Biomarker Predicts Response to CAR-T Therapy for Patients With CLL

Researchers may have found the reason some patients with advanced chronic lymphocytic leukemia (CLL) do not respond to chimeric antigen receptor (CAR) T-cell therapy, according to a study published in Nature Medicine(online: April 30, 2018; doi:10.1038/s41591-018-0010-1).

While 80% of patients with advanced acute lymphoblastic leukemia (ALL) treated with CAR T-cell therapy have a dramatic response, only 26% of patients with CLL have demonstrated a response in clinical trials.

A team led by J Joseph Melenhorst, PhD, and Joseph A Fraietta, PhD, both from the University of Pennsylvania, studied CAR-T therapies and their ability to overcome immunological tolerance and mediate tumor rejection in patients with CLL.

Researchers retrospectively studied 41 patients with advanced, heavily pre-treated and high-risk CLL who received at least one dose of CD19-directed CAR T-cells. Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy, including age, tumor burden, or prior therapies.

The research team compared the gene expression profiles and phenotypes of T-cells in patients who had complete, partial, or no response to the therapy. The analyses showed that the CAR T-cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T-cells and possess the IL-6/STAT3 signature, while non-responders expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T-cells to persist, expand, and fight the cancer

Patients with CLL possessing a subset of vital, healthier T-cells prior to CAR T-cell therapy had a partial or complete clinical response to the treatment, while those lacking enough of those T-cells did not respond. These healthier “early memory” T-cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO. The findings show the potential to improve responses by enhancing a patient’s immune cells with emerging cell manufacturing techniques before CAR T-cell therapy.

The new findings point to a new T-cell biomarker as a much-needed patient-selection tool, but they also present an opportunity to potentially improve the immunological health of a patient with emerging cell manufacturing techniques before CAR T-cell therapy, as well as inform the design of a more effective CAR T-cell.

To validate the biomarker findings, the researchers screened for the early memory T-cells in a group of eight patients with CLL, before and after CAR T-cell therapy. They identified the complete responders with 100% specificity and sensitivity.

The findings also underscore the potential utility of increasing the therapeutic efficacy of T-cells for CAR T-cell therapy by selecting the subpopulation of T-cells responsible for driving responses for cell manufacturing. However, it will not happen without overcoming some challenges first, the authors concluded.—Janelle Bradley