Senescent BALB/c mice are able to develop resistance to Leishmania major infection.

With advancing age, the immune system of animals and humans undergoes characteristic changes, usually resulting in increased susceptibility to infections and malignancies and deficiency in mounting Th2 immune responses. This PhD thesis addresses the question whether the age-related decline in Th2 responses is dominant enough to reduce the generation of Th2 cells and even to bias Tcell differentiation towards a Th1 pattern providing resistance to diseases that require Th1 immune responses for healing. We investigated this issue on the model of experimental leishmaniasis in mice. In this model, genetically resistant mice (like C57) heal cutaneous lesions and clear the infection with L. major by mounting a Th1 immune response with high levels of IFN-gamma; by contrast, genetically susceptible mice (BALB/c) do not heal and succumb under progressive dissemination of the parasites. Surprisingly, susceptible senescent BALB/c mice developed a milder infection than the young ones and in 60% of the cases even healed ulcerations, similarly to the resistant, C57BL/6 mice. Moreover, some senescent BALB/c mice mounted a L. major-specific Th1 response, with elevated release of IFN-gamma upon infection. By sharp contrast, young BALB/c mice developed a susceptibility-characteristic Th2 response. This observation was further sustained by the finding that macrophages from senescent BALB/c mice spontaneously produce higher levels of IL-12 than macrophages from young mice. IL-12 is the main cytokine responsible for the initiation of a host-protective Th1 immune response. Besides aging, we have identified the infection with Murine Hepatitic Virus as a possible second signal, which might have driven the immune response towards a Th1 pattern in senescent mice raised in conventional conditions. Our results are both remarkable and important, as they show for the first time that BALB/c mice might become resistant to infection with L. major without any treatment

Real-world outcomes using PD-1 antibodies and BRAF plus MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland

BackgroundProgrammed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. MethodsMulticenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. ResultsIn total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. ConclusionsDespite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk