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Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, bearing a survival estimate below 10% at five years, despite standard chemoradiation treatment. At recurrence, systemic treatment options are limited and the standard of care is not well defined, with inclusion in clinical trials being highly encouraged. So far, the use of immunotherapeutic strategies in GBM has not proved to significantly improve patients' prognosis in the treatment of newly diagnosed GBM, nor in the recurrent setting. Probably this has to do with the unique immune environment of the central nervous system, which harbors several immunosuppressive/pro-tumorigenic factors, both soluble (e.g., TGF-ß, IL-10, STAT3, prostaglandin E2, and VEGF) and cellular (e.g., Tregs, M2 phenotype TAMs, and MDSC). Here we review the immune composition of the GBMs microenvironment, specifically focusing on the phenotype and function of the T cell compartment. Moreover, we give hints on the therapeutic strategies, such as immune checkpoint blockade, vaccinations, and adoptive cell therapy, that, interacting with tumor-infiltrating lymphocytes, might both target in different ways the tumor microenvironment and potentiate the activity of standard therapies. The path to be followed in advancing clinical research on immunotherapy for GBM treatment relies on a twofold strategy: testing combinatorial treatments, aiming to restore active immune anti-tumor responses, tackling immunosuppression, and additionally, designing more phase 0 and window opportunity trials with solid translational analyses to gain deeper insight into the on-treatment shaping of the GBM microenvironment.
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Introduction: Identifying which patient may benefit from immunotherapeutic early-phase clinical trials is an unmet need in drug development. Among several proposed prognostic scores, none has been validated in patients receiving immunomodulating agents (IMAs)-based combinations. Patients and methods: We retrospectively collected data of 208 patients enrolled in early-phase clinical trials investigating IMAs at our Institution, correlating clinical and blood-based variables with overall survival (OS). A retrospective cohort of 50 patients treated with IMAs at Imperial College (Hammersmith Hospital, London, UK) was used for validation. Results: A total of 173 subjects were selected for analyses. Most frequent cancers included non-small cell lung cancer (26%), hepatocellular carcinoma (21.5%) and glioblastoma (13%). Multivariate analysis (MVA) revealed 3 factors to be independently associated with OS: line of treatment (second and third vs subsequent, HR 0.61, 95% CI 0.40-0.93, p 0.02), serum albumin as continuous variable (HR 0.57, 95% CI 0.36-0.91, p 0.02) and number of metastatic sites (<3 vs ≥3, HR 0.68, 95% CI 0.48-0.98, p 0.04). After splitting albumin value at the median (3.84 g/dL), a score system was capable of stratifying patients in 3 groups with significantly different OS (p<0.0001). Relationship with OS reproduced in the external cohort (p=0.008). Then, from these factors we built a nomogram. Conclusions: Prior treatment, serum albumin and number of metastatic sites are readily available prognostic traits in patients with advanced malignancies participating into immunotherapy early-phase trials. Combination of these factors can optimize patient selection at study enrollment, maximizing therapeutic intent.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Pronóstico , Estudios Retrospectivos , Carcinoma de Pulmón de Células no Pequeñas/patología , Nomogramas , Selección de Paciente , Neoplasias Pulmonares/patología , Inmunoterapia/efectos adversos , Albúmina SéricaRESUMEN
Historically, patients with brain metastases (BMs) have been characterized by few systemic treatment options and poor prognosis. The recent introduction of next-generation anticancer therapies such as molecular targeted agents and immunotherapy have revolutionized the clinical decision-making process of this sub-population, posing new challenges to physicians. In this review, current evidence for the use of checkpoint inhibitors and targeted therapies in patients with BMs are discussed, with a focus on lung cancer, breast cancer, melanoma and renal cell carcinoma, providing suggestions and potential workflows for daily clinical practice. Several other on-going and future challenges, such as clinical trials design, ways to improve CNS penetration of novel drugs and unique molecular characteristics of BMs, are also discussed. The aim is producing an updated and easy-to-read guide for physicians, to improve decision-making in clinical practice.
