Checkpoint Inhibitors Augment CD19-Directed CAR T-Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has been shown to lead to high rates of complete response in relapsed B-cell acute lymphoblastic leukemia (B-ALL). However, relapse-free survival declines to 60% within the first 12 months, often from CD19-positive relapses due to early CAR T-cell loss, according to a group of researchers who presented at the ASH annual meeting.

The authors suspected that the programmed cell death 1 (PD-1) checkpoint pathway may be involved in CAR T cell exhaustion; they tested their hypothesis by administering PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T-cell therapy. Led by Amanda M. Li, MD, of the Division of Oncology at British Columbia Children’s Hospital in Canada, the authors concluded that “this cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T-cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T-cell effect and persistence.”

The study included 14 patients aged 4–17 years with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1) who had been treated with CD19-directed CAR-cell therapy at the Children’s Hospital of Philadelphia and had demonstrated repeated early CAR T-cell loss or partial or no response. The patients received a PD-1 inhibitor (pembrolizumab n=13 or nivolumab n=1) no sooner than 14 days after CAR T-cell infusion and after resolution of cytokine release syndrome (CRS) symptoms. Doses could be repeated as often as every three weeks.

Three of six patients who were treated with CD19 CAR T cells and a PD-1 inhibitor for early B-cell recovery re-established B-cell aplasia, which indicates CAR T-cell function, for five to 15 months. Two of them maintained B-cell aplasia with continued pembrolizumab treatment. Further, four patients started pembrolizumab for bulky extramedullary disease that was unresponsive or relapsed after CAR T cells; two had partial response and two had complete responses. One patient experienced significant CAR T-cell proliferation within days of pembrolizumab administration, which also was correlated with disease response as shown on radiographs. However, four patients failed to achieve complete response with the addition of pembrolizumab, although they had partial responses. One patient’s disease progressed.

The researchers reported no unexpected or fatal toxicities. Three of the 14 patients had symptoms of cytokine release syndrome and fever within two days of pembrolizumab administration. The study had one case each of acute pancreatitis, hypothyroidism, arthralgia, and urticaria; four patients had grade 3-4 cytopenia. However, the events were tolerable or reversible. Two patients discontinued pembrolizumab due to delayed adverse events after multiple doses; their disease relapsed or progressed.