Efficacy of chimeric antigen receptor (CAR) T-cell (CAR-T) therapies in chronic lymphocytic leukemia (CLL) have lagged behind the efficacy they appear to have in other hematological malignancies such as acute lymphoblastic leukemia or diffuse large B-cell lymphoma.
There’s a growing recognition that some of the CAR-T shortfalls in CLL are due to an impaired fitness of T cells in CLL patients. Some research has shown, however, that sustained remission of CLL is associated with enrichment of a less-differentiated, early-memory phenotype of T cells in the apheresis product used to make CAR-T therapies.1 Such findings have galvanized interest in approaches to enhance this T-cell population during the immunotherapy manufacturing process as a possible route for overcoming treatment resistance.
Now, a small study in the International Journal of Cancer reported that culturing CLL patients’ T cells with the tyrosine kinase inhibitor ibrutinib — which among other effects, inhibits a pathway involved in T-cell differentiation — boosted the viability, function, and expansion of CLL patient-derived CAR T cells as well as enriching them with a less-differentiated phenotype.2
“In culture, they could prevent the T cells from differentiating when they treat with ibrutinib, and that’s [creating] the seed population that you want for adoptive T-cell therapy,” noted Joseph A. Fraietta, PhD, assistant professor of microbiology and director of the solid tumor immunotherapy laboratory at the center for advanced cellular therapeutics at the University of Pennsylvania, who wasn’t involved in the research. “If the results hold up, this could be a giant step forward, I think, for these patients who need CAR T-cell therapy to get into long-term durable remission.”
For the study, a team of researchers from Germany extracted peripheral blood mononuclear cells from 8 CLL patients and 9 healthy people. They cultured them into CD19-directed CAR-T cells using standard protocols, but under 2 different conditions: 1 without ibrutinib, and 1 in the presence of ibrutinib.
In a series of analyses, the authors found that although cell proliferation during CAR-T generation was generally much lower in CLL-derived cells compared with healthy ones, the absolute numbers of CLL patient-derived CAR-T cells were substantially higher when they were cultured with ibrutinib supplementation. The ibrutinib-supplemented CAR T cells also produced more cytokines in an assay in which the cells were stimulated with a B lymphoblast cell line, and also expressed fewer cell exhaustion markers such as LAG-3, TIM-3, and PD-1, which can impede T-cell function.
Cultivating the CLL patient-derived and healthy cells with ibrutinib had no impact on the proportions of CD4+ and CD8+ T cells, but it did on the proportion of early T cells that were in a less-differentiated state. Stem cell memory-like T cells and what the authors called “naive-like T cells” are thought to be important for the generation of CAR T cells and their long-term persistence in vivo. Ibrutinib supplementation enriched both products derived from CLL patients and from healthy people with these phenotypes, the authors reported.