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Antineoplásicos , Neoplasias Encefálicas , Neoplasias Renales , Neoplasias Pulmonares , Melanoma , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Melanoma/terapia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Antineoplásicos/uso terapéutico , Inmunoterapia , Neoplasias Renales/tratamiento farmacológicoRESUMEN
PURPOSE: Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable tumor DNA source for liquid biopsy. We prospectively investigated the use of CSF for molecular characterization of newly diagnosed gliomas. EXPERIMENTAL DESIGN: We recruited two cohorts of newly diagnosed patients with glioma, one (n = 45) providing CSF collected in proximity of the tumor, the other (n = 39) CSF collected by lumbar puncture (LP). Both cohorts provided tumor tissues by surgery concomitant with CSF sampling. DNA samples retrieved from CSF and matched tumors were systematically characterized and compared by comprehensive (NGS, next-generation sequencing) or targeted (ddPCR, droplet digital PCR) methodologies. Conventional and molecular diagnosis outcomes were compared. RESULTS: We report that tumor DNA is abundant in CSF close to the tumor, but scanty and mostly below NGS sensitivity threshold in CSF from LP. Indeed, tumor DNA is mostly released by cells invading liquoral spaces, generating a gradient that attenuates by departing from the tumor. Nevertheless, in >60% of LP CSF samples, tumor DNA is sufficient to assess a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) and MGMT methylation that, combined with imaging, enable tissue-agnostic identification of main glioma molecular subtypes. CONCLUSIONS: This study shows potentialities and limitations of CSF liquid biopsy in achieving molecular characterization of gliomas at first clinical presentation and proposes a protocol to maximize diagnostic information retrievable from CSF DNA.
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Neoplasias Encefálicas , Glioma , Humanos , Glioma/diagnóstico , Glioma/genética , Glioma/patología , Mutación , Pronóstico , Biopsia Líquida , ADN de Neoplasias , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Biomarcadores de Tumor/genéticaRESUMEN
Background. O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild-type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤2, and radio-chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time-dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut-off of 15% for MGMT methylation. The 2-year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p < 0.00001). However, we also found a non-linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0−4%, 18.9 months for MGMT in 4−40%, and 29.9 months for MGMT in 40−100%. Conclusions. Our findings suggested a non-linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild-type glioblastoma patients treated with chemoradiotherapy.
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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.
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INTRODUCTION: Clinicians should address the different health needs of cancer survivors (CS). We investigated concerns about physical/psychosocial symptoms and quality of life (QoL) of CS enrolled in our survivorship program. Our primary aim is to describe the CS population and their quality of life, considering both physical and psychosocial issues, with the intent to identify some possible association with the most frequently observed variables. METHODS: Adult patients, after ≥ 5 years from achieving complete hematologic or solid tumor remission, were included. The self-administered questionnaire used in the survey was based on the "Cancer Survivors Survey of Needs" (Mayo Clinic). RESULTS: We analyzed data from 191 CS. The median age was 63 years (53 years at diagnosis), and 70% of patients were females. A total of 93 patients (49%) reported a quality of life (QoL) score > 2. The most common psychosocial symptom concerns were fear of relapse (53%), genetic counseling (43%), living with uncertainty (35%), defining a new sense of normal (31%), and managing stress (28%). Females are more at risk to develop the following concerns compared with males: pain (40% vs 21%), sleep disturbance (54% vs 30%), weight gain (42% vs 21%), osteoporosis (41% vs 11%), body changes (45% vs 13%), hair or skincare issues (42% vs 16%), hot flashes (40% vs 11%), fear of recurrence (74% vs 54%), and living with a sense of uncertainty (53% vs 29%). Younger patients reported a higher score (> 2) for physical and psychological concerns compared with older patients. CONCLUSION: In this study, differences in physical and psychological symptoms/stressors among women and younger patients were identified. Female and younger patients appear to report physical and psychosocial concerns more frequently than other subgroups of patients. These observations should be validated and deepened in larger, prospective studies and considered during the long-term follow-up of these subgroups of patients.
