The future of cancer neuroscience

0:00This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world. And it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody.

0:36In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here, and that you'll share it with your friends, family, neighbors, co-workers as well. Right from the beginning, it was enormously hopeful. We saw patients have marked clinical improvements, as dramatic as wheelchair-bound to walking. I mean, it was really clear, clear clinical benefit. We also saw, in many cases, marked shrinkage of the tumor by MRI scans. There was one patient in the first dozen or so that we treated who actually had a complete response, meaning that his tumor completely disappeared.

1:23This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. If you're enjoying the show or if it's helped you in any way, please consider sharing it with friends, family, and colleagues. Word of mouth is a great way to spread news about the podcast and to make sure that everybody is clued in to the future of everything. Today, Michelle Mangier will tell us that in order to take on the most devastating childhood cancers, we have to understand how cancer cells work, how the nervous cells work, and how the immune cells work. It's a complicated dance of three complex cell types, and it's the future of cancer neuroscience.

2:03Before we get started, a reminder to please tell your friends, family, and colleagues about the podcast and spread news about the future of everything.

2:18So when we think about devastating childhood cancers, we think about the terrible toll they take on the children, their families, and how difficult and aggressive these cancers can be. Well, it turns out that those cells in the cancers are not just the cancer cells. The cancer cells have a very complicated relationship with the nerve cells, the normal nervous cells that surround them. It turns out that they talk to one another and the cancer cells are relying on the signals from the normal nervous cells. In addition, there are immune cells that get involved in the activity and so you have this complex and tangled web of cancer cells, nervous cells, and immune cells, all malfunctioning to create these terrible diseases.

3:05Well, Michelle Monge is a professor of pediatric neurology, neurosurgery, pediatrics, pathology, and psychiatry and behavioral health And she's an expert at how childhood cancers grow and maybe how they can be treated. She'll tell us that understanding the basic science of the interactions between these three different cell types is critical. And she'll also tell us that we're starting to see human trials where we're making a little bit of progress that gives us hope in battling childhood cancers. Michelle, what led you to focus on the interactions between cancer cells and nerve cells? You know, when I was in medical training, when I was training to be a neurologist and take care of people with brain cancer, I noticed two things that made me start thinking about the way that cancer cells may be interacting with neurons.

3:59Number one, I noticed, and I hope this doesn't sound in any way flippant, I don't mean it to be. But cancers of the brain tended to happen in the very best brains. It was as though it was a seed that needed to grow in rich soil. If I met a patient before their diagnosis and they were very intelligent and very creative, very kind, I was more worried it was going to be a more aggressive kind of cancer, like a gliboblastoma. And it was such a consistent observation that it made me wonder about the way that cancer was interacting with the mechanisms of, you know, neural development and plasticity that create good brains.

4:40And the second observation was that in childhood, tumors like gliomas happened in very predictable places at very predictable ages, so much so that there was an attending of mine, a mentor who said to me one day in clinic, if you tell me the age of the patient, I'll tell you where their glioma is. And I thought that was such an important clue. And one of the most robust regulators of brain development is brain activity itself. And so thinking about cancers as diseases of dysregulated brain development, I started to wonder how this really robust regulator of the development and plasticity of the nervous system, and the activity of neurons themselves might be influencing cancer.

5:25So I asked the question. That is an amazing story and so many things that we have to explore. I know that we're going to talk about neurons and their interactions with cancer cells and glial cells, which are an important part of the nervous system. I think it might be useful to do a quick neuroscience review of what's going on And what are the key cells we need to know about to understand the significance of these relationships? Yeah. So the electrically active cells in the brain, the ones that are doing a lot of the work that are involved in brain functions, like moving and sensing and various cognition and emotional functions of the brain, those are neurons.

6:08Those are the cell types that electrically communicate with each other and that form circuits that are really important for the way that the nervous system functions. Their job is not possible without the interactions and support of a number of other cell types in the brain. And those are, we generally refer to as glial cells that historically it's a Latin word for glue or a Greek word for glue. And we used to think about them just as sort of these intervening, you know, kind of support like cells. We now understand how absolutely crucial their functions are. And the types of glial cells are number one, astrocytes.

6:48These are cells that help to form the establishment and support the function of connections between neurons called synapses. They also have crucially important metabolic and other kinds of signaling roles in the nervous system. They have some immune functions. another kind of cell type is called an oligodendrocyte which is a long word but what it means is it's a cell type with multiple processes that wrap around axons and form an insulation like on a wire that enables fast electrical conduction from one place to another in the nervous system and that also provides important metabolic support for the axon now those oligodendrocytes are formed by a precursor cell type called an oligodendrocyte precursor cell.

