Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Rare Diseases/drug therapy , Follow-Up Studies , Humans , International Agencies , Neoplasms/classification , Neoplasms/pathology , Prognosis , Rare Diseases/classification , Rare Diseases/pathology , Survival RateABSTRACT
PURPOSE: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter. EXPERIMENTAL DESIGN: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed. RESULTS: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2-82.2] in the temozolomide arm and 69.6% (95% CI, 55.8-79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77-1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04-0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus. CONCLUSIONS: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797-806. ©2016 AACR.
Subject(s)
Brain Neoplasms/drug therapy , Chemoradiotherapy/methods , Glioblastoma/drug therapy , Sirolimus/analogs & derivatives , Adult , Aged , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , DNA Methylation , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Female , Glioblastoma/mortality , Glioblastoma/radiotherapy , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Promoter Regions, Genetic/genetics , Proportional Hazards Models , Sirolimus/administration & dosage , Temozolomide , Tumor Suppressor Proteins/genetics , Young AdultABSTRACT
Adjuvant formulations boost humoral responses by acting through several, yet incompletely elucidated pathways. In this study, we show that oligomycin or 5-aminoimidazole-4-carboxamide-1-ß-D-ribonucleoside (AICAR) enhances Ab production when coinjected with T cell-dependent Ags. Oligomycin and AICAR lead to intracellular ATP reduction, suggesting that metabolic stress could be sensed by immune cells and leads to increased humoral responses. AICAR promotes IL-4 and IL-21 by naive Th cells but does not affect dendritic cell activation/maturation in vitro or in vivo. Accordingly, the adjuvant effect of AICAR or oligomycin does not require MyD88 or caspase-1 expression in vivo. Because AICAR is well tolerated in humans, this compound could represent a novel and safe adjuvant promoting humoral responses in vivo with a minimal reactogenicity.
Subject(s)
Immunoglobulin G/biosynthesis , Inflammasomes/metabolism , Stress, Physiological/immunology , Adenosine Triphosphate/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Adjuvants, Immunologic/pharmacology , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Animals , Carrier Proteins/metabolism , Cells, Cultured , Inflammasomes/physiology , Inflammation/chemically induced , Inflammation/immunology , Inflammation/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Oligomycins/pharmacology , Ribonucleotides/pharmacology , Up-Regulation/immunologyABSTRACT
DiC14-amidine cationic liposomes were recently shown to promote Th1 responses when mixed with allergen. To further define the mode of action of diC14-amidine as potential vaccine adjuvant, we characterized its effects on mouse and human myeloid dendritic cells (DC). First, we observed that, as compared with two other cationic liposomes, only diC14-amidine liposomes induced the production of IL-12p40 and TNF-alpha by mouse bone marrow-derived DC. DiC14-amidine liposomes also activated human DC, as shown by synthesis of IL-12p40 and TNF-alpha, accumulation of IL-6, IFN-beta and CXCL10 mRNA, and up-regulation of membrane expression of CD80 and CD86. DC stimulation by diC14-amidine liposomes was associated with activation of NF-kappaB, ERK1/2, JNK and p38 MAP kinases. Finally, we demonstrated in mouse and human cells that diC14-amidine liposomes use Toll-like receptor 4 to elicit both MyD88-dependent and Toll/IL-1R-containing adaptor inducing interferon IFN-beta (TRIF)-dependent responses.