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Supervivientes de Cáncer , Calidad de Vida , Adulto , Supervivientes de Cáncer/psicología , Femenino , Hospitales , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/psicología , Estudios Prospectivos , Calidad de Vida/psicología , Sobrevivientes/psicología , SupervivenciaRESUMEN
Introduction: Adult-type diffuse gliomas are malignant primary brain tumors characterized by very poor prognosis. Dendritic cells (DCs) are key in priming antitumor effector functions in cancer, but their role in gliomas remains poorly understood. Methods: In this study, we characterized tumor-infiltrating DCs (TIDCs) in adult patients with newly diagnosed diffuse gliomas by using multi-parametric flow cytometry and single-cell RNA sequencing. Results: We demonstrated that different subsets of DCs are present in the glioma microenvironment, whereas they are absent in cancer-free brain parenchyma. The largest cluster of TIDCs was characterized by a transcriptomic profile suggestive of severe functional impairment. Patients undergoing perioperative corticosteroid treatment showed a significant reduction of conventional DC1s, the DC subset with key functions in antitumor immunity. They also showed phenotypic and transcriptional evidence of a more severe functional impairment of TIDCs. Discussion: Overall, the results of this study indicate that functionally impaired DCs are recruited in the glioma microenvironment. They are severely affected by dexamethasone administration, suggesting that the detrimental effects of corticosteroids on DCs may represent one of the mechanisms contributing to the already reported negative prognostic impact of steroids on glioma patient survival.
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Neoplasias Encefálicas , Glioma , Humanos , Adulto , Pronóstico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Corticoesteroides/uso terapéutico , Células Dendríticas , Microambiente TumoralRESUMEN
BACKGROUND: Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. METHODS: Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of P < .1. RESULTS: Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti-PD-1, anti-CSF-1R, anti-TGFß, anti-cereblon), fifteen patients combination regimens (anti-PD-L1 + anti-CD38, anti-PD-1 + anti-CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than 6 years. Univariate analysis identified O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. CONCLUSIONS: A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.
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(1) Background: We investigated the role of [11C]-methionine PET in a cohort of newly diagnosed glioblastoma multiforme (GBM) patients to evaluate whether it could modify the extent of surgical resection and improve radiation therapy volume delineation. (2) Methods: Newly diagnosed GBM patients, ages 18-70, with a Karnofsky performance scale (KPS) ≥ 70 with available MRI and [11C]-methionine PET were included. Patients were treated with different amounts of surgical resection followed by radio-chemotherapy. The role of [11C]-methionine PET in surgical and RT planning was analyzed. A threshold of SUVmax was searched. (3) Results: From August 2013 to April 2016, 93 patients were treated and included in this analysis. Residual tumor volume was detected in 63 cases on MRI and in 78 on [11C]-methionine PET, including 15 receiving gross total resection. The location of uptake was mainly observed in FLAIR abnormalities. [11C]-methionine uptake changed RT volume in 11% of patients. The presence of [11C]-methionine uptake in patients receiving GTR proved to influence survival (p = 0.029). The threshold of the SUVmax conditioning outcome was five. (4) Conclusions: [11C]-methionine PET allowed to detect areas at higher risk of recurrence located in FLAIR abnormalities in patients affected by GBM. A challenging issue is represented by integrating morphological and functional imaging to better define the extent of surgical resection to perform.
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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.
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INTRODUCTION: 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, in particular, the effects of cancer and/or treatment on fertility. AREA COVERED: Whereas the fertility risk of cytotoxic agents for both men and women is well recognized, the impact of molecular-targeted therapy (MTT) on fertility parameters, their teratogenic potential and pregnancy outcome/management in case of an accidental exposure are not established. We update available clinical data on the impact of new MTTs on fertility in both sexes, their potential teratogenic effects and the outcome of pregnancy during accidental exposure. Agents are categorized by class and the potential relevance of their target signaling pathways to gonadal maturation. EXPERT OPINION: The majority of MTTs have worrying preclinical data discouraging their use during pregnancy and reinforcing the idea that they can induce impairment in gonadal function. However, it does not mean that all MTTs result in permanent infertility and that they should be completely avoided during pregnancy. The current review provides a critical evaluation on the most commonly used MTTs, offering a possible guide for clinicians.
