Ravi Patel, MD, PhD, radiation oncologist at UPMC Hillman Cancer Center and assistant professor, Department of Radiation Oncology and Bioengineering at the University of Pittsburgh School of Medicine, talks about new treatments in metastatic melanoma cancer.
You’re a clinician-scientist, clinician-researcher?
PATEL: Yeah. So, my job is that I see patients, but I also have a research lab where I’m trying to come up with new treatments for cancer. You know, we have very good treatments here at Hillman for cancer patients, but unfortunately there are some patients that we just can’t cure their cancer and there’s room to do better. And as a researcher, that’s what my work focuses on is how can we improve outcomes? And so, I have a research lab that studies those types of questions.
I want to just start there. We had talked just a little bit about melanoma. Can you describe what you and your colleagues are studying currently in terms of treating melanoma that just seems to be resistant to other treatments and to immunotherapy?
PATEL: Really the treatment of melanoma has been revolutionized over the last 10 years. As many people know, Jim Allison won the Nobel Prize and Dr. Honjo for their discovery of immune checkpoints, and we’re able to now cure patients with metastatic cancer or extend their survival quite significantly. But there’s still a significant proportion of patients that become resistant to these standard immunotherapies and, when they become resistant, there’s few effective treatments. One thing that we’ve found preclinically in research models is that radiation can stimulate an immune response or re-stimulate a response in these resistant tumors. But radiation therapy is a quite toxic therapy that can only be usually delivered locally to a single site. What my work, and my colleagues at Wisconsin when I was there, we were looking at low-dose radiation therapy that’s delivered to all sites of tumors where we can stimulate an immune response. And unlike the radiation that we’re using typically to treat patients where the goal of the radiation is to kill the cancer cells with a high dose, in this setting we’re just delivering a very low dose to stimulate the immune system, not necessarily to kill cancer cells.
So that radiation is not, if you’re thinking of radiation, it’s that targeted therapy, just point it at that cancer spot. This is different.
PATEL: Different, yeah. It’s actually kind of like a drug. It’s injected just like chemotherapy, but it’s preferentially taken up by tumor cells. And because we’re delivering such a low dose, about one to 5% of the dose that we would use for therapeutic radiation to kill cancer cells, it’s much less toxic. And really what we found was that delivering higher doses isn’t better. And when we deliver this low-dose radiation, we can restore efficacy of these immunotherapies that we’re using in the clinic. So, we were quite excited by that result.
You’ve delivered this in conjunction with the immunotherapy, so it’s not like you stopped one and go on to the other. Can you explain how that works?
PATEL: Actually, either one of these therapies alone isn’t very effective. It’s almost like there was no treatment. But when we give the combination, we studied the timing of the radiation, low-dose radiation therapy versus the immunotherapy, and we found that if we give it before or after, it doesn’t make too much of a difference, but we have to give them together. And when we give them together and we’ve studied it in three different tumor models, a melanoma model, a neuroblastoma model, and a breast cancer model we found that, in these resistant tumors, we’re able to cure 50% of those tumors in these mice models.
Does it seem to be more effective or more reactive in the melanoma model? Is that where you’re seeing the most success, doctor?
PATEL: So, I think that’s where we’re going to clinically try this therapy first, but interestingly we found it to be effective in multiple different tumor models. And the radiation we’re using isn’t targeting melanoma specifically. We found that this agent that we used in my study has uptake in over 70 different types of tumors. So, it’s really histology independent. How well it works does depends on the immunogenicity of the tumor, and we do typically think of melanomas as more immunogenic tumors. But I think this type of tumor, this type of treatment can be translated beyond just melanoma into other cancers as well.
You’ve tested this in both a mouse model and a canine model. Can you tell me a little bit about that and what you found?
PATEL: So, we collaborated with the veterinary school at the University of Wisconsin. Just like humans, many pets get cancer, and they would go to the veterinary school. And we had a clinical trial where we were testing this low-dose radiation therapy in people’s pets who have cancer. And we found that we were able to deliver this low-dose radiation quite effectively to all sites of disease in these canine patients. And so, it supports that, even in naturally-arising cancers, we can deliver this low-dose radiation safely and without toxicity. And that gives us more support to try and move this into clinical trial in patients.
