Vital Science

S3, E02: Can MILs Strike a Killer Blow to Cancer?

 

About this Podcast Episode

From a young age, Kim Noonan knew what she wanted in life — a career in science and a desire to help.

When her mother succumbed to gastric cancer, it drove her even more to help people, especially cancer patients. Today, she’s at the forefront of a potentially game-changing development in cancer therapy — using bone marrow-infiltrating lymphocytes (MILs) designed to target and kill cancerous tumors of all shapes and sizes.

Find out how her early work with myeloma patients started her road to discovering MILs, the origin of WindMIL Therapeutics, challenges associated with manufacturing MIL-based therapies, and what the future holds for this revolutionary treatment.

Learn more about WindMIL Therapeutics and the science behind their work with bone marrow immunology.

  • Episode Transcript

    Kim Noonan:
    Yeah, I hope to see this therapy help patients who have cancer live longer lives. We've seen some evidence of that already with some of our earliest treated patients. We have patients now who were treated with MILs that are alive 14 years, 12 years, 10 years.

    Chris Garcia:
    When we think of cancers like lung cancer, breast cancer, or colon cancer, the first therapies that come to mind are often those that attack the tumor locally, like surgery or radiation. While these options have a therapeutic value, they are not a cure for all patients. And unfortunately, it can come at a high cost to both the patient and the healthcare system. But what if we could effectively treat different types of cancer by looking beyond disease regions of the body? What if the key to killing cancer cells lies in a biological resource we all have access to, our bone marrow?

    I'm Chris Garcia. And in this episode of Vital Science, Gina Mullane speaks with Dr. Kim Noonan of WindMIL Therapeutics, a scientist whose research on T cells 20 years ago, led her down an unexpected path toward a promising new cancer treatment. We'll discuss the therapeutic value of marrow infiltrating lymphocytes, or MILs, their role in CAR-T therapy, and what this novel treatment can mean for cancer patients in years to come.

    Gina Mullane:
    Hi, Kim, it's really nice to speak with you today. And I'd love to know lots about your research and the science behind the work you do every day. But before we get there, I'd love to hear about you. Tell me a little bit about your background and how you got into this field of research.

    Kim:
    Sure. So great to be here today. Thank you for the invitation. I always liked science, my entire life. When I was in grade school even, I liked science and I wanted to be a medical doctor, I think starting in something like the sixth or seventh grade. And I was pretty determined about that. I said it my entire high school career. I was pre-med in college, and studying biology at the University of Pittsburgh at the Honors College pre-med, doing my volunteer hours, doing all the things.

    And then I got a scholarship to work in a laboratory one summer, and I got hooked. I got hooked by the lab. I've always liked lab classes my entire life also, but I didn't really realize how much I would enjoy the science, the scientific part behind medicine. And so all the science I've ever done has been translational in nature, which means that eventually some part of it goes to the clinic. But it was science that I got hooked on.

    Gina:
    And is there anything in particular that drives you to work so hard on the research that you do? Is there a personal story or is it just the impact of the work that you do on people around the world?

    Kim:
    Yeah, I would say that I always ... my greatest goal in life was to help people. And no matter what I did, I wanted to help people. And so, as I said, there has always been a translational aspect to all the work I've done, but my super personal part of the story is that almost eight years ago now, my mother was diagnosed with gastric cancer. And I had been working in the field of tumor immunology for 20 years. And then I thought I had a handle on what it was like to understand the patient's aspect of the story, but it was very, very different when it was my own mother.

    So my driver has been to help people. I have maybe even a stronger driver now, we did lose my mom six years ago. And yeah, so I want to help people. I want to help people who have cancer, in particular, now. And that's what drives me every day.

    Gina:
    I'm sure that's a story that many can relate to and very admirable. And I'm really thrilled to be talking to you today, knowing that. Now that we have a little bit about your background and what led you to this point in time, when you started your early research, it was focused on peripheral blood lymphocytes of myeloma patients. Can you tell us a little bit about that early work and the implications on disease?

    Kim:
    Very early on, when I started working in the field on multiple myeloma, the overall survival rate at that time, in the early 2000s, was about three to four years for these patients. And so it was a very grim diagnosis.

    Chris:
    Multiple myeloma is a cancer of the plasma cells, which are a critical component of our immune system found in bone marrow. While the median survival for a patient with multiple myeloma today is eight to 10 years, 20 years ago, prior to the development of novel therapies like proteasome inhibitors and monoclonal antibodies, the median survival for these patients was just three years.

