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IFN-gamma signature-driven neoadjuvant domatinostat, nivolumab and ipilimumab in stage III melanoma – the DONIMI trial

ABSTRACT: Low baseline Interferon gamma (IFNg) response signature is associated with lack of response to neo-adjuvant anti-PD1 + anti-CTLA4 therapy in patients with melanoma. Domatinostat, a class I specific histone deacetylase inhibitor is known to induce IFNg response in patients with advanced stage melanoma. Thus, addition of domatinostat to anti-PD1 + anti-CTLA4 might result in increased response to treatment. However, the effect of this combination therapy on tumor growth has not been evaluated in the pre-clinical setting. We therefore evaluated whether addition of domatinostat results in immune modulation and tumor growth control in the MeVa2.1.dOVA murine melanoma model. We provide pre-clinical evidence to use this combination in melanoma patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE217162 | GEO | 2023/03/13

REPOSITORIES: GEO

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Project description:Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (B2M), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified B2M aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping B2M, and absence of tumor-specific B2M protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that B2M LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of B2M was found only in nonresponders. We also found evidence for association of LOH overlapping IFNGR1 with poorer overall survival exclusively in the anti-PD1 cohort. Thus, B2M loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.

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IFN-gamma signature-driven neoadjuvant domatinostat, nivolumab and ipilimumab in stage III melanoma – the DONIMI trial

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