Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Despite significant efforts, no therapies have demonstrated valuable survival benefit beyond the current standard of care. Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape and improved patient survival in many advanced malignancies. Unfortunately, these clinical successes have not been replicated in the neuro-oncology field so far. This review summarizes the status of ICI investigation in high-grade gliomas, critically presenting the available data from preclinical models and clinical trials. Moreover, we explore new approaches to increase ICI efficacy, with a particular focus on combinatorial strategies, and the potential biomarkers to identify patients most likely to benefit from immune checkpoint blockade.

Mutations in isocitrate dehydrogenase (IDH)1 and its homolog IDH2 are considered an earliest “driver” genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). IDH-mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply “precision oncology” in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which IDH mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.

As the population of young cancer survivors is increasing and a trend toward postponing pregnancy later in life is reported, more efforts are focused toward understanding treatment-induced sequelae...

The advent of immunotherapy has transformed the treatment paradigm for metastatic non-small cell lung cancer (NSCLC). In the past few years, several studies have investigated the potential role of immune checkpoint inhibitors (ICIs) in resectable and unresectable locally advanced disease, achieving remarkable results that led to their approval in clinical practice. However, there is limited evidence on immunotherapy rechallenge after recurrence, with the majority of available knowledge coming from retrospective studies which involve heavily pretreated patients with advanced NSCLC. The recent introduction in the curative setting and the potential regulatory restrictions raise questions about the optimal choice of first-line and subsequent therapies for patients with systemic relapse. The role of immunotherapy readministration in this new scenario needs to be clarified, as well as the identification of patients for whom it is more appropriate, including clinical characteristics, duration of response, switching to other ICIs, reasons for discontinuation and immune-related toxicity. Here, we review literature on rechallenge with immunotherapy, including efficacy, safety profile and potential predictive factors of response.