In this Spotlight Interview, we feature CDN’s own Dr. Leslie Kean, Director of the Pediatric Bone Marrow Transplant Program at Boston Children’s Hospital and Dana-Farber Cancer Institute.
Before moving to Boston seven years ago, Dr. Kean worked at the Fred Hutchinson Cancer Research Center and Seattle Children’s, where she served as a transplanter and Associate Director of the Childhood Cancer Research Center. She shares her remarkable journey from early work in yeast genetics to leading-edge immunology, and the groundbreaking research her lab is doing to prevent graft-versus-host disease (GVHD). From her passion for pediatrics to her pioneering efforts with Abatacept, this conversation offers a compelling look at the science and purpose driving her work.
We know you’re also an MD by training. Can you share how having both a medical background and a strong scientific focus has shaped your work?
Dr. Keane: I began my scientific training by starting my PhD in biochemistry at Stanford, where I focused on yeast genetics. As an undergrad, I worked in bacterial genetics, and I really enjoyed conducting large screens and selections, working with big data in both organisms. When I moved to Atlanta for family reasons, I also realized that I had always wanted to be an MD, even though I initially resisted that idea because it felt like it would please too many people. I was so passionate about science. But eventually, I realized that being an MD would bring me joy as well.
I completed my PhD and medical training in Atlanta, and that shift really changed my perspective on my work. I view science as my art—something I do out of love and obsession with the questions it raises. But when I started my medical training, it became clear to me that I should be focusing on questions that are as close to the patient as possible. For me, combining my scientific training with medicine felt like the right approach. Instead of continuing with bacterial and yeast genetics, I shifted toward studying more complex organisms, particularly developing an interest in immunology. While my PhD is in biochemistry, my postdoctoral training and the rest of my career have been centered on immunology.
When would you say you transitioned into focusing more on pediatrics and bone marrow transplant? What was it about that area that really captured your interest?
Dr. Keane: I’ve always loved working with kids, so I knew from the beginning that pediatrics was the path for me. I was drawn to hematology and oncology, which led me to bone marrow transplant. The field really resonated with me because the science is so close to the patient and involves complex clinical scenarios. Many of these kids are critically ill, but their stories are full of hope and triumph. I love being able to support families and children on their journey, no matter where it leads.
While I was in Atlanta, I focused on bone marrow transplant for my clinical work, but I also wanted to explore transplant immunology further. The best transplant immunologist at Emory was Dr. Chris Larson, a physician-scientist studying the immunology of solid organ transplants. He had revolutionized the way we think about immune tolerance in transplants, and I joined his lab as a postdoc. He was also doing non-human primate research, which piqued my interest. I’ve always been drawn to complex systems, so the opportunity to learn non-human primate immunology was a perfect fit for me.
Until recently, genetic tools for non-human primates were very limited, so we had to rely on systems approaches to understand the immunology. This led me to systems immunology. I was working on solid organ transplant research and taking care of kids with graft-versus-host disease (GVHD), a complication that occurs after bone marrow transplant. I now spend most of my time studying GVHD, but I also work on autoimmune diseases. Since I was caring for kids with GVHD, I decided to create systems that would allow me to study it in non-human primates. That’s how I started my lab, over 20 years ago.
That’s a really important distinction you made between transplant rejection and graft-versus-host disease (GVHD). I think many people confuse the two because both seem like the body is rejecting something. However, in some cases, the transplant is perfectly accepted, and it’s incredible to see patients thrive and live their lives. Could you explain the difference between rejection and GVHD?
Dr. Keane: In contrast, bone marrow transplant is a different story. Solid organ transplants, such as kidneys, are among the most successful due to factors including the availability of kidney replacement therapy (dialysis), which allows patients to survive while waiting for a transplant. In addition, our kidneys are a paired organ, so living donor options are more feasible. However, for other organs like the liver, there is no replacement therapy, and liver failure can be fatal within days or weeks. Finding a living donor for liver or lung transplants is much more challenging than for kidneys.
