Checkpoint Inhibition May Improve CAR T-Cell Persistence

Checkpoint inhibition showed promise for augmenting or extending response to chimeric antigen receptor T-cell therapy in some patients with relapsed B-cell acute lymphoblastic leukemia.

Shannon L. Maude, MD, PhD

Shannon L. Maude, MD, PhD

Shannon L. Maude, MD, PhD

Checkpoint inhibition showed promise for augmenting or extending response to chimeric antigen receptor (CAR) T-cell therapy in some patients with relapsed B-cell acute lymphoblastic leukemia (ALL), according to results of a small clinical study.1

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 American Society of Hematology meeting in San Diego. “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 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.1

1. 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.

<<< 2018 ASH Annual Meeting

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