Maggie: [00:00:07] Welcome to the Hearts and Minds Podcast. I'm Maggie O'Neill, head of Marketing and Operations. Thank you for joining us today on the Hearts and Minds Podcast, we have a series of interesting and curious conversations with the brilliant minds that are part of Hearts and Minds. We are lucky enough to work with extraordinary individuals and we want to invite you to join these conversations on impact and investing. Today, I'm joined by Hearts and Minds Chief Executive Officer Paul Rayson, to chat with one of our phenomenal scientists, Professor Matthew Call. Hi, Paul.
Paul: [00:00:35] Hi, Maggie.
Maggie: [00:00:36] How are you today?
Paul: [00:00:37] I'm very well and very excited about the conversation we had with Matthew.
Maggie: [00:00:41] Yeah, it's pretty mindblowing the research that he's working on. So tell us a little bit more. It's immunotherapy, precision medicine.
Paul: [00:00:47] Oh, it's super exciting. The work that Matthew's team does is to teach and train the body's own immune cells to target and kill cancer cells, basically. And they work at such minute scale. But it's fascinating. Gives real hope for cancer treatment in the future.
Maggie: [00:01:04] Yeah, honestly, sounds like stuff of science fiction, really, but really exciting to hear that it's almost a reality. So it's a fantastic conversation and a wonder to sort of actually understand it in plain English. I know that we often walk away from some of these conversations completely lost in the science of it all, but Matt has a particular ability to translate that for us laypeople.
Paul: [00:01:23] Yeah, great scientist and a great communicator.
Maggie: [00:01:26] All right, well, let's not waste any time. He's Matt Call.
Paul: [00:01:33] Today, I'm joined by Associate Professor Matthew Cole. Matt is an immunologist and structural biologist at WEHI in Melbourne, formerly known as the Walter and Eliza Hall Institute. Matt and his team at WEHI work in the area of immunotherapy for cancer treatment or more specifically CAR-T Cell Therapy. Now if that doesn't mean anything to you, in simple terms, this involves re-engineering and training the body's ownT-cells to better identify and kill cancer cells. Now, this form of cancer treatment has proven effective against many forms of blood cancers like leukaemia and lymphoma, and has the potential to transform cancer treatment for many patients. Now a bit more about Matt's history. Matt completed his Ph.D. in Immunology at Harvard Medical School and the Dana-Farber Cancer Institute in Boston and completed postdoctoral training in Biophysics at Harvard Medical School. He then established an independent research program at WEHI in Melbourne in 2010. Matt has worked in the field of molecular immunology for 23 years and he and his team have published many scientific discoveries in leading academic journals. Matt, it's fantastic to have you as a guest of Hearts and Minds. I find your research both fascinating and mind boggling. It can be very complex, but at a basic level, the work you do enhances the body's own immune system to more effectively identify and destroy certain types of cancer cells. So I thought we'd start with your motivations to become a scientist. Was it something you always wanted to do from childhood, or was it a curiosity that developed over time? Matt.
Matt: [00:03:16] Thanks, Paul. Yeah, it's wonderful to be here. So I grew up in Dallas, Texas, and always had a love for nature. That's probably where my scientific career began. As part of that, I had many snakes and lizards as pets and really developed a fascination with reptiles. For me, I think that was a way to dive deep into a topic and discover something about a new species of snake and read up on how to take care of it and bring it into my collection. And I actually ended up having an Australian carpet python long before I had any idea I would be living and working in Australia one day.
Paul: [00:03:53] So you could have been a herpetologist?
Matt: [00:03:55] I could have been a herpetologist. In fact, that was my first dive in the scientific literature. I subscribe to herpetology journals, most of which I didn't understand, but all through high school my favourite classes were always biology, chemistry and physics. And I went to university planning to be a medical doctor, mainly because I didn't know what else you could do with a love for biology and chemistry. So early in university, I got into a research lab and discovered that problem solving was where my real passion lies. And so from there I was the research scientist.
Paul: [00:04:29] And what led you to the specific fields of immunotherapy and structural biology?