7:35And those are really important in the development of oligodendrocytes and of myelin, but also they persist throughout the lifespan. And we now understand have multiple roles, but one key one is to, to modulate and change the myelinated sort of insulating infrastructure of the brain in response to experience. So if you think about kind of the pathways between parts of the nervous system like roads, the myelin is very much like the paving on the road. And you might want to change the way different roads communicate with each other based on, you know, the function of the town. The traffic patterns.

8:15In this metaphor, in this case, in the function of the brain. So in activity and experience dependent ways, different pathways become faster or more coordinated with each other in their dynamics. And that really depends upon communication between neurons and the oligodendrocyte precursors. Great. Okay. So we have our tutorial. Thank you. And at least three important cells and with the precursors, at least four. Now, I just want to mention that the glial cells also come up because I know you study a couple of cancers, which have been a source of some of these insights, which have the word glia in them.

8:53And so maybe it's a good time also to give us now our tutorial on some of these terrible brain tumors that are most common in children and what goes wrong. So the most common and one of the most aggressive kinds of brain cancer is called a glioma. And these are cancers that under the microscope resemble glial cells. We have found that in the childhood nervous system and in the adult nervous system, many forms of these gliomas actually arise from those oligodendrocyte precursor cells. Gliomas include diseases like glioblastoma. They also include a disease called diffuse intrinsic pontine glioma or DIPG.

9:39DIPG is one member of a broader family of high-grade gliomas, really aggressive cancers that happen in the midline of the nervous system called diffuse midline gliomas. And these happen in places like the thalamus, the brainstem, and the spinal cord. And these diffuse midline gliomas, with DIPG being the most common, is the leading cause of cancer-related death in kids. It's the most common glial malignancy or glioma in kids. And it's just an incredibly aggressive disease that has a near universally fatal prognosis. Yes. And maybe later on, we'll get to some really interesting things your lab has been doing for treatment.

10:17But now somebody who's not really thoughtful or knowledgeable might say, okay, the cancer cells are growing, whatever their origin was, they're just kind of pushing out the other cells and they're doing their own thing. But that doesn't seem to be quite the case. It seems like you and your colleagues have discovered that there's actually a communication going on, which I find surprising, between the cancerous cells and the other neuronal cells that are kind of not cancerous. They're just part of the nervous system. Of course, we're in the brain. And of course, there's a lot of neurons there. So how did we get to there?

10:52And what are the significance of those interactions? Thanks for asking about that. And I should mention one other clinical observation that kind of brings us to this point and very relevant to what you just said. We learned in medical school that brain cancers are mass occupying lesions that push the normal tissue out of the way and that they're a problem because they're taking up space. But when people come in with a new brain cancer diagnosis, and especially a new glioma diagnosis, they walk into clinic often or they walk into the emergency room. They are walking and talking and functioning almost normally.

11:29And maybe they presented because they noticed slight weakness in one limb or another or they've had a seizure. But then you do an MRI scan and you realize that three quarters of their brain is involved with this cancer. so this is a different disease process than anything else that affects the brain any other disease that affects that much territory in the nervous system would cause profound symptoms but clearly the tumor infiltrated nervous system is working or working as well as it can and so there's something really fundamentally different going on and now we understand that that is true because the cancer actually needs the function of the nervous system.

12:09So taking a step back and hypothesizing that the neurons, which we had kind of previously thought of as victims, might actually be playing an active role in the cancer progression. When I started my laboratory about 15 years ago, I was really compelled by this question of whether the activity of the nervous system might be influencing the cancer that grows within it. And it was very fortunate at the time there had been so many incredible advances in the technologies of modern neuroscience that it was really straightforward to ask this question in a way that really wasn't possible before. So we used a technique called in vivo optogenetics, which happened to be developed here at Stanford.

12:50And that allowed us to control very specific genetically identified and regionally specific populations of neurons within a defined circuit. So we could very carefully modulate the activity of that circuit and then see if a patient-derived glioma growing within that brain region changed in its behavior. And when we did that first set of experiments, we found that indeed, if you stimulate the activity of particular populations of neurons, the cancer grows faster and it grows larger. And so this was the first demonstration that brain activity can influence brain cancer growth. And it sounds like going back to some of your very early clinical observations that you mentioned, this might be the link between those patients who came in intellectually active, socially active, with all of that brain activity being manifest.

13:45You're now seeing at the cellular level that all of that activity might have been kind of tragically feeding a cancer. Yeah, no, that's exactly right. The cancer is hijacking the neural circuits that it grows within. It's really taking advantage in a very profound way of the patient. So I guess what people would ask next is, do we then have to tell the brain to calm down, stop thinking, stop doing? I mean, that's hard to imagine, but does that lead us to these crazy hypotheses about how we may be able to intervene? My answer to that question is generally no. That is not going to be overall beneficial for a patient.

