Melody Swartz and Jeffrey Hubbell
Big Brains podcst

Engineering A Cure For Cancer, with Jeffrey Hubbell and Melody Swartz (Ep. 83)

How immunotherapy is changing everything

Melody Swartz and Jeffrey Hubbell
Big Brains podcst

Show Notes

The race to cure cancer has been running a long time, but two University of Chicago scientists are working to bring that closer to reality. Thinking like engineers rather than doctors, Profs. Jeffery Hubbell and Melody Swartz of the Pritzker School of Molecular Engineering are bringing new approaches to the field of immunotherapy—and helping us rethink cancer research.

Swartz has even developed what she calls a cancer “vaccine”—a way to train the immune system to recognize cancer cells as bad. By tinkering with the different parts inside our bodies, Swartz’s and Hubbell’s labs are searching for ways to utilize immunotherapy while eliminating its downsides. If their biggest ideas pass clinical trials, we could enter a new era of fighting not only cancer, but a host of other diseases.

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(Episode published December 23, 2021)

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Transcript:

Paul Rand: Are you a big brain, or do you have one in your life? Let everybody know with our new podcast's merchandise. Visit our new website, bigbrains.uchicago.edu to shop for a variety of gifts, from coffee mugs to throw pillows to decals. Know that when you make a purchase, you're helping support the podcast. Use promo code BRAINS21.

Paul Rand: Approximately 40% of us will be diagnosed with cancer in our lifetimes. The race to find a cure has been running for so long that the phrase “a cure for cancer” has become somewhat of a cliche. But in the last few years, a new way of fighting cancer has started to bring us closer to being able to use that word seriously. It's called immunotherapy.

Tape: It's not a miracle cure for cancer, but for specialists and patients alike, this is a remarkable moment in time.

Tape: Now, a blockbuster series of studies is finding these drugs could change the way most lung cancer patients are treated.

Tape: The emerging field of immunotherapy and its potential to help fight cancer in some patients.

Paul Rand: As promising as immunotherapy is, it comes with potentially disastrous side effects and only works for a minority of patients. Far from a cure. But two scientists here at the University of Chicago are changing all that.

Jeffrey Hubbell: What we're trying to do is develop new technologies, which then leads to new patents, new intellectual property, new commercialization efforts, where you can move forward from A all the way down the road to Z someday.

Melody Swartz: The idea is not to find a particularly—just to say, this is a cure—but coming up with new ideas that could help those people and make different types of immunotherapies for different types of cancers.

Paul Rand: That's Jeffrey Hubbell and Melody Swartz. They're professors at the Pritzker School of Molecular Engineering at University of Chicago, and they're reengineering how the medical field thinks about and uses immunotherapy. They've even developed something called a cancer “vaccine.”

Melody Swartz: I would say it's very different than anything else that's out there. This is more ... We're trying to not hit it so much with a sledgehammer, but try to fine-tune and understand what helps drive a broader and long-lasting immune response. That's what our vaccine is more focused on as opposed to other approaches.

Paul Rand: They may not use the word “cure,” but if there's going to be one, this seems pretty darn close.

Jeffrey Hubbell: Hope springs eternal.

Paul Rand: It does. From the University of Chicago Podcast Network, this is Big Brains, a podcast about the pioneering research and pivotal breakthroughs that are reshaping our world. On this episode, the power of immunotherapy and the fight against cancer. I'm your host, Paul Rand.

Swartz and Hubbell are developing exciting new ways to eliminate cancer. But their approach is unique. They don't think like doctors.

Melody Swartz: I was actually pre-med when I started undergrad. But I pretty much hated molecular biology.

Paul Rand: They think like engineers.

Melody Swartz: I just like taking things apart and seeing how things work, how things fit together, and how we can understand something from many different angles.

Paul Rand: They're a married team, but each has their own lab at the Pritzker School of Molecular Engineering that focuses on molecular engineering and immunoengineering. Basically approaching the body more like a machine and designing ways to tinker the parts to make the system work better.

Jeffrey Hubbell: We've really tried to establish research groups that focus on new molecules, new materials, new quantum materials and quantum information processing approaches for other parts of the PME, so that new enabling technologies, but that can be translational. Meaning I can turn it to some clinical impact or societal impact or technological impact.

Paul Rand: This engineering mindset may be exactly what cancer research needs.

Melody Swartz: Engineers are trained to think about problem solving. You learn approaches and tools and methods, and it teaches you also to think about complex system. When I look at problems like in physiology or an immunology, immunophysiology, really, I guess that has to do with where and when in the body things are taking place and how. It's perfect for an engineer to look at that, because I think we're asking questions that are different than those that a cancer biologists or immunologists would ask. This might come out of the wrong way, but I think being ignorant about a field—it's easier to question dogmatic assumptions when you're slightly ignorant, because you don't have any preexisting idea about how things are supposed to be.

