CAR T-Cell Therapy in Managing Various Lymphomas

Caron A. Jacobson, MD: We’re talking about finding a potentially curative regimen for people who failed a therapy that was potentially going to cure their lymphoma. There are a lot of lymphomas that we don’t have conventional cures for. And when we get to the second- and third-line treatments for those lymphomas, even though they have generally longer natural histories, response durations are short and people relapse, and we start to see decreased life expectancy. What we’ve already seen for mantle cell lymphoma, knowing that patients who relapse after BTK [Bruton tyrosine kinase] inhibitors have a short survival, on the order of months, has been impressive. Some data were presented in indolent lymphomas as well, especially late lines of therapy.

Stephen J. Schuster, MD: A lot of that will be your data, and they are very important data. For indolent lymphomas, people are less impressed. There is a business of progression of disease within 2 years as a subset, maybe 20% or so of patients have a bad indolent lymphoma. But having been in practice for 40 years, I’ll say that when you’ve taken care of these patients for 10 to 15 years, and they’ve been through a number of treatments, guess what? They’re not progressing within 2 years. It’s a bad disease. And Caron’s right. We need something for those patients too. It’s just not captured the same way, because we’re looking at patients with much shorter follow-up. At the other end of the indolent lymphoma natural history, it gets bad.

David Miklos, MD: It’s important to remind the audience that we’re the gateway drug, right? We’re the gateway drug to cellular immunotherapies for the nonblood cancers or the diseases that need alternative therapies beyond chemotherapy. The lessons we learn in lymphoma, leukemia, mantle cell, and myeloma, like everything that’s ever happened in hematology, will be important guides for how you combine therapies, how you target. We’re the gateway drug.

Stephen J. Schuster, MD: You’re right. Rituximab taught us that patients can respond to immunotherapy when they’re resistant to chemotherapy. You hit an external target with immunotherapy, and you can get a response in a disease that is resistant to all kinds of toxic substances that kill cells by getting into them. We saw that with Rituxan, but then there were Rituxan failures or Rituxan chemotherapy. Now we’re at the cellular end of immunotherapy, as opposed to serotherapy, and we’re seeing the same thing again. Patients who are resistant to those drugs that kill cells internally—like chemotherapy, small molecules—can respond to immunotherapy. And those are unresponsive to intracellular agents and rituximab or anti-CD20s. You can get at them with a T-cell–based therapy, another extracellular agent.

Matthew J. Frigault, MD: We were trying to do a GVL [graft versus leukemia] and allogeneic transplant to a much larger degree with a shorter period of toxicity and fewer toxicities. It’s less of a bazooka approach of an allogeneic transplant and more targeted.

Stephen J. Schuster, MD: What do you think? Is allogenic going to disappear, Matt?

Matthew J. Frigault, MD: It depends on the disease, the context, and whom you talk to. There are going to be a subset of patients once we can risk stratify. I think there are going to be various clinical characteristics or drug characteristics or product characteristics in terms of persistence, and what may be important for 1 disease in terms of persistence may not be the same for another. Depending on what we see and how we risk stratify, I can see a world where we have low-risk AML [acute myeloid leukemia] that you can cure with consolidation therapy, and a low-risk lymphoma or leukemia that you don’t need a transplant for. For others, you may want to transplant at 3 to 6 months.

David Miklos, MD: There’s an important point to make here, though, and that is that the lymphocytes that give rise to lymphoma are long-lived cells. They’re far beyond the hematopoietic stem cell stage, sometimes a lifetime’s worth, whereas the cell contributing to AML and MDS, myeloproliferative disorders, that’s about 14 days down the pipeline. We are continually going to be facing the problem that the patient needs not only a cellular therapy, for AML or myeloproliferative disorder, but a lot of repair.

Stephen J. Schuster, MD: Loretta is going to tell us about AlloCAR T therapies. There’s always going to be AlloCAR T if you believe in CARs. We’re not addressing stem cell diseases. We’re taking care of neoplasms of mature cells. There always will be diseases where we have to replace stem cells. The only way I can think of is CAR. I’m sure with the way technology is moving, we’ll be differentiating our skin cells. You’re going to need different stem cells, not your own, for certain diseases. It’s never going to disappear, in my opinion. And you know I believe very much in CAR T-cell therapy.

Transcript Edited for Clarity