 53.3%, and 46.7%. CRRs reached 13.3% in cohorts 3 and 4. Median PFS was 5.5 and 8.2 months in cohorts 1 and 2 and not estimable in cohorts 3 and 4. Thus, the combination showed limited benefit in primary resistance but meaningful activity in patients relapsing after adjuvant PD-1 therapy [62].

Notably, a real-world analysis from Austria reported real-life outcomes of T-VEC across 10 melanoma centers in Austria, Switzerland, and Germany, including 88 patients treated between May 2016 and January 2020. The ORR was 63.7%, with CRR in 43.2% and partial responses in 20.5%, while 9.1% had stable disease and 27.3% progressed. Median time to response was ~4 months; median PFS was 9 months, with 1-, 2-, 3-year PFS rates of 45%, 35%, 28%, respectively. OS was 82%, 71%, 65%, 65% at 1, 2, 3, 4 years, and the median was not reached. Together, these data support meaningful real-world activity and favorable tolerability of T-VEC in routine practice [63].

T-VEC has also been examined in a neoadjuvant setting. Final 5-year results from an open-label, randomized phase II trial (NCT02211131) evaluated neoadjuvant T-VEC followed by surgery versus upfront surgery in 150 patients with resectable stage IIIB–IVM1a melanoma and injectable lesions. Patients in the T-VEC arm received up to six doses prior to surgery; both groups could receive adjuvant therapy per investigator discretion. At a median follow-up of 63.3 months, the neoadjuvant T-VEC arm showed improved 5-year recurrence-free survival (RFS; 22.3% vs. 15.2%), event free survival (EFS; 43.7% vs. 27.4%), and overall survival (OS; 77.3% vs. 62.7%) compared to surgery alone. Distant metastasis-free survival (DMFS) also favored the T-VEC group (hazard ratio 0.73). No new safety concerns were identified [64]. These findings could be indicative that intratumoral T-VEC possibly induces durable systemic effects and supports its use as a neoadjuvant strategy in resectable advanced melanoma.

Moreover, T-VEC is being investigated in combination with BRAF/MEK inhibitors to enhance its therapeutic effect. Preclinical studies in both murine and human xenograft models have shown that combining T-VEC with the mitogen-activated protein kinase (MEK)1/2 inhibitor trametinib boosts viral replication within tumors, leading to increased melanoma cell death and delayed tumor progression. This dual approach also promoted cytotoxic T cell infiltration and raised PD-1 expression in the TME, suggesting enhanced immune engagement [65]. Further, adding an anti–PD-1 antibody to this regimen has resulted in complete tumor clearance in over 80% of treated mice, along with extended survival and minimal toxicity [66]. Based on these promising findings, a phase Ib clinical trial (NCT03088176) is currently underway to evaluate T-VEC in combination with the BRAF-/MEK-inhibitor combination dabrafenib plus trametinib in patients with advanced BRAF-positive melanoma [67].

Across all studies, T-VEC demonstrated a favorable safety profile, with the most common adverse events being mild systemic symptoms and local injection site reactions. Grade ≥ 3 TRAEs were reported in 7.3–29.7% of patients. (Table 2) Similar to other immunotherapies, cases of vitiligo have been observed following T-VEC treatment, likely reflecting an exaggerated immune response targeting melanocytes [68].

RP1 is a next-generation oHSV-1 designed to improve efficacy compared to T-VEC. It uses a more cytotoxic HSV-1 backbone and retains T-VEC’s transgenes whilst incorporating the fusogenic GALV-GP-R− protein. This enhancement is intended to boost tumor cell killing and immune activation. In preclinical models including murine lymphoma and human lung and breast cancer cells RP1 showed superior efficacy, particularly when combined with anti–PD-1 therapy [50]. This prompted clinical trials of RP1 in solid tumors, including melanoma, with ICI.

An update of the Phase I/II trial IGNYTE (NCT03767348) combining RP1 with nivolumab in advanced anti-PD1-refractory melanoma was presented at the 2025 ASCO Annual Meeting. In 140 patients, the confirmed ORR was 32.9% (CR 15%, PR 17.9%), median duration of response was 33.7 months, with 1-, 2-, and 3-year overall survival rates of 75.3%, 63.3%, and 54.8%, respectively. [53] Deep/visceral injections (lung or liver) yielded a better outcome than superficial injections alone (ORR 42.9% vs 30%), without introducing major safety issues; low-grade pneumothoraces were observed in lung-injection subjects. Grade 3 TRAEs occurred in 9 and grade 4 events in 4 percent of patients. No grade 5 events were reported. The long-lasting systemic response of this combination in a difficult-to-treat setting will advance to a confirmatory Phase III IGNYTE-3 (NCT06264180) trial. Recruitment started in July 2024; primary completion is expected by January 2029. Notably, the FDA had granted Priority Review for RP1; however, in July 2025, the agency issued a Complete Response Letter (CRL), stating that the available data from IGNYTE were insufficiently controlled to support approval [69].

