Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have terrible prognoses and novel cell therapies provide a glimmer of hope. While the CAR T therapy known as Kymriah led to complete remission in over 90% of patients with advanced acute lymphoblastic leukemia (ALL), only 26% of CLL patients responded to it in clinical trials. A new study, led by researchers at the University of Pennsylvania, sheds light why some patients with advanced CLL don’t respond to CAR T cell therapy.
The study looked into 41 patients with advanced, heavily pretreated and high-risk CLL who received at least one dose of CD19-directed CAR T cells. These CAR T cells are generated by isolating T cells from a patient’s blood, genetically introducing a special receptor to target cancer cells, and infusing the engineered cells back into the patient. Consistent with previously reported findings, the authors were unable to pinpoint patient- or disease-specific factors predicting which subjects responded best to CAR T therapy.
The team performed several genomic, phenotypic, and functional evaluations of the T cells from patients who had complete, partial, or no response to the therapy. Transcriptomic profiling revealed that CAR T cells from complete-responding patients were enriched in genes that regulate early memory and effector T cells, including IL-6/STAT3 signatures. T cells from non-responders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. The differences in these T cell profiles point to intrinsic T cell fitness as an underlying factor in the response of CLL to CAR T cell therapy. If the pre-existing T cells are “weak,” they are less capable of fighting the cancer. This study identifies the specific baseline T cell qualities that distinguish the weak versus strong T cells. Understanding how patients’ immune systems are primed before the therapy is administered may make it possible to predict treatment outcomes with the CAR T cell therapy.
The article, titled “Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia,” was published in Nature Medicine.