Paul Rand: I actually think that if some ignorance is helpful here, I think I could be brilliant in your field.

Melody Swartz: Well, you know how sometimes just asking a question and when you don't know anything? It sometimes could be a really important question that everybody took for granted.

Paul Rand: Let's start with the right questions. What is the immune system? On a simple level, it's your body system for fighting off invaders, like an internal police force. But to understand immunotherapy, we have to go much deeper.

Jeffrey Hubbell: Immune system is divided into two parts, one that responds very quickly, for example, to infection, and one that responds a little bit more slowly, but a lot more specifically. The very quick system is called the innate immune system, and it's evolved to recognize bacteria and fungi and certain parasites, organisms that divide really quickly so that you need to respond to them really quickly before they kill you. The more sophisticated response, for example, the one that occurs to viruses like we're all thinking about right now is called an adaptive immune system. It takes some days to respond, but it responds with great specificity so that response, for example, against a flu virus, would be different than response against a COVID-19 virus.

Paul Rand: The system is made up of different kinds of cells that all play a different role.

Jeffrey Hubbell: There are cells called antigen-presenting cells that are patrolling doing surveillance, looking for non-self constantly.

Paul Rand: Non-self. It basically means anything that isn't considered part of your body. These antigen-presenting cells are like detectives try to discover evidence of a problem and bring that back to something called T-cells.

Jeffrey Hubbell: T-cells or T-lymphocytes are really one of the main agents, the main actors in that adaptive immune response. A certain class of those T-cells has the ability to kill other cells that are infected or they mutated. They can recognize signals presented on those cells and they kill them. Those are called cytotoxic T-lymphocytes or CTLs. They are what we're particularly interested in in cancer immunotherapy because they have the capability to kill cancer cells that possess these mutated proteins.

Paul Rand: Ideally, our immune system would identify cancer as a foreign agent and take it out. But there's one big problem. Because cancer is a corruption of our own bodies, our own cells, the immune system can't always see it, almost like it's wearing a disguise.

Jeffrey Hubbell: There are off signals on healthy cells to educate T-cells that this is self, that this protein or this target is self. Those are mediated by immune checkpoints, ways that either the normal cells of the body like healthy cells or mutated a cell like a tumor cell, unfortunately, communicates to a T-cell to say, "Hey, I'm self." In cancer that normal mechanism gets hijacked such that then successful cancer cells express a lot of these checkpoint molecules to tell, in a dishonest way and in a tricky way, to tell the T-cell that, "Hey, I'm normal self," but in fact it's not normal self.

Paul Rand: This is what cancer immunotherapies try to fix.

Melody Swartz: Cancer immunotherapy is anything that would activate your immune response to recognize and kill or help the immune system kill tumor cells.

Paul Rand: Like a training program for your immune system.

Melody Swartz: That's the goal of cancer immunotherapy, and it can be done in a lot of ways.

Jeffrey Hubbell: One approach that we're exploring is to deliver to tumors agents that amplify the immune system, that amplify the response of these antigen-presenting cells so that they collect these mutated proteins from the tumor, and then present them to T-cells in a way that is more immunogenic. That's education.

Paul Rand: Some immunotherapies focus on the T-cell, like CAR T-cell therapies.

Melody Swartz: You can inject T-cells that are taken from your body, engineered to be hyper-aggressive, recognize your tumor, and then they re-inject it back in your body and then they fight the tumor.

Paul Rand: Or you can focus on the checkpoints, what cancer uses to disguise itself.

Jeffrey Hubbell: The more broadly used immunotherapy therapies would be these checkpoint blockade agents or checkpoint inhibitors. Those are by and large antibody drugs, protein drugs that recognize a target in an extremely specific way and can get in the way, can just block it, block it mechanically. There are antibodies that have been developed to checkpoint molecules with names like program death-1 or programmed death ligand-1. Very interesting names, and they block that blocking response. They block the ability of the tumor cell to trick the T-cell into thinking that it's not mutated after all.

Paul Rand: Immunotherapy has been one of the most exciting advancements in cancer research in decades. Since winning the Breakthrough of the Year award from Science Magazine in 2013, it's also been named the Advance of the Year by the American Society of Clinical Oncology. Twice. But as mentioned earlier, it's not without it's downsides.

