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Neuro-oncologist Manmeet Ahluwalia, MD details precision medicine-based approaches, immunotherapies and targeted therapies – the way of the future for glioblastoma treatment.

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Novel Therapies in the Treatment of Glioblastoma

Podcast Transcript

Dr. Alex Rae-Grant:  Neuro Pathways, the Cleveland Clinic Podcast from medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology and neurosurgery. Welcome to another episode of Neuro Pathways. I'm your host Alex Rae-Grant, neurologist in Cleveland Clinics Neurological Institute. In an effort to explore the latest advances in neurological practice, today we're talking with Dr. Manmeet Ahluwalia about novel therapies in the treatment of glioblastoma. Dr. Ahluwalia is a medical oncologist and Associate Director and Head Of Operations, The Brain Tumor And Neuro Oncology Center in Cleveland Clinic's Neurological Institute. Manmeet, welcome to Neuro Pathways.

Dr. Manmeet Ahluwalia:  Thank you for having me, Alex.

Dr. Alex Rae-Grant:  Manmeet, I know you're not a native Clevelander as am I. Talk to us about your own personal journey to get where you are today practicing here at Cleveland Clinic.

Dr. Manmeet Ahluwalia:  Oh, sure. Absolutely. So I was born and raised in India. Did most of my high school education as well as my medical school in New Delhi, which is the capital of India. My family at the same time had immigrated to Canada where I did a post-doc at University of Toronto. While I was working there, I had the good opportunity to get into a residency program here at Cleveland Clinic at Fairview Hospital, which is one of the hospitals in the Cleveland Clinic Health System. And when I was doing my residency in internal medicine, I had an opportunity to work with the colleagues here in the Brain Tumor Neuro-Oncology Center and I kind of got more drawn towards research in brain tumors.

I then went away to do my fellowship at Roswell Park Cancer Institute, which was the first cancer center in the United States. And when I completed my fellowship, the group here was interested in recruiting me to come and develop a clinical trials program. So I came back to Cleveland in 2009, and I've been here over a decade now, working with the team in the Brain Tumor Neuro-oncologist Center, working on clinical trials for our patients with glioblastoma and other brain tumors.

Dr. Alex Rae-Grant:  So I guess for our audience, let's first have you tell us a bit more about what glioblastoma or GBM is and why it's such a difficult tumor to treat.

Dr. Manmeet Ahluwalia:  So glioblastoma, as you're aware, is the most commonly diagnosed primary malignant tumor in the United States each year. Anywhere between 12,000 to 15,000 patients will have this diagnosis every year. This is the most aggressive kind of malignant tumor that we see in our clinic every day. Typically this tumor is one of the most difficult ones to treat because it tends to be extremely aggressive, fast growing, and it spreads like spiderwebs. So essentially what you see on contrast enhancing imaging, the tumor has spread much more than that and hence we always do T2-FLAIR and other images to see what's the extent of the disease impact.

The tumor also is very heterogeneous. There are multiple pathways which sometimes are redundant. So if you try to tackle it with one targeted therapy, the other redundant pathway might get over activated. So it's an extremely difficult tumor to treat. And when we treat it and we have some success, resistance tends to develop fairly quickly. So hence this has been one of those cancers which has been most difficult to treat.

Dr. Alex Rae-Grant:  What would be some of the signs and symptoms that our audience may see in a patient with glioblastoma? What would they be looking for?

Dr. Manmeet Ahluwalia:  Yeah. So a patient can have a myriad of symptoms and that could basically be depending on where you have the glioblastoma. So anything like a space occupying lesion can have the same symptoms. So we can have patients who can present as seizures, patients can have progressive headaches. Obviously if they tend to happen more in the morning, they are a little bit more worrisome because of the increased intracranial tension that can happen. Anything that can involve areas of speech, memory issues and people who are losing strength on one side of the body. All these things if they're going on for a period of time can point out to a possibility of having a brain tumor.

And so typically the neurologist, or primary care physicians who sees such patients will order a CAT scan or an MRI which may allude to a space occupying lesion or a tumor more suggestive of a glioma or a high grade glioma. And then that's typically when patients tend to see a neurosurgeon who then ends up doing a biopsy or a resection to find out what's going on and what's the diagnosis.