14:27Patients need to be able to use their brain. Our job as scientists and as doctors is to figure out how to disintegrate this cancer, how to block its ability to hijack and take advantage of these signals. And so the next question is, well, what are those signals exactly? How is it doing this so that we can figure out how to stop it? And so what can you tell us about those interactions, which are obviously critical for the growth? I'm sure there are many things going on, but it sounds like you've uncovered one facet that cannot be ignored. Yeah. I think we've uncovered two key facets, two key broad categories of ways that the cancer takes advantage of the nervous system.

15:08And one is that, you know, there are activity-regulated growth signals, plasticity signals, that the brain normally uses to communicate with other cell types relevant to normal cognition, to normal learning and memory. And the cancer takes advantage of those. So things like neurotrophins, which are molecules and signaling pathways that are normally involved in brain development and prostacy. The cancer takes advantage of those, and there are these activity-regulated molecules secreted that drive the cancer group. More insidious, because that was where we started, and we found several of those, and we can target them, at least in the laboratory, that helps.

15:48but that didn't explain the very profound effect of neurons and neuronal activity on cancer group. I mean, it is a major, major component of the driving force of this cancer. And so when we dug deeper, we discovered that the cancer cells are actually electrically integrating into the brain. They're forming the exact same kind of electrical points of communication that neurons usually use to communicate with each other and with normal oligodendrocyte precursors. So they're synaptically integrating into the brain. And these neuron to cancer cell synapses are fundamental to the cancer progression.

16:32Wow. So that's a cause for pause. So I think what you just told me is that the cancer cells are not just surrounded by, I'll call them normal neurons, but they create communication channels with them. Do you have a sense of whether the communication is mostly from the cancer cell to the neuron saying, hey, why don't you let me grow and wreak havoc and don't worry about it, like kind of tricking? Or is it the nervous system sending signals that nourish and encourage the cancer or perhaps both? Yeah. So the synaptic communication is unidirectional as far as we can tell. So it goes from neuron to cancer.

17:12And interestingly, again, the cancer doesn't invent much that's new. There are these unidirectional synapses between neurons and normal algodendrocyte precursor cells. So that communication is from neuron to glial precursor cell or malignant gliomaso. And the cancer then receives these electrical signals that alone are sufficient to drive its growth, invasion, and probably resistance to our therapies. But it's not that the cancer doesn't influence the nervous system. It just doesn't do it through the electrical, direct electrical pathway, at least as far as we know right now. But instead, the cancer changes through secreted factors and a variety of different kinds of secreted factors, the activity of the nervous system.

18:00So it increases the excitability of the neurons, which increases the input that it receives, but also causes things like glioma-associated seizures. It also functionally remodels neural circuits to increase the inputs, the structural inputs, into the cancer. And this contributes, we think, to some of the tumor-associated cognitive and other kinds of neurological symptoms the patients experience. So the cancer is really hijacking the nervous system. And the nervous system in this hijacked state is driving the growth of the cancer. So that bi-directional communication that I was imagining does occur.

18:40It's the synapse is doing from neuron to cancer, but then the cancer is doing all of these other things, basically saying, feed me. I mean, you know, to be very simple, it's hijacking and saying, I need you to do more of the things that I love in order to grow. Exactly. And as a consequence of that, do less of the things that the nervous system was previously doing. And this contributes, we think, crucially to the progressively debilitating symptoms that patients experience. This is the Future of Everything with Russ Altman. We'll have more with Michelle Monge next.

19:29Welcome back to the Future of Everything. I'm Russ Altman and I'm speaking with Michelle Monge from Stanford University. In the last segment, we learned that cancer cells and neuronal cells talk to one another. They create synapses, they release other chemicals, and they are codependent. But worst of all, the cancer cells are sending these feed me signals that then trick the neural cells to stimulate them and their growth. Well, in the next segment, Michelle is going to tell us about an exciting new treatment that is still early, but is showing promise and may be the beginning of the end of these terrible childhood diseases.

20:06Now, I know that recently, back at the end of 2024, you and your group announced some very intriguing, along with your collaborators, intriguing new results on a therapeutic approach that shows a little bit of promise and might be a first step. Can you tell me about that? Yeah, absolutely. So, you know, exactly as you said, as we recognize that these are cancers, diffuse intrinsic pontine glialna, glioblastoma, that are like truly integrating into the nervous system, both structurally and electrically, the question became how do we disintegrate them? You know, how might we attack the cancer cells without harming the normal nervous system?

20:42And that got me thinking about strategies to one by one pick out these cancer cells from the healthy nervous system. And at the time, this is now going back about 10 years to make it a longer story, CAR T-cell therapy was emerging as this incredibly promising cancer cellular therapy strategy, engineered T cells of the patient's own immune system or, you know, from, you know, standard off the shelf CAR T cells, engineered to specifically target the cancer cells and just kill the cancer cells. And this had shown enormous promise in acute lymphoblastic leukemia and then later in other hematological malignancies.

