According to results from a small clinical study, checkpoint inhibitors in combination with chimeric antigen receptor T-cell therapy showed promise for improving CAR T-cell persistance in some patients with relapsed B-cell acute lymphoblastic leukemia. <br />
Shannon L. Maude, MD, PhD
According to results from a small clinical study, checkpoint inhibitors in combination with chimeric antigen receptor (CAR) T-cell therapy showed promise for improving CAR T-cell persistance in some patients with relapsed B-cell acute lymphoblastic leukemia (ALL).
Overall, seven of 14 patients had complete or partial responses to treatment with a programmed cell death-1 (PD-1) inhibitor. Responding and nonresponding patients had different characteristics, which might inform future use of checkpoint inhibitors after CAR T-cell therapy.
“PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and can improve CAR T-cell persistence,” Shannon Maude, MD, PhD, of Children’s Hospital of Philadelphia, said during a press conference at the 2018 ASH Annual Meeting. “This strategy may particularly benefit patients with early B-cell recovery and bulky extramedullary disease.”
CAR T cell therapy can induce complete responses in more than 80% of patients with relapsed ALL, but relapse-free survival declines to 60% at 12 months because of CD19-positive and negative relapses. CD19-positive relapses that occur during this time result primarily from early CAR T-cell loss.
One potential mechanism for loss of CAR T-cell response is exhaustion of activated T-cells by the stimulation of immune checkpoint pathways, such as programmed cell death-1 (PD-1). Maude and colleagues hypothesized that inhibition of PD-1 or its ligand (PD-L1) might reduce T-cell exhaustion and improve CAR T-cell function and persistence.
To test the hypothesis, investigators studied 14 pediatric patients with early CAR T-cell loss or partial or response to CAR T-cell therapy. Anti-PD-1 treatment began no earlier than 14 days after completion of CAR T-cell infusion and after resolution of cytokine release syndrome symptoms. Patients could receive additional anti-PD-1 therapy as often as every 3 weeks.
The patients ranged in age from 4 to 17 years, and all but one had relapsed ALL. The remaining patient had relapsed B-cell lymphoblastic lymphoma. The anti-PD-1 agent was pembrolizumab (Keytruda) in 13 cases and nivolumab (Opdivo) in the other.
The 14 patients included 4 who had partial or no response to CAR T-cell therapy, 6 who had poor persistence of response, and 4 who had bulky extramedullary disease.
All 4 patients with partial or no response to CAR T-cell therapy had disease progression after administration of the PD-1 inhibitor. However, 3 of the 6 patients with poor persistence had return of B-cell aplasia and sustained complete response. All 4 patients with bulky extramedullary disease responded to checkpoint inhibition, as 2 patients had complete responses and 2 had partial responses.
Adverse events included mild symptoms of cytokine release syndrome and fever, typical of CAR T-cell proliferative response, which was observed in 3 patients within 2 days of initiating pembrolizumab. Early and delayed adverse events associated with PD-1 inhibition occurred but were generally tolerable or reversible upon discontinuation. They included 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 cases of grade 3-4 cytopenias. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both relapsed or had progressive CD19-positive disease a few weeks after discontinuation.
“In the context of CAR T-cells, this combination therapy could overcome (PD-1/PD-L1 associated) resistance in some patients,” said Maude. “These are children who would otherwise have no other therapeutic options, so efforts to maximize their response is critical.”
Follow-up will continue for the 14 patients treated with immune checkpoint inhibitors. Additionally, investigators will explore other combination strategies that might help improve outcomes for patients treated with CAR T-cell therapy.
Li AM, Hucks GE, Dinofia AM, et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia. Presented at: Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego. Abstract 556.