Matt: [00:04:35] Yeah. So immunotherapy really, I've been working on only for the last five years or so. I think immunology more generally for me was very interesting in university because it's really complex and very medically relevant, but also happens to have been my worst subject in university in terms of marks. So maybe I had a bit of a chip on my shoulder when I decided to go get a Ph.D. in Immunology. I came across structural biology as part of my Ph.D. work, and structural biology is really the study of how biomolecules are built and how they work and living systems. And I came in to structural biology as a necessity to solve a particular problem in my Ph.D. work. But this experience was really eye opening to me, understanding biology at that level. So that's when I decided to go on for further training in that area in a more specialised lab as a postdoc.
Paul: [00:05:31] So studying the body's immune system, it's amazing and we're learning more every day about it. Are you able to general level to describe how our immune system works?
Matt: [00:05:41] Yes. So at the most general level, our immune system recognises and eliminate things in the body that aren't part of us. So we usually think of this in the context of viral or bacterial infections. But transplant rejection and allergies are also the immune system at work, in these cases, recognising things that are certainly foreign but not intrinsically dangerous. So this works at many levels, but I think it's simpler to focus onT-cells and B cells because these are the immune cells that are responsible for the most remarkable feature of our immune system, which is immune memory. So ourT-cells go about killing cells that have been infected by, say, a virus and our B cells produce the antibodies that then circulate around the body and gum up the invaders so that they can't do damage. The first time our immune system sees a particular virus, for example, there's only a very small number of these T and B cells that are capable of responding, but these rapidly make copies of themselves and clear the infection, which takes maybe a week or two in the first instance. But a portion of those then stick around, sometimes for our entire lifetimes in order to make a stronger, faster response next time. So this is the basis of immune memory and what vaccines are based on. And when it works well, we say we are immune to a disease. And in that case, you may not ever even know that you've come into contact with a particular virus or bacterium because your body fights it off so quickly.
Paul: [00:07:16] SoT-cells are working in the background all the time at the cellular level. How does the T-cell actually identify a foreign substance like a virus or a bacteria? And then once it identifies it, how does it know how to respond?
Matt: [00:07:31] Yes. So more specifically than the immune system actually responds to molecules, usually proteins that don't belong in the body. We call these antigens. And antigen is just a fancy word that means any substance that generates an immune response against it, so anti-gen, some antigens can be cancer specific, but some are viral or bacterial, and our T-cells detect antigens using a sensor that we call an antigen receptor. This is a molecular switch on the surface of the cell that turns on biochemical circuits that then activate the T-cell to do its job. So a really amazing feature of the immune system is that these antigen receptors are generated by semi random gene combinations that happen very early in our lives. So by the time we reach puberty, most humans and all of the T-cells that they're ever going to have in terms of different specificities, and so probably a few hundred million different flavours of T-cells in our bodies can collectively recognise almost anything. But each T-cell has only one kind of receptor on it. And when the right T-cell meets the right antigen, that process of activating and copying begins. This happens in the lymph nodes, which is why our nodes swell when we get sick. Some of those T-cells become killers. They eliminate the threat. This can be cancer or a virus, and some turn into those memory cells that then generate our ability to make stronger responses. Interestingly, some really seminal work on two central aspects of how this process works were the topics of two Nobel Prizes, two Melbourne scientists, in fact, and that's Macfarlane Burnet in 1960 and Peter Doherty in 1996. Burnet was a very high director at the time, so he's one of our scientific heroes at my institute.
Paul: [00:09:37] Yeah. Now, I'm aware of Sir Frank Macfarlane Burnet and he had I think if I get the quote right, he said that cancer is failed immune surveillance, is that right?
Matt: [00:09:50] Yeah, something like that.
Paul: [00:09:52] So the proteins on the antigen and the T-cell, the binding, a lot of it's about the shape of the molecules. Is that right? And if that's right, you know, how many possible combinations of shapes are there or are there other attractors that cause this identification bonding.
Matt: [00:10:10] Yeah, it's a great question. You're absolutely right about shape. I mean, I guess two things there. One is we can understand a lot about what a molecule does and how it does it just by studying it shape. Often use the analogy of taking a tool out of a tool box and handing it to you. And even if you haven't seen that particular tool before, you probably know enough about what other tools do to have a look at it and take a pretty good guess at what it does. And that's kind of how we treat structural biology for the purposes of understanding what a molecule does. Its shape is absolutely important and we think of this receptor antigen interaction as like a lock and key type interaction. So there has to be very specific shape complementarity. That also means that the potential combinations are essentially infinite, which is one of the things that makes it so mind boggling that, you know, a limited amount of genetic diversity and our immune system can recognise what is essentially an infinite universe of antigens because our immune system is designed to respond to things it hasn't seen before.