Can you talk to me again about what adding the radiotherapy to the immunotherapy, does it boost the immunotherapy or what’s a good way to describe what it does to get the immunotherapy to do the work that it needs to do?
PATEL: So, one of the hallmarks of cancer is that it suppresses the immune system. We know from AIDS patients who develop very weird cancers that don’t happen in a normal population or patients who are in immunosuppression after transplant they get more cancers. So, we know the immune system is really important for holding cancer back. When we give treatments like chemotherapy or immunotherapy, cancers become resistant to those therapies. What radiation does that we found was that it stresses those tumors. It up-regulates genes that activate an immune response and it also removes some immunosuppressive signals that are there, present in the tumor when they acquire resistance. It acts almost as a reset of the tumor microenvironment to allow new immune cells to come in and restore efficacy of these immunotherapies that we’re using.
Was the jump from, as you mentioned, the canine and the mouse models, very successful, to actually having this in human clinical trial. What do you still need to do before it gets to that point and what kind of a time frame before you can do clinical testing?
PATEL: I was working with a particular agent, NM600. The nice thing about this agent is that it’s histology independent. It has uptake in all kinds of tumors of different histologies. I was working with a company that patented this compound and they’re working on getting an IND or finalized safety approval. And hopefully I think they want to move it into clinical trials in the next year or two as an early-phase clinical trial. But this concept, I’m also working with other companies that have radiopharmaceuticals, this concept doesn’t depend on just this agent. We can deliver low-dose radiation with agents that are already past FDA approval, and I’m talking to a few companies to try and move that along.
When you deliver this, is it IV or is it pill form?
PATEL: It’s IV.
So, it’d be almost like a chemo drip.
PATEL: Yep, exactly.
It would be an IV drip to administer…?
PATEL: Yep.
And again, time frame is hard to tell at this point?
PATEL: Yeah. I’m hoping, I’m hopeful that, in the next year or two, we’ll have a trial. I think there’s interest in this concept,
PATEL: Especially after we published our results. I think that there has been interest that I think, in the past, people have been trying to deliver very high doses of radiation, and that has lots of toxicity, and that kind of hindered people from going towards this direction. I think that now that we’re finding that we can deliver much lower doses, it’ll make this treatment much more attractive because we don’t have to deal with all those toxicity concerns.
It might sound like a simple question, but why is it so important that clinicians have something else to offer these patients for whom the immunotherapy is just not working? About what percentage of patients have immunotherapy and have no response to it?
PATEL: So, in melanoma, if you count when we’re going for a cure, many patients sometimes have an initial response and then eventually the immunotherapy stops working. So, it varies, but about 60% of patients will eventually progress or develop resistance. Some patients, they’re just not able to tolerate the immunotherapy as well. They get toxicity, or they might not be able to tolerate the strongest immunotherapies. So, there is a need to have better treatments.
You said about 60% will not have a full response to it?
PATEL: Or a long-term cure. And that’s really 10 years ago, we weren’t talking about curing patients, we were talking about just extending survival. And that’s really shown how things have changed. Now we’ve set our goals higher. Our thinking has changed, it’s not just good enough to extend survival, we want to eradicate someone’s cancer even when it’s in the metastatic setting.
Is there anything I didn’t ask you, doctor, that you would want patients to know about the study that you’re doing? About the potential for this as a treatment down the road?
PATEL: I’m excited about this work. I think that it has a lot of potential not just for melanoma, but for all different types of cancer. I think when I’ve actually had patients come and ask me about this treatment. It’s hard because you want to have something there for them right away. So, I want my patients to know I’m working on getting this moving forward. And all of us at the Hillman Cancer Center, both on the clinical side and on the research side, the reason we’re doing this is for our patients to try and improve their outcomes. Cancer is a difficult diagnosis. And being in the clinic, it’s an honor to be a part of my patients’ care, and I know that that’s the reason we’re doing all this research.
Radiopharmaceutical that you mentioned was it MX?
PATEL: Sorry, it’s NM600.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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