Harnessing the immune system with immune-checkpoint(s) blockade (ICB) has dramatically changed the treatment landscape of advanced melanoma patients in the last decade. Indeed, durable clinical responses and long-term survival can be achieved with anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and anti-Programmed cell Death-1 (PD-1) monoclonal antibodies (mAb) either alone or in combination. Despite these unprecedented results, due to intrinsic or acquired resistance to ICB-based immunotherapy, about half of metastatic melanoma (MM) patients neither respond to therapy nor experience durable clinical benefit or long-term survival. To improve the efficacy of ICB therapy among a larger proportion of MM patients, in addition to the targeting of immune-checkpoint(s) inhibitors (ICI) such as CTLA-4 or PD-1, several co-stimulatory molecules, such as Inducible T-cell COStimulator (ICOS), CD137 and OX40, have been investigated in MM, with initial signs of activity. Thus, a number of MM patients have been exposed to co-inhibitory and co-stimulatory mAb in the course of their disease. Being aware of the clinical outcome of such patients may pave the way to novel and more effective clinical approaches and therapeutic sequences for MM patients. Here we report a paradigmatic clinical case of a cutaneous MM patient who achieved multiple and durable complete responses, leading to an extraordinary long-term survival with sequential ICB therapies, suggesting the possibility to build a highly effective continuum of care with co-inhibitory and co-stimulatory therapeutic mAb.
Association of DNA hypomethylating agents (DHA) with immune-checkpoint inhibitors (ICI) is a promising strategy to improve the efficacy of ICI-based therapy. Here we report the five-year clinical outcome and an integrated multi-omics analysis of pre- and on-treatment lesions from advanced melanoma patients enrolled in the phase Ib NIBIT-M4 study, a dose-escalation trial of the DHA agent guadecitabine combined with ipilimumab. With a minimum follow-up of 45 months the median OS was 25.6 months; the 5-year OS rate was 28.9% and the median DoR was 20.6 months. Specific genomic features and extent of T and B cellmediated immunity discriminated lesions of responding compared to non-responding patients. Enrichment for proliferation and EMT-related gene programs, and immune escape mechanisms characterized lesions from non-responding patients. Integration of a genetic immunoediting index (GIE) with an adaptive immunity signature (ICR) stratified patients/lesions into four distinct subsets and discriminated 5-year OS and PFS. These results suggest that coupling of immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.
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