CAR-T Cell Therapy Use in B-Cell Malignancies - Episode 5

The Promise of CAR T-Cell Therapy for ALL


Krishna V. Komanduri, MD: I want to move now to our discussion of individual diseases that especially have seen early, and often dramatic, responses in the context of clinical trials so far. So, the first topic that I’d like us to address is acute lymphoblastic leukemia. And Michael, as the pediatrician in the group, obviously this is a disease where we’ve seen absolutely remarkable advances in the chemotherapy setting over decades, and certainly, this is where we started to really make advances in combination chemotherapy and hematologic malignancies in general. And now we’ve seen these remarkable breakthroughs with CAR T cells. So, can you talk about the unmet need for patients, especially those with relapsed and refractory ALL?

Michael Pulsipher, MD: Yes. It’s very important to point out that most patients with ALL on the pediatric side don’t need CARs. They are effectively treated with standard chemotherapy with cure rates in the 80% to 90% range. But of course, those who are refractory initially, those who have early relapse, those who have certain genetic abnormalities and relapse multiple times, we used to—of course, just at some certain point with patients who would relapse after transplant or patients who’ve relapsed multiple times—have not much offer and they have about a 10% survival rate.

But with treating these same patients who we would have put on hospice previously, we now have 75% of them alive at 1 year and 60+% of them cured, we think, over long term. So, the key thing to keep in mind is patients who have refractory disease, patients who have relapsed more than once, patients who relapsed after transplant, and patients who have primary refractory disease, those are the ones who we’re targeting with great benefit.

Krishna V. Komanduri, MD: So, I want to move from pediatric ALL to adult ALL, and David has certainly had a lot of experience with treating adults.

David Maloney, MD, PhD: We have a lot of experience with the product 4-1BB CAR in adult ALL and again, showed a very high remission rate of 90+%. The challenges in the adult population have been seen though, and this has been seen with increased toxicity. I’m not sure whether the toxicity is actually worse or whether older adults are just not as able to tolerate the types of toxicity that the pediatric population can.

Now this is an awkward situation for everybody because the FDA has approved this product, the tisagenlecleucel, up to age 25. So, I cannot think of any difference between a 25-year-old and a 26-year-old. Yet right now, a 26-year-old cannot get this product on label. And I think that’s really too bad.

We desperately need new clinical trials in the adult population to keep going forward because there’s no doubt that this is an active treatment. I have a 72-year-old, who I treated now almost 4 years ago, who’s in remission for ALL with this. And so, we need to get this into the adult population.

Stephen J. Schuster, MD: The KTE products are being studied in adult ALL and at this meeting there are data being presented which I think are really encouraging. Follow-up is not as mature as with the pediatric data, but I think this will be something that will be used in adult ALL. David?

David Maloney, MD, PhD: Yes. I think people are recognizing that there are several factors that impact the toxicity and the effect. And as Mike mentioned earlier, you need to probably have some target or some antigen around to get the T cells kick started, right? They have to encounter antigens to grow. This can be normal B cells or it can actually be leukemia. So, in our studies, we actually have more trouble in MRD—only positive patients getting the T cells going, whereas if someone has a lot, more than 10%, the T cells will go. But there’s likely a correlation of toxicity in those patients with very, very high tumor burdens. So, there’s probably a sweet spot that you’d like to have their disease somewhat controlled.

Stephen J. Schuster, MD: The ideal tumor burden, so to speak.

David Maloney, MD, PhD: And I think the ideal cell dose is yet to be determined. Now I know on the tisagenlecleucel T there were no dose relationships between a relatively wide range of doses.

But in our studies in Seattle, and I believe in the KTE study that will be presented, they’re decreasing the dose because of excessive toxicity at higher cell doses. So, I think we still have a lot to learn about the right dose of CAR T cells to use as we’re treating these patients.

Stephen J. Schuster, MD: Yes, and there will be differences among the products.

David Maloney, MD, PhD: Yes, products are different.

Transcript Edited for Clarity