Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial

Abstract

Background Endogenous or iatrogenic antitumor immune responses can improve the course of follicular lymphoma (FL), but may be diminished by immune checkpoints in the tumor microenvironment. These may include effects of programmed death (PD)-1, a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. In a Phase II trial, we determined the activity of pidilizumab, a humanized anti-PD-1 monoclonal antibody, with rituximab in patients with relapsed FL. Methods FL patients with rituximab-sensitive disease relapsing after 1–4 prior therapies were eligible. Pidilizumab was administered at 3 mg/kg every 4 weeks for 4 infusions, plus 8 optional infusions every 4 weeks for patients with stable disease or better. Starting 2 weeks after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 weekly for 4 weeks. The primary endpoint was to assess the overall response rate. Analysis was by intention to treat. Peripheral blood and tumor biopsies were studied to assess immunological effects of pidilizumab. This trial has been completed and was registered at www.clinicaltrials.gov as NCT00904722. Findings The combination was well-tolerated, with no autoimmune or therapy-related grade 3/4 toxicities. The most common grade 1 adverse events were anemia (14 patients) and fatigue (13 patients), and the most common grade 2 adverse event was respiratory infection (5 patients). Overall 19/29 (66%) and complete 15/29 (52%) response rates in 29 evaluable patients were high, with tumor regression in 25/29 (86%) of patients. Median progression-free survival was 18.8 months (95% CI: 14.7 months to not reached). The median response duration for the 19 responders was 20.2 months (95% CI: 13.9 months to not reached). Correlative studies of blood and tumor provided insights into predicting response and understanding mechanisms involved. Interpretation Pidilizumab with rituximab is well-tolerated and its activity compared favorably to historical retreatment with rituximab monotherapy in patients with relapsed FL. Our results establish that immune checkpoint blockade is worthy of further study in FL. Funding National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech Ltd, and UT MD Anderson Cancer Center.

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…95 Pidilizumab, a humanized IgG1 antibody thought to target PD-1, showed interesting results in DLBCL and FL. 96,97 However, it has become clear that its mechanism of action is not checkpoint inhibition, but innate immune system activation, which needs further elucidation. A phase II clinical trial testing the efficacy of pidilizumab as consolidation treatment in stage III-IV DLBCL in first CR is underway, and it will be interesting to see -once its mechanism of action is clarified -whether this antibody represents another platform for possible combinations with ICI.…”

Lectin-like transcript 1 is a marker of germinal center-derived B-cell non-Hodgkin's lymphomas dampening natural killer cell functions

“…Recent findings have highlighted the benefit of combining blockers of ICPs, such as anti-PD1, with rituximab in patients with relapsed FLs. 47 The use of therapeutic agents targeting ICPs has been shown to enhance endogenous antitumor immune responses in several settings and has raised new hopes in cancer treatment. 13 The involvement of LLT1/CD161 interaction in the regulation of antitumor responses is still to demonstrate but current findings strongly suggest it can modulate NK and T cell responses.…”

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

“…8 This issue is particularly relevant when considering the ongoing trials of immune checkpoint-targeting therapeutic regimens for these aggressive lymphomas. [9][10][11][12][13] To maximize the effects of these innovative therapies, the determinants of response in B-NHL patients must be better understood. In particular, the various immune escape pathways might constitute a mechanism for immune resistance and beyond, to immune checkpoint therapeutic resistance.…”