Liora Schultz, MD: Fighting for a Pediatric Cancer Cure That Lasts

Liora Schultz, MD, is an associate professor of pediatrics at Columbia University Irving Medical Center and a recent new member of the Precision Oncology and Systems Biology (POSB) program at the Herbert Irving Comprehensive Cancer Center (HICCC). As the director of the Pediatric Cellular Immunotherapy Program at Columbia and a founding director of the Pediatric Real World-CAR Consortium, Schultz is committed to advancing immune therapies, specifically CAR T-cells, for treating children with cancer.  

Can you tell us about your background and research interests? 

I'm a pediatric leukemia doctor who studies new ways to use the immune system to treat children with cancer. My work focuses on engineered cell therapies, including CAR T-cell therapy, which modifies a patient’s own immune cells to recognize and fight cancer. I’m also interested in using these therapies to remove B-cells in children with other conditions that may benefit from B-cell depletion. 

What led you to focus your research on CAR T-cell therapy? 

Since CAR T-cell therapy was FDA approved in 2017, there's been limited data collected on patients’ long-term outcomes after treatment. What we have learned in the field is that CAR T-cell therapy is strikingly effective for leukemia, and the majority of patients will achieve early remissions. When CAR T was approved, those early remissions were seen as a fundamental advance in the field. But over time, we've learned that early remission is not our sole desired endpoint. The magnum opus is to achieve remissions that are durable: lasting cures.  

Even though about 80-90% of patients achieve early remission following CAR T-cell therapy, about 50% of those patients will ultimately relapse. And, at this point, we don't know why some patients achieve lasting durable responses, and others don’t. In this commercial era, there are minimal data capture requirements in terms of clinical outcomes in pediatric CAR T-cell recipients, and this created a massive gap, and loss of critical clinical insight that can guide care.  

In 2019, you founded the Pediatric Real World CAR Consortium and still direct the program today. Can you tell us more about how this collaborative environment helps amplify gains made in pediatric cancer? 

The Pediatric Real World CAR Consortium is an international network of sites or pediatric centers that deliver commercial CAR T-cell therapy. Our mission is to create a forum for scaled multi-institutional data and sample sharing to yield biologic and clinical signal to help further tailor which features of CAR T-cells are most primed to achieve durable cure, To date, 50 centers participate in this consortium, which gives us data sets far more robust than what we can gather at a single center. 

We conducted an initial retrospective study across 200 patients which gave us clinically modifiable factors that influence durability of CAR T-cell responses, and survival, and more recently, collected an expanded data set oh almost 700 pediatric and young adult CAR T-cell recipients. These studies continue to shift clinical practice by highlighting which patient features are associated with best and worst treatments responses and toxicity outcomes.  

With this data, we anticipate in the future being able to tailor CAR T-cell delivery so that the patients that are at the greatest risk of relapse receive consolidative or alternative therapies, while patients predicted to have durable responses can be spared toxic therapies, like stem cell transplants that are associated with infertility and long-term health problems.  

What are you looking forward to expanding through your translational work at Columbia and through the consortium? 

Looking ahead, one of the biggest challenges is finding ways to make CAR T-cell therapy effective against more types of cancer, including T-cell and myeloid leukemias and, over the next decade, solid tumors. We have set up a pediatric task force to advance this effort with key leading collaborators including Max Mamonkin, PhD, Sascha Hubner, MD, and Michel Sadelain, MD, PhD, to translate novel approaches to CAR T-cell therapies for extended indications beyond B-cell leukemia, the singular approved pediatric indication for CAR T-cells. 

Beyond that, we have incredible opportunities at Columbia as a children's center to use these therapies beyond cancer, including rheumatoid diseases and autoimmune diseases that are B-cell mediated. We’re also exploring potential applications for organ transplantation. By working with our transplant colleagues, we hope to understand whether CAR T-cell technology could one day help more patients become eligible for organ transplants and help prevent or treat organ rejection. 

What brought you to Columbia? 

Columbia is making a massive institutional effort to promote and advance cell and engineered therapy. I believe Columbia is uniquely positioned to successfully unify the preclinical leaders in the field who are developing novel therapies and building gene therapy facilities, and, those like myself, on the translational front. This was my draw, as I anticipate this scientific alliance will propagate growth and development that will shift paradigms in how we approach cancer therapy. It is most exciting to contribute to this forefront effort from its infancy.  

What is the biggest challenge in progressing CAR T-cell therapy? 

The most important reform in the field is that, right now, CAR T-cells are primarily used for children with B-cell acute lymphoblastic leukemia (ALL) whose cancer has returned or has not responded to standard treatment. Newly diagnosed children and young adults with B-cell leukemia (more than 3000 patients annually) are currently treated with two and a half years of chemotherapy , newly interspersed with brief courses of immunotherapy. By comparison, a course of CAR T-cell therapy only requires about one month of active treatment. Because it is a living drug, in the ideal scenario, while the CAR T-cell product is delivered as a singular infusion, it can achieve immune memory and provide ongoing leukemia surveillance and protection. 

The challenge is that standard treatment for newly diagnosed leukemia is highly effective, with survival rates above 95%. While CAR T-cell therapy can produce lasting remissions for many children with leukemia, only about half of patients achieve immune memory and long-term protection and cure from CAR T cells. 

 So, we can’t yet replace a treatment that cures more than 90% of newly diagnosed patients with a CAR T-cell treatment that has a lower long-term success rate. But the fact that some patients can achieve a lasting cure after just one CAR T-cell infusion, and a much shorter, more tolerable course of treatment is incredibly promising and compelling. I believe in the upcoming decade, it is our mission to understand how to improve CAR outcomes to the point that we can comfortably offer CAR T-cells in the newly diagnosed setting without compromising survival rates.  In this reimagined setting, a newly diagnosed child with B-cell leukemia can be offered a one-month highly tolerable treatment, rather than a >2 year course of toxic chemotherapy.

What is your hope for the potential of CAR T-cell therapy? 

I believe that we can reform how patients with leukemia are treated, where instead of a two-and-a-half-year treatment course, it's a one-month treatment. Patients would no longer be chained to the hospital for two and a half years receiving toxic chemotherapy. If I do nothing else in my career but work only towards that goal, whether we completely replace chemotherapy, or just significantly shorten duration and decrease toxicities, that will be meaningful. It is my dream that the image of a leukemia child as one who is bald and emaciated will one day be remembered as a relic of the past.