A New Oncolytic Herpes Virus Could Be an Effective Second-Line Treatment for Advanced Melanoma

A genetically modified HSV-1 could help some melanoma patients live longer. The Keck Medicine of USC physician who led the research shares how.

A cancer-fighting herpes virus helped treat one-third of patients with advanced melanoma that was refractory to immunotherapy. Research from the IGNYTE clinical trial, whose study sites included Keck Medicine of USC and other locations worldwide, showed that a genetically modified herpes simplex virus type 1 (HSV-1) in combination with an immunotherapy (nivolumab) could be a promising new second-line treatment for advanced or nonresponsive melanoma after immunotherapy alone.  

Ahead, In discusses how this new oncolytic virus works to target and destroy melanoma tumors. He also discusses the implications of this new treatment for patients who are unresponsive to first-line melanoma treatments and provides insights on the safety and effectiveness of the therapy. 

How are oncolytic viruses like this genetically modified HSV-1 made? 

In: Cancer research with oncolytic viruses has been ongoing for almost 100 years. Dating back to the 1940-1950s, researchers would inject cancer patients with strains of normal viruses, because exposing patients to the virus would lead the body’s immune system to fight the cancer. These initial studies weren’t very successful, but over the last two to three decades, advances in gene-editing technology and the ability to modify different viruses have dramatically improved to the point where scientists have been able to develop better cancer-killing viruses. In particular, these new genetically modified viruses can be designed so that they don’t make patients sick from the virus. And they’ve also been modified so that they are better at killing cancer as well.  

To create RP1, the genetically modified herpes simplex 1 virus that we are using in this clinical trial, researchers first selected a strain of HSV-1 that was particularly effective at killing cancer in its native state and then chose to modify this strain by deleting two genes which normally would lead to the virus having the ability to infect humans and make them sick. By deleting those genes, the modified virus loses the ability to cause symptoms, such as bad cold sores. In addition, the virus is less apt to infiltrate and impact normal, healthy tissue in the body. So, that’s one very important aspect of the modifications that makes the therapy safer. (Disclosure: In has served on advisory boards for the manufacturer of the RP1 drug, from which he has received honoraria.) 

How is RP1 designed to target and destroy cancer tumors while generating an anti-tumor immune response?  

In: In addition, researchers then made another modification, which was to insert a gene into the virus so that the virus would release a factor, called GM-CSF, which stimulates the production of white blood cells. By doing this, the drug actually stimulates the immune system at the same time.  

Lastly, another gene was inserted into the virus DNA that affects how the tumor cells will be killed; specifically, the tumor cells infected by the RP1 virus will fuse together with other tumor cells, thus leading to further killing of the cancer.  

How does nivolumab enhance the effect of RP1? 

In: Cancer cells have the ability to hide from the immune system. Our body contains different proteins that prevent our immune system from attacking itself. Cancer cells can mimic that process. So, nivolumab is a medicine that helps reverse that process.  

Because it’s such a powerful drug that helps our immune system fight cancer, using nivolumab together with RP1 leads to a synergy that’s better than using either drug alone. Nivolumab is important in helping RP1 to work, especially for the other tumors that are not directly injected with RP1. 

Is there any difference in how effective the treatment is in superficial tumors versus deep tumors? 

In: Our expectation was that whether you injected superficial or deep tumors, we would see good responses in any injected tumors.  

And although our phase 2 study wasn’t necessarily designed to study this, in one sub-analysis that we just published earlier this year, it did seem that the overall chance of having a response to treatment might be better if you inject deeper tumors. The larger, ongoing phase 3 trial might help us more definitively answer that question. 

Why did the treatment also shrink or eliminate tumors that you did not inject? Is that a new finding with this therapy? 

In: Prior to the development of RP1, there was another FDA-approved oncolytic virus therapy that we had been using for melanoma treatment, called talimogene laherparepvec (T-VEC), which is a similar drug to RP1. T-VEC was very effective but only worked in tumors in which it was actually injected, which limited its use to very select patients.  

