Alfred L. Garfall, MD
Chimeric antigen receptor (CAR) T-cell therapy has been progressing through clinical trials in various hematologic malignancies over the past 5 years. Response among malignancies has varied, though.
In acute lymphoblastic leukemia (ALL), CAR T-cell therapy has induced extremely high response rates. Conversely, patients with chronic lymphocytic leukemia (CLL) have had comparatively lower response rates, said Alfred L. Garfall, MD, who discussed the role of CAR T-cell therapies in hematologic malignancies at the 2017 International Congress on Hematologic Malignancies.
A new area of investigation is in multiple myeloma. Garfall, an assistant professor of medicine at the Hospital of the University of Pennsylvania, said that the multiple myeloma community is very hopeful about CAR T cells in this setting, as preliminary trials have shown durable responses in some patients.
“This durability is the real promise of the therapy—the ability to induce a long-lived immunity against the cancer,” said Garfall.
In the multiple myeloma sphere, a novel study of next-generation BCMA-targeted CAR T cells opened this past month at Memorial Sloan Kettering Cancer Center. These new CAR-modified T cells have a built in “off switch” to deactivate the CAR T cell if severe toxicities occur. This study is open for patients with multiple myeloma who have refractory, persistent, or progressive disease after 2 prior lines of therapy, including treatment with an immunomodulatory drug and a proteasome inhibitor.
In an interview with OncLive
during the meeting, Garfall discussed the latest developments with CAR T-cell therapy in hematologic malignancies.
OncLive: Could you give an overview of your presentation on CAR T cells?
The use of CAR T cells for hematologic malignancies is really a remarkable translational medicine story that has played out over the past 20 years. It has really come into clinical application in the last 5 years, initially with pilot studies and now there are several multisite studies for different B-cell malignancies targeting CD19 with CAR T cells. Currently, we are moving into other targets besides CD19, such as BCMA for multiple myeloma, and we may even see the first FDA approval of a CAR T-cell therapy in the next 1 to 2 years.
In my presentation, I talked a little bit about the data that have emerged from the various B-cell malignancies—namely, CLL, ALL, and non-Hodgkin lymphoma—and compared and contrasted some of the response rates and toxicity profiles and talked a little bit about the clinical aspects of administering CAR T-cell therapy to patients.
I also focused on the use of CAR T cells for multiple myeloma. This is a promising area for which we have data over the last few months on studies that have come out of 3 different institutions including our own targeting BCMA, a novel target in multiple myeloma. An important demonstration of the potential for CAR T cells targeting antigens other than CD19, which is where most of the work has been done so far.
What responses are seen with each malignancy?
The studies have now progressed to the point where there are enough patients treated in these different diseases in different centers to ascertain some patterns of response and resistance. There are 2 interesting patterns that have emerged if you look at CLL and ALL as opposite ends of the spectrum. In B-acute lymphoblastic leukemia, there are very high response rates—over 90% response rates—in patients who are refractory to all available therapies. But, a sizable portion of them—about 25% to 50%—will relapse and, in most cases, those relapsed patients will have CD19-negative disease. So, the leukemia has managed to downregulate or eliminate the target of the CAR T cell.
The opposite is the case in CLL. Patients who initially respond tend not to relapse, but the response rates are lower overall. Therefore, a different problem exists in CLL. The T cells that you get from CLL may not be as active intrinsically as the T cells you get from ALL patients, as the disease does not have the propensity to escape the T cells the way ALL does. So, you have 2 different mechanisms of resistance and 2 different patterns of response and they lend themselves to different strategies to improve the efficacy and prevent resistance in each case.