Abstract 913: Defining melanoma patients unresponsive to single agent anti-PD-1 therapy but responsive to combination anti-PD-1 + anti-CTLA-4 therapy

Abstract Background: A proportion of patients that fail single agent anti-PD-1 therapy will subsequently receive and respond to combination anti-PD-1 and anti-CTLA-4 immunotherapy. The clinical and biological characteristics of these patients remain poorly defined and as such there are presently no reliable validated biomarkers to distinguish patients requiring the addition of anti-CTLA-4 in the context of anti-PD-1 therapy. Clinical cohort and methods: We performed RNA sequencing, immunofluorescence-IHC, and multiparameter image-mass cytometry (IMC) on formalin-fixed paraffin embedded (FFPE) tumors at baseline and post anti-PD-1 therapy from n=15 stage IV melanoma patients who failed anti-PD-1 therapy and went on to receive combination immunotherapy (7 non-responders; 8 responders). Results: Tumor pathological parameters including TIL and neutrophil densities, fibrosis, necrosis and mitotic rates identified were not different between responders and non-responders. While T-reg, cytotoxic CD8 and CD39+ resident CD8 T cells densities were not significantly different, the proportion of TCF7+ CD8 T cells was significantly higher at baseline (p=0.01) and in all tumor samples (p=0.007) in responders compared to non-responders. RNA differential gene expression analysis revealed higher expression of cancer testis antigens (CTAs) in responding patient tumors. Hierarchical clustering of differentially expressed genes separated responding patients from non-responding patients. Conclusions: The proportion of TCF7+ CD8 T cells and the presence of melanoma cancer testis antigens may be a predictive biomarker of response to combination immunotherapy in patients failing anti-PD-1 monotherapy but requires further validation. Citation Format: Jarem J. Edwards, Inês Pires da Silva1, Angela Ferguson, Peter Johansson, Jordan Conway, Grace Attrill, Robyn P.M Saw, John F. Thompson, Alexander M. Menzies, Umaimainthan Palendira, Georgina V. Long, Richard A. Scolyer, James S. Wilmott. Defining melanoma patients unresponsive to single agent anti-PD-1 therapy but responsive to combination anti-PD-1 + anti-CTLA-4 therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 913.