Paul: [00:11:28] Are you able to do experiments at volume such that AI can then help you find the successful shape or connection?
Matt: [00:11:34] Yeah, there are lots of areas where that's becoming useful and we do a lot of things that we would describe as a screen where essentially we're taking tens, hundreds or thousands of possible solutions to a problem and designing experiments that will essentially select the right answer even though we might go into the experiment not knowing what that's going to be. And as you can imagine, that kind of scientific approach often requires some pretty serious compute power in order to look at all of those possible combinations and identify the right ones. So there's a lot of power and diversity, but it takes a lot of brain space and computer space to understand diversity and find a needle in a haystack sometimes. And that's what you're looking for.
Paul: [00:12:23] And so what happens when the immune system and T-cells are amazing, but sometimes they don't work effectively. They either don't identify the baddie or the antigen or they don't respond properly. So why is it that sometimes our immune system doesn't work?
Matt: [00:12:41] Yeah, good question, Paul. So that semi random genetic process that I was talking about that generates immune diversity and that's different in each of us and that can leave gaps. So some individuals will have stronger or weaker immune responses than others, even when the antigen is the same. More importantly, maybe viruses and bacteria have also evolved ways to suppress immune responses. And we can think about this as a bit of an evolutionary arms race. The immune system develops mechanisms to recognise viruses. Viruses develop ways to fool the immune system. The flip side of that is immune overreaction, that happens when regulatory mechanisms break down. So allergy, for example, as a response to, say, pollen, which is again certainly foreign but not dangerous, or autoimmune disease such as type one diabetes, where the insulin producing cells in our pancreas end up the targets of our immune system. Also on the overreaction side, sepsis, which is blood borne bacterial infection and severe COVID 19 disease, are examples where the immune responses really run amok. And in these cases, it's not actually the virus or bacteria that does the damage. It's the immune response to them that ends up damaging the body.
Paul: [00:14:07] And that's fascinating with COVID. So I didn't know that most people that, you know, suffer and eventually die from COVID are not dying from the disease, but from the body's own immune response. Is that right?
Matt: [00:14:19] Yeah. It ends up what we think of as a systemic inflammatory response that ultimately results in long and multi-organ failure. And so that's why in really severe cases that end up on respirators and can ultimately die of lung, liver and kidney failure.
Paul: [00:14:38] Yeah. So let's turn to cancer now. I understand our immune system andT-cells are very good at identifying foreign substances like viruses and bacteria, but cancers are often different. Why are they more difficult to identify and for the immune system to respond to?
Matt: [00:14:55] Yeah, that's a great question. And it really comes down to the importance of why immunotherapy is necessary. So how much of a role the immune system plays in cancer suppression has been a point of debate for a very long time in the field of immunology. The fundamental problem is that cancer cells are really not foreign. They come from our own healthy cells that have had a series of genetic modifications and a process we call transformation to go from healthy cells and turn into cancer cells. So in many cases our immune system simply doesn't see cancer. That means that the T-cells, antigen receptors are not useful because they don't see the cancer cell as foreign. And we also know that, like viruses and bacteria, cancers can actively suppress immune responses even when they do develop. And so that impairs our body's ability to fight cancer. So it's either invisible or it's actively suppressing the immune system.
Paul: [00:16:00] And this is really where your area of research comes into being, that the current treatment regimes for cancer are fairly blunt instruments into either chemotherapy or radiotherapy or surgery, which, you know, aren't very precise in targeting cancer, whereas your particular area of research, which is CAR T-cell therapy, is a much more targeted response and has great, you know, opportunity in this area which comes to your particular area of study CAR T-cell therapy. Are you able, possibly, to describe in simple terms what CAR T-cell therapy is?
