Chimeric antigen receptor (CAR) T-cell therapy does not always lead to a durable response, and we are trying to figure out why, noted Michael R. Green, PhD, University of Texas MD Anderson Cancer Center.
Chimeric antigen receptor (CAR) T-cell therapy does not always lead to a durable response, and we are trying to figure out why, noted Michael R. Green, PhD, associate professor of lymphoma and myeloma and director, Translational and Laboratory Research, Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center.
Tell us about your study on the mechanisms of anti-CD19 CAR T-cell therapy, Yescarta (axicabtagene ciloleucel [axi-cel]), for diffuse large B-cell lymphoma.
Cellular therapy, in general, has been a breakthrough in cancer therapy, but in the space of relapsed/ refractory large B-cell lymphoma, CD19 CAR T cells have dramatically improved patient outcomes. But approximately 50% of patients will not have a durable response to CAR T cells, and treatment-associated adverse events continue to be a problem in the clinic to manage.
There are several potential factors that can contribute to these problems. One is with the CAR T-cell product itself, [the second] would be patient-intrinsic characteristics, and [the third] would be tumor-intrinsic characteristics. And so here we're primarily focused on characteristics and heterogeneity of the CD19 CAR T-cell products that are being infused into the patient.
What were the molecular/cellular features of patients who better responded axi-cel?
So the answer to that is 2-fold. Really what we identified were features that were more desirable and other features that were less desirable. And it’s really the mixture of desirable and undesirable phenotypes within the final product that were associated with outcome. So when we were looking for associations with clinical response measured by PET CT at the 3-month follow up, what we found was a significant enrichment of central memory CD8 T-cell phenotypes within patients that had a complete response and less of those within the infusion products of patients that have partial response or progressive disease.
We also looked at other measures of response using circulating tumor [CT] DNA to measure molecular response within the first week following infusion, which was itself associated with clinical response measured by PET CT. But when we looked with its characteristics associated with molecular response by CT DNA, we found a very strong enrichment for exhausted CD8 T cells among those patients that had a poor molecular response.