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Antineoplásicos/efectos adversos , Fertilidad/efectos de los fármacos , Terapia Molecular Dirigida/efectos adversos , Animales , Antineoplásicos/administración & dosificación , Supervivientes de Cáncer , Femenino , Humanos , Masculino , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Embarazo , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Resultado del EmbarazoRESUMEN
By the beginning of the global pandemic, SARS-CoV-2 infection has dramatically impacted on oncology daily practice. In the current oncological landscape, where immunotherapy has revolutionized the treatment of several malignancies, distinguishing between COVID-19 and immune-mediated pneumonitis can be hard because of shared clinical, radiological and pathological features. Indeed, their common mechanism of aberrant inflammation could lead to a mutual and amplifying interaction.We describe the case of a 65-year-old patient affected by metastatic squamous head and neck cancer and candidate to an experimental therapy including an anti-PD-L1 agent. COVID-19 ground-glass opacities under resolution were an incidental finding during screening procedures and worsened after starting immunotherapy. The diagnostic work-up was consistent with ICIs-related pneumonia and it is conceivable that lung injury by SARS-CoV-2 has acted as an inflammatory primer for the development of the immune-related adverse event.Patients recovered from COVID-19 starting ICIs could be at greater risk of recall immune-mediated pneumonitis. Nasopharyngeal swab and chest CT scan are recommended before starting immunotherapy. The awareness of the phenomenon could allow an easier interpretation of radiological changes under treatment and a faster diagnostic work-up to resume ICIs. In the presence of clinical benefit, for asymptomatic ICIs-related pneumonia a watchful-waiting approach and immunotherapy prosecution are suggested.
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COVID-19/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neumonía/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Anciano , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , COVID-19/inmunología , COVID-19/virología , Diagnóstico Diferencial , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/efectos adversos , Lesión Pulmonar/diagnóstico , Lesión Pulmonar/diagnóstico por imagen , Lesión Pulmonar/patología , Lesión Pulmonar/virología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/virología , Masculino , Nasofaringe/metabolismo , Nasofaringe/patología , Metástasis de la Neoplasia , Pandemias , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Neumonía/virología , SARS-CoV-2/patogenicidad , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Tratamiento Farmacológico de COVID-19RESUMEN
OBJECTIVES: Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia, correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. We evaluated the prognostic relevance of TMT measured on brain MRIs acquired at diagnosis in patients affected by glioblastoma. METHODS: We retrospectively enrolled 51 patients in our Institution affected by methylated MGMT promoter, IDH1-2 wild-type glioblastoma, who underwent complete surgical resection and subsequent radiotherapy with concomitant and maintenance temozolomide, from January 1, 2015, to April 30, 2017. The last clinical/radiological follow-up date was set to September 3, 2019. TMT was measured bilaterally on reformatted post-contrast 3D MPRAGE images, acquired on our 3-T scanner no more than 2 days before surgery. The median, 25th, and 75th percentile TMT values were identified and population was subdivided accordingly; afterwards, statistical analyses were performed to verify the association among overall survival (OS) and TMT, sex, age, and ECOG performance status. RESULTS: In our cohort, the median OS was 20 months (range 3-51). Patients with a TMT ≥ 8.4 mm (median value) did not show a statistically significant increase in OS (Cox regression model: HR 1.34, 95% CI 0.68-2.63, p = 0.403). Similarly, patients with a TMT ≥ 9.85 mm (fourth quartile) did not differ in OS compared to those with TMT ≤ 7 mm (first quartile). The statistical analyses confirmed a significant association among TMT and sex (p = 0.0186), but none for age (p = 0.642) and performance status (p = 0.3982). CONCLUSIONS: In our homogeneous cohort of patients with glioblastoma at diagnosis, TMT was not associated with prognosis, age, or ECOG performance status. KEY POINTS: ⢠Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia and has been correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. ⢠We appraised the correlation among TMT and survival, sex, age at surgery, and performance status, measured on brain MRIs of patients affected by glioblastoma at diagnosis. ⢠TMT did not show any significant correlation with prognosis, age at surgery, or performance status, and its usefulness might be restricted only to patients with brain metastases and recurrent or treated glioblastoma.
