Abstract 2855: Immunomodulatory activity of nivolumab monotherapy in patients with advanced melanoma
Authors: Urba Walter J. , Martín-Algarra Salvador , Callahan Margaret , Wolchok Jedd D. , Sharfman William H. , Sosman Jeffrey A. , Bhatia Shailender , Hwu Wen-Jen , Gajewski Thomas F. , Slingluff Craig L. , Shen Yun , Horak Christine E. , Hodi F Stephen 
Published: August 2015

Abstract
Background: Nivolumab, a fully human anti-programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has shown encouraging clinical activity in melanoma. We evaluated the pharmacodynamic effects of nivolumab on immune endpoints in patients (pts) with advanced melanoma in an exploratory phase 1 study (NCT01621490).
Methods: 85 pts (41 and 44 anti-CTLA-4 therapy-naïve and refractory, respectively) received nivolumab 3 mg/kg IV Q2W in 56-day cycles. Tumor biopsies were obtained at baseline (B/L) and on treatment during Cycle 1, Week 4 (C1Wk4). Response was assessed during the last week of each cycle. The primary objective was to evaluate the pharmacodynamic activity of nivolumab on immune biomarkers, including circulating T-cell subsets (by multiparametric flow cytometry), serum interferon (IFN) and IFN-induced factors (by multiplex immunoassay), and T-cell infiltration in the tumor microenvironment (by immunohistochemistry for CD3, CD4, CD8, PD-1 and FOXP3). Secondary objectives included safety, efficacy, and the association between tumor PD ligand-1 (PD-L1) expression and clinical responses.
Results: Across all 85 pts, the objective response rate was 25%, with 2 pts having a confirmed complete response. The safety profile was consistent with prior nivolumab monotherapy trials. Of 85 pts, 34 had evaluable biopsies at B/L and C1Wk4. Increases in tumor infiltrating lymphocytes (TILs) at C1Wk4 relative to B/L were seen in most pts; 65% of pts had an increase in CD3+ T cells. Expression of other TIL markers CD4, CD8, FOXP3 and PD-1, correlated well with one another and CD3 after treatment (C1Wk4; r = 0.69-0.93, P&lt;0.0001). Increased TIL, in particular CD3+ and CD8+, was associated with response; 100%/88% of responders had elevated CD3+/CD8+ TILs compared with 54%/58% of non-responders. PD-L1 expression was not consistently modulated between B/L and C1Wk4 (30 matched samples); however, highest PD-L1 expression (C1Wk4) was accompanied by highest TIL levels (C1Wk4). No consistent change in the frequency of activated peripheral T-cell subsets (HLA-DR+ or ICOS+, CD4 and CD8 T cells) was seen with nivolumab treatment, but peripheral increases in serum IFN-γ-stimulated cytokines were observed. Mean concentrations of serum CXCL9 and CXCL10 increased 2.2- and 1.1-fold from B/L, respectively, 43 days after initial dose; no association was apparent between the increases and response.
Conclusions: Nivolumab monotherapy is marked by increased TIL, inclusive of cytotoxic CD8 T cells, and FOXP3+ T regulatory cells and these increases are associated with response. Unlike ipilimumab, nivolumab treatment does not demonstrate consistent increases in circulating activated T cells. However, increases in peripheral IFN-γ-stimulated cytokines, CXCL9 and CXCL10 are observed, presumably derived from the tumor microenvironment. Further characterization of the effects of nivolumab on the tumor microenvironment is ongoing.
Citation Format: Walter J. Urba, Salvador Martín-Algarra, Margaret Callahan, Jedd D. Wolchok, William H. Sharfman, Jeffrey A. Sosman, Shailender Bhatia, Wen-Jen Hwu, Thomas F. Gajewski, Craig L. Slingluff, Yun Shen, Christine E. Horak, F Stephen Hodi. Immunomodulatory activity of nivolumab monotherapy in patients with advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2855. doi:10.1158/1538-7445.AM2015-2855