The Phase Ib trial NCT04197882 investigated OrienX010, an HSV-1–based OV expressing GM-CSF, in combination with toripalimab as neoadjuvant therapy for resectable stage IIIb–IV (M1a) acral melanoma. Among 30 enrolled patients, 27 completed surgery and neoadjuvant toripalimab therapy. The study reported radiological and pathological ORRs of 36.7% and 77.8%, respectively, including complete response rates (CRR) of 3.3% and 14.8%. Pathological response rate refers to the proportion of patients whose resected tumor specimens show a defined degree of tumor regression, defined by the proportion of remaining viable tumor cells on histopathologic examination after neoadjuvant therapy [70]. At a median follow-up of 35.7 months, the 1- and 2-year RFS rates were 85.2% and 81.5%, while the EFS rates were 83% and 73%, respectively. Grade 3 TRAEs occurred in 17% of patients, but no grade 4 events were observed. Notably, pathologic responses were associated with high densities of tertiary lymphoid structures and tumor-infiltrating lymphocytes [71]. These results underscore the potential of HSV-1–based OVs in hard-to-treat melanoma subtypes like acral and uveal melanoma.

MVR-T3011 is a novel oncolytic HSV-1, similar in design to T-VEC and RP1. Delivered intratumorally, it selectively targets tumor cells while sparing healthy tissue, by exploiting defects in the immune response pathways specific to cancer cells. Its dual expression of IL-12 and the fragment antigen-binding region (Fab) fragment of an anti-human PD-1 antibody allows it to modulate the TME in a unique way by simultaneously stimulating local immune activation and relieving checkpoint-mediated suppression directly within the tumor [72]. Currently, a Phase I/IIa trial (NCT04370587) is assessing the agent alone or in combination with pembrolizumab in advanced solid tumors, including melanoma. A recent update from the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO) presented data from 29 patients who received MVR-T3011 alone or with pembrolizumab, with a median follow-up of 14.1 months. Among 12 advanced melanoma patients previously treated with PD-1 or PD-1/CTLA-4 therapy, MVR-T3011 monotherapy resulted in an ORR of 25% and a 12-month PFS rate of 36.4%. TRAEs occurred in 76% of patients (10% with ≥G3), with pyrexia, fatigue, and flu-like symptoms being most common; no dose-limiting toxicities or new safety concerns were observed. CD8+ T cell infiltration increased in 47% of evaluable tumors and was more pronounced in those with clinical benefit [73]. The study is projected to complete by October 2025.

HF10 is a mutated strain of Herpes Simplex Virus type 1 (HSV-1) which has previously demonstrated oncolytic activity [74]. A phase II trial published in 2017 evaluated intratumoral HF10 in combination with ipilimumab in patients with unresectable metastatic melanoma and reported an objective response rate (ORR) of 41% at 24 weeks [75]. Another single-arm phase II study assessed the safety and efficacy of a 12-week neoadjuvant regimen combining nivolumab with HF10 in patients with resectable stage IIB–IVM1a melanoma. Pathologic analysis revealed a complete response (0% viable tumor) in 5 of 6 participants. The sixth patient experienced disease progression that precluded surgery. Upon recommendation from the Data and Safety Monitoring Committee (DSMC), the study was terminated early in 2022 [76].

The Phase I/II trial NCT03458117, completed in 2023, evaluated T-VEC monotherapy in patients with cutaneous lymphomas and advanced NMSC. Among 26 treated participants, the cohort included cutaneous B-cell lymphoma (n = 19), cutaneous T cell lymphoma (n = 5), CSCC (n = 1), and Merkel cell carcinoma (n = 1). An ORR of 32% was observed, with 84% of injected lesions showing clinical improvement. Notably, a 40% response in non-injected lesions was reported [79]. These findings confirm tolerability and also systemic activity of T-VEC monotherapy in NMSC and suggest a rationale for future trials exploring OV alone and in combination with ICI.

Another phase II trial (NCT03714828) presented at the American Association of Cancer Research (AACR) Annual Meeting 2024 evaluating T-VEC in cSCC showed a 100% ORR, with 90.9% achieving a CR and 9.1% a PR. Of 24 injected lesions, 96% showed a CR. Median time to response was 35 days, and median duration of response (mDoR) was 209 days. Compared to 2022 interim data, responses were faster and more durable, and patients had significantly fewer invasive tumors one and two years after treatment compared to prior timepoints (p = 0.0156 and 0.0312) [80, 81].

