PracticeUpdate Conference Series ASH 2018

Combining CAR T-Cell Therapy With PD-1 Checkpoint Inhibitors Could Improve Response Persistence The approach appears to show themost promise in patients with B-lymphoblastic malignancies and early B cell recovery or bulky extramedullary disease.

T he use of checkpoint inhibitors to augment CD19- directed chimeric antigen receptor (CAR) T-cell therapy could both enhance and sustain the benefits of CAR T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL), according to the results of a study presented at ASH 2018. Previous research has shown CD19-directed CAR T-cell therapy can induce complete remission in up to 90% of patients with relapsed or refractory B-ALL. However, according to Shannon Maude, MD, PhD of the Children’s Hospital of Philadelphia, who presented the study, relapse-free survival drops to 60% within 12 months due to both CD19-positive and negative relapses. These relapses occur during this time because of early CAR T-cell loss, said Dr. Maude. “Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, and that one such pathway – PD-1 – may be involved in early loss of CD-19 CAR T-cells,” said Dr. Maude during her presentation. “Therefore, the combination with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence.” Dr. Maude and her colleagues reported on their experience at the Children’s Hospital of Philadelphia in using PD-1 inhibitors in patients with relapsed or refractory B-lymphoblastic malignancies treated with CD19-directed CAR T-cell therapy. Fourteen patients 4 to 17 years of age, treated with CD19-directed CAR T-cell therapy, and who had repeated CAR T cell loss or a partial/no response to the therapy received a PD-1 inhibitor as early as 14 days after CAR T cell infusion and after the resolution of cytokine release syndrome symptoms.

Of those 14 patients, 13 had relapsed B-ALL and the other had B lymphoblastic lymphoma. All were treated with CD19-directed CAR T-cell therapy in combination with the PD-1 inhibitors pembrolizumab (n=13) or nivolumab (n=1). Outcomes were reported in three settings. The first setting involved patients with partial or no response to CD19-directed CAR T cells, where Dr. Maude and colleagues hypothesized that the activation of the T cells may lead to activation of the checkpoint path- way and block a full response. “In that group of patients, we added PD-1 blockade and, unfortunately, did not see an effect in this small group, where 4 of 4 patients had progression of their disease with 1 patient’s progression marked by reduced CD190 progression, which was probably the mode of escape from CD19 CAR T cells,” Dr. Maude said. The second setting included 6 patients who responded to CAR T cells but had poor persistence marked by early B cell recovery. These patients were reinfused with a CAR T-cell product followed by infusion with PD-1 blockade. Of these patients, 3 had return of B-cell aplasia and sustained complete response with B-cell aplasia, showing continued persistence of their CAR T cells. “In the third situation, we had patients with bulky extramedullary disease and we hypothesized that the PD-1 checkpoint pathway may be activated though the microenvironment in that extramedullary situation,” she explained during her presentation. “We added PD-1 blockade and saw 2 of 4 patients had sustained complete response, and 2 of 4 had a partial response.”

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PRACTICEUPDATE CONFERENCE SERIES • ASH 2018