Alex Biese: Hi, my name is Alex Biese. I’m the assistant managing editor of CURE magazine. In this edition of “Speaking Out” video series on behalf of the Emily Whitehead Foundation. We’re speaking with Dr. Bruce Levine of the University of Pennsylvania Perelman School of Medicine about CAR-T therapy. Dr. Levine, thank you so much for taking some time to talk with us about this topic today.
Bruce Levine: Well, it’s a pleasure to be with you. And thank you so much for highlighting the Emily Whitehead Foundation and their tremendous work.
Biese: Absolutely, it is our It is our pleasure. So, CAR-T therapy, I think anyone who observes or works in the oncology space has been hearing a fair bit about CAR-T lately. But for anyone who isn’t familiar, what is CAR-T cell therapy and on a fundamental level, how does it work?
Levine: Well, at the most basic level, CAR-T cell therapy is a way to teach your immune system to recognize cancer. Now, we know that cancer is derived from our own cells, the immune system evolved to tell self from non-self. So how could the immune system recognize cancer if it’s derived from your own cells? Now, there are some rare immune cells that can recognize some cancer mutations, particularly for some virally induced cancers. But in large part, the immune system is unaware and unable to react to cancer.
So, what we do is to teach immune cells, specifically T cells, to recognize cancer by inserting a chimeric receptor. Now, some people may know that the chimera is a mythical beast composed of the head of a goat, the body of a lion and the tail of a serpent and in our case, we’re creating a molecular chimera with parts of an antibody domain to recognize antigen or cancer antigens. And then, this molecule continues inside the cell and inside the cell are signaling domains that tell the T cell, “Hey, this is something you want to pay attention to and start to react.”
And we’re doing this outside of the body. So we’re removing immune cells, we’re collecting them, and they go to a laboratory where that gene encoding the chimeric receptor can be delivered to the T cells, the T cells grow up in the lab for a short period of time and then they’re frozen and they are tested according to criteria for safety, purity, potency and identity and then can be released back to the patient. So, it’s a complex process. Going back to the preclinical work, it’s a complex process to manufacture and execute this therapy. And you could think of it like a remote, genetically engineered immune cell transplant.
Biese: And then when you’re dealing with pediatric patients with cancer specifically, does the approach to CAR-T differ at all in treatment course or intensity or anything like that?
Levine: So, the treatment, the conceptual part of the treatment, and the execution is more or less the same. Some things that may differ are in some of the preconditioning chemotherapy that the patients receive (or) some of the treatment that they receive after to manage side effects.
The first approved CAR-T cell therapy was actually approved in a pediatric indication, acute lymphoid leukemia (ALL), and that is Kymriah (tisagenlecleucel). There are preclinical studies in other cancers, in some solid cancers, neuroblastoma and high-grade glioma or brain cancers. And those do look promising. It will take some time to move those forward into latter-stage clinical trials and regulatory approval and commercial development. But the field of CAR-T cell therapy and immune cell therapy, genetically engineered immune cell therapy, has benefited from these early approvals of the CAR-T cells and blood cancers, and there’s been a lot of investment not just by granting agencies but importantly (by) commercial investors creating companies to develop these therapies.
And it’s also important to note this is worldwide. There are approvals in Europe, Japan, Australia, dozens of countries around the world for these CAR-T cell therapies and blood cancers.
Biese: And then in terms of things like efficacy and survivorship, how does CAR-T compare to other forms of treatment for children with cancer?
Levine: Well, we know that the standard chemotherapy for pediatric ALL is an intensive two-and-a-half-year regimen and there are both short term and long-term effects. With CAR-T cells it’s a one-time infusion, there may occasionally be a second infusion, but there is long-term durable benefit in many cases and the long-term effect is B cell aplasia or absence of B cells and that results in reduced levels of immunoglobulins and that’s managed by giving supplemental immunoglobulin to the patient.
So, on the whole if you look at the long-term effects of conventional chemotherapy (compared to) to CAR-T cell therapy, it’s a whole different kettle of fish and we get patients who enroll in our clinical trials who want CAR-T who want to avoid a stem cell transplant because the current indication is for relapsed or refractory situations.
In adults (with) lymphoma, CAR-T cell therapy has now moved to second line, we’ll see how that progresses in children, in ALL, but we’re optimistic about that. And I think for perspective this is really a whole new pillar of cancer therapy. One looks back at the evolution of surgery, radiation and chemotherapy, cellular therapy and gene therapy is the next pillar of medicine. It requires a paradigm shift in thinking about how we develop this therapy but importantly, how we deliver it and the information that we’re providing to patients about these new types of therapies.
Biese: And what role have the folks at the Emily Whitehead Foundation played in really helping to advance and develop and encourage these sorts of advancements in treatment?
Levine: Well, (there are) several ways that the Emily Whitehead Foundation has contributed. Firstly is serving as a resource, listening board (and) forum for patients to share experiences on how they found CAR-T, undergoing the treatment and what happens after CAR-T. The Whiteheads receive inquiries from children with all types of cancers globally to partake of the resource of the Whitehead Foundation and their patients and friends.
And also, through raising funds for patient support and also through raising funds for grants for pediatric cancer research. And a particular emphasis of the Whitehead Foundation funding is early career researchers. And why is that important? Well, the federal granting agencies and even philanthropies tend to look at established investigators, and that’s all well and good but for younger investigators to gain a foothold and to gain the data and to become educated and trained and contribute to the field, it’s really necessary to provide some seed money, some spark to them, so that they can begin to build teams to conduct translational and clinical research.
Biese: Doctor, thank you so much for providing some insight on this really important topic today. We really appreciate it. I hope you have a great day.
Levine: Thank you very much.
Transcription edited for clarity and conciseness.