Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies.

BACKGROUND: We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138). PATIENTS AND METHODS: Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs. RESULTS: Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines. CONCLUSIONS: Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065023 and NCT03739138.

Incidence and survival of pediatric soft tissue sarcomas in moscow region, Russian Federation, 2000-2009.

The aim of the study was to assess the incidence and survival rates of soft tissue sarcomas (STSs) in children 0-14 years of age in Moscow Region, Russian Federation. The database of childhood population-based cancer registry of Moscow Region was used as a data source. Tumors were stratified according to International Classification of Childhood Cancer, 3d ed. Sixty-eight cases of STS were registered from 2000 to 2009. Crude incidence rate was 0,78, and age-standardized incidence rate using World Standard Population was 0,81 per 100.000 children/year. The highest age-specific incidence was observed in infants: 1,76 per 100.000 children/year. Rhabdomyosarcoma (RMS) was the most common histological type comprising 54,4% of all STS. 5-year observed survival (OS) of all patients with STS was 64,1 (95% CI 55,0-73,2). There was no statistically significant difference in OS between RMS-59,2 (95% CI 47,0-71,4) and nonrhabdomyosarcoma STS-69,3 (95% CI 55,8-82,8) (P = 0.63). Incidence and survival rates of STS observed in the study were comparable to the other Eastern European countries.

Serial monitoring of human systemic and xenograft models of leukemia using a novel vascular disrupting agent.

Advances in the treatment of acute leukemia have resulted in significantly improved remission rates, although disease relapse poses a significant risk. By utilizing sensitive, non-invasive imaging guidance, detection of early leukemic infiltration and the extent of residual tumor burden after targeted therapy can be expedited, leading to more efficient treatment planning. We demonstrated marked survival benefit and therapeutic efficacy of a new-generation vascular disrupting agent, combretastatin-A1-diphosphate (OXi4503), using reporter gene-imaging technologies and mice systemically administered luc+ and GFP+ human leukemic cells (LCs). Before treatment, homing of double-transduced cells was serially monitored and whole-body cellular distributions were mapped using bioluminescence imaging (BLI). Imaging findings strongly correlated with quantitative GFP expression levels in solid organs/tissues, suggesting that the measured BLI signal provides a highly sensitive and reliable biomarker of tumor tissue burden in systemic leukemic models. Such optical technologies can thereby serve as robust non-invasive imaging tools for preclinical drug discovery and for rapidly screening promising therapeutic agents to establish potency, treatment efficacy and survival advantage. We further show that GFP+ HL-60 cells reside in close proximity to VE-cadherin- and CD31-expressing endothelial cells, suggesting that the perivascular niche may have a critical role in the maintenance and survival of LCs.