CAR T-Cell Therapy in DLBCL

Nathan H. Fowler, MD:Thank goodness there are a lot of other things in this space. There are a lot of drugs that are being developed for patients who either relapse after a transplant, or are ineligible for a transplant, or cannot get into remission prior to transplant. There recently was the FDA approval of the combination of the drugs bendamustine-rituximab plus polatuzumab. This is an anti-CD79b antibody, and this is also approved in patients with relapsed large-cell lymphoma.

There are ongoing trials with many other targeted drugs—drugs that are targeting different cell surface antigens. We have several combination trials ongoing looking at the potential benefit of drugs like venetoclax and other next-generation immunomodulatory drugs. Hopefully, as these trials continue to progress, we’ll see other good options for patients with relapsed large-cell lymphoma.

I think 1 of the most exciting things to come out in the last couple [of] decades for large-cell lymphoma is CAR [chimeric antigen receptor] T-cell therapy. The reason CAR T cells are so exciting is because they use a very novel mechanism to target the relapsed large-cell lymphoma. This is a mechanism, or I should say an approach that has been very successful in children with relapsed B-cell leukemia, and is also being used in many other different types of B-cell malignancies. Essentially, what we do is take the patient’s own T cells and train them in the lab to recognize cancer cells. These T cells are then reinfused into a patient, where they expand and then go on the attack. What happens is these T cells then find, recognize, and kill malignant B cells within the patient.

These approaches, again using CAR T cells in relapsed large-cell lymphoma, have been associated with long-term or durable remissions in anywhere from 30% to 50% of patients. Many of these patients had failed a prior autologous stem cell transplant or were ineligible for a stem cell transplant. Again, the most exciting thing is not just how they work but that these drugs are working very well, potentially curing patient populations for which we did not have a lot of options previously.

These drugs are associated with adverse effects, so they are not without risk. Many times, patients can develop very severe cytokine release syndrome. This is a syndrome that can lead to multiorgan damage. It can sometimes lead to very severe neurological changes in the patients—everything from seizures, to patients having respiratory failure, to confusion. Unfortunately, at least today, we do not have a good way to predict for whom or when adverse effects will occur.

Many of these patients are watched very closely for the first 2 weeks after receiving CAR T cells. It’s quite uncommon to have late adverse effects with CAR T cells, with the exception of cytopenias. If patients make it the first 2 weeks and have a remission, especially a complete remission, it’s likely that they can maintain a durable remission or a cure. So these are very exciting times.

There are several next-generation CAR T cells being developed, and hopefully some of these next-generation drugs will result in a very—or I should saymore—favorable adverse-effect profile with, potentially, even higher complete response rates.

CAR T cells are approved for patients who relapse after autologous stem cell transplant. I think this is the place most clinicians are using them. We are now seeing ongoing trials that are looking at CAR T cells before transplant. These are very interesting trials in which they’re randomizing patients to receive CAR T-cell therapy or salvage chemotherapy followed by stem cell transplant. In the future, we may actually see CAR T cells moving into earlier lines of therapy. There are a couple of trials looking at CAR T cells in the frontline setting in patients who are beginning to fail treatment early or who have PET [positron emission test] scans and are not in complete remission early. I think this really is the future of CAR T cells. We’re going to see them move into different spaces, potentially into earlier lines of therapy. And as we see some of the next-generation CAR T cells emerge, we may see them used in other types of malignancies, potentially some of the low-grade lymphomas and other types of leukemia. I think we’re just beginning to see where CAR T cells will be used across many different B-cell cancers.

In my own practice, I generally use CAR T cells—or, I should say, commercial CAR T cells—in patients who I cannot get into remission prior to stem cell transplant. I think the ideal patient would be a young, fairly fit patient who gets, for example, R-ICE [rituximab, ifosfamide, carboplatin, etoposide] chemotherapy, potentially another chemotherapy as salvage therapy prior to autologous stem cell transplant, and does not achieve a remission. This is a great candidate for CAR T-cell therapy, because many of these patients—again, as I mentioned—will achieve a complete remission, and some of them will achieve a complete remission that’s durable. The other population of patients who I’m using CAR T-cell therapy on in my practice are patients who fail autologous stem cell transplant and have a good performance status. This is really another ideal candidate for CAR T cells—patients who are otherwise healthy and failed autologous stem cell transplant, for whom I’m trying to achieve a durable remission.

Transcript edited for clarity.