An ongoing phase II trial (NCT03069378) is assessing the efficacy of T-VEC combined with pembrolizumab in patients with locally advanced or metastatic cutaneous sarcomas. Both agents were administered concurrently on day 1 and every 3 weeks. In an expansion cohort, ORRs of 11% for undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma (MFS), 43% for angiosarcoma (AS), and 0% for epithelioid sarcoma (ES) were reported. The highest observed ORR was 71% in AS (5/7). Median PFS was 14.9 weeks for UPS/MFS and 54 weeks for angiosarcoma. The treatment regimen was generally well tolerated with only one patient developing a grade 3 TRAE (immune-mediated hepatitis) [82]. The results support the safety and potential efficacy of OV–ICI therapy in advanced sarcomas, especially angiosarcoma.

T-VEC is also being investigated in other rare NMSCs. NCT04065152 (KAPVEC) is a Phase II, multicenter intralesional T-VEC trial targeting classic and endemic Kaposi sarcoma. The study aims to determine whether the agent’s combined PR/CR rate exceeds 40%, following a lead-in phase of T-VEC administration every 2 weeks for up to 6 cycles. Results have not yet been reported, and data are currently pending.

T-VEC is also being explored in the neoadjuvant treatment of NMSC. In a phase II exploratory study involving 18 patients with BCC deemed difficult to resect, intralesional T-VEC was administered over six cycles (13 weeks) prior to surgery. The primary endpoint—avoiding the need for skin grafting or flap reconstruction—was achieved in 53% of patients. Additionally, partial and complete responses were reported in 24% and 35% of cases, respectively [83].

Across these studies, T-VEC demonstrated a similarly favorable safety profile, with adverse events primarily consisting of mild constitutional symptoms (fever, flu-like symptoms, and local ulceration) and injection site reactions. Grade ≥3 TRAEs were reported in 3.4–12% of patients.

As outlined in Table 2, the Phase I/II trial IGNYTE (NCT03767348) investigates RP1 alone or in combination with nivolumab in a variety of advanced solid tumors, including melanoma and NMSCs. The ASCO 2025 update focused exclusively on anti-PD1-refractory melanoma. However, interim results also showed promising ORRs for CSCC (47.1%), BCC (25%), Merkel cell carcinoma (75%) and angiosarcoma (66.7%) [84].

The Phase II CERPASS trial (NCT04050436) is evaluating cemiplimab with or without RP1 in unresectable CSCC. In December 2023 Replimune reported that the trial did not meet its two primary endpoints (ORR and CRR) as the predefined threshold for statistical significance (p < 0.025) had not been reached. The ORR was similar in both study groups (52.5% for RP1 plus cemiplimab vs. 51.4% for cemiplimab alone, p = 0.692). CRR, however, was increased in the combination arm with RP1 versus cemiplimab alone (38.1% vs. 25%, p = 0.040), almost reaching statistical significance. Duration of response was also increased with an HR of 0.45. Final results of the trial regarding DoR, PFS, OS as well as biomarker analyses are awaited [85].

The ongoing Phase Ib/II ARTACUS trial (NCT04349436) is testing RP1 monotherapy every two weeks up to a maximum of 25 doses in 23 SOTRs with advanced skin cancers. Interim data show an ORR of 34.8%, CRR of 21.7% and PR of 13%, with a DCR of 39.1%. Common side effects included fatigue, chills, and fever [86]. Importantly, no case of allograft rejection was reported in this cohort including patients with hepatic and lung allografts. These results are especially significant, as SOTRs are generally at high risk for NMSCs and are usually excluded from immunotherapy due to rejection risk. Continued investigation may establish RP1 as a valuable option for these immunocompromised patients, potentially expanding beyond skin cancers.

The mechanism of action of the novel oHSV-1 MVR-T3011 has been elucidated above and is summarized in Table 1 [72]. Currently, there are two trials for NMSCs investigating this OV: an ongoing Phase I/IIa trial (NCT05602792) is evaluating MVR-T3011 as monotherapy in a variety of solid tumors. Interim results presented at the 2023 ASCO Annual Meeting showed an ORR of 11% and a DCR of 49% among 55 evaluable patients (however, only for HNSCC, sarcoma, melanoma, and breast cancer). Common TRAEs included pyrexia, flu-like symptoms, elevated TSH, proteinuria, facial edema, leukocytosis, transaminitis, and anemia [87]. Results on NMSC are currently being awaited.

Another Phase I/IIa trial (NCT04370587) is assessing MVR-T3011 alone or in combination with pembrolizumab in a variety of advanced solid tumors. In the latest update from January 2023, 29 patients had been treated with MVR-T3011 alone or in combination with pembrolizumab. However, reported outcomes focused solely on melanoma patients, while data on NMSC are still pending [73]. Analysis of the final results will help elucidate the potential of this therapeutic approach.