Dr. Alex Rae-Grant:  So maybe we can discuss some of the standard treatment options for GBM. What are the routine things that we do to treat that?

Dr. Manmeet Ahluwalia: Sure. Great question. So typically as I said, if something is seen on MRI that's worrisome for a tumor, most of these patients end up seeing a neurosurgeon. Sometimes patients can have sudden seizures, they may end up in an ER and then they will be admitted to the hospital and a neurosurgery consult is referred. So a neurosurgeon will review the pictures and at our place, typically two neurosurgeons often confer with each other to look at what's the best way to go in terms of navigation to get these tumors out. And what's the maximum amount of tumors they can resect. Because the dogma in glioblastoma is maximum possible safe resection. So we don't want to over-resect and leave someone paralyzed because then their performance status will suffer and they may not be able to get aggressive treatment. Because even when you can get the entire enhancing disease out, which is termed as a gross total resection, there are still spiderwebs for which they need radiation and chemotherapy.

So once the patients have undergone a resection, which is maximum possible and safe, they are typically seen in clinics by a radiation oncologist and a medical or neuro-oncologist. And typically the treatment consists of six weeks of chemotherapy and radiation, followed by six additional months of chemotherapy. Now this is considered standard of care and very often we recommend clinical trials because the NCCN guidelines, which are a compendia of all the top cancer hospitals in the country in the United States, when they got together and they published the guidelines, the number one recommendation for patients with glioblastoma is to get treatment on clinical trials or standard of care. Clinical trials is preferred.

Dr. Alex Rae-Grant:   So can you talk about some of the most recent research with glioblastoma? What kinds of things are people looking at for this condition?

Dr. Manmeet Ahluwalia: Sure, absolutely. So there've been multifaceted research that is ongoing. We are looking at targeted therapies which are drugs that go after some particular genetic alterations that exist in tumors. So they could be genomically-based approaches which could be top down or bottom up. And top down approach, for example in precision medicine is that you profile say 500 patients with glioblastoma and you find out three or four most commonly active pathways where you can get designed drug A for a particular pathway, drug B for a different pathway. So that's the way to go after giving patients precision medicine based approaches. And we are doing that at Cleveland Clinic in collaboration with other institutions. The other approach could be a bottoms-up approach where we give patients a particular targeted drug. We know, unfortunately not everyone responds. So when the trial is completed we find out maybe 20% of the patients have responded. Then we go and nowadays we are doing whole exome sequencing, adding a transcriptome so a lot of genomics-based approaches which help us profile the tumor to find out why some patients respond while others don't. So then the next phase of trial can comprise of these genetically enriched patient subgroup where they're more likely to respond to some treatments. So that's one way of research that we and others are doing.

Other big excitement as you know about in cancer is immunotherapy. So we are testing a number of immunotherapy based approaches here at Cleveland Clinic, either at Cleveland Clinic or in our collaborations with multiple other partners around the country. And the immunotherapy based approaches are broadly in three categories. One of them can be vaccine based approaches, where we give patients vaccines which go after these particular peptides that are expressed by the tumor. So we can build up the immune system to go after the tumor. Other one is genetically engineered viruses where we operate on these patients. At the time of surgery, we put in the resection cavity, we put injections of these genetically engineered viruses which can then go and selectively invade cancer cells. Because when you give these genetically engineered viruses, the normal cells of the body are able to clear them. But because the cancer cell has dysregulated systems, they are not able to clear the cells.

So they go and selectively infect these cancer cells. And then we can give drugs now, which may convert some of the antifungal. So for example, we have Toca 511 which is a genetically engineered virus with the cytosine deaminase gene inserted in it. So these patients then when they get antifungal like 5-Flucytosine, it gets converted into 5-Fluorouracil floater Eurocell, which is a chemotherapy inside the cell. So you don't get systemic toxicity. That only happens inside the cell because the virus is only in that particular cell. So we are awaiting ways now to getting rid of systemic toxicities because a lot of our cancer drugs have fair amount of side effects.

