Disabling Immune Tolerance by Programmed Death-1 Blockade With Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial

TLDR

The PD‑1 immune checkpoint pathway is exploited by tumors such as diffuse large B‑cell lymphoma to evade immune surveillance. The study evaluated whether PD‑1 blockade with pidilizumab after autologous hematopoietic stem‑cell transplantation can break immune tolerance in DLBCL patients, with correlative lymphocyte subset analysis. Sixty‑six DLBCL patients received three doses of pidilizumab beginning 1–3 months post‑transplant. Pidilizumab was well tolerated and achieved a 16‑month progression‑free survival of 72 % overall (51 % overall response rate), with comparable outcomes in high‑risk patients, and was associated with increased PD‑L1‑bearing lymphocytes, indicating clinical activity of PD‑1 blockade after AHSCT.

Abstract

The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade.We conducted an international phase II study of pidilizumab, an anti-PD-1 monoclonal antibody, in patients with DLBCL undergoing AHSCT, with correlative studies of lymphocyte subsets. Patients received three doses of pidilizumab beginning 1 to 3 months after AHSCT.Sixty-six eligible patients were treated. Toxicity was mild. At 16 months after the first treatment, progression-free survival (PFS) was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point. Among the 24 high-risk patients who remained positive on positron emission tomography after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82). Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1E-bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab.This is the first demonstration of clinical activity of PD-1 blockade in DLBCL. Given these results, PD-1 blockade after AHSCT using pidilizumab may represent a promising therapeutic strategy in this disease.