Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie. And today, we're offering updates on a previous version of brain tumor therapy podcast. In this panel is Dr. MR Chambers. She's a veterinarian, a neurosurgeon and a professor at UAB Medicine; and Dr. James Markert, he's the James Garber Galbraith Endowed Chair of Neurosurgery at UAB Medicine.

Doctors, welcome back. I'm so glad to have you updating this fascinating topic. And Dr. Markert, I'd like to start with you. Tell us a little bit about the thought previously regarding brain tumor therapies. We did a previous podcast on this topic, you and I. What's different now? Why are we updating this?

Dr. James Markert: Well, I think that we have published some additional studies in this area and we wanted to make sure that this information was getting out. And there's been a lot of effort as you know from our previous discussions in trying to improve the outcomes for these patients. Unfortunately, malignant glioma, in particular glioblastoma, remains a fatal disease. And despite all the different efforts that have been made in refining surgery, radiation treatment, and chemotherapy, we still are left with a situation where we're unable to cure this disease. So our efforts at UAB have been centered on trying to develop new therapies to help with outcome in this particular patient population.

And our work has particularly involved the use of immunotherapies or trying to use the immune system to help combat these terrible cancers. Our laboratory has been working on the use of specific viruses, mutant viruses called oncolytic viruses. They can actually be utilized to infect cancer cells, in this case malignant glioma cells and kill the cells directly, as well, as provoke an antitumor immune response by the patient's immune system. We wanted to speak to you to give you an update on some of the studies that have been done since the last time we spoke with hopes of continuing to develop these therapies in such a fashion that we're able to help extend survival in this terrible disease process.

Melanie Cole, MS (Host): Well, I'm so glad that you did, because it is such an interesting topic and really all of these parts to it are what are so interesting. I feel now, Dr. Chambers, there are many shared factors between people and their pet dogs. I would like you to give us an update on anything that has changed in research studies that you're involved in, that other providers may not know about. Tell us about some of the new publications and what's changing in that regard.

Dr. MR Chambers: Right. Thank you. The first ever combination immunotherapy trial is underway. We have collaborated with regional veterinary colleges. Including Georgia, Auburn, Mississippi state, as far as Purdue and we're part of a group through the NIH Moonshot with other veterinarians who are studying combinations of immunotherapy for these dogs with spontaneously occurring gliomas.

So in our trial, we're using the same oncolytic herpes virus that we use in the human, combined with checkpoint inhibitors in the dogs. Well, we have several publications to date regarding the trial design, the safety data, which was our first step to demonstrate that the virus was indeed safe in the dog, and now we're looking at its effectiveness. And so we've published our interim in the Journal of Translational Genomics and Genetics. So we're very excited. We've completed stage one, which is treatment with the virus and we're enrolling dogs now in stage two, which is the combination therapy, the virus plus a checkpoint inhibitor.

Melanie Cole, MS (Host): Dr. Chambers, how do you see these clinical trials going from bench to bedside?

Dr. MR Chambers: Well, I think the work with the dogs, the most important part of this work is to demonstrate that the dog is indeed a sound and ethical model for the humans. So this is a translational model. That's the very reason for this study, is to compare and contrast the responses in the dogs with the humans. Knowing how similar they are, we can then take results from the dog, which developed much more rapidly than the human to clinical trials for humans. And so it expedites and facilitates study of different combinations of therapies to then translate directly to the human.

Melanie Cole, MS (Host): Dr. Markert, what about you? What would you like to tell us about some of the new publications and research that you find is so exciting?

Dr. James Markert: Well, I'd like to talk about first a study that we just published in clinical cancer research and then three additional studies that are in progress or about to be in progress. The first step, a study that we published with a group at Nationwide Children's Hospital was based upon a study that we did several years ago here at UAB, but new techniques and new technology has allowed us to go back to those tumor samples from that study and really educate ourselves more about the immune response that is occurring in these patients when they have a response to the treatment.

And what we found in these patients who were treated with the virus through direct inoculation into their tumors, and then subsequently within two to five days after that initial treatment had a craniotomy and a resection of their tumor followed by additional treatment with more virus right at that same operative setting, we were able to use the tumor specimens that we resected and look at what was happening in response to the treatment of the virus. And what we found using this new technology called RNA-seq and NanoString was that the tumors when analyzed after treatment had a remarkable activation of immune system pathways consistent with a response that indicated the tumors were being besieged, if you will, by the immune response to the viral infection. And when we look specifically at patients who had had the best response to treatment with the virus in the longterm, we found that even very early in the short-term, we could see some profound immune responses occurring, particularly with regards to certain subpopulations of cells, namely cytotoxic CD8 and CD4 cells, as well as NK cells. So, this is very exciting to see that we could see this early on in response to the viral treatment. And it has given us new ideas about how to play in future studies so that we might be able to look at results early after treatment and perhaps better adapt the treatment for patients in future studies.

The other studies that I wanted to mention were using different viruses that have been created and approved by the Food and Drug Administration for use in clinical trials since that first study. And these viruses are one that has been utilized in the canine studies as well, one called M032, which is a virus that is still a herpes simplex virus, but we engineered it genetically, so that it also expresses interleukin-12, which is a cytokine that produces an antitumor immune response, almost like a vaccine effect against the particular tumor antigens. And we've recently finished enrollment in this study with a total of 21 patients that have received this virus. And we're very excited to see the early data from this. We still in fact are analyzing a lot of the data and some of the data has not actually even been collected yet because we have surviving patients that we're still collecting data on.