With RP1, which can be viewed as a next-generation version of T-VEC, we have observed that even non-injected tumors are responding to treatment. One of the big differences between RP1 and T-VEC is the additional genetic modification to RP1 that creates what we call a fusogenic glycoprotein, which triggers what’s called immunogenic cell death, a specific and important way that it kills these cancer cells. We think this helps better educate the immune system to attack the non-injected tumors. This effect of killing other non-injected tumors is known as the abscopal effect. In other words, tumors that were out of the scope of what was injected were also responding. And that’s always been a goal with these therapies. So, to finally see that happening is very powerful. 

Are there other cancers that might be treated with this method, or has it specifically only been researched in melanoma? 

In: The mechanism of action for RP1 is not specific to melanoma. These oncolytic viruses really should work in any cancer type because, at the end of the day, we’re using a virus to directly kill the cancer cells, and this virus won’t distinguish between different cancer types.  

The IGNYTE trial did include other cohorts looking at other cancer types. For example, there have been other skin cancer types for which this drug does seem effective, and going forward, the drug manufacturer will be looking at its use for other cancer types as well. There definitely are further implications for this drug and for the field in general. 

What scientific questions are you hoping to answer in the phase 3 clinical trial?  

In: In the initial trials, we were trying to look at whether this combination provided some meaningful benefit and outcomes for patients for whom other treatments had failed or patients who had already progressed after getting standard melanoma immunotherapy. The initial IGNYTE trial suggests RP1 with nivolumab could be a good second-line treatment, and the goal of the phase 3 trial is to try to prove that it might be a superior second-line treatment compared to other available options.  

In addition to patients getting RP1, the study will include a comparison group where patients will get other available treatments. The goal will be to determine whether patients treated with the RP1 injection live longer than the ones who don’t. 

How does this treatment improve melanoma survival rates? 

In: That will be an important question for us to answer with the phase 3 trial. But so far, from the IGNYTE trial, we saw that among the patients treated with RP1, 75% of them were alive after the first year, about 64% were alive at the second year and 54% were alive at year three. That’s quite promising. We’ll need more time to see how these patients fare beyond, and the phase 3 trial should provide more information about that as well. 

What is the first-line treatment for this type of melanoma? 

In: For patients with advanced melanoma, the first-line treatment is usually a PD-1 blocking drug, either nivolumab or pembrolizumab. And then oftentimes that’s combined with a second drug called ipilimumab, a drug that blocks the CTLA-4 protein. These are systemic drugs given intravenously, and they are used to treat many different tumor types. When we use PD-1 and CTLA-4 for our first-line melanoma patients, about 50%-60% of patients will do really well on them and may even potentially be cured. But nearly half of the patients will not respond well, and it’s still unknown how to best treat that other 50% of patients. That’s where this new second-line treatment could make a difference. 

Why do you inject this treatment into tumors if it also works systemically? 

In: When we look at those 50% of patients for whom first-line immunotherapy doesn’t work, it’s not really clear why those patients don’t respond to those therapies. It is generally felt that those tumors may be protected so that white blood cells cannot get into the tumors and thus are not able to fight these cancers effectively. So, one way to overcome this immune suppression is to inject these treatments directly into the tumors. This concept, using “intratumoral therapy,” is a rapidly growing area of research in the scientific community.  

But beyond that, we also know that if you introduce a medicine directly into a tumor, you can potentially use a higher dose of the medication because it will stay in the tumor and won’t cause as many bad side effects as a more systemic drug would. So, the hope with these intratumoral treatments is that they are both more effective and also safer. 

How safe is this treatment?  

In: I would argue that RP1, compared to almost any other therapy, is probably one of the safest drugs that we’ve studied in patients with melanoma. It does have a very consistent side effect profile in that it consistently may cause cold or flu-like symptoms with each treatment; the good news is that while these flu-like symptoms may be uncomfortable, they are not dangerous, and the symptoms eventually dissipate on their own. Even our older patients have handled this treatment very well, and we’ve had patients even in their 90s who handled this treatment very well. 

Phase 3 clinical trial now open 

Phases 1 and 2 of the IGNYTE clinical trial examined the safety, side effects, best dosing and effectiveness of administering RP1 along with nivolumab in a limited patient population. In and his fellow researchers have launched the phase 3 trial, known as IGNYTE-3, to confirm their findings in a global population of more than 400 participants. 

Keck Medicine will again be one of the sites participating in the clinical trial, with In heading up the site. Patients interested in participating can contact Sandy Tran at sandy.tran@med.usc.edu. 

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