What’s Next For CAR T: The Potential of Engineering Immune Cells to Treat Cancer
It is not often that an entirely new, effective, class of therapy is discovered, especially in a disease as difficult to treat as cancer. It is even less common that a completely new therapeutic is effective in a large majority of patients right from the start.
It is not often that an entirely new, effective, class of therapy is discovered, especially in a disease as difficult to treat as cancer. It is even less common that a completely new therapeutic is effective in a large majority of patients right from the start.
But chimeric antigen receptor T cell therapy—CAR T-cell therapy— is anything but typical.
CAR T-cell therapy is created by collecting a patient’s T-cells, genetically modifying them to fight cancer, and then infusing them back into the patient. The first therapy in this class, tisagenlecleucel (Kymriah), was FDA approved in August 2017 in pediatric patients with acute relapsed/refractory lymphoblastic leukemia (ALL), after demonstrating an impressive overall remission rate of 83 percent within three months of treatment.
While the high efficacy results were extremely surprising, the rate at which the therapy got to market was perhaps even more surprising, said Stephan Grupp, MD, PhD, the Director of Cancer Immunotherapy and Cell Therapy/Transplant Section at the Children’s Hospital of Pennsylvania in Philadelphia.
“While this is an area that we have been working on for a number of years, the era of this actually working didn’t start until about 2010,” said Grupp, in an interview with R&D Magazine. “In pediatrics, where the approval was obtained, the first patient wasn’t treated until 2012. It is a very rapid pace to go from first patient treated to FDA approval in 5 ½ years.”
Following Kymriah’s approval, the FDA approval a similar CAR T-cell therapy, axicabtagene ciloleucel (Yescarta) to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment.
Grupp recently spoke on the significance of CAR T-cell therapy at the Society for Immunotherapy of Cancer’s (SITC) 32nd Annual Meeting, as part of his keynote address “The CAR T Revolution in Leukemia” on Friday, Nov. 10.
In an interview with R&D Magazine prior to the meeting, Grupp shared his insights on CAR T-cell therapy’s impact—not just in leukemia and lymphoma but potentially in solid tumors as well—and how researching this type of highly personalized therapy is transforming the industry.
R&D Magazine: What makes CAR T-cell therapy such an exciting advancement?
Grupp: CAR T-cell therapy is a brand new area of medicine—there has never been anything like this before. Not only is it immunotherapy, which is very exciting, but it is a kind of immunotherapy that really hasn’t existed before. This is a brand new area of investigation, a brand new area of research, a brand new area to figure out clinically—all of those things.
The second thing that makes it so exciting is that it works extremely well in leukemia patients. We are talking about around a 90 percent remission induction, with a large fraction of these patients remaining in remission for long periods of time, including patients remaining in remission for years. We are hopeful that we may be looking at the possibility of a cure for some patients. That’s great.
From my personal point of view as a pediatric oncologist, it has been tremendously exciting that the first therapy that got approved in this area was in kids, because if you know anything about drug development you know that never happens.
R&D Magazine: How did this move through the pipeline so quickly?
Grupp: People were really excited about this data, which tends to push things along. But the other key thing was the results in the initial patients were compelling enough that it was possible to design a research strategy that didn’t require years of huge nationwide randomized trials. We could get to the finish line with a lot smaller number of patients because the difference in outcome between what was available at the time as standard treatment and what we were doing, was so significantly different that essentially we were able to get the answers we needed in a phase II trial. That was a huge aspect of this.
R&D Magazine: What sort of impact will this have for pediatric and young adult patients with ALL?
Grupp: To be fair, a lot of pediatric leukemia patients do beautifully with conventional chemotherapy and don’t need anything to do with this stuff. However, for these relapsed patients, there was really nothing available to them, so this has really revolutionized the care of those patients. Beyond that, typically what you do for a relapsed leukemia patient is you send them to bone marrow transplant, which is what I do clinically. Now we are seeing—for at least this particular cell therapy which lasts for years in many patients—is that this cell therapy has the potential to substitute for transplant instead of just making it easier for the patient to get to, or bridge to, transplant. Now we are looking at not bridge to, but bridge over transplant; we want to skip the transplant part. That is a big value to these patients.
R&D Magazine: Is engineered T-cell therapy being investigated in other areas?
