Purpose: Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti–PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer.Patients and Methods: Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014.Results: Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination.Conclusion: This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLS are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high-grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and it was a favorable prognostic factor for patients with HGSC. Coexistence of CD8 ⁺ T cells and B cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLS. CXCL13 expression was predominantly coincident with CD4 ⁺ T cells in TLS and CD8 ⁺ T cells in TILs, and it shifted from CD4 ⁺ T cells to CD21 ⁺ follicular DCs as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLS and enhanced survival by the infiltration of CD8 ⁺ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4 ⁺ T cells and that TLS facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.

5511 Background: Programmed death-1 (PD-1) is a co-inhibitory receptor expressed on activated T cells which regulates antitumor immunity. Nivolumab is a fully-humanized IgG4 that blocks the engagement of PD-1 by PD-1 ligands. Here we report the first trial for clinical application of nivolumab in ovarian cancer patients. Methods: Nivolumab was administered every 2 weeks to patients with advanced or relapsed, platinum–resistant ovarian cancer, at the doses of 1 or 3 mg/kg during two cohort examination (10 patients each). The phase II efficacy trial defined 1^st endpoint of response rate, and second endpoints of safety, and disease control rate. Patients receivednivolumab up to 6 cycles (4 doses/cycle) of treatment or until PD or disease progression. Response rate was assessed by RECIST v1.1, and adverse events were evaluated by CTCAE v4.0. The data were cut-off on January 1, 2014. Results: Fifteen patients were treated with nivolumab (1 mg/kg: n=10, 3mg/kg: n=5), and evaluated. Median duration of therapy was 14 wks. There was one patient who had severe adverse drug reaction with fever, disorientation and gait disturbance. Clinical response rates were shown in Table. At the time of data cut off, one of the three partial responders had responses for 5 months, and the other two were on study with response for 4 and 10 months. Conclusions:Nivolumab at 1 mg/kg cohort is well tolerated and has encouraging clinical efficacy for advanced or relapsed, platinum-resistant ovarian cancer patients. 3 mg/kg cohort is now under investigation. Clinical trial information: UMIN000005714.