ABSTRACT: Epigenetic immunomodulation by association of guadecitabine with ipilimumab (NIBIT-M4 Phase Ib trial, NCT02608437) has been shown to be safe and tolerable in advanced melanoma and to have significant immunomodulatory and antitumor activity [Di Giacomo et al. Clin Cancer Res. 2019 Dec 15;25(24):7351-7362]. Here we carried out a multi-omics assessment of pre-therapy (week 0, w0) and on-treatment (week 4, w4 and week 12, w12) tumor biopsies from enrolled patients looking at the specific parameters that could explain clinical benefit vs treatment failure. Available whole exome sequencing, reduced-representation bisulfite sequencing and RNA sequencing data, together with focused analysis of immune-related signatures by custom NanoString panels, were integrated with existing information on tumor immune contexture data by immunohistochemistry. Results indicated that clinical benefit vs progressive disease could be explained, even at the single patient level, by applying a multifactorial code integrating information from a variety of parameters investigated on sequential biopsies. Crucial parameters included: tumor genomic/transcriptomic landscape, immune structure of the tumor microenvironment (inferred by deconvolution of gene expression data or assessed by immunohistochemistry), profile of genes and molecules relevant for antigen processing and presentation (immunoproteasome subunits, HLA class I molecules on tumor cells), tumor classification by the immunological constant of rejection (Bertucci et al. British Journal of Cancer 2018; 119:1383–1391), genetic immunoediting score (the ratio between the observed versus the expected number of neoantigens), enrichment for differentiation-, metabolism-, proliferation- and immunity-related pathways as well as analysis for signatures related to B cell content and differentiation, TLS formation, follicular T helper cells, TEX subsets, tumor-associated endothelial cells, ICB response and guadecitabine-specific gene upregulation.
