The Evolution of Chimeric Antigen Receptor T Cell Therapy - Episode 10
David Maloney, MD, PhD: All right, so how are we going to move this forward into adults? We talked briefly about it before but adults can get ALL [acute lymphoblastic leukemia] too, and clearly this is active. They don’t seem to do as well. So what are the long-term data with adults so far?
Michael Pulsipher, MD: The long-term data have come out from a number of groups. Seattle is a great group showing this and Memorial Sloan Kettering Cancer Center has a lot of patients. The trials are going, the long-term data are coming out. Most of the time it’s compared with transplant, and most of the problems have been with toxicity. So the ongoing studies I hope will lead to, in the next 1 to 2 years, approval of this in adults. We’ll see as far as how long it takes to get FDA filings done with this. But I really think the solution for adults is the efficacy is there and we know that. It’ll get patients into remission. So we need to get them into remission without high levels of toxicity and we need to figure out whether they need a transplant.
David Maloney, MD, PhD: I think the current, furthest along, commercial clinical trial is really the ZUMA-3. That was presented at this meeting as well.
Michael Pulsipher, MD: Presented at this meeting and had 72% response rate with a complete remission and they had 1 additional patient who was empty marrow, whatever that meant. So, in a very highly refractory population using a CD28 vector, they can get patients into remission. A large majority of patients can get into remission. They now just need to make sure they’re safe enough to get them to a transplant in the case of the ZUMA vector. Or regarding the other protocols that are moving along with 4-1BB vectors, we need to really follow them and see whether they have persistence in a small portion of population.
Matthew Lunning, DO: My hope is that we’ve gotten better with more experience in diffuse large B-cell lymphoma managing the toxicities with the neurotoxicity and the CRS [cytokine release syndrome], such that when we reenter deeper and broader in multi-institutional aspects of adult ALL, maybe the toxicity profile will change because we have gotten better at seeing it earlier. It’s already happening, but we were at a place where few centers were able to do it, and now it’s going to expand back again to multiple centers.
Michael Pulsipher, MD: Absolutely. Early on in ALL therapy we weren’t only just looking over the edge, we were leaning over the edge of the cliff and someone was holding on to our belt before we gave anticytokine therapy. And now we’re stepping back. Patients with persistent high fevers, patients with any lowering of blood pressure, they’re getting it. And it’s helping. People are handling it better.
David Maloney, MD, PhD: But do you think that the toxicities are different in adults, or is it just a continuum between the pediatric and the adult population?
Michael Pulsipher, MD: I think it’s a continuum. But I also think adults are more fragile. Remember that comorbidities and all sorts of challenges that occur with patients lead to more toxicity. So if you’re in a situation where you have more toxicity, you’re going to cause a problem. I think it’s very similar to pediatric transplant. We can get away with a lot more because kids can tolerate it more.
Leo I. Gordon, MD, FACP: Also one question is, if we change the costimulatory molecule—say from CD28 or 4-1BB—or start combining them, do we need to be mindful of the lymphodepleting chemotherapy? Because might we engender a more rapid rise and maybe more toxicity? Is that a concern?
Michael Pulsipher, MD: Absolutely. I think we’ve got to remember that whenever we mess with our CAR T cell, it’s a different product, and we need to be sensitive that it needs to be optimized for what it is.
David Maloney, MD, PhD: Yes, I think that our group has shown pretty clearly just using one product that the depth of lymphodepletion, the type of chemotherapy, the intensity of that chemotherapy greatly changes the proliferation of the CAR T cells, and that the proliferation of the CAR T cells has a big impact in terms of the toxicity both in terms of cytokine release syndrome and neurologic toxicity.
Interestingly in our previously published work, we actually developed a differential dosing so that we gave fewer CAR T cells to patients who actually had more leukemia. And we gave more CAR T cells to people with less leukemia. Because if you think about the ALL setting, the patients aren’t usually given a lot of rituximab or anti-CD20 therapy beforehand. Whereas in the large cell lymphoma patients, those people are completely B-cell depleted from all their prior rituximab or other anti-CD20 antibodies. And so you can still have normal B cells in the ALL population that can still contribute to that CAR T expansion. So it’s not completely clean, but I think we might find in the future that there is going to be a variable dosing where people with less disease may need slightly more CAR T cells.
Michael Pulsipher, MD: And the Penn [University of Pennsylvania] group has shown that with their vector as well, that split dosing may be important. And we have to keep in mind that if you give someone inotuzumab, then you’re going to wipe out their B cells sometimes for months. And so you don’t want to take them to CAR T cells very soon if they don’t have any antigen to present.
David Maloney, MD, PhD: Right. So we think that there can be CRS that’s impacted by the amount of disease in the bone marrow or the amount of B cells. But we don’t really manage it differently. I think the management is the same for people with CRS. And I think that this is really an excellent point that we have all moved our strategies up to where we don’t wait until people are in the ICU [intensive care unit] on their third vasopressor to then give them their tocilizumab. And so we’re intervening much earlier in most of these patients
Michael Pulsipher, MD: Absolutely.
Transcript Edited for Clarity