Brain Matters – July 2016

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This month Michael Lim, MD, talks about using viruses and other aspects of immunotherapy for brain tumors.

Program Notes

0:22 Polio virus and brain tumor treatment
1:21 Genetically modify viruses to attack tumors
2:21 Implanted melanoma tumors
3:22 Myeloid cells play an important role
4:23 May not need a neurotropic virus
5:25 Timeline relative to tumor development
6:28 At one point one drug cocktail but a different one at another
7:23 Building on fantastic data from other tumors
8:10 End

Transcript

Elizabeth Tracey: Welcome to Brain Matters for this month. I'm Elizabeth Tracy.

Michael Lim: And I'm Michael Lim. I'm one of the brain tumor surgeons here at Johns Hopkins and director of the Brain Tumor Immunotherapy Center.

Elizabeth Tracey: Thank you so much for joining me this month. Recently, of course, on 60 Minutes, there was a major story that has gotten a lot of attention, and that was the use of poliovirus as a potential, what shall we call it, inducer of an immune response for people with a certain type of brain tumor. Please tell me more about that.

Michael Lim: It's an exciting for a tumor that's been very tough to beat. A genome glioblastoma is a very aggressive type of tumor. Oftentimes the prognosis is poor for patients. The concept behind the polio virus was initially to try to find a virus that would infect only tumor cells. As you know, polio is a type of virus. It's an RNA virus that infects brain or spinal cord cells. In the past, when the polio virus infected, for example, the spinal cord, it was a major cause of neurologic deficits in people. Finding a vaccine for it was a big deal. Now we're taking that idea of a very aggressive virus and trying to turn it against this aggressive tumor. I think initially the thoughts were to try to design this virus to specifically attack tumors, and they genetically modified these viruses to attack tumor cells. And as they started giving them to patients with glioblastoma, they found some really impressive results. One thought is that the viruses are eliciting an immune response, and perhaps this virus acted as a primer to generate a very vigorous immune response.

Elizabeth Tracey: So many things about this are just so very fascinating to me. Historically, of course, we've viewed the brain and the central nervous system as a protected space, where the thought for so long was that there wasn't much of an immunological response going on there. And it sounds like, wow, we're really learning a lot about that response.

Michael Lim: That's very true. I think that the brain is actually a place that can mount a very vigorous immune response. And we've seen that in patients who've had conditions such as multiple sclerosis, or brain abscesses. I think that the brain is a unique environment. We had a very neat paper recently that showed that the brain itself acts and behaves very different immunologically than the periphery. We did a set of experiments where we took mice and we implanted melanoma tumors in the flank, in the back of a mouse, and in the brain of a mouse, and we found that when the tumors were in the brain, the tumors themselves were actively deleting or getting rid of T-cells that would have otherwise acted against the tumor. And what we've learned is that the brain probably needs other ways to prime the immune response.

Elizabeth Tracey: This is so fascinating to me. Tell me about the migration of things like T-cells, because clearly they're not being developed in the brain. So how do they get into the brain? And gosh, did we even know that they were there for such a long time?

Michael Lim: Immune cells traffic in and out of the brain. The methods of surveillance in the brain may be a little different than in the body. For example, you need another partner to these lymphocytes or T-cells called myeloid cells, otherwise known as macrophages or dendritic cells and microglia. And it turns out that those populations of cells are the ones that alert the T-cells or the lymphocytes to come in and activate them. Like in the polio virus, they think that these myeloid cells play a very important role in mounting or turning the immune system on.

Elizabeth Tracey: This is so fascinating to me because I can recall a day when everyone was speculating on the role of microglia. And what in the world are they doing in there anyway?

Michael Lim: I think it's very exciting because now we've come another step in understanding the role of microglia. We think that there's a big role in surveillance.

Elizabeth Tracey: So let's return to the poliovirus and its neurotropic capabilities, if you will. Aren't there other viruses? And I'm thinking about the herpes virus family, for example, that are also neurotropic.

Michael Lim: There are other viruses that are neurotropic. herpes virus is, as you mentioned, one. There are other clinical trials that are ongoing looking at modifications of the herpes virus. With today's technology, they've been able to actually modify a lot of different viruses. They've taken adenoviruses and even cold viruses and re-engineered them so that they can specifically target molecules on different cells. So you may not even need to have a neurotropic virus.

Elizabeth Tracey: I guess one of the questions from a patient's standpoint might be, why did some people respond so dramatically to this particular intervention and others really didn't seem to respond much at all?

Michael Lim: I think it comes back to the basics of the tumor itself. When we say glioblastoma, I think it's the misconception to think that it's one disease. I think what we've learned is that the glioblastomas themselves are very heterogeneous. They're a very diverse population of tumors that look histologically or under the microscope very similarly, but there are variations in the way they behave. Like in other types of tumors, like for example with breast cancer and lung cancer, we become better at characterizing the subtypes of tumors and are able to now direct certain therapies. I think we are going to figure out which tumors are more susceptible to viral treatments. other tumors may be more susceptible to a vaccine. And I think we'll see other tumors that are going to be susceptible to targeted therapies.

Elizabeth Tracey: I've had other people who are cancer experts express to me the idea that there is a timeline relative to how tumors develop and the mutations that are present. Would that suggest to you that potentially vaccines might be important at one stage of the disease, but maybe something else is going to be required at another?

Michael Lim: So I think you brought up a great point. When I talk the heterogeneity of tumor. It's specific to one snapshot in time. We've had experiments in our lab where we found that when we simulate these glioblastomas earlier on, the T cells have a very different phenotype that mark what we call exhaustion compared to a late stage tumor. And so one set of antibodies that would cure a mouse at certain time points, but if you waited to a later time point, it turned out that we needed a different set of antibodies. Those are examples in our laboratory. We think that that's probably even more complex in a real-life clinical setting. And so I think you're absolutely right. We may not find a cure for glioblastoma, but we may find ways to keep it in check and that over time we may have cocktail A and five years later they may need to have cocktail B.

Elizabeth Tracey: Would you suggest then that in the designation of these cocktails that some genetic assessment and maybe even an epigenetic assessment might be necessary?

Michael Lim: I think that complements exactly what personalized medicine is doing today. As patients get treated, the whole concept of doing personalized medicine and getting your tumor, for example, genetically analyzed, I think that should be a moving target. So I think that as people live longer and progress through their disease states, that these tumors are reassessed and given different cocktails.

Elizabeth Tracey: If you had to sum up right now the state of immunotherapy with regard to brain tumors, what would you say?

Michael Lim: I think that we're at a very exciting time. We're building on some fantastic data from other tumors, as you know, with melanoma, renal cell carcinomas, or renal cell cancer, and lung cancer. And now with bladder cancer, there's been FDA approval of some of these immunotherapy drugs, like the checkpoint inhibitors. And if you look at their data, it's a revolution, because we are now seeing a subset of patients that what we deemed incurable are being cured. And so I think we all recognize that the immune system plays a critical role in potentially curing people with cancer. It's just that different tumors are going to require a different set of keys. I think we have a great set of initial keys to work with, and I think in the next five years to 10 years, I'm optimistic that we'll find something very exciting.

Elizabeth Tracey: Outstanding. One's brain matters. Thank you so much.

Michael Lim: Thank you.