Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels, and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome.

Purpose of Review In this review, we analyzed the current landscape of non-PD-(L)1 targeting immunotherapy. Recent Findings The advent of immunotherapy has completely changed the standard approach toward advanced NSCLC. Inhibitors of the PD-1/PD-L1 axis have quickly taken place as first-line treatment for NSCLC patients without targetable “driver” mutations. However, a non-negligible portion of patients derive modest benefit from immune-checkpoint inhibitors, and valid second-line alternatives are lacking, pushing researchers to analyze other molecules and pathways as potentially viable targets in the struggle against NSCLC. Summary Starting from the better characterized CTLA-4 inhibitors, we then critically collected the actual knowledge on NSCLC vaccines as well as on other emerging molecules, many of them in their early phase of testing, to provide to the reader a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 inhibitors.

The therapeutic approach to patients affected by advanced non-small-cell lung cancer (NSCLC) is facing rapid and continuous evolution. In recent years, the emergence of new treatment strategies, such as immunotherapy and tyrosine kinase inhibitors, has revolutionized the treatment algorithm and the prognosis of patients with NSCLC. In the nononcogene-addicted disease, immune-checkpoint inhibitors, either as single agents or combined with chemotherapy, outperformed standard chemotherapy in both untreated and previously treated patients. However, many patients still do not derive the expected benefit from current treatments. Despite representing the only biomarker currently used in clinical practice to guide treatment selection, PD-L1 expression has been proven an imperfect predictor of immunotherapy outcomes. The evaluation of clinical factors remains essential to detect patients that would benefit the most from a particular treatment approach, but the identification of additional biological and molecular predictive tools is a priority. Herein, we provide a comprehensive though concise review of the current treatment approaches to advanced NSCLC in patients without molecular driver alterations, with an additional focus on special populations, concomitant medications, and other considerations that might be useful for daily clinical practice.

Introduction: The best treatment for advanced, PD-L1-high non-small-cell lung cancer remains a debated issue. Methods: A meta-analysis of randomized clinical trials (RCTs) was performed to compare the efficacy and safety of PD-(L)1 inhibitors alone or plus chemotherapy (CT) for advanced, PD-L1-high non-small-cell lung cancer. Results: 14 RCTs were included. The combination of a PD-(L)1 inhibitor with CT resulted in the improvement of progression-free survival (HR: 0.59; 95% CI: 0.43–0.79; p = 0.0005) and objective response rate (RR: 1.66; 95% CI: 1.14–2.42; p = 0.008). No overall survival difference was documented (HR: 0.99; 95% CI: 0.77–1.27; p = 0.95). The risk of grade ≥3 treatment-related adverse events was significantly reduced with immune-checkpoint inhibitor single-agent therapy compared with immune-checkpoint inhibitors plus CT (RR: 0.38; 95% CI: 0.32–0.45; p = 0.00001). Conclusion: The combination of a PD-(L)1 inhibitor and CT appears to be associated with improved PFS and ORR, but similar OS, compared with PD-(L)1 inhibitor single-agent therapy in patients with PD-L1-high non-small-cell lung cancer.