Jeffrey Hubbell: These checkpoint blockade agents are prone to cause autoimmunity. I mentioned that these checkpoints are one of the ways that we don't develop autoimmunity in the first place. There can be patients with an underlying inflammatory or autoimmune bias that get pushed over an edge and become autoimmune, or even in patients that don't have that underlying bias, autoimmune-like responses can occur.

Melody Swartz: If you were to make the analogy of immune suppression to prevent organ transplant rejection, for example, somebody might be on immune suppressants. That makes their whole entire immune system suppressed. Checkpoint inhibition is the opposite of that, right? Your immune system is at a heightened state of activity, but not specifically only against tumors, but against anything else too.

Jeffrey Hubbell: For example, there are cases of Type 1 diabetes that occur in adults because of treatment with these drugs, that it turns on autoimmunity in the pancreas, or more problematically inflammation in the liver. So, autoimmune-like responses in the liver that lead to sometimes dose-limiting toxicity.

Paul Rand: There's another problem.

Jeffrey Hubbell: These checkpoint blockade agents, these checkpoint inhibitors work really, really well, but unfortunately in a minority of the cases. Don't get me wrong, if I had cancer, I would want to be treated with one as well as I could.

Paul Rand: Why is it that it's only a minority?

Melody Swartz: It only works on tumors where there's already immune recognition and there's already T-cells inside that tumor. All it does is boost their activity. If the tumor is never recognized by immune system in the first place, then boosting the T-cells isn't going to necessarily do anything.

Jeffrey Hubbell: That's what we mean by an inflamed tumor. Inflamed tumors respond well, but poorly inflamed tumors don't respond well.

Paul Rand: But Swartz's and Hubbell's labs have come up with unique solutions to this problem.

Jeffrey Hubbell: What we're doing is trying to develop molecular therapies to enhance tumor inflammation, to take a poorly inflamed tumor and to make it strongly inflamed tumors.

Paul Rand: Okay. You're affecting the tumor so that the immunotherapy that exists would actually work on it in the way it works for all other people?

Jeffrey Hubbell: That's right. There are classes of molecules that are immune regulators called cytokines, and a particular subclass of that called interleukins. These interleukins are partly the way that that immune cells communicate with each other to turn down immunity, to recruit immune cells, to activate immune cells, to make immune cells proliferate and grow. What we're doing is we've developed an engineering approach for these cytokines, these interleukins, to make them accumulate in tumors to be more effective in the tumor, simply because they stay there longer. In some of our mouse modeling, some of our animal studies, we see very strong monotherapy efficacy. Meaning where there was enough immune activation going on, that we simply have to push it over an edge, and we can do that. In other tumors, it's beneficial to have these checkpoint inhibitors on board as well.

Paul Rand: The work then that you guys are working on is how do you tap into this immunotherapy so that it actually helps them flame the tumors and makes them accessible to the treatment, but also without the side effects, if I'm understanding it right?

Jeffrey Hubbell: That's right. Also, with lower side effects. Drug developers refer to a therapeutic index or a therapeutic window. Meaning a drug level or an activity level that's high enough to be effective, but not so high as to be toxic. One of the things that we've seen that we can do in our preclinical studies is lower the doses of some of these important agents so as to have a more lower toxicity profile, but still a very beneficial efficacy profile.

Paul Rand: This isn't the only new immunotherapy breakthrough they've engineered. Two years ago, Hubbell's lab devised a unique immunotherapy that uses the tumor's own collagen against it.

Jeffrey Hubbell: Yeah. All tumors exist of tumor cells in what's called the stroma, the stuff that the tumor lies upon, and that stroma has a lot of protein compounded in it, including collagen. Collagen is the main structural protein of the skin, the tendon, the ligaments and bone, and also the main structural protein of tumors. When a drug in enters a tumor, it enters the tumor because the vasculature in the tumor is a little bit leaky. The drug leaks out of the vasculature into the tumor. The problem is it leaks into the tumor and then it leaks out of the tumor. It's not present in the tumor particularly long. What we've done is develop a molecular engineering approach where we have the agent, like the cytokine, bind to collagen in the tumor, which is everywhere in the tumor, so that when it leaks out, it gets hung up and retained in the tumor for prolonged periods of time. This allows us to use the doses in the bloodstream that are infrequent because doses in the tumor itself could be prolonged, and thus present in a much more effective manner.

Paul Rand: Not to be outdone, Swartz's lab this year developed an incredible immunotherapy called a cancer vaccine, which may provide all of the benefits of immunotherapy without the downsides. While she won't call it a breakthrough, I'm not sure what else it can be called.