    In the early 2000, Kim was working on several sponsored research projects related to multiple myeloma, alongside scientist and physician, Dr. Ivan Borello, at Johns Hopkins University. One of these projects involved investigating the clinical value of peripheral blood T cells for patients with myeloma. At the same time, Kim was also studying the bone marrow microenvironment and how T cells might influence bone disease. When her initial research on peripheral blood T cells found them to have no anti-myeloma effect, Kim began to worry that her research on bone marrow T cells might also lead to a dead end.

    Fortunately, she was keeping up with the industry, including the work of Steve Rosenberg at the NIH, who was studying tumor infiltrating lymphocytes, or TILs. She was also following the research of immunologist Carl June, who at the time was studying how to activate and expand T cells, and now leads a preclinical study for WindMIL at UPenn. Connecting the dots between this research on her own, she honed in on the potential of marrow infiltrating lymphocytes, or MILs, found in bone marrow.

    Through a series of experiments, Kim and her colleagues were able to show that contrary to the T cells from peripheral blood that had failed in earlier research, the T cells from bone marrow were able to recognize tumor cells. And if you could take those MILs, activate and expand them and give them back to the patient, they would go on to attack and kill cancer cells. This promising new discovery ultimately led Kim's team to be granted an IND for a clinical trial with multiple myeloma patients in 2007. Since then, 150 patients have been dosed with the cell therapy.

    Gina:
    It really puts things into perspective to hear about all the research that led up to your discovery of MILs. Can you speak to some of the potential advantages of MILs versus other types of cell therapies?

    Kim:
    So the bone marrow, as it turns out, is a reservoir for antigen-experienced memory cells. So antigen is the identity of something, so the identity of a tumor cell can be it's antigen. And so a T cell needs to recognize that identity. And so these antigen-experienced memory cells ... memory means that something has been in your body and you've created memory for it. So for instance, when you get a vaccine and then you get a booster, what you're doing is you're boosting the memory to that vaccine.

    And so these antigen-experienced memory cells home to the bone marrow, where they remain quiescent, which means that they're just sort of waiting there quietly, not undergoing a lot of metabolism. Just being very still and calm until they're needed again. And then they can be pulled back out into the periphery, if that's into the tumor bed or wherever they need to be.

    Chris:
    It's clear that Kim was excited by what she was discovering about MILs in the lab, but how would all of this translate to the clinic? She had been focused on treatment for multiple myeloma patients, which makes sense, because if you were looking for T cells that recognize tumor cells, you would naturally go to where the tumor cells reside. For multiple myeloma, that's the bone marrow. But as it turns out, bone marrow is a unique reservoir for antigen-experienced cells, even for solid tumors related to other types of cancer, like those in breast cancer patients.

    This realization meant that the clinical value of MILs could expand far beyond multiple myeloma, to the treatment of other cancers. After more than 20 years of partnership, Kim and Ivan knew they had a promising new therapy on their hands. And it wasn't long before others in the scientific community began to take notice.

    Gina:
    And so what led to the birth of WindMIL Therapeutics?

    Kim:
    Yeah, it was a very interesting time. So around the year 2013, Science Magazine named immunotherapy the breakthrough of the year. And that's when PD one and the checkpoint inhibitors were all coming into vogue to be used for cancer patients. And it was a revolution. These chemotherapies that really did a lot of damage, we always knew we wanted to get away from that. And how could we utilize the immune system to do that? And finally, around 2013, it seemed like we were making headway.

    And at the same time, the TILs from the NIH and Steve Rosenberg's lab and then CAR-T from Carl June's lab were becoming in vogue as well, simultaneously. And so a lot of money came into the field. Carl's technology was picked up by Novartis for a very large sum of money. And a lot of investors were suddenly seeing, hey, what is this immunotherapy? What, particularly, is adoptive immunotherapy? Which is what we do, taking someone's T cells and giving them back to them. And a lot of investment was coming in. So it was a story of serendipity.

    Chris:
    Today, we have multiple immunotherapy treatments for various types of cancer. But back in 2013, when Science Magazine named it the breakthrough of the year, immunotherapy was just making a name for itself, thanks to the individual breakthroughs of dozens of scientists, each approaching it in a unique way.