Then the third is the immunotherapies, which are drugs which boosts the immune system to go and kill the cancer. So as you know, cancer is our own rogue cell that has had genetic changes and it evades the immune system. Because the immune system can actually clear some of the cancer cells. But it's only when the immune system is overwhelmed by the cells that have, in a way they induce a shield around themselves and our immune system cannot recognize it. So there are drugs which maybe target the PD-1 pathway, and the drugs are pembrolizumab and nivolumab. They are the two most commonly used drugs. Or you can have drugs that target the CTLA pathway. That's the peripheral part of the body where the immune system, the T cells are boosted. And we have drugs like ipilimumab, which are approved for them. So some of these drugs have shown great promise in lung cancer, kidney cancer, now some forms of breast cancer like triple negative breast cancer, but in a number of other cancers like melanoma as well. So we are looking at some of these research in glioblastoma to see how we can help our patients live longer and also a better quality of life.

Dr. Alex Rae-Grant:   So I know this is a question that I get asked in my practice and let me kind of ask you. I think you've probably said it before, but let's say your cousin had a glioblastoma, what would you be recommending to your cousin as a pathway to follow?

Dr. Manmeet Ahluwalia: Yeah, so great question and so what I always tell patients or friends or colleagues is that if someone gets this diagnosis of glioblastoma, the most important thing is to reach out to a brain tumor center of excellence, which typically happens at large tertiary care centers or large comprehensive cancer programs. Because that's the place which has the right team. They have neurosurgeons who only do brain tumor surgery. You don't want your spine surgeon to be operating on a highly complex brain tumor if you can make that happen. So we have dedicated group of neurosurgeons here at Cleveland Clinic who just do two brain tumors.

In fact, we have surgeons who just do glioma-based surgery, who do tend to operate on glioblastoma multiple times a week. You want to go and get operated by such physicians if you can obviously. Then you have radiation oncologists who just tend to treat brain tumors and not other cancers in the body. Similarly, we have medical neuro-oncologist who just treat these patients day in, day out. It's this whole team-based approach where all physicians of different subspecialties come together. We discuss our cases at tumor board where all of us sit down and we pick a particular plan of action for every patient based on what's their tumor type, what kind of surgery they have, what their genetic alterations are, what kind of clinical trial will be the best for them. And often, as I said, you would want to go to a place that has clinical trials. Clinical trials tend to occur more likely at places with large comprehensive cancer programs or brain tumor programs, and we have a fairly robust clinical trials program here at our place and a number of other good centers have the same.

So I would always tell people that if you are going to seek care in the community, which is okay because a fair amount of care is still given in the community, always try to reach to a center of excellence for a second opinion to make sure that the care you're getting in the community is as good as you would get at the centers and explore the possibility of a clinical trial.

Dr. Alex Rae-Grant:  So Manmeet, you may have touched on this before, but what is there on the horizon that really gets you excited about the field?

Dr. Manmeet Ahluwalia: Sure. So obviously in cancer as I talked about, we used chemotherapies for decades and we've gotten fair amount of mileage out of those toxic chemotherapies, but we also realize that these drugs tend to be pretty tough on patients and there's only so much chemotherapy these patients can take. So in the last decade or two, our efforts have been more focused on genomically-based efforts or immunotherapy-based approaches.

So we have multiple clinical trials here at Cleveland Clinic which are focusing both on genomically based approaches where we profile patients tumor and based on what the genetic pathways alterations may exist, use a particular drug, A, B, or C depending on what is the pathway driving that particular tumor. Or we have trials here right now which are using immunotherapy drugs like pembrolizumab and nivolumab, which has the most cutting edge immunotherapy drugs we have targeting the anti PD-1 pathway. We have trials of those drugs. We also have had fair amount of success with vaccine-based efforts. We have a vaccine serviwin, which is a commonly expressed peptide in glioblastoma and we've seen some very interesting and encouraging results that has led to an FDA designation of orphan drug status for this vaccine. We have an upcoming trial where we're combining an immunotherapy with vaccine to say, "Okay, with one immunotherapy based approach we can get say X amount of success and we're getting Y amount of success with a different approach. Can now we combine X and Y together and get even more synergy between the two approaches?"

And then we've been working with a genetically engineered virus, the Toca 511. Now, that I mentioned before in the podcast we have a large 900 patient trials that will be starting towards the end of this year, which is being led by some of the investigators here at Cleveland Clinic working with multiple investigators at some of the key centers in the United States. So overall we are very excited about these new promising options, which are definitely helping our patients have more opportunities than a standard of care will afford them. Also but more importantly, some of these therapies, like for example, vaccine, we have seen minimal toxicity. So patients can get vaccine for years compared to a chemotherapy where you traditionally, because of all the myelosuppression that occurs with chemotherapy, you tend to stop a chemotherapy maybe six months or a year later. So those are some of these approaches which excite us.