Matt: [00:16:38] Sure, I'll back up a little bit and start with what immunotherapy is more generally, because as you've alluded to, the very development of a cancer means that the immune system doesn't understand it's supposed to eliminate it. And so immunotherapy, broadly speaking, is a group of treatments in which we teach the immune response to recognise and eliminate cancer. So there are two main types of immunotherapy that your listeners may have heard of. One is called immune checkpoint inhibitors. These are drugs that interrupt the processes that cancer uses to suppress an immune response. This has been very effective, first in kidney, lung, liver cancers and some other solid cancers and in fact was the subject of another Nobel Prize given in 2018. The problem with checkpoint inhibitors is it depends on the existence of T-cells that are intrinsically capable of mounting an immune response to cancer. And as we discussed previously, sometimes those simply don't exist. And so CAR T-cell therapy, the second type of immunotherapy active in the clinic right now is a therapy that creates T-cells that know exactly what to do. We do that by taking them out of the body, genetically modified them with instructions to kill cancer and putting them back into operation.
Paul: [00:18:07] Well, that's pretty extraordinary. How do you begin to go about? Well, I can get the taking the T-cells out of the body bit, but modifying so they are better at identifying and killing cancer. How do you do that?
Matt: [00:18:22] Yeah. So a CAR T-cell is the CAR in CAR T-cell actually stands for chimeric antigen receptor. We've already talked about the term antigen receptor as a switch on the T-cells. The chimeric part of that is interesting. It denotes the fact that we make these synthetic immune receptors by stitching together pieces of natural immune receptors. This is a bit of a Frankenstein molecule, and it's also evocative of the ancient Greek mythical beast, the Chimaera, which has the body of a lion, the head of a goat and a tail that's maybe a snake. These natural immune receptors that we sort of cut apart and put back together to make a CAR have been the subject of my research for almost my entire career. So we can isolate T-cells from a patient's blood, give it a gene that encodes in the antigen receptor, that tells it very specifically to recognise a cancer specific antigen and then go and kill any cell that has that antigen. So we're redirecting all of those T-cells to do one thing.
Paul: [00:19:39] I knew the snake influence would come in there somewhere. Now I get the explanation, but the microscopic level at which you're working on, we're talking about cells and molecules and atoms. Can you give a sense of, you know, how you possibly manipulate something so small? What's the order of magnitude we're talking about here?
Matt: [00:19:57] It's a very, very small scale, Paul. And this still really blows my mind. So we're studying and manipulating atoms and molecules to make new things out of them by analogy to engineers that build bridges or robots, more familiar materials we call this molecular engineering. So when we're down to such a small scale, we need a special unit to measure distances. And so we do this in a unit called Angstroms. And just to give you an idea of how small this is, we're all familiar with a metre cut into a thousand pieces. That's a millimetre you and I can imagine what a millimetre looks like. If we take one of those millimetres, cut it into a million parts. This is already difficult for our brains, I think, to understand, and then just for good measure, take one of those millionth of a millimetre and cut it into ten again, that's an Angstrom. And the relationship between an angstrom and a millimetre. Is the same as the relationship between a millimetre and ten kilometres. So this is the scale that we're shrinking things down to. These things are smaller than the wavelength of visible light, so we can't see them in a traditional sense. What that means is that we have to use indirect methods. We use things like X-rays, electron beams, and really strong magnets to manipulate the atoms in that molecule and infer the structure of the molecule. So with very recently developed computational techniques, we can, at this scale design new molecular structures that don't exist in nature and design them to do exactly what we want. So our work uses these tools and techniques to design synthetic immune receptors that give us very precise control over what T-cells do. And due to the work of many others before us over decades, we know how to put them blueprints for these new structures into T-cells in the form of a gene. And that is how the T-cell then makes these receptors itself once it's back in the body. So it is a really small scale, but it's essentially building new structures to do the things that we want done.
Paul: [00:22:30] Well, that's amazing. So you're working at, you know, ten millions of millimetre.
Matt: [00:22:36] Exactly.
Paul: [00:22:37] So you're not using tweezers and a microscope. You're actually making these molecular biology and not obviously knowing the impact until you observe it I suppose, which is amazing. So brilliant stuff. So this precision, this re-engineering of T-cells to identify and target cancer cells is a, you know, a brave new world that has great opportunity. But I understand one of the challenges you're working with to make this more effective is balancing the effectiveness of the immune response with the potential side effects or toxicity that is created by the body when targeting these cancer cells. Can you describe the side effects and the toxicity and how you begin to address that challenge?
