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Mohammed M. Milhem, MBBS, discusses the unique elements of oncolytic vaccines in oncology and ongoing research with RP1 in melanoma and other solid tumors.
Oncolytic vaccines, such as vusolimogene oderparepvec (RP1), have generated significant excitement throughout oncology, explained Mohammed M. Milhem, MBBS, citing the ease of administration, mild toxicity profile, and fast-onset responses as distinguishing features of this class of agents for patients who develop progressive disease on standard frontline therapy with PD-1 inhibitors.
In an interview with OncLive®, Milhem, the Holden Chair of Experimental Therapeutics, associate director of clinical research and director of the Melanoma Program, Holden Comprehensive Cancer Center, director of the Division of Hematology, Oncology, and Blood & Marrow Transplantation, and a clinical professor at the University of Iowa Hospitals & Clinics, discussed the unique elements of oncolytic vaccines in oncology and ongoing research with RP1 in melanoma and other solid tumors.
Milhem: RP1 is an oncolytic virus, and it’s second in its class. RP1 was preceded by talimogene laherparepvec [T-VEC; Imlygic], which is now FDA approved. [Both agents are] a live herpes virus that has been genetically engineered to make granulocyte-[macrophage] colony-stimulating factor [GM-CSF]. [RP1] is a little different than the current virus that exists in our FDA pool, in that it’s a little bit more potent, it has more replication, and it might cause more cell fusion as they bombard each other. [RP1] makes GM-CSF, which is a beacon for white cells to come to the area so that they can be there [to] affect the immune system [with] cells like T cells, B cells, and macrophages––things that can present the tumor antigens to the immune system.
[RP1] is an intratumoral injection, so you have to inject it into the tumor. The herpes virus has lost its virulence against the human disease, so it doesn’t make herpes, it just attacks the tumor cells. There is a limiting ability for it to go beyond that and make herpes. [RP1] replicates within the tumor, so the mechanism of action is such that it goes inside the tumor cell, takes over the DNA, the DNA is then replaced by the viral DNA, which makes the GM-CSF. The tumor makes its killer. GM-CSF is made in large amounts and white cells come. [RP-1] is an oncolytic virus, which means it lyses the cells and breaks them up so that all the antigens are present for those white cells to take their presentation to the immune system.
In the presence of a PD-1 inhibitor where you block programmed cell death on the T cells, you might have a more robust presentation of the tumor to the immune system, where T cells are working a little bit harder because of the PD-1 [inhibitor], and that’s the idea behind the whole trial.
In the field of immune therapy when you don’t see the drugs that work the best fail, the space becomes incredibly narrow. Our problem right now is in patients who fail on a PD-1 inhibitor or the combination of a CTLA-4 inhibitor and a PD-1 inhibitor.
[That scenario] tells us that there are other mechanisms in the immune system that are required for us to activate that we don’t yet understand or know. A monoclonal antibody to me is like a dirty drug; it’s a little antibody that binds a receptor that’s found on a surface. We haven’t gone into the second-generation immune therapies, which are coming, that are a little bit more targeted, that can influence the cells, that can cause the cells to migrate or to go into the tumor environment and fight. In that space, that’s what’s missing.
Our current knowledge is not enough to truly tell us what the next step is. It’s a space that needs to be examined and studied. In the absence of an actionable mutation like BRAF or NRAS, there are a limited number of options that are available. We have, in the United States, about 9000, maybe even more clinical trials with immune therapy, but a lot of them still don’t give us the answer of what to do in someone who has failed frontline therapy with the basic treatments that we currently have. It’s a crowded space, but it’s incredibly narrow in us trying to define what the next step is for those patients. This is where this potential treatment has an opening to improve the outcomes of patients in that space.
I was one of the clinicians that started using intratumoral injections, and it may appear to be a daunting task to inject, but, in reality, it’s a combination of two groups of people: it’s the oncologists and the interventional radiologists. If you have a good interventional radiology group, you can target almost any lesion. What’s good about the RP1 trial is that the investigators weren’t afraid to inject visceral lesions like the liver; they weren’t afraid to go for deep nodes, which are deeper in the retroperitoneum. They allowed a variety of injections. The more common places that a lot of injectables are going into are the skin lesions and the lymph nodes that you can see or feel to make it easier for people to inject.
The easy way for us to understand it is that it’s just like a biopsy. You’re going in for a biopsy, you have a needle in there, all you do is inject something into the tumor and come out. Intratumoral injection is the same as getting a biopsy of that patient; it’s just more frequent. You have to be very consistent, and your methodology needs to be pretty consistent in how you deliver that drug. In general, it’s not so daunting.