21:30And I thought maybe it could work, you know, in brief. And I believe there were a couple of kind of miracle melanoma cures from these kinds of technologies. Yeah, yeah. So, I mean, immunotherapy is incredibly promising. The checkpoint blockers were just transformative for recurrent and metastatic melanoma. CAR-T cell therapy, as another immunotherapy example, has been really transformative for difficult-to-treat hematological malignancies. And the promise is there for solid tumors and for kind of network tumors, if you will, like we've been. And so very serendipitously, and speaking to being at a wonderful place like Stanford, Crystal Makal, who's really been a pioneer in CAR T-cell therapy, had come to Stanford in the mid-2010s, around 2015, 2016.

22:19And just around that time, we started thinking about this. And so we screened the surface of diffuse midline glioma cells like DIPG and looked for what might be a good handle, a good target for a CAR T cell and found very high and uniform expression of one particular antigen on all of the cells. It was really quite amazing. It's driven by the canonical mutation in this tumor type and that mutation results in strong upregulation of this particular. And just so I can make sure I'm following, you need to find something that's on the surface of the cancer cells, but that is either absent or very rarely found on the kinds of cells you don't want to kill, which are the normal.

23:04Exactly. Exactly. So the idea is that you take an immune cell, a lymphocyte in this case, and you bioengineer it to express what's a chimeric antigen receptor or CAR. And that is something that on one end is like the business end of an antibody that recognizes one molecule. And then it's fused through this, you know, chimeric, this engineered, you know, chimeric antigen receptor to the co-stimulatory domains to activate the lymphocyte. So that there's one step, the lymphocyte sees, if you will, the molecular target through this chimeric antigen receptor and is immediately turned on to kill that cell.

23:47So what you're looking for is a marker that is on the surface of a cancer cell, but not on the surface of the normal cells or is very highly expressed in the cancer cell and lowly expressed in normal cells. So we found one of those, and it's a fatty sugar, and it's a dicylo ganglioside called GD2. So together with Crystal's lab, we took her GD2 targeting CAR T cells and put them into our mouse models of DIPG and other diffuse midline gliomas, and it cured the mice. It was just amazing. Now, it's a lot easier to cure a mouse than to cure a patient, but we were really encouraged by this and developed a clinical trial of GD2 targeting CAR T-cell therapy for diffuse midline gliomas of the brainstem and spinal cord.

24:34We opened in this. So, I want to find out about how that worked, but before that, I have a vague memory that the immune system in the brain is a little bit different from the immune system everywhere else. And so do we have a robust immune system in the brain that can be used in the same way we use it for treating other cancers of the blood or solid tumors in the pancreas or the liver? And did that represent a big challenge to your team in making sure that these cells got into the right places? This is a great question. So it was previously thought that the nervous system was immunoprivileged, that the immune system only accessed the brain and spinal cord in limited ways.

25:15And that is not the case. We now understand that there's routine trafficking of the adaptive immune system into the nervous system, but the lymphocytes and other adaptive immune cells are coming from the skull bone marrow and they're monitoring the brain and then going out through the meningeal lymphatic system into lymph nodes that are in the neck.

25:43So for the brain. But certainly CAR T cells that are administered into the blood, we found in mice and confirmed in humans, get into the brain very well. That's one route of administration. Another route of CAR T cell administration is directly into the cranium. We can put the CAR T cells into a fluid filled space called the lateral ventricles in the brain. And either way that we do that in mouse models, the CAR T cells get throughout the tumor and cure the tumor in mice. Okay. So that's great news. And thank you for that. Thank you for allowing me to disrupt your flow. So then you said, okay, it worked great in mice, but mice are not little humans.

26:26They're very different. And so you then looked at an initial human trial? So we opened a clinical trial that's still ongoing in 2020. And we've reported the results of the first arm of this trial. And in this first arm, we administered the CAR T cells first intravenously after a preparatory regimen to sort of modulate the patient's immune system so they don't reject the CARs using the standard lymphocletum chemotherapy. And then in patients who had a good therapeutic response to that with improvements either in the clinical symptoms or clear shrinkage of the tumor on MRI scans, they were eligible for subsequent infusions of CAR T cells directly into the lateral ventricles.

27:13And do we have any readouts yet? It was right from the beginning. It was enormously hopeful. We saw patients have marked clinical improvements, as dramatic as wheelchair-bound to walking. I mean, it was really clear, clear clinical benefit. We also saw in many cases, marked shrinkage of the tumor by MRI scans. There was one patient in the first dozen or so that we treated who actually had a complete response, meaning that his tumor completely disappeared. And he remains tumor-free and thriving now over four years since his first therapy, which is pretty amazing for a diffuse. That's breathtaking because I believe that this was uniformly bad news otherwise.