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Vusolimogene oderparepvec An oncolytic herpes simplex virus given by injection into the tumour, approved by the FDA in August 2026 in combination with nivolumab for advanced cutaneous melanoma that has progressed on a PD-1 blocking antibody. It kills tumour cells directly and turns the tumour into a target the immune system can then see elsewhere in the body.
- Works in melanoma that has already failed a PD-1 checkpoint inhibitor
- Responses appeared in lesions that were never injected, including visceral ones
- Complete response in 15 percent of a heavily pretreated population
- Median duration of response of 33.7 months
- Most treatment-related adverse events were grade 1 or 2, with no grade 5
- Herpetic infection or reactivation
- Complications of the injection procedure itself
- Immune-mediated reactions, compounded by the nivolumab it is given with
- Grade 3 events in 9.3 percent and grade 4 in 3.6 percent
Overview
Melanoma that progresses on a PD-1 checkpoint inhibitor has been one of the harder problems in solid tumour oncology, because the standard next options are limited and the disease has already demonstrated that it can ignore the main immune brake being released [1].
Vusolimogene oderparepvec is a herpes simplex virus type 1 that has been engineered four ways. The neurovirulence factor ICP34.5 and the antigen-presentation inhibitor ICP47 are deleted, which stops it behaving like wild-type herpes and stops it hiding infected cells from T cells. Two genes are added: a fusogenic glycoprotein from gibbon ape leukaemia virus, which makes infected tumour cells fuse with their neighbours and die in a way that spills antigen, and human GM-CSF, which recruits the cells that pick that antigen up.
The pivotal evidence is the IGNYTE trial, published in the Journal of Clinical Oncology in 2025. Of 140 patients with melanoma that had confirmed progression on anti-PD-1, 65.7 percent with primary resistance and 46.4 percent already exposed to both anti-PD-1 and anti-CTLA-4 therapy, the confirmed objective response rate on independent central review was 32.9 percent, with complete responses in 15.0 percent. The median duration of response was 33.7 months. Survival was 75.3 percent at one year and 63.3 percent at two [1].
The result that matters most is where the responses appeared. They occurred with similar frequency, depth and duration in lesions that were never injected, including visceral ones, which is the difference between a local treatment and a systemic one [1].
The approval is an accelerated one, granted on response rate and duration, and it followed two complete response letters.
- The responses in lesions that were never injected were similar in frequency, depth, duration and timing to the responses in lesions that were, which is the whole argument for calling an intratumoral therapy systemic [1].
- The virus carries a fusogenic protein borrowed from gibbon ape leukaemia virus, which makes infected tumour cells fuse with their neighbours and die together.
- Two herpes genes are deleted rather than added: ICP34.5, which makes wild-type HSV-1 neurovirulent, and ICP47, which would otherwise hide infected cells from T cells.
- Laboratory work found the interferon response starts in the immune cells rather than the tumour cells, and is passed to the tumour without the two needing to touch [2].
- The FDA issued two complete response letters before approving it.
Mechanism
Two mechanisms run at once, and the second is the point of the drug.
The direct one is lysis. The virus replicates preferentially in tumour cells, and the added gibbon ape leukaemia virus fusogenic glycoprotein causes infected cells to fuse with neighbouring cells, so a single infected cell takes a group with it. That form of death is immunogenic: it releases tumour antigen alongside viral danger signals rather than quietly disposing of the cell.
The indirect one is a remodelling of the immune environment, and laboratory work has pulled the sequence apart. Virus in the tumour is sensed by immune cells rather than by tumour cells; those immune cells mount an interferon response through STING and transmit it to the tumour cells without needing contact, and the tumour cells respond through JAK-STAT signalling by raising surface MHC class I and PD-L1 [2]. Raised MHC class I makes the tumour visible to T cells. Raised PD-L1 is what makes the nivolumab half of the combination do work it could not do alone, which is the argument for pairing an oncolytic virus with a checkpoint inhibitor rather than giving either by itself [2].
In IGNYTE this showed up as broad immune activation associated with response, including increased CD8 T cell infiltration and increased PD-L1 expression, and clinically as responses in lesions that were never injected [1].
receptor fingerprint
Tumour cell lysisAgonist
STING pathwayAgonist
PD-L1 expressionInducer
MHC class I expressionInducer
GM-CSFAgonist
Safetyrisks and cautions, not medical advice
The label carries warnings for accidental exposure, herpetic infection or reactivation, complications of the injection procedure itself, and immune-mediated adverse reactions. Healthcare providers, caregivers, close contacts, pregnant women and newborns are told to avoid direct contact with injected tumours, dressings and body fluids, because the treatment is a live virus and it is shed. Herpetic infection or reactivation is to be assessed and treated as clinically warranted.