Now, with bone marrow, we have quite the opposite scenario.. When you donate bone marrow, the donor’s body can regenerate that marrow within weeks, and this is why the National Marrow Donor Program exists, and why HLA matched BMT can come from unrelated donrs. Bone marrow transplants have a higher success rate of matching because HLA (human leukocyte antigen) matching is more available than in solid organ transplants. The donor’s marrow provides the recipient with a whole new immune system that’s trained and educated, producing the possibility for immune tolerance. In fact, a successful bone marrow transplant often involves plans to eventually stop immunosuppression.
However, just like solid organ transplants, bone marrow transplants have potential toxicities. The two main complications are rejection and graft-versus-host disease (GVHD). Rejection after bone marrow transplant is relatively rare, but GVHD is a major risk and can be deadly. With GVHD, instead of the recipient’s T cells attacking the new organ, the donor’s T cells attack the recipient’s tissues, treating them as foreign. This is the opposite of rejection. While patients are often on immunosuppressive drugs for GVHD, the ultimate goal is to reduce or stop these medications over time if possible.
Just to clarify, are bone marrow transplants typically given to patients with leukemia who need their immune systems depleted, or are there other conditions that also require this type of transplant?
Dr. Keane: Bone marrow transplants are used for both malignant conditions, like leukemia and lymphoma, as well as non-malignant hematologic diseases. Some examples of non-malignant conditions include sickle cell disease, thalassemia, bone marrow failure syndromes including aplastic anemia, and certain inborn errors of metabolism. So, there are a variety of reasons, especially in pediatric cases, that people might need a bone marrow transplant.
What are some of the strategies that you’ve seen be successful, or that you’ve personally worked on, to help treat patients with GVHD?
Dr. Kean: The history of transplant is relatively young, beginning in the 1970s. Initially, rejection was the main issue, not GVHD, as patients would reject their transplants before GVHD could even occur. To address rejection, doctors started using a single immunosuppressive agent, but they found that while it prevented rejection, it didn’t prevent GVHD. In the 1980s, a two-drug regimen was developed, typically using a calcineurin inhibitor (such as Tacrolimus or cyclosporine) and a proliferation inhibitor (such as low-dose methotrexate). This strategywas adopted for human use and remained the standard for decades.
However, in the last 10 years, there has been significant progress. New approaches include using cyclophosphamide post-transplant (called post-transplant cyclophosphamide or PTCy) to deplete T cells, which has demonstrated improved outcomes in comparison to the two-drug regimen. Additionally, my lab’s work on T cell signaling pathways, specifically co-stimulation pathways, led to the clinical studies that resulted in FDA approval of the first drug for GVHD prevention—Abatacept, a T cell co-stimulation blocker. There’s also been tremendous progress in GVHD treatment, with multiple targeted therapies emerging in the past 10 years.
Can you explain a bit more about how Abatacept works? You mentioned earlier that there were two agents used in combination, but now Abatacept targets a specific co-stimulatory molecule on T cells. Is there anything else involved in the process, or is it just targeting that one pathway?
Dr. Keane: Abatacept (CTLA4-Ig) is a drug that blocks signal 2 by inhibiting the co-stimulatory interaction between CD28 on T-cells and CD80/86 on APCs. In mouse models, if T-cells were activated via signal 1 but signal 2 was blocked, the T-cells would become tolerant to that antigen and wouldn’t respond again. While this doesn’t exactly apply to humans, it shows the potential of modulating co-stimulation.
Abatacept was initially approved for rheumatoid arthritis, but my work on bone marrow transplants led me to explore its use in GVHD prevention. We conducted studies in non-human primates and later in humans, showing that adding Abatacept to a standard transplant regimen—using a calcineurin inhibitor (like tacrolimus) and methotrexate—helped prevent acute GVHD, especially in patients with mismatched donors. This combination led to significantly better survival rates, and the research eventually resulted in Abatacept’s FDA approval. The pivotal trial for this approval was actually an investigator-initiated study funded through RO1 grants.
Diseases such as GVHD are orphan indications, affecting relatively few patients, which means that they are often not of particularly high interest to pharmaceutical companies. However, when we demonstrated that Abatacept could prevent GVHD, we were able to partner with Bristol Myers Squibb to push the treatment through for FDA approval. This wouldn’t have been possible without the NIH and foundation funding to support the research. The study we conducted became the pivotal trial for approval, and I was involved in the entire FDA approval process. Now, anyone who needs it can access Abatacept to help prevent acute GVHD, which is a major breakthrough.