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Neoplasias Encefálicas , Glioblastoma , Sarcopenia , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Metilación de ADN , Metilasas de Modificación del ADN , Enzimas Reparadoras del ADN , Glioblastoma/complicaciones , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Humanos , Pronóstico , Estudios Retrospectivos , Sarcopenia/complicaciones , Sarcopenia/diagnóstico por imagen , Sarcopenia/patología , Músculo Temporal/patologíaRESUMEN
OBJECTIVE: Anaplastic gliomas (AGs) are an extremely heterogeneous group of primary brain tumors. More recently, new discoveries have indicated that isocitrate dehydrogenase (IDH) mutation status is the most important parameter predicting survival. The primary aim of the present analysis was to identify prognostic factors, other than IDH status, that eventually impact survival. METHODS: Patients with available clinical, imaging, and molecular profile data who were amenable to resection were evaluated. The extent of resection (EOR) was defined as gross-total resection (GTR), near-total resection (NTR), subtotal resection (STR), or partial resection (PR). Residual tumor volume (RTV) was quantified. Following surgery, patients received adjuvant chemotherapy alone, radiation therapy plus concomitant and adjuvant temozolomide (TMZ), or sequential radio-chemotherapy. Clinical outcome was evaluated by neurological examination and MRI 1 month after treatment and every 4 months thereafter. Tumor progression was defined according to the Response Assessment in Neuro-Oncology (RANO) working group. RESULTS: Among 402 patients referred to the authors' institution for AG, 142 were included in the present analysis. Eighty-eight (62%) were male and 54 (38%) were female, with a median age of 43 years (range 19-70 years). At admission, most patients had a Karnofsky Performance Scale score of 90-100 (84.5%) and were symptomatic (93.7%). Forty-eight (33.8%) patients had newly diagnosed anaplastic oligodendrogliomas (AOs), and 94 (66.2%) had anaplastic astrocytomas (AAs). Most of them had mutant IDH tumors (67.6%) and methylated O 6-methylguanine-DNA-methyltransferase (MGMT) promoter status (71.8%). GTR was performed in more than half of the patients (56.3%). RTV was detected in 83 (58.5%) patients. Following surgery, 72 (50.7%) patients received radiotherapy with concomitant and adjuvant TMZ, 48 (33.8%) received sequential radio-chemotherapy, and 22 (15.5%) received adjuvant chemotherapy alone. The median follow-up time was 40 months (range 16-146 months). The median PFS time and the 1-, 3-, and 5-year PFS rates were 35 months (95% CI 27-76) and 78.9% ± 3.4%, 49.7% ± 4.6%, and 42.7% ± 5.4%, respectively. The median OS time and the 1-, 3-, and 5-year OS rates were 91 months (95% CI 66-95) and 90.1% ± 2.5%, 70.9% ± 4.2%, and 61.8% ± 4.9%, respectively. Prognostic factors predicting survival other than molecular profile were the EOR and the RTV (p < 0.0001). Sequential radio-chemotherapy was the more effective treatment administered. CONCLUSIONS: In addition to IDH status, EOR and the RTV have proved to statistically impact survival. The pivotal role of adjuvant radiotherapy has been recorded in all AG patients, regardless of tumor features.
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INTRODUCTION: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed. METHODS: Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled; they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages. RESULTS: Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity. CONCLUSIONS: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.
