Novel Treatment Strategies and Stem Cell Transplantation - Episode 4
Sherif S. Farag, MD: Sherif Farag, MD, hematologist, Indiana University [IU] Health.
CAR [chimeric antigen receptor] T-cell therapy is basically engineering T cells, immune cells, by introducing a DNA that encodes for a specific receptor to recognize cancer cells—either leukemia or lymphoma cells—as well as containing activating molecules that allow the T cells to recognize specifically the cancer cells, become activated and kill the lymphoma or leukemia cells. This DNA is introduced into the T cells through a viral vector, and then the cells are expanded, frozen, and shipped back to the center, the patient, before infusion.
Once we identify a patient is suitable CAR T-cell therapy, the first thing is actually to collect cells. So we perform an apheresis on the patient. Usually, a single apheresis is required. Then the cells, depending on the manufacturer, are either cryopreserved in house and are sent in a cryopreserved fashion, or we send the cells fresh.
The manufacturing time for the transfection and expansion of these CAR T cells takes about 2 to 3 weeks. Then the cells are shipped back to us when the patient is ready to proceed.
Once we receive the cells in our laboratory, the next thing will be to admit the patient or treat them as an outpatient, depending on their circumstances, with lymphodepleting chemotherapy. We use fludarabine and cyclophosphamide. They receive that over 3 days, and 2 days later, the cells are thawed and infused into the patient. We usually admit them for the infusion because we have found that some patients actually start to develop cytokine release syndrome pretty early, within sometimes even hours of the infusion, although more typically it’s a day or 2 later. And so, we’re able to monitor the patient closely.
We recommend that patients are referred early because the process of getting to CAR T-cell therapy can be a bit lengthy in these unstable patients. We want to see the patient early so that we can decide whether CAR T-cell therapy is appropriate. We take into account the need to collect the stem cells, the manufacturing process, which could take 2 to 3 weeks, and then we try to expedite the infusion of the cells after their lymphodepleting therapy as soon as possible.
I guess the right time is yet to be determined, but at the moment, the 2 products that are FDA approved are approved for patients with diffuse large B-cell lymphoma that is resistant to chemotherapy, either initial chemotherapy or where relapse has occurred and the patient is resistant to chemotherapy.
The other product is approved for acute lymphoblastic leukemia in children and young adults up to the age of 25, again, in the refractory setting, either primary refractory or relapsed and refractory leukemia. Now it is possible, and probably likely, that as the trials are done, the introduction of this therapy earlier in the phase of the disease may give better outcomes. However, that remains to be seen.
Diffuse large B-cell lymphoma, for example, in patients who may have had induction chemotherapy, a small fraction of patients, maybe about a third or less, will not achieve a complete remission. So these patients would usually receive some sort of salvage chemotherapy. If they’re resistant to salvage chemotherapy, usually we define that as less than a 50% reduction in the volume of tumor cells, these patients would be eligible for CAR T cells, assuming of course that they are sufficiently fit to withstand therapy.
Similarly, in a relapsed patient with diffuse large B-cell lymphoma, we usually approach the patient using some sort of salvage chemotherapy to try and induce a response, again, if they are resistant. These patients are candidates for CAR T cells, as currently approved.
I think patients who have leukemia that is resistant to primary therapy, or if they have relapsed and have resistant disease, do not do well with what has been used up to this point, which is allogeneic stem cell transplantation. The outcomes of patients with active leukemia undergoing allogeneic stem cell transplantation are generally poor. That’s where CAR T cells have really offered hope. A significant proportion of patients with resistant disease that is not really suitable for allogeneic stem cell transplantation now have hope with CAR T-cell therapy.
About 80% to 90% of patients with acute lymphoblastic leukemia are achieving a remission with CAR T-cell therapy. And now, with longer follow-up, it appears that many of these remissions are quite durable.
I think the main direction at the moment is to broaden the use of CAR T cells in other subtypes of lymphoma. And potentially, as we also identify molecules for which we can manufacture CAR T cells to target against these molecules in different kinds of cancers, we will be able to broaden the use of CAR T-cell therapy to a number of different malignancies.
The closest, probably, is the use of BCMA [B-cell maturation antigen]-targeted CAR T cells. BCMA is expressed on multiple myeloma cells, and there are ongoing clinical trials in patients with multiple myeloma exploring this. We actually have a clinical trial comparing CAR T cells to chemotherapy in patients with myeloma who have had at least 2 prior regimens of treatment. It’s a comparative study to see if CAR T cells will perform better than what we currently have for this group of patients.
In other subtypes of lymphoma, there are clinical trials that are looking to broaden the use of CAR T cells, not just in diffuse large B-cell lymphoma, but potentially in follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma. These are different types of lymphoid disorders.
There’s also a lot of research going on in terms of broadening that to target breast cancer cells, head and neck cancer cells, cervical cancer cells, and the list goes on.
I think it’s important for referring doctors to recognize the presence of CAR T-cell therapies, and really, even if in doubt about the exact indication, they should refer patients early so that we can see them and make a decision on whether they’re appropriate for therapy. The patients, of course, can be quite dynamic. They may initially be considered for autologous stem cell transplantation, and then maybe their disease shifts in a way that they become more eligible for CAR T-cell therapy. So knowing that early is important.
We have a very strong infrastructure at IU Health for CAR T-cell therapies. We are approved by FACT [Foundation for the Accreditation of Cellular Therapy] for immune cellular therapy. And we have a comprehensive program for lymphoma, myeloma, and leukemia that includes other therapies as well. So we’re able to provide a balanced option for patients with these diseases.
Even though CAR T-cell therapy is being done under the bone marrow transplant program, the physicians in the bone marrow transplant program are also members of disease-specific groups—lymphoma, myeloma, leukemia. So when a patient comes in potentially for CAR T-cell therapy, they are also evaluated for other options and other clinical trial options that may be available. I think we even have CAR T-cell research protocols that may be less accessible to other centers.
We’re approaching all of our referring doctors, letting them know about the availability of the therapy, and the timeline for the manufacture and the treatment. We usually have the patient for a few weeks, to get them through the therapy and deal with the post-therapy issues that can arise. Then the goal is to get them back to the referring physician. We sometimes still have to monitor them because there may be longer-term problems—immune deficiency problems—that may occur. But really, the goal is to be able to comanage these patients after CAR T-cell therapy with their referring oncologist. We don’t want to take their patient. We want to serve the patient well and comanage these patients as required.
Transcript Edited for Clarity