Just to follow up on what you mentioned, in mice, the treatment induces tolerance. In humans, not so much. Does this mean that some patients don’t need to take Abatacept for life? Is it just a matter of taking it for a certain period to help their immune system become tolerant?
Dr. Kean: I don’t know for sure. With bone marrow transplants, tolerance can happen naturally, so it’s difficult to pinpoint if Abatacept is specifically helping some patients. My best guess is that there are certain patients who might otherwise die from acute GVHD, but with the help of Abatacept, they’re saved during that critical window and eventually become tolerant later on.
That’s really interesting. Earlier, you mentioned doing a lot of non-human primate work as well. How have these models helped you better understand the disease?
Dr. Leslie Kean: From my perspective the NHP work has been truly revolutionary. Mouse models are critical for investigating immune questions, but as you get closer to the clinic, there are some limitations. For one, mice are inbred, and we know that immune systems of wild-caught or “dirty” mice are much different. This has taught us how much more difficult it is to control the immune response in outbred, pathogen-exposed humans. Non-human primates are outbred and pathogen-exposed, so they more accurately replicate the immune system we see in humans.
Also, when testing a drug, some drugs created for humans won’t cross-react with their mouse counterparts, so you can’t test directly these agents in mice. However, in non-human primates, most drugs cross-react, which allows us to ask questions in a model system that’s more faithful to human immunology and test the drugs directly. That’s been key.
In addition, applying systems biology and single-cell techniques has enabled us to deeply dig into the mechanisms that control immunologic outcomes. Historically, non-human primate work has been limited by a lack of high-quality cellular and molecular immunology, but systems immunology approaches have allowed us to overcome that barrier.
On another front, Abatacept is a biological agent. If you were to explain the difference between a biological and non-biological drugs to someone who isn’t familiar with these terms, how would you explain it in simple terms?
Dr: Leslie Kean: So, when I think about it, especially in the context of our work, we treat patients with drugs such as post-transplant cyclophosphamide, which is a nitrogen mustard developed during World War I. It’s a biological agent in that it affects biological systems, but it’s not targeted in a precise way. It’s a very broad, non-specific drug. And honestly, I think we can do better. I believe the future lies in deeply understanding transplant biology and using more targeted agents. When I refer to a biologic agent, I really mean a targeted therapy—a drug, antibody, or even a cellular therapy—that’s been specifically designed to target something in the immune system. Abatacept is an example of this kind of approach. It’s targeted and purpose-built to block a specific molecule involved in immune activation. And with non-human primate models, we can conduct more controlled experiments to understand how these targeted therapies work, which leads to stronger inferences about their mechanisms of action and how they can benefit patients.
That’s super, right?? …when you’re targeting a specific pathway, it’s like tuning a fine instrument—you’re focusing in on exactly what needs to be changed without messing with the rest of the system. That’s the kind of strategy that holds a lot of potential for improving treatments while making them safer for patients.
Dr: Leslie Kean: Absolutely, and while agents like cyclophosphamide have been essential and play a key role, there are definitely limitations. The real goal is to evolve toward a future where all our treatments are more targeted, optimizing their effectiveness and minimizing unnecessary side effects.
How do you think the single-cell perspective of these complex systems provides deeper insights, and in which areas do you see it being most beneficial?
Dr. Leslie Kean: I think it’s indispensable. Let me give you an example. So, in the Abatacept clinical trial known as ‘ABA2, which was the trial that led to the FDA approval, we included real-time immunologic studies as well as a purpose-built biorepository. When I started this trial, single-cell techniques didn’t even exist—this was back in 2010. At that time, we sorted CD4 and CD8 cells and did bulk RNA sequencing on them. But we also created a cryopreserved, state-of-the-art PBMC biorepository to prepare for future studies.