Matt: [00:23:23] Yeah, that's exactly right, Paul. And this is really the crucial point for the work that my group does in this space. So the immune response can be too strong or too weak, when it's too weak, it's simply ineffective. And when it's too strong, we end up with these responses like I talked about, and sepsis or severe COVID 19 disease. So the more that we understand about how the design, the synthetic immune sensors, the CARS and they see also the less likely we are to air on one side or the other, that is response that's too strong or too weak. Current CAR T-cell therapies in the clinic are used mainly for blood cancers, and one of the major problems that occurs in the clinic is that they're generally too potent. So they cause a systemic inflammatory response, again like sepsis or severe COVID 19 and can result in multi-organ failure. This is a syndrome we call cytokine release syndrome. And these cytokines, these are inflammatory hormones. Some of this is natural to the immune response centres, in fact necessary for efficacy. But too much is bad and there's a very, very fine line to walk here. So we're using our knowledge of the receptor structure and the tools and techniques that we just discussed to fine tune the safety, efficacy balance and really individually for each cancer, because each type of cancer will have a slightly different line that needs to be achieved.
Paul: [00:24:58] So that's the work you're working on right now, is to fine tune these responses to get a better balance between effectiveness and potential side effects. So what are the next major milestones in this journey of research so that this precision medicine, if you like, becomes more available, more affordable, more widespread?
Matt: [00:25:20] So the broad goal here, I think, is to make CAR T cell therapy both safe and effective for as many types of cancer as possible. And the next frontier really is to determine how it can best be used in combination with other leading cancer treatments to be as effective as possible. So currently, CAR T-cells are only approved for several types of blood cancers. And as we discussed, safety is a major issue here. So the next major milestone is to get a really good handle on this safety efficacy balance for blood cancers, for solid tumours such as liver, skin, brain. There are several problems that need to be overcome to make CAR T-cells are really good for these cancers. And in fact, using checkpoint inhibitors, the first immunotherapy that we discussed in combination with ALS is an area where lots of clinical trials are focusing. But ultimately, if we can make it safe enough for patients, then we can bring it forward as a more early stage treatment and open it up to a lot more patients earlier in their treatment experience.
Paul: [00:26:37] It really is the Holy Grail, isn't it, that the checkpoint inhibitors stop I assume, stop the cancer growing, but the stuff you're doing actually uses the body to, you know, eradicate or kill the cancer? That's huge. That really is the future of cancer treatment. So I guess it's still some way off. But how do you feel about that? You know, this is your area of research and you're right at the cutting edge of, you know, some way off, but treating cancer in a very precise way, how does that make you feel?
Matt: [00:27:08] Look, it's an incredibly exciting and promising area to be working. And I have to admit that when I was an early PhD student in the early 2000, sitting in my advanced immunology lectures, our lectures discussed the theoretical possibility of using the immune system to fight cancer. But at that time it was still really only a theoretical possibility. And so I think it's rare. You know, in my professional lifetime I've seen that come to fruition mainly through the work of others. But most of my career I've been what we would call a basic immunologist. So studying how things work for the sake of understanding them and knowing that they would be broadly important for human health, but not focusing on preventing or treating one particular disease. And so finding that the decades of my research on immune receptors has become particularly useful in one cancer treatment area is really edifying. And I think, you know, the potential for a durable cure and in a single treatment is the vision that keeps us going and keeps us motivated to develop better and safer CAR T-cell therapies.
Paul: [00:28:29] Yeah, no, it is amazing. And it's worth calling out, you know, the importance of Australia. We mentioned two Nobel Prize winners that were from Australia and you're working here in Melbourne at WEHI. We're pretty good at this stuff, aren't we, medical research.
Matt: [00:28:43] Yeah, absolutely. It's a really, really vibrant, very talented, very well interconnected and very collaborative research community. And I think that, you know, Australian science in general is strong. But of course my experience is in medical science and moving from an area like Boston, a region around Harvard Medical School where there were hospitals and companies and universities all together. This is really what the Melbourne Parkville medical precinct looks and feels like to me. So it's a very exciting place to live and work.
