RESUMO
BACKGROUND: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. METHODS: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. FINDINGS: Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. CONCLUSIONS: Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions. FUNDING: BBVA Foundation; 202-2021 Division of Medical Oncology and Hematology Fellowship award; Princess Margaret Cancer Center.
Assuntos
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Fatores Imunológicos/metabolismo , Fatores Imunológicos/uso terapêutico , Oncologia , Microambiente Tumoral/genéticaRESUMO
The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m(2)) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting > or = 6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting.
Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Depsipeptídeos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células de Transição/patologia , Depsipeptídeos/efeitos adversos , Progressão da Doença , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Peptídeos Cíclicos , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologiaRESUMO
BACKGROUND AND PURPOSE: The aim was to demonstrate similar pain relief with two schedules of radiotherapy for painful bone metastases. MATERIALS AND METHODS: A total of 160 patients were assigned to receive a single 8-Gy fraction or 30 Gy in 10 fractions. Pain intensity was measured on an ordinal pain scale of 0-10. Partial response was defined as a pain reduction of two points or more and complete response as a pain score of zero at the treated area. Response follow-up was at 3, 12, 24 and 48 weeks. RESULTS: The overall response was 75% in the 8-Gy arm and 86% in the 30-Gy arm. Complete response and partial response rates were 15% and 60% in the 8-Gy arm, 13% and 73% in the 30-Gy arm. Acute toxicity was of 18% in the 30-Gy arm and of 12% in the 8-Gy arm. These differences were not statistically significant. The re-treatment rate was 28% vs 2% in the 8-Gy and 30-Gy arms, respectively, these were statistically significant. CONCLUSIONS: A single-fraction regimen of 8 Gy was as safe and effective as a multifraction regimen of 30 Gy for painful bone metastases in terms of pain relief.