PD-1-inhibitors augment CAR-T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia in a small, single-center study. Half of the patients treated for early B-cell recovery re-established B-cell aplasia.
CD19-directed CAR T-cell therapy has been shown to be effective in patients with relapsed B-cell acute lymphocytic leukemia (B-ALL). Many patients will have durable or long-term responses with long-lasting CAR-T-cells. For some patients however, the anti-tumor effects of CAR-T-cell treatment are shortlived. This may, in part, be caused by a reaction of the patient’s immune system against their very own CAR-T-cells. This may occur through the immune system’s checkpoint pathways.
In the first study of its kind in this patient population, researchers at Children’s Hospital of Philadelphia (CHOP) investigated whether adding checkpoint inhibitors to the CAR-T-cell therapy regimen to prevent this effect could extend treatment response and improve outcomes for children with relapsed B-ALL.
This small, single-center study included a total of 14 children ranging in age from 4–17 years – 13 with heavily pretreated relapsed B-ALL and one with lymphocytic lymphoma (previous treatments included bone marrow transplant and one or two types of CAR-T). All received CD19-directed CAR-T-cell therapy and the PD-1-inhibitors pembrolizumab or nivolumab. Patients in the study were given either pembrolizumab or nivolumab. PD-1-inhibitors were administered no sooner than 14 days after patients received their CAR-T-cell infusion, as levels of CAR-T-cells often decline 14 days following infusion of the CAR-T-cell therapy, and because CRS is typically experienced within the same window.
Half of patients maintained either partial or complete disease responses. Patients were followed for a median of 13,3 months following additional treatment with a checkpoint inhibitor. Half of the patients (3 of 6) treated for early B-cell recovery re-established B-cell aplasia (a sign that the CAR-T-cell therapy is working). 4 patients started pembrolizumab for bulky extramedullary disease that either returned after CAR-T-cell therapy or did not respond to the treatment at all, and demonstrated 2 partial and 2 complete responses. Among 4 patients who failed to achieve disease remission with initial CAR-T-cell infusion, no complete responses were achieved with the addition of pembrolizumab, although partial responses were observed.
„When we give a checkpoint inhibitor, it seems to release the immune blockade on the T-cell, removing the restriction that’s holding it in check and, in turn, allowing the T-cell to have greater activity,‟ Dr. Maude said. „So in the context of CAR-T-cells, this combination therapy could overcome that resistance in some patients. These are children who would otherwise have no other therapeutic options, so efforts to maximize their response is critical.‟
Mild CRS symptoms and fever typical of CAR-T-cell proliferative responses were seen in three of 14 patients within two days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1-inhibition were tolerable or reversible upon discontinuation.
Li AM et al.: Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia. ASH Annual Meeting 2018, abstract #556