Paul: [00:29:23] And a key ingredient, of course, is research funding, which, you know, is obviously very important to continue this work. But also the mix of funding is important, isn't it, that you have this government funding, but there's also philanthropic funding and the mix is important because often government funding is safe research funding, whereas philanthropic funding enables you to do, you know, the more cutting edge or unconstrained research which does often lead to these breakthroughs. So tell me about the mix of funding and philanthropic in particular.
Matt: [00:29:56] Yeah, you're absolutely right, Paul. Most of our research funding does come from government sources, and because these are taxpayer dollars, there's really an imperative to fund projects where a large part of the principal work has already been done and only about 10% of these research proposals are successful. And Australian medical research. This approach makes for pretty safe investments, as you said, where there's a very high likelihood of health benefit within a few years. But somebody has to support the work that takes the project from the idea on paper to the point where there's enough preliminary results to support a successful grant proposal from a major funder. And so our philanthropic supporters are really crucial partners, people who recognise the enormous value of funding, promising early stage ideas. You know, a few tens or hundreds of thousands of dollars can launch a project into a place where government agencies will then come in and invest the millions that it takes to bring an idea to full fruition. We've. Seen this work successfully in our own research and that of many of our colleagues. And we're really fortunate to have the support of organisations like Hearts and Minds Investments, because the impact of this type of funding is really so much larger than the nominal dollar value.
Paul: [00:31:28] We're happy to help in any small way. What you're doing is quite amazing. I do want to mention you're part of a team, of course, takes a team to do this work, but your partner, Professor Melissa, was also part of the team, which must make for some interesting conversations, you know. Do you talk about the structure of T-cells around the dinner table?
Matt: [00:31:49] Absolutely we do. And on road trips and at the cafe on weekends and on the way to and from work together. So Melissa and I met in training in Boston very early in our careers, and we always wanted to work together. And our current roles, we have a lot of separate responsibilities and professional activities. But I think running our research program together really allows us to share our excitement about new ideas, the thrill of new discoveries, and gives us a partner with which to regroup with some perspective after experimental failures which are frequent in this line of work. So our research is such a huge part of our lives. I really can't imagine having a partner that didn't share my passion for it. So we really love working together.
Paul: [00:32:41] Yeah, well, that's wonderful. Just a little bit more about yourself. You know, when you're not in the future curing cancer and your pet reptiles, what are your other interests besides work?
Matt: [00:32:52] Well, my pets now have moved from reptiles to more traditional forms. I have two cats, Melissa, and I love tending our home garden where we grow mostly fruit and veg.
Paul: [00:33:04] Genetically modified.
Matt: [00:33:06] Not genetically modified, although very carefully selected for good traits. So that's the slow way to genetically modified. And we love travelling to see new places and spend a lot of time visiting our family and other parts of Australia and New Zealand where most of our family is from. And in the US where all of my family still live.
Paul: [00:33:29] Well, that's wonderful. Matt, we'll wrap up here. You know, it's extraordinary what you do. You're on the forefront of potentially finding very precision type treatments for cancer. It's a long road. It's hard, you know, there is failure along the way, but making great progress. So we're very pleased to continue to support this work and wish you all the luck. But thank you very much for joining us today and explaining some quite complex concepts. But I think we all have a better understanding now of CAR T-cell therapy and precision cancer treatment. So thank you and all the best.
Matt: [00:34:03] Thank you, Paul. It's great to be with you today. And thanks again for your support.
Maggie: [00:34:09] What an extraordinary conversation that was. I hope you feel like you've got a better understanding of CAR T-cell therapies and incredible work. Professor Matt Call and his team are leading at WEHI. A massive thank you to Matt for taking time out of his busy schedule to talk us through this important work and to help translate the complex science into relatively plain English. And big thank you to TDM Growth Partners, who is one of our core fund managers and who have nominated WEHI, and specifically Matt and Melissa Call's work as a beneficiary of HM1 funding. It's incredible stuff. Last but not least, thank you to you for joining us today and listening to the Hearts and Minds Podcast. We'll be back next week with another episode to ensure you never miss a conversation. Please subscribe wherever you're listening to this podcast right now, and better yet, send it on to someone in your network you think will enjoy the conversation. Thank you for your support. Until next time, stay curious.