Grupp: The first approval was in pediatric ALL with Kymria and the second was in adult lymphoma with the Kite product. Novartis, I believe has just submitted their licensing application for Kymriah in adult lymphoma as well, so that is three potential approvals.
The next question is— can we make this work outside of B-cell cancers like ALL and lymphoma? There are a lot of trials that are looking at approaches for other kinds of leukemia. I think that next year we are going to see trials in acute myeloid leukemia, which is another kind of acute leukemia in children and adults, which is very exciting.
We are already seeing data on a non-CD19 target called BCMA, which is relevant to patients with multiple myeloma, and there is clearly efficacy data there that looks very exciting.
Then, the other big area is solid tumors. Clearly, we have shown that this works in leukemia and lymphoma and with the BCMA data we see that it works with targets other than CD19. However, solid tumors are a whole different ballgame. We are not currently making this work in solid tumors, but there are a lot of reasons to believe we could in the next three or four years. If that happens—and it’s a big if—then this goes from being an amazing and exciting advance for patients with blood cancers, to really an important and potentially field-altering advance for patients with cancers of all sorts. That is unproven, but I think we have a really good idea of the steps we need to take to achieve this.
R&D Magazine: What are some of those steps?
Grupp: In blood cancers, you can identify a target, make a powerful T-cell, and the powerful T-cell will kill the cancer cells and it will also grow to the level to be able to control very large amounts of disease, literally pounds of disease in a patient. The secondary problem in solid tumors is that you have to get the T-cells into these tumors. Solid tumors are awesome at locking T-cells out. They’ve learned how to exclude CAR T-cells very well.
The next step is overcoming this secondary trafficking problem. There are five different ways you can imagine that might work, and it’s just a matter of testing them and seeing what will or will not work in those circumstances. The good news in that regard is that there is a lot of excitement and attention being focused on this, and therefore there are a lot of resources that are available, so this is something we really hope will be moving forward very quickly. In my opinion, it is going to be a couple of years before we have any initial answer as to if this might work.
R&D Magazine: Could combination therapy approaches play a role?
Grupp: Absolutely. You need the CAR T-cell to kill the cancer. You need the T-cell approach to proliferate so there are enough T-cells to kill enough cancer cells, but the trafficking issue is going to be overcome by some combination. One of the obvious combinations that people are going to be trying is a CAR T-cell therapy with a checkpoint inhibitor. Now you have both fields in the immunotherapy world working together, which is exciting. There are other combinations that are being considered as well. However, it will for sure be some combination of a CAR T-cell and something else that will overcome the trafficking problem.
R&D Magazine: How have these types of therapies, which could potentially be used across many different types of cancer, changed how research is done?
Grupp: This is what industry calls a matrix environment and what we call Big Science. You need people with expertise across the spectrum. You absolutely still need the tumor specific expert to help you in each area and then you need people to help you understand how cell therapy is delivered clinically and we are developing a group to do that. Then you need people that understand cell manufacturing, which is so important, how you make these cells is really, go-or-no-go for success in these situations. You need people to understand how to genetically modify the cells. There are all these completely indispensable and non-overlapping expertise areas that are involved, so you really have to build a team of very disparate expertise to tackle these problems. The team can be reconstituted for different types of cancer and the approach can be slightly different, but a lot of the pieces end up being the same.
R&D Magazine: Since these types of therapies are so personalized, are there many big challenges logistically getting them to market?
Grupp: If you had asked me four years ago when I first saw this therapy working in patients if I could see a drug company handling all the logistics for this—collecting cell products from patients all over the world, shipping them to a place to manufacture the cells, shipping the cells back successfully, overcoming all the regulatory barriers—I would have told you it was not possible. However, it has happened. The drug companies involved, and Novartis was the first one into this, have really figured out how to make this work at the kind of scale that you need to deliver this initially across the U.S. and hopefully very soon across the EU. I’ve seen it happen, I was the lead investigator for the registration trial in pediatric ALL and I saw this go to 25 centers in 11 countries. There were enormous challenges to overcome.
One of the advantages we had was that the bone marrow transplant field had already figured out some pieces of this. We’d figured out how to collect cells, we’d figured out how to preserve cells, we’d figured out how to ship them various places safely, we’ve figured out all of the sort of identity chain issues—making sure there were no mix-ups. The nucleus of all of this had sort of existed for decades and that made implementing this way easier—it was still super hard— but it was easier than it would have otherwise been.
ارسال به دوستان