When we performed RNA sequencing on the bulk samples, we found that patients who didn’t receive abatacept and developed GVHD had a significant proliferation signature, which was interesting. However, with bulk RNA sequencing, you can’t dive much deeper into those findings—everything gets averaged out. That’s where single-cell techniques come in. After adequately preparing the cryopreserved samples, we used single-cell RNA sequencing and TCR sequencing. This allowed us to focus our analysis on the proliferating cells, and we identified a candidate gene we believe is central to GVHD in the absence of abatacept.
We then analyzed samples from patients who received abatacept to see what happens to that gene, and we found that in those patients, the gene’s transcription was stabilized, which has been shown in other systems to suppress T cell activation. In contrast, in patients who didn’t receive abatacept, this transcription factor’s expression was significantly downregulated, which could explain the therapeutic effects of abatacept. This kind of insight wouldn’t be possible with bulk sequencing alone.
Single-cell techniques were absolutely necessary here. The bulk sequencing gave us initial clues, and then our biorepository allowed us to pull out cells and apply today’s technologies to dig deeper. By also doing single-cell TCR sequencing, we were able to explore multiple layers of immune responses. So, I’d say single-cell techniques were key to understanding the underlying mechanisms of the treatment’s success.
What do you think are the biggest challenges or unanswered questions in the field right now that you’re particularly excited for your lab to help address and tackle?
Dr. Leslie Kean: We think about this all the time. One thing that we’ve realized, especially with the work in the Abatacept study, is that while we were initially limited to sorting blood cells and doing bulk RNA sequencing, we were preparing ourselves for the next generation of technology. As I’ve mentioned, a lot of the current focus has been on blood, but the big leap for us now is into tissue-based immunology.
In the lab, we’ve started working with tissue samples, including gastrointestinal samples from patients with the autoimmune diseases Ulcerative Colitis and Crohn’s Disease. We have studied a unique cohort of patients, for whom we have performed the single cell analyses at their time of diagnosis—before they’ve been treated with any immunosuppressive therapies. In contrast, transplant patients, especially those with GVHD, have already been exposed to immunosuppressive medications, so analyzing the tissue samples from these patients can be trickier.
Now, with the foundation we’ve established with the UC and CD patients, we’re collecting biopsies from GVHD patients to investigate the tissue-specific mechanisms driving the disease and how those mechanisms can be linked back to what’s happening in the blood. This focus on tissue-based immunology is really at the cutting edge of the field right now, and we’re excited to explore these pathways more deeply in our work.
If you had to pick one scientific advancement from the past decade that stands out to you the most, whether it’s in your field or beyond, what would it be? What’s something that really caught your attention?
Dr. Leslie Keane: There’s so much to be excited about in science! I’m a huge fan of the history of scienceIf I had to pick something that stands out in the last decade, it would definitely be CRISPR and the subsequent advancements that have come from . When I started my career doing bacterial and yeast genetics, we had this saying, where we called out “the awesome power of yeast genetics.” I used to joke that I was trying to make primates like yeast, using systems-based approaches to apply the power of genetics to primates. And CRISPR has really made that possible. It’s allowed us to do genetic screens in mice, non-human primates, and human cells, which is remarkable. The pace of discovery is accelerating, and truly standing on the shoulders of giants. CRISPR and genetic screens in complex systems are driving forward advancements like never before. For example, gene therapies It’s an exciting time in science, for sure!
If you weren’t a scientist, would you what would you be doing?
Dr. Keane: Well, I’m not sure because I truly love being a scientist, but there are a couple of other things I really enjoy. First, I love working with kids. I have a deep connection with them—my family even jokes that I have the soul of an eight-year-old boy because I relate so well to children 🙂 That’s probably why I ended up in pediatrics. So, I think I might have become a teacher. But beyond that, I almost quit science in 1989. Before I truly understood that science was my art, I was also passionate about environmental activism. I worked for Greenpeace, and at the time, I took a year off after completing my master’s in Cambridge and was about to start graduate school at Stanford. I was feeling uncertain about what to do with my life and overwhelmed by the state of the world. I thought the planet was falling apart and science wasn’t important in comparison, so I threw myself into activism. But eventually, I realized that I could still be passionate about activism and care for the world, while also doing what I loved in science.