Melody Swartz: Everything is just a little step. I don't know, breakthrough is not a word I would use. The more we do, the more we try things in humans, the more we learn and the more we can fine-tune things. I hope that this could become something that would not only be feasible, but if it shows good efficacy, I think it could also be quite inexpensive as a cancer immunotherapy. It could be more accessible to more people.

Paul Rand: That, I'll say it, breakthrough treatment after the break.

Paul Rand: With inflation in the US at its highest point in 30 years, and the Great Resignation causing uncertainty for employers, what's the future of the global economy in 2022? Find out on Jan. 12 at Economic Outlook, Chicago, a hybrid, in-person and virtual event hosted by the University of Chicago Booth School of Business. Chicago Booth professors, Austan Goolsbee, Randall Kroszner, and Raghuram Rajan will discuss inflation, labor markets and the future of the global economy with moderator, Kathleen Hays. Join us to get expert insights from these renowned economists. Register at chicagobooth.edu/eo.

Paul Rand: Like our immune system, we've all become intimately familiar with vaccines over these last two pandemic years. During the same period, Swartz had her own vaccine breakthrough, but not for viruses, but for cancer.

Melody Swartz: Just like a normal vaccine, you might have a killed virus, you might have like attenuated virus every year the flu or some known antigens that are from that particular thing, and then you present it to the immune system and you let them get educated on that, and then they'll go and kill the tumor.

Paul Rand: Swartz's cancer vaccine is one of a kind, and it could be a massive development in cancer research. But to understand it, we need to know about another system be on the immune system. That's the lymphatic system.

Melody Swartz: Lymphatic vessels were long considered just to be the drainage system, the sewer system of, you can say, of your body, and they were considered not that important. They're vessels throughout your body, they drain fluid, and interestingly, they pass through lymph nodes and lymph nodes are where immune responses are initiated. Strangely enough, when I started in this field, nobody was even asking, "How do lymphatics contribute to immunity?" They're clearly part of the immune system, but that wasn't even explored incredibly.

Paul Rand: But when Swartz's engineering brain looked at the lymphatic system, it started to piece things together.

Melody Swartz: While lymphatics drain fluid, they also are the main route for immune cells to go from a tissue into the lymph nodes. The T-cells use lymphatics to traffic, but the lymphatics also can attract the T-cells. In tumors, one of the main findings we have is that when the tumors engage lymphatics, it also makes the tumor much more attractive to T-cells.

Paul Rand: If the lymphatic system is the drainage network your immune system uses to get around, what happens when a tumor gets its cells into the pipes? Well, now, it has access to the entire body.

Melody Swartz: One of the paradoxes of lymphatics in the tumor micro environment, they're always considered bad. All right? If you have lymphatic involvement, that means the tumor can induce lymphatics to grow into it, they can activate the lymphatics. That's always associated with metastasis.

Paul Rand: Metastasis, when your body develops tumors in secondary locations when it spreads.

Melody Swartz: There been so many clinical studies showing that in melanoma and carcinoma and so many soft tissue cancers, that involving lymphatic vessels is correlated with metastasis, correlated with poor survival. The more lymphatic vessels around a tumor, the worse prognosis for the patient. Lymphatics are bad for cancer, right? It's assumed that that's been because they're an escape route. But the lymph node is where they escape to, and the lymph node is where all of your adaptive immune responses are mounted. It was always very puzzling to us why lymphatics would be a hospitable place for tumor cells to disseminate, to move to other places. You don't escape to the police station, and that's a really lame analogy but ... They're playing on both teams.

Paul Rand: If only there were a way to get the good of lymphatics without the bad.

Melody Swartz: The thing is that we figured out a way to turn that into a therapeutic by taking the tumor biopsy or tumor cells from surgery, making them express a growth factor that will attract the lymphatics. That's considered normally bad. Right? But we then irradiate the cells so they can't divide. They're essentially like a dead ... They're almost dead, they're dying. Then we inject them somewhere completely remote, anywhere really, that has nothing to do with that tumor. Yeah. Like a vaccine. It's exactly like a normal vaccine. It'd be like a flu vaccine. You take that flu, you make it so that it's not effective, you make the virus attenuated or killed, and then you inject it with something called an adjuvant, which helps boost the immune response. That's exactly what we're doing. But our vaccine or tumor vaccine are engaging the lymphatic system to bring broader and stronger immune response.

Paul Rand: Engaging the lymphatics makes the response to the tumor even more powerful than many other immunotherapies. But what about the threat of metastasis? Well, like with other vaccines, the immunity to the cancer would be systemic, meaning it would actually spread throughout the entire body. If the cancer metastasizes somewhere else, the T-cells generated by Swartz's vaccine could still find it and kill it.