    And so it was even more serendipitous that following the publication of their 2015 paper in science translational medicine, Kim and Ivan were approached by investors who saw something special in their particular breakthrough. MILs had a great potential and offered something they had not seen elsewhere. After some deliberation, the pair decided to take investors up on their offer, founding WindMIL Therapeutics in the spring of 2016.

    Gina:
    And so fast forward a few years from that, you received FDA clearance for your IND application and started phase two study of MILs in non-small cell lung cancer, is my understanding. How significant was this milestone for MILs therapy?

    Kim:
    That was a very important milestone for us. All of our early work really focused on hematologic malignancies, particularly multiple myeloma. And as a field, cell therapy really was seeing a lot of success, particularly with CAR-19 T cells in different heme malignancies. But solid tumors was a place where no one was really breaking through completely, except for TILs in melanoma. And so getting an indication in solid tumor was really important to us.

    And again, it was a patient population with a very high unmet clinical need. The patients that we were treating were relapsed or refractory to PD one. And so being able to get the IND through and have our first solid tumor indication was extraordinarily important for us as a company. And really showed that we were going to put some focus into understanding how to treat solid tumors with adoptive cell therapy and MILs.

    Gina:
    And so it really broadened your research possibilities for MILs, it sounds like.

    Kim:
    It did. With that study, we also opened around six or seven phase zero studies. So phase zero studies are extraordinarily special studies. They are studies that give potential promise of future therapies for patients, but a phase zero study in and of itself doesn't give any therapy to a patient. It's really a patient donating their time, and importantly for us, their blood and their bone marrow for research.

    And we opened seven of these in different solid tumors so that we could do the research to see if we would be able to create MILs that were antigen or tumor specific for those solid tumors. So all of that happened simultaneously. And really important for us, to understand how MILs work in solid tumors, which is a newer field for us.

    Gina:
    Interesting. And getting more into the science, if you don't mind, I know you did some preclinical studies comparing novel chimeric antigen receptor engineered MILs, or the CAR MILs, to CAR T therapy. How do they differ?

    Kim:
    Yeah, so the difference is not the CAR. We're using the same CAR, if you put it into a peripheral T cell or into our MIL cell. The difference really is taking advantage of the biological properties that are associated with MILs.

    Chris:
    As Kim mentions, CAR therapy with T cells, also known as CAR- T therapy has been a much investigated avenue for cancer treatment. While CAR-T therapies to date have shown promise, there have also been certain limitations to their effect. One is that T cells often becoming exhausted before they can clear out all cancer cells. But as we know, the T cells derived from bone marrow behave differently.

    And the team at WindMIL has developed the manufacturing process that changes their phenotype in a way that makes them more polyclonal, more polyfunctional, and more active. This means they are able to persist longer, giving them the stamina to clear out cancer cells and achieve better clinical outcomes before dying off.

    Gina:
    It sounds like MILs could be a potential game changer for CAR T therapy. How do you see your research playing into future cancer treatment?

    Kim:
    There's a lot of properties of our cells, when we look at them in the laboratory, that really look like the types of cells that give you better clinical outcomes in patients. And so we're very hopeful to see this translate into patients. CAR T therapy has really revolutionized cancer therapy, particularly in heme malignancies, it hasn't had a dent yet in solid tumors. And so we're hoping that the things that we're learning about our MILs can help us to work better in heme malignancies, and also hopefully be a breakthrough in solid tumors.

    I think that all of us do you understand that the heterogeneity of a solid tumor is important to understand, and MILs can cover that heterogeneity. But we also have to think about the tumor micro environment, and those are some other things that we'll continue to tackle as we begin our first clinical studies with CARs and different tumor subtypes. And really look at the immune correlates coming from the patients from those studies and understanding the clinical outcomes and what those immune correlates are telling us, so we can continue to better our therapy.

    Gina:
    And I'm sure there are many ... and when I ask you this question, many challenges come to mind. But are there any notable hurdles that your team will look at to overcome as they move forward with the research?

    Kim:
    There are a lot of hurdles to overcome with new therapies like cellular therapy. Now, I've told you that this has been in the clinic for, maybe the last five to 10 years, and we've had MILs in the clinics as 2007. But this model does not match the typical pharmaceutical model that everyone's used to. It doesn't look to the FDA like anything they'd seen before. The manufacturability when you're doing autologous ... which means I take cells from a cancer patient and make their product from their own cells. Making an autologous product every time a patient comes in is a challenge.

