ASH 2018: Inhibiting the immune system’s natural response may boost benefits and sustainability of CAR T therapy

1 Dec 2018
ASH 2018: Inhibiting the immune system’s natural response may boost benefits and sustainability of CAR T therapy

CD19-directed CAR T-cell therapy has been shown to be effective in patients with relapsed B-cell acute lymphocytic leukemia (B-ALL).

Many patients will have durable or long-term responses with long-lasting CAR T cells.

For some patients however, the anti-tumour effects of CAR T-cell treatment are shortlived.

This may, in part, be caused by a reaction of the patient’s immune system against their very own CAR T-cells.

This may occur through the immune system’s checkpoint pathways.

In the first study of its kind in this patient population, 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. “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.”

This small, single-centre study included a total of 14 children ranging in age from 4-17 years — 13 with heavily pretreated relapsed B-ALL and one with lymphocytic lymphoma (previous treatments included bone marrow transplant and one or two types of CAR-T).

All received CD19-directed CAR T-cell therapy and an immunotherapy called a checkpoint inhibitor, intended to inhibit the immune checkpoint PD-1 (programmed cell death 1).

Patients in the study were given either pembrolizumab or nivolumab.

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 CRS is typically experienced within the same window. 

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 re-established B-cell aplasia (a sign that the CAR T-cell therapy is working).

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 CRS 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.

Source: ASH