Melody Swartz: This approach of harnessing lymphatics, that's completely new. There's no therapy. You doing this to help boost an immune response, this is a completely new concept.

Paul Rand: It's important to note that Swartz's cancer vaccine is still awaiting clinical trials, but the idea alone is a massive upgrade for immunotherapy. Remember all those dangerous side effects over other therapies? Well, you wouldn't have them with hers.

Melody Swartz: The difference in having a cell therapy where it's a vaccine, it's actually much, much easier because, first of all, you're not taking out precious cells that you need. You're taking out tumor cells. These are going to be taken out anyway, right? During the surgery or during a biopsy. Then you're irradiating them so they're not even barely ... They're dying slowly over a period of two weeks. Then you're injecting them in as a vaccine, intramuscularly. In terms of safety, it's much less risky than CAR T-cell therapy because you're only using your own tumor cells to educate the immune system, and you're also only educating T-cells against your tumor cells. You're not going to have these side effects that you would have with drugs or therapies that boost your immune system everywhere.

Paul Rand: Not only would it be safer, but you also fix the second problem with other immunotherapies. Her vaccine could also work with any kind of cancer, inflamed or not.

Melody Swartz: Because you're using your own tumor cells, it could theoretically work for any ... We have to obviously to test everything, but it could work for any type of cancer.

Paul Rand: But it still gets better?

Melody Swartz: We did studies to show that it was very long lasting because some of the mice, they were basically cured, and then COVID hit and then we found a year later, we realized they were still in their cages and so they were old, and they still didn't have cancer. Then we rechallenged them with tumor cells and the immune system completely killed this new rechallenged tumor cell a year later.

Paul Rand: Wow.

Melody Swartz: Yeah, we were very excited that this worked so well and it had such a robust and also a long lasting immune response, and that's something that also, I think, needs to be more focused on in the whole area of cancer immunotherapy. A lot of it is aimed at just hitting it as hard as you can, activating your T-cells as much as you can just to be as aggressive. But then these T-cells can just flame out. They can be overactivated and then they die off, and then you don't have any memory recall response. You can also have situations where if you don't completely eradicate every tumor cell, then they can grow back and be even more aggressive. I think it could also be quite inexpensive as a cancer immunotherapy, so it could be more accessible to more people.

Paul Rand: You're hoping now that you're going to take this, you're going to go able to go into human clinical trial, is that right?

Melody Swartz: That's the hope.

Paul Rand: Swartz and Hubbell's research is groundbreaking, and they've both expanded their discoveries beyond just cancer. Immunotherapy can be used to fight all kinds of diseases, and Hubbell has an immunotherapy that he thinks could cure MS, multiple sclerosis, and that therapy is already in clinical trials.

Jeffrey Hubbell: Yeah, that's the field of immunological tolerance. In a vaccine, we try to induce an immune response. We are also working on what are called inverse vaccines, meaning we will still have a bit and piece that would be pathogenic, but instead of to induce a response, we want to induce a regulatory immune response, educate the immune system to say, "Hey, this is self." For example, in multiple sclerosis where we have ... Our partners in clinical trials with our technology. There we say, "With multiple sclerosis, we know what proteins a patient has developed autoimmunity too." That's really reasonably well characterized based on mechanistic studies over the last decades by other investigators. Then could we take those proteins and rather than vaccinate, could we inverse vaccinate against those proteins to turn on regulatory immunity?

There, we developed technology that's still molecular engineering technology in the laboratory to ask, "Instead of how do you deliver those molecules with a signal of danger, how do you deliver them with a signal of self to educate the body, the immune system to say, 'Hey, these are self?'" Right now, we're fortunate to have our technology in clinical trials in multiple sclerosis and in clinical trials in another disease, celiac disease.

Our objective is to cure the disease. A vaccine prevents disease for a long time, meaning there's memory to the vaccine. We've shown in our small studies that there's all also memory to these inverse vaccines, meaning you learn that they're self, and then you remember that that is self instead of something foreign. We may need to boost a patient that we don't yet know. That takes more clinical studies to come to understand. But yeah, we do indeed hope to be able to cure these diseases.

Paul Rand: Big stuff.

Jeffrey Hubbell: Hope springs eternal.

Paul Rand: It does.

Jeffrey Hubbell: We come up with ideas in the laboratory, we work hard to test and try to get proof of concept, but then the proof of the pudding is in the clinic.

Matt Hodapp: Big Brains is a production of the UChicago Podcast Network. If you like what you heard, please give us a review and a rating. The show is hosted by Paul M. Rand, and produced by me, Matt Hodapp. Thanks for listening.

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