    So I would say that for us as a field, having the pharma industry understand how adoptive cell therapy is different than typical pharma, having the FDA have further and further understanding of that. And then overcoming manufacturing challenges when you're trying to produce a product for a patient that is very ill and you don't have a lot of time and you need to put a good product out for that patient. Those are the challenges as a field that we face.

    Gina:
    You're right. There's no tried and true roadmap for how to bring a cell or a gene therapy to market. I'm sure that hasn't been easy. Have you found CROs to be helpful in charting your course?

    Kim Noonan:
    Absolutely. So there are several things that we can lean on a CRO for. So for instance, as a company, we have not yet decided to take our dollars and spend them in the brick and mortar of a manufacturing facility. So we lean on the CRO for our CMO to manufacture our product and to do all the quality work and regulatory work so that we can get that product safely out to a patient. We lean on the CRO to actually transfer the cells back from the patient to the manufacturing organization and back out to the patient again.

    And then we've done some of our immune correlate work with some collaboration/CRO type groups, so that our own laboratory isn't overwhelmed with some of the technology that can be quite expensive to bring in-house. So there's quite a few things that we use CROs for. Manufacturing, quality, and some of our immune correlate work.

    Gina:
    Well. There certainly is an enormous unmet need for current cancer treatments. And you and the team at WindMIL Therapeutics are really doing some exciting things. Where do you see ... if you just look forward, where do you see MILs having the greatest impact on cancer patients? What would you like to see the future look like with this incredible therapy?

    Kim:
    Yeah. I hope to see this therapy help patients who have cancer live longer lives. We've seen some evidence of that already with some of our earliest treated patients. We have patients now who were treated as MILs that are alive 14 years, 12 years, 10 years. It's very, very gratifying to think that we had some small part in that. And want to continue to be able to do that, not just for patients with heme malignancies, but patients with solid tumors.

    And then overall, more than anything else, that the understandings that we have from our therapy and the understandings we have from the impact this therapy has on patients, can be used so that the field can deepen its understanding of how to apply adoptive cell therapy so that more and more patients can be helped with this type of therapy. That's what I want to do. I want to make sure that we have an impact on the field, so that patients can have a better outcome with their cancers. That's really important to me.

    Gina:
    Those are some incredible outcomes for these patients. I know with certain types of cancer treatment, there can be a trade-off with the pain and side effects of the procedure. What is the bone marrow collection process like for these patients?

    Kim Noonan:
    It sounds pretty scary to most people. And it's funny because, because I come from a background of heme malignancies and I worked in it for so long, unfortunately, patients who have heme malignancies get a lot of bone marrow procedures to understand where their disease is. And a lot of times, they get bone marrow stem cell transplants. And when they get a bone marrow stem cell transplant, they take them to the operating room and they take about one liter of bone marrow out, which is just, a lot.

    And so for us, for our manufacturing process, it's under conscious sedation. And it is a 30 minute total procedure, about 15 minutes in the bone marrow. We take 200 MLs of bone marrow. We've had no problems whatsoever getting that bone marrow from anyone. But it is something that does come up as we meet people, like, bone marrow, that's really invasive. But if you think about bone marrow collection compared to getting TILs, for instance, you actually have to go in and do surgical resection to get TILs.

    And so on the level between getting a blood draw and getting TILs, we're probably somewhere in the middle. And then per timing and pain, it's like I said, 30 minutes conscious sedation, which means it's like the twilight. You're awake, but you don't feel any pain and you don't remember. And we haven't had any problems. And those phase zero studies are particularly important. I mentioned them on purpose because, again, those patients donate bone marrow to us knowing they're not getting any therapy. We're just taking that back to the research lab.

    Chris:
    With autologous therapy, patient's cells are used to treat themselves. But with allogeneic therapy, a donor's cells can be used to treat another, which means we need a way to safely deliver the treatment to where it's needed when it's needed. This requires a network of storage and distribution channels that are equipped to maintain the safety and integrity of the product as it moves from donor to patient.

    The good news is, as we've learned in last season series on drug repurposing, one scientific breakthrough can provide the foundation for another. In this case, the supply chain that's been established for stem cell transplant provides an excellent model. With these learnings from the stem cell industry, the possibility of allogeneic MILs treatment may not be so far out of reach.