A number of the trials that we are doing is stemming out of bench research that is being conducted at Cleveland clinic. A particular one that I would like to give an example of is myeloid derived suppressor cells are particular cells that exist in the tumor and glioblastoma, which make the tumor a very immunosuppressive environment. So immunotherapies don't work very well. So we are now using drugs that can go after these MDSCs or myeloid derived suppressor cells, and we're combining that with bevacizumab. That's a way to suppress the blood supply to the tumor. So the combinatorial approach is one of the things that we are excited about. There are other approaches as well and a number of other trials that are stemming out of laboratory-based research being done at Lerner Research Institute here at Cleveland Clinic, where we are combining years and decades worth of basic research that has been done in labs, taking those drugs which have come out of the work the scientists have done and taking it to the patients to offer this cutting edge treatments for our patients.

Dr. Alex Rae-Grant:   You know, it's interesting you mentioned that there were 12 to 15,000 new cases per year. Given all the different new approaches that you guys are bringing to bear, it does sound like a majority of those patients should be enrolled in some kind of clinical trial to try to get better answers quicker.

Dr. Manmeet Ahluwalia: I agree completely with you. I think that's a big effort in the brain tumor world these days because as I said, the NCCN panel recommends that clinical trials are preferred as the first line of treatment for these patients. Despite that, unfortunately when a recent survey was done in collaboration with the National Brain Tumor Society, only eight to 10% of patients with glioblastoma are actually being treated on clinical trials. And that's why we feel it's critical when patients get the diagnosis of a complex disease like glioblastoma that they reach out to our Brain Tumor Center of Excellence to try to see their eligibility for a clinical trial, to see what would be the best treatment for them at that center, or to make sure that the treatment that they're getting close to home is what Brain Tumor Center of Excellence would do in their case.

Dr. Alex Rae-Grant:  So any closing remarks, any other major take-aways? I know we've really emphasized a number of things here. Anything else we should be saying?

Dr. Manmeet Ahluwalia: So I would want to end on this note of promise. I think we've definitely made a lot of head ways into profiling our patients. So five or 10 years back, genomic profiling of our tumor patients was extremely expensive and sometimes was cost prohibitive. But in the last few years, these approaches are available broadly and they can help us pick the patients for clinical trials based on genomically-based approaches. We have a number of immunotherapy-based approaches which are showing promise in early phases and now we are looking at the combinatorial approaches to make sure that we are benefiting our patients. Through the years, even when we have had a failed trials for people who have been clinical investigators, we always have a group of patients or a subset of patients who definitely get benefit, and get a long term benefit. Now I think with this genomically-based approaches, we are in a better position to identify on a biomarker-based efforts, which are those patients who are more likely to get that benefit.

So we are extremely excited. Taking care of patients with brain tumor is a team sport, and we have some exceptional group of physicians here at Cleveland clinic, neurosurgeons, radiation oncologists, medical neuro-oncologist who work with our caregivers. We have a social worker, we have a neuro psych support here, so it's a whole team. It takes a village to take care of these patients. So my recommendation in summary to people is if you get this diagnosis, still be hopeful, reach out to the nearest best brain tumor center of excellence. See what are the best options for you, and then figure out a plan that you want and how you want to get treated.

Dr. Alex Rae-Grant:  That sounds great. So Manmeet, thank you so much for joining us. It's been nice chatting with you and I appreciate your time and insights.

Dr. Manmeet Ahluwalia: Thank you so much for having me.

Dr. Alex Rae-Grant:  This concludes this episode of our Neuro Pathways podcast. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast. Subscribe to the Neuro Pathways podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinics Neurological Institute on our Consult QD website, consultqd.clevelandclinic.org/neuro or follow us on Twitter @CleClinicMD, all one word. That's @C-L-E Clinic M-D on Twitter. Thank you for listening. Please join us again soon.

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Neuro Pathways

A Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology and neurosurgery. Learn how the landscape for treating conditions of the brain, spine and nervous system is changing from experts in Cleveland Clinic's Neurological Institute.

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