Checkpoint inhibitors may boost benefits and sustainability of CAR-T-therapy

<p class="article-intro">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.</p> <hr /> <p class="article-content"><p>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&rsquo;s immune system against their very own CAR-T-cells. This may occur through the immune system&rsquo;s checkpoint pathways.<br /> In the first study of its kind in this patient population, researchers at Children&rsquo;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.<br /> This small, single-center study included a total of 14 children ranging in age from 4&ndash;17 years &ndash; 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.<br /> 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.<br /> &bdquo;When we give a checkpoint inhibitor, it seems to release the immune blockade on the T-cell, removing the restriction that&rsquo;s holding it in check and, in turn, allowing the T-cell to have greater activity,‟ Dr. Maude said. &bdquo;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.‟<br /> 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.</p> <p><br /><strong>Reference:</strong><br />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</p></p>