    Kim:
    So autologous therapy is when ... I will be the cancer patient. So I have cancer, and we go into my bone marrow and take bone marrow T cells and create a MILs product and give that back to me. An allogeneic product means that I have cancer, and Gina you're my donor. So we go to your bone marrow, take your bone marrow T cells and make a MILs product and give it to me.

    I'm indebted to every single patient and every single family. There's zero question about that. But those patients that have donated to us just for research, it's truly a gift. Not just to us as a laboratory or a company, but ... I'm not trying to overstate that it's really a gift to humankind. Because they're trying to help people in the future. They want to be part of the solution. And that's just, it's amazing. It is amazing how many cancer patients are willing to do so.

    Chris:
    But allogeneic therapy is not without its challenges. Our body's natural immune response when coming in contact with someone else's cells or immune system is to attack. This could result in graft versus host disease, where the donated cells attack the patient's normal tissue. Or host versus graft disease, where the patient's immune system attacks the donated cells. Overcoming this barrier on a cellular level is a focus for WindMIL, because of MILs can become an allogeneic therapy, it can be used as an off the shelf treatment option.

    Gina:
    So what are the benefits of this treatment becoming allogeneic? Would it allow treatment to be available to more patients?

    Kim Noonan:
    I would say it allows us to reach more patients, maybe not many more from one donor. But it also allows it to be waiting for a patient so the patient isn't waiting for the therapy. Because a lot of times patients don't have time to wait for therapy. Their cancer is progressing rapidly and they need treatment now. And it takes us, right now, it takes us seven to 10 days to create the product. But between testing and shipping, it's about 21 days by the time we take the host patient's bone marrow and return their MILs to them.

    And 21 days in the life of a cancer patient can be a very long time when they're very ill. So the promise of something off the shelf is something that I think that we could all try to work towards. Or the promise of reducing manufacturing times or the promise of reducing release times and shipping times, whether or not you just ... everyone's product gets made right where they are at the point of service. These are all things that we're all looking at as an industry to try to make this a better therapy for patients.

    Gina:
    There's so much promise with cell therapy, yet the challenges not only scientifically are huge at times, but even just some of the logistical challenges that you spoke to. So I was just wondering if you could share your thoughts around the cell collection or the marrow collection, the logistics that are required there. What are the challenges of today and what is your hope for the future, so that we can, if you will, simplify perhaps the process by which we go about collecting and developing these therapies?

    Kim:
    So I think there's a lot of work that's being done on the supply chain logistics side. There are quite a few companies that have popped up thinking about how we might be able to overcome some of those logistics issues.

    Chris:
    The good news is, as we've learned in last season series on drug repurposing, one scientific breakthrough can provide the foundation for another. In this case, the supply chain that's been established for stem cell transplant provides an excellent model. With these learnings from the stem cell industry, the possibility of allogeneic MILs treatment may not be so far out of reach.

    Gina:
    That's wonderful. Is there anything we didn't talk about today that you think would be good for our audience to know? Any question I didn't ask or something you'd like to share?

    Kim:
    I just want to be sure that I represent all the people that worked on this before WindMIL existed. It's a company where there are a lot of scientists and other people working to make sure that this therapy can come to the forefront. For me, I've been working on this since 2004, 2005, and so it's been a dream of mine. And so I understand how I can have long days and work on weekends. It's my dream.

    But I think it's important to understand that it's their dream as well. And I'm just so grateful for that. And they all have the same wish. And that is really just to help patients who are our daily inspiration and why we're able to do what we do every day.

    Gina:
    Wonderful. Well, it's been a real pleasure speaking with you, and learned a lot. And I'm really impressed by the work of your company. And it was just really fun getting to hear your background and getting to know you a little bit.

    Kim:
    Thanks, Gina. I really appreciate it. And really appreciate being invited here today.

    Chris:
    Dr. Kimberly Noonan is the Executive Vice President, Chief Science and Technology Officer, and Co-Founder of WindMIL Therapeutics. In our next episode of Vital Science, we'll continue our exploration of next generation cell and gene therapies with Dr. Karin Agerman who joins us from CombiGene. Tune in to hear about how CombiGene's groundbreaking lead candidate for drug resistant focal epilepsy patients, which transports therapeutics using a novel adeno-associated virus. Until next time, thanks for listening.