Checkpoint inhibitors enhance CAR T-cell therapy in relapsed B-cell acute lymphoblastic leukemia

Issue: December 25, 2018

Shannon Maude

SAN DIEGO — Checkpoint inhibitors appeared to safely and effectively improve outcomes with CD19-directed chimeric antigen receptor T-cell therapy among children with relapsed B-cell acute lymphoblastic leukemia, according to a study presented at ASH Annual Meeting and Exposition.

Perspective from James K. McCloskey, MD

The PD-1 checkpoint pathway may be involved in chimeric antigen receptor (CAR) T-cell exhaustion, and addition of checkpoint inhibitors may overcome this effect and help increase CAR T-cell function and persistence, according to the researchers.

“For a fraction of patients who do not have durable remissions with CAR T cells, we can potentially improve upon the function and persistence of their CAR T cells by adding checkpoints,” Shannon Maude, MD, PhD, attending physician in the Cancer Center of The Children’s Hospital of Philadelphia, told HemOnc Today.

Previous research has shown CAR T-cell therapy can lead to complete response rates of 80% to 90% among patients with B-cell ALL. However, RFS declines to 60% within the first year because of CD19-positive and -negative relapses. Further, CD19-positive relapses usually occur due to CAR T-cell loss, according to study background.

Researchers hypothesized that inhibiting the PD-1/PD-L1 checkpoint decreases T-cell exhaustion or loss that causes CD19-positive and -negative relapses in this population.

The analysis included 14 patients (age range, 4-17 years) with pretreated, relapsed B-ALL (n = 13) or B-cell lymphoblastic lymphoma (n = 1) who demonstrated repeated early CAR T-cell loss or partial/no response to CAR T-cell therapy.

Patients received CD19-directed CAR T-cell therapy (CTL019, n = 4; CTL119, n = 10) in combination with pembrolizumab (Keytruda, Merck; n = 13) or nivolumab (Opdivo, Bristol-Myers Squibb; n = 1). Researchers administered the checkpoint inhibitor at least 14 days after CAR T-cell infusion and after symptoms from cytokine release syndrome cleared.

Three of six patients treated with CD19 CAR T cells in combination with a checkpoint inhibitor re-established B-cell aplasia — an indicator of CAR T-cell function — for 5 to 15 months. Two of those patients had persistent B-cell aplasia while taking pembrolizumab.

Researchers observed two complete and two partial responses among four patients with bulky extramedullary disease unresponsive to or who relapsed after CAR T-cell therapy.

One patient experienced CAR T-cell proliferation days after beginning checkpoint inhibitor treatment.

Partial responses, but no complete responses, occurred with the addition of pembrolizumab among four patients who did not go into remission after CAR T-cell infusion. Further, one patient progressed with CD19-negative/dim disease.

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“This is still a small study, so we need to look at this more broadly and identify biologic features that will tell us the mechanism of why patients are responding and why they’re not, and if there are predictors in those who would most benefit,” Maude said.

Cytokine release syndrome occurred among three of the 14 patients within 2 days of starting checkpoint inhibitor therapy. Other adverse effects, including acute pancreatitis, hypothyroidism, arthralgias, urticaria and cytopenias, were tolerable or reversable after discontinuation.

Two patients who stopped checkpoint inhibitor therapy due to adverse events experienced relapse or disease progression within weeks.

“We plan to study this in a larger group of patients still selecting particular populations that we think would benefit,” Maude said. “We’re hoping to expand this in the group of patients who are not having the same excellent response to CAR T cells that we saw, so we can determine if it helps that response rate.” – by John DeRosier

Reference:

Li A, et al. Abstract 556. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures : Maude reports a consultant role with Novartis. Please see the abstract for all authors’ financial disclosures.

Perspective

James K. McCloskey, MD

Researchers evaluated the use of checkpoint inhibitors in patients who failed to respond or had an unsatisfactory response to CAR T-cell therapy. This is a product that was incredibly effective; it was one of the best response rates we have ever seen in a relapsed, refractory setting.

Patients who failed on or have unsatisfactory response to CAR T-cell therapy have a poor prognosis. There is no standard approach for those patients.

Researchers sought to evaluate whether we can salvage the CAR T-cell response in patients who are not performing as well as we would like.

For patients who maintain CD19 expression, the most common reason they fail to respond to therapy is failure of the CAR T-cell product, either due to immune destruction or failure of the product to expand and remain in circulation.

In this trial — which is an early and small trial — we saw that we could apply another immune-modulator to allow reactivation of the CAR T cells. The checkpoint inhibitors are a class of drugs that have offered a hope for improved responses to all other immunotherapies. Although it was small, it was still substantial to see them respond and regain function of that CAR T-cell product.

Engaging the immune system post-transplant or post-CAR T is important. It’s possible that maintenance therapy with checkpoint inhibitors postinfusion of the CAR T product might lead to better outcomes and lower rates of relapse. It’s certainly a promising concept.

James K. McCloskey, MD

Hackensack University Medical Center

Disclosures: McCloskey reports no relevant financial disclosures.