It’s also rewarding on the patient side, especially if they have superficial tumors because if they do respond, they see it right away. If it’s in your lung, and it’s hidden, you don’t see it while you’re getting your therapy. You don’t know if [the tumor] grew five times before you do your scan before it shrunk. This is an opportunity for the patients to see their disease disappear before their eyes if it’s working. If it’s not working, they can also see that, and that’s also frustrating, but at least there’s an immediate gain in that there might be that immediate response that some people get. It’s also a faster time to response if people do respond.
Good interventional radiologists can access almost any tumor. The hardest space to inject would be the lung because you risk all the complications with injecting the lung, but in general, a lot of lesions are accessible to the needle.
The superficial [lesions] can be done in the clinic. In the [RP1] trial, there’s a lot of emphasis on shedding and trying to understand how viral shedding works. There’s a lot of capture in explaining that, which is important because if it does get approved by the FDA, then these practices would have to be materialized and put into place. But, in general, in the clinic, it’s easy; you find your lesions. I tend to go for the ones that are growing the fastest or look the biggest, and then sort of work my way down once they start to respond to the other lesions that are around. There is a set amount that you have to inject; it’s built on the size of the tumor and each injection is given based on the size of the tumor. There’s really no guidance on exactly how you do this; you learn it as you go.
The deeper lesions are usually done through ultrasound, sometimes CT-guided biopsies. It’s important to get the patient on a regular schedule. In the RP1 study, 9 injections are given every 2 weeks. Once we picked the schedule, we made sure that they were scheduled out for 9 times because it’s an ultrasound, [so you’re on] interventional radiologist’s time. That’s the only difference [between the clinic and an academic center] is that we have to plan out ahead. When it’s in clinic, it’s a lot easier. You don’t have to plan that out. You can have the variability and start whenever you want. With the ultrasonographer and the interventional radiologist, there was a little bit more planning [because] the interventional radiologist [is really the person] who does the injection.
It’s this refractory space. It’s where we need a signal and a drug that can work. The interesting thing about RP1 is that it’s nonspecific for cancer; it doesn’t have to be [used only in] melanoma, it can be [used in] cutaneous squamous cell or head and neck cancer. It would be nice to get it into tumors that don’t work at all like sarcoma. It’s meant to be a drug that’s agnostic to tumor type, it should be able to go into any tumor, it should be able to replicate within it, it should be able to create GM-CSF in large amounts and bring the white cells [into any tumor].
Whether the immune system will recognize the tumor, [we don’t know]. Maybe you can think of it as an in-house vaccine where you’re building this immune system to try to educate it about how it’s going to use it. That’s probably the first step to try and get it in another cancer. Then, [we would like to] move it into other tumor types that truly speak to its agnostic role, like the PD-1 inhibitors that can now treat more than one cancer.
It [really has to do with] the rapidity with which the tumors shrink. The adverse effect [AE] profile is quite interesting, too. When you do inject the tumors and they do make GM-CSF, patients do get the flu. They do feel achy, they get a fever, [but we encourage] our patients by saying not to worry because that means their immune system is working, which is great. This is a good symptom, but it’s a limited time. It’s only for 1 day when they get that injection, and it’s well tolerated. I haven’t seen people get into trouble because of that. In general, the AEs that have been published so far, there aren’t that many AEs except for this acute reaction that occurs just as you inject patients. It shouldn’t be a daunting treatment. Injectables are an interesting way to put the drug into the tumor microenvironment.
Viral biology is interesting because it stays within the tumor. What’s hard is when you take saline or you take another injection and you try to inject it into the tumor, it kind of seeps out of the tumor. You want it to stay in the tumor microenvironment and by forcing it to be a virus which then binds the cell, goes in and changes its DNA, puts its DNA inside the tumor, you’re really telling it to stay inside the tumor microenvironment.
The more robust we can get it to replicate within the tumor microenvironment and reach out to as many cells in that area, [the better]. Maybe [we should] move the injection in more than one place so that we have adequately put it in the places that it needs to be. It would be nice to figure out better ways to keep the drugs inside the tumor microenvironment. But that’s a challenge across a lot of injectables. One of the things that I’m paying attention to when people are presenting new molecules to me is how long is it going to stay inside that microenvironment?
With a virus that advantage is there already [because] it forces itself into the cell, it stays in the environment, it’s fighting, it replicates, it makes more of it, and then it just keeps on infecting the cells as it goes forward. It’s very interesting and is certainly is an area that I’m excited to learn more about and to see evolve over the next year or so.