ASH 2018: Checkpoint Inhibitors Plus CAR T-Cell Therapy in Relapsed ALL
CD19-directed chimeric antigen receptor (CAR) T-cell therapy has been shown to be effective in patients with relapsed B-cell acute lymphocytic leukemia (B-ALL). However, in some patients, the antitumor effects of CAR T-cell treatment are short-lived, which may, in part, be caused by a reaction of the patient’s immune system.
In the first study of its kind in this patient population—presented by Li et al at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 556)—researchers at Children’s Hospital of Philadelphia (CHOP) investigated whether adding another immunotherapy agent to the CAR T-cell therapy regimen to prevent this effect could extend treatment response and improve outcomes for children with relapsed B-ALL.
“We see excellent responses to CAR T cells, but unfortunately, some patients relapse due to early loss of these cells,” said senior study author Shannon Maude, MD, PhD, of CHOP, in a statement. “We wondered whether the loss of CAR T-cell activity might be mediated, in part, by naturally occurring checkpoint mechanisms in the body’s immune system and whether interrupting or inhibiting these checkpoints could prolong the CAR T cells’ effect.”
Study Methods
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 1 with lymphocytic lymphoma (previous treatments included bone marrow transplant and one or two types of CAR T-cell therapy). All received CD19-directed CAR T-cell therapy plus a programmed cell death protein (PD-1) inhibitor—either pembrolizumab (Keytruda) or nivolumab (Opdivo). Researchers administered checkpoint inhibitors 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 cytokine release syndrome is typically experienced within the same window.
Results
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 reestablished B-cell aplasia. Four 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 two partial and two complete responses. Among four 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 cytokine release syndrome 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.
Dr. Maude and her team will continue following these patients and exploring combination strategies to improve outcomes with CAR T-cell therapy.
This study was supported, in part, by a grant from the V Foundation.
Disclosure: See the study authors’ full disclosures at ash.confex.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