But in fact, we do see that some patients are living much longer than they should even though the fact that some of these patients have been treated with multiple previous treatments, like three surgeries in some cases, multiple chemotherapies. Many of these patients are quite far down the road and yet still had nice responses to treatment. And what we also found was that some of these patients went on after viral treatment to get a resection of their tumors later than that first study that I talked about. So instead of being two to five days later, the patient might come in a month later or six months later with a tumor that might look bigger on a MRI scan. So we would take them to the operating room and resect the tumor, and then look at this with our pathologist. And what we saw in almost every case was that these tumors now had a distinct infiltration of immune cells, indicating that the virus could produce a change, if you will, in the immune system's ability to recognize the tumors, and that the response was a lasting, a durable one. So these are very exciting findings.

We similarly in the second study that I mentioned, which utilizes a different virus, a virus called C134 and that virus does not express IL-12, but instead expresses a gene from a similar virus called CMV, which helps increase the immune response against the tumor and also helps the virus replicate a little bit better in the tumor cells. Again, with this virus when we've gone back and resected patients' tumors months or after treatment, we have seen this increase in immune response to the tumor. So this is a very exciting finding in both cases. And it indicates that we're able to take these tumors, which really are below the surveillance of the immune system in ordinary circumstances and bring them into the floor, if you will, so that the immune system can find and recognize these tumors and we hope have the potential to treat them better in the future.

Melanie Cole, MS (Host): That's fascinating. And Dr. Chambers, what would you like to add to this?

Dr. MR Chambers: Well, even as I was listening, Dr. Markert made a great point that these viruses stimulate the immune system, then sort of ramps up this response and the immune system can recognize and attack. So we're seeing this in the dogs as well. With our interim results, we have NanoString and we're working on RNA-seq now, but our NanoString results have shown infiltration of immune cells into the tumor microenvironment. So this is a powerful treatment. And as we develop more and different viruses, I think we'll see even better responses.

The great thing about these studies is that we can translate not only from the dog to the human, but from the human to the dog. So we can share information from one study to the next. And so our next study on the dogs would be to combine different immunotherapies and to come back after treatment and rebiopsy. You know, as Dr. Markert pointed out earlier, we are delivering this virus into the tumor or the tumor bed. And so it's not an intravenous or an oral delivery, we're actually putting the virus into the residual tumor. And we can come back and test that tumor tissue or the tumor microenvironment to see what kind of response we're having. And in fact, we use NanoString on the dogs and we've seen a significant change in the tumor microenvironment to an immune response signifying that we are having an effect with the virus alone.

Melanie Cole, MS (Host): You are the doctors that are advancing medicine. You really are. And I'd love for you both to give us a final thought. And Dr. Chambers, starting with you. You're speaking to other providers that are as interested as I am in the research that you're doing. What do you want them to know about what's coming up, getting involved in your clinical trials or any publications you want them read?

Dr. MR Chambers: Right. Of course, they can look at our publications from the dog as well as Dr. Markert's publications treating the humans. I think the most important message that I have is how exciting this is going forward, how immunotherapy and combination immunotherapies do have an application toward gliomas or spontaneously occurring tumors in the dog. And most importantly, that we can share information from this translational model and advance the field.

Melanie Cole, MS (Host): I'm sure that you can. And Dr. Markert, last words to you. Anything that you would like to say at this point, letting other providers know about this exciting work that you're doing at UAB Medicine?

Dr. James Markert: I just want to say that one thing that is really unique about the work being done here at UAB is that we have recapitulated this data, this exciting new antitumor immune data using this kind of viral platform, if you will, in multiple different settings. And I think that really speaks to the validity of the approach.

You've heard today Dr. Chambers talking about the findings in canines, and you've heard from me today about the findings in adult humans. Dr. Greg Friedman, another oncologist here has published along with us in the new England Journal of Medicine that we have similar findings in a group of pediatric patients with tumors. And so I think we're really beginning to demonstrate that across a wide variety of diseases and even different species, we can demonstrate these findings and show their validity.

I think another thing that we haven't had time to talk about today, but something that we will be hearing more about in the future, is that these therapies can be used in combination with other anti-tumor immunotherapies out there. And in fact, soon we will have a study open at UAB that's been approved by the FDA that will use something called an immune checkpoint inhibitor in combination with our virus. And Dr. Chambers has already done this in the canine model with an immune checkpoint inhibitor. We're using a slightly different one in people that's approved for use in humans. But we feel like this sort of one-two punch, if you will, of using the virus in combination with other immunotherapies is going to really lead our field forward into the future. And we hope to deliver the kinds of outcomes that we all want to see for these patients.

Melanie Cole, MS (Host): This is next level medicine. And I thank you both so much. And I hope that as these trials continue that you will join us again and update us as anything, because this is really fascinating. And thank you so much for sharing it with us today.

A physician can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST or by visiting our website at uabmedicine.org/physician.

That concludes this episode of UAB MedCast. Please remember to subscribe, rate and review this podcast and all the other UAB Medicine podcasts. I'm Melanie Cole.