In IGNYTE the treatment-related adverse event rates were 77.1 percent grade 1 or 2, 9.3 percent grade 3 and 3.6 percent grade 4, with no grade 5 events; most of what patients experienced was mild or moderate [1]. The immune-mediated toxicity profile of nivolumab applies on top, since the drug is only approved in combination with it.
A deletion of ICP34.5 is what removes the neurovirulence of wild-type HSV-1, and a deletion of ICP47 restores antigen presentation; both are structural rather than dose-dependent protections. That does not make the virus inert, and the contact precautions in the label exist because it is not.
History
The virus was built at Replimune as RP1, the lead of a platform of engineered herpes simplex viruses. It entered the clinic in September 2017 in IGNYTE, a phase 1/2 study of RP1 alone and with PD-1 blockade across solid tumours, and was studied separately in organ transplant recipients with skin cancers, a population usually excluded from immunotherapy trials. The melanoma cohort read out with a 32.9 percent confirmed response rate and a 33.7 month median duration of response [1]. The path to approval was not smooth: the FDA issued two complete response letters before granting accelerated approval on 6 August 2026, in combination with nivolumab, for unresectable advanced cutaneous melanoma that has progressed on an anti-PD-1 based regimen.
Reputation
Oncolytic virus therapy has had one approved product in melanoma for a decade, talimogene laherparepvec, and its reputation has been that it works locally and rarely does much at a distance [3]. Vusolimogene oderparepvec is watched because its responses in uninjected and visceral lesions were similar in frequency, depth and duration to the injected ones, which is the claim the field has been trying to substantiate since the beginning [1]. Enthusiasm is tempered by the regulatory history, two rejections before approval, and by the fact that the pivotal data are single-arm; the population studied, melanoma already progressing on anti-PD-1, had few good alternatives, which is both why the result matters and why it is hard to benchmark.
Subjective profileweighing the evidence above
A genuine result in a setting that had almost nothing: melanoma still growing on a PD-1 inhibitor, with a third of patients responding, one in seven completely, and responses running to a median of nearly three years. The finding worth taking seriously is that uninjected and visceral lesions responded like injected ones, which is what separates this from a decade of oncolytic viruses that only ever worked where the needle went. The caveats are real and structural: a single arm with no control, two prior rejections, an approval that is conditional on a confirmatory trial, and a treatment that is a live virus requiring eight visits and household precautions.
Resources
No suppliers are provided for compounds like this. This entry is here for reference.
Research
- 1.RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE).
- 2.Effects of oncolytic immunotherapy with RP1 (vusolimogene oderparepvec) on immune cells mediate responsiveness to anti-PD-1 via STING-mediated interferon signaling.
- 3.Advances in Oncolytic Viral Therapy in Melanoma: A Comprehensive Review.
3 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is this really a live virus being injected into a tumour?
Yes. It is a herpes simplex type 1 virus with two of its genes deleted and two others added. The deletions remove the neurovirulence of wild-type herpes and stop it hiding infected cells from the immune system. It still replicates, it is still shed, and the label carries contact precautions for the people around the patient.
How can injecting one tumour help the others?
The virus kills tumour cells in a way that releases their antigens alongside danger signals, and the GM-CSF it carries brings in the cells that collect those antigens. The immune response that follows is systemic. In the trial, uninjected and visceral lesions responded at a similar rate and for a similar length of time to injected ones.
Why is it given with nivolumab rather than alone?
The virus raises PD-L1 on the tumour, which is the brake nivolumab releases. Laboratory work traced the sequence: immune cells sense the virus, mount an interferon response through STING, and the tumour responds by raising both MHC class I and PD-L1. The two drugs are doing consecutive halves of one job.
Who is it for?
Adults with unresectable advanced cutaneous melanoma whose disease has progressed on a PD-1 blocking antibody. That is a population with limited options, which is the reason the approval happened on a single-arm trial.
What does the treatment schedule look like?
Eight injections, one every two weeks, with the volume set by the size of the tumour up to 10 mL per visit. Superficial lesions are injected directly; deep and visceral ones are injected under imaging guidance. Nivolumab starts in week 3.
Limitations of the evidence
- Accelerated approval on a single-arm trial; no randomised comparison exists
- Only approved in combination with nivolumab, so the two contributions cannot be separated
- Requires eight visits over sixteen weeks for injection, some under imaging guidance
- Restricted to cutaneous melanoma; the other tumour cohorts are still in trials
- It is a live virus, and household contacts have to take precautions
Adverse effects
- Herpetic infection or reactivation
- Complications of the injection procedure itself
- Immune-mediated reactions, compounded by the nivolumab it is given with
- Grade 3 events in 9.3 percent and grade 4 in 3.6 percent
Notes and cautions
- Caregivers, close contacts, pregnant women and newborns are told to avoid contact with injected tumours, dressings and body fluids.
- The confirmatory trial is a condition of the accelerated approval.
- Talimogene laherparepvec, the first approved oncolytic virus in melanoma, is the comparison everyone reaches for, and no trial has run the two against each other [3].