Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients’ response to therapy.,Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin.,In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations.,In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes.,Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression.,Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression.,On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy.,We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype.,In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient.,Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients’ response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (ClinicalTrials.gov NCT03385226, NCT04118868).
Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages.,The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.,Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers.,Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety.,Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.,The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively.,The median duration of response was 25.5 months (range 9.0-65.0).,Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0).,The median PFS was 3.0 months (95% CI 2.4-3.6).,The median OS was estimated to 16.1 months (95% CI 12.9-19.3).,Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%).,The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%).,A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).,The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma.,This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.