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Cell-free circulating tumor DNA (ct-DNA) reflecting the whole tumor spatial and temporal heterogeneity currently represents the most promising candidate for liquid biopsy strategy in glioma. Unlike other solid tumors, it is now widely accepted that the best source of ct-DNA for glioma patients is the cerebrospinal fluid, since blood levels are usually low and detectable only in few cases. A cerebrospinal fluid ct-DNA liquid biopsy approach may virtually support all the stages of glioma management, from facilitating molecular diagnosis when surgery is not feasible, to monitoring tumor response, identifying early recurrence, tracking longitudinal genomic evolution, providing a new molecular characterization at recurrence and allowing patient selection for targeted therapies. This review traces the history of ct-DNA liquid biopsy in the field of diffuse malignant gliomas, describes its current status and analyzes what are the future perspectives and pitfalls of this potentially revolutionary molecular tool.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/líquido cefalorraquídeo , ADN Tumoral Circulante/líquido cefalorraquídeo , ADN de Neoplasias/metabolismo , Glioma/líquido cefalorraquídeo , Biopsia Líquida/métodos , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , ADN de Neoplasias/genética , Genes Relacionados con las Neoplasias/genética , Glioblastoma/líquido cefalorraquídeo , Glioblastoma/genética , Glioblastoma/patología , Glioma/genética , Glioma/patología , Humanos , Mutación , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Células Neoplásicas Circulantes/patologíaRESUMEN
Glioma is the most common primary brain cancer, and half of patients present a diagnosis of glioblastoma (GBM), its most aggressive and lethal form. Conventional therapies, including surgery, radiotherapy, and chemotherapy, have not resulted in major ameliorations in GBM survival outcome, which remains extremely poor. Recent immunotherapy improvements for other tumors, coupled with growing knowledge of the complex interactions between malignant glioma cells and the immune system, led to an exponential increase in glioma immunotherapy research. However, immunotherapeutic strategies in GBM have not yet reached their full potential, mainly due to the limited understanding of the strong immunosuppressive microenvironment (TME) characterizing this tumor. Glioma-associated macrophages and microglia (GAMs) are key drivers of the local immunosuppression promoting tumor progression and its resistance to immunomodulating therapeutic strategies. Together with other myeloid cells, such as dendritic cells and neutrophils, GAMs actively shape glioma TME, modulate anti-tumoral immune response and support angiogenesis, tumor cell invasion and proliferation. In this review, we discuss the role of myeloid cells in the complex TME of glioma and the available clinical data on therapeutic strategies focusing on approaches that affect myeloid cells activity in GBM.
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Neoplasias Encefálicas/inmunología , Glioma/inmunología , Macrófagos/inmunología , Microglía/inmunología , Células Supresoras de Origen Mieloide/fisiología , Animales , Terapia Biológica , Humanos , Terapia de Inmunosupresión , Microambiente TumoralRESUMEN
Glioblastoma is the most common and lethal malignant brain tumor in adults, with a very poor prognosis of less than two years despite surgical resection followed by radiotherapy and chemotherapy. To date, targeted agents and antiangiogenic therapy have failed to show survival benefits and novel treatment approaches are urgently needed. Immune checkpoint inhibitors have recently revolutionized the landscape of cancer immunotherapy achieving regulatory approvals for a number of other 'historically' resistant cancers. These exciting successes have generated great interest in investigating if these agents could be such effective also in brain tumors field. Moreover, the traditional dogma that considers the central nervous system (CNS) as an immune-privileged site lacking the potential for immunosurveillance has been challenged as it has become clear that the CNS is immunoactive. Critical barriers to an effective antitumor immunity in brain tumor patients are still represented by the peculiar CNS immunological milieu and the numerous systemic and local immunosuppressive forces exhibited by malignant gliomas to avoid immune recognition and cellular death. This review describes the current status of checkpoint modulation as treatment for malignant gliomas. We start illustrating the compelling molecular and immunological rationale, than we show striking preclinical evidence of activity and discuss available data from prospective clinical trials. Furthermore, we explore the role of predictive biomarkers of responsiveness to checkpoint blockade in the context of gliomas, along with the development of combinatorial and potentially synergistic approaches with other established anti-cancer treatments or complementary immunotherapeutic modalities.