Brain Glucose Metabolism as a Readout of the Central Nervous System Impact of Cigarette Smoke Exposure and Withdrawal and the Effects of NFL-101, as an Immune-Based Drug Candidate for Smoking Cessation Therapy.

Neuroimaging biomarkers are needed to investigate the impact of smoking withdrawal on brain function. NFL-101 is a denicotinized aqueous extract of tobacco leaves currently investigated as an immune-based smoking cessation therapy in humans. However, the immune response to NFL-101 and its ability to induce significant changes in brain function remain to be demonstrated. Brain glucose metabolism was investigated using [18F]fluoro-deoxy-glucose ([18F]FDG) PET imaging in a mouse model of cigarette smoke exposure (CSE, 4-week whole-body inhalation, twice daily). Compared with control animals, the relative uptake of [18F]FDG in CSE mice was decreased in the thalamus and brain stem (p < 0.001, n = 14 per group) and increased in the hippocampus, cortex, cerebellum, and olfactory bulb (p < 0.001). NFL-101 induced a humoral immune response (specific IgGs) in mice and activated human natural-killer lymphocytes in vitro. In CSE mice, but not in control mice, single-dose NFL-101 significantly increased [18F]FDG uptake in the thalamus (p < 0.01), thus restoring normal brain glucose metabolism after 2-day withdrawal in this nicotinic receptor-rich region. In tobacco research, [18F]FDG PET imaging provides a quantitative method to evaluate changes in the brain function associated with the withdrawal phase. This method also showed the CNS effects of NFL-101, with translational perspectives for future clinical evaluation in smokers.

Use of BRASS in sedated critically-ill patients as a predictable mortality factor: BRASS-ICU.

Objectives: To demonstrate that a BRASS score≥ 3 at admission of intubated, ventilated and sedated patients is predictive of mortalityMethods: we have realized an Observational prospective multicenter study.All Major patients without neurological history, admitted to ICU for a non-neurological cause, sedated and admitted under mechanical ventilation were included.Results: One hundred and ten patients were included, the BRASS score as well as the FOUR and RASS scores were collected.At day 28, patients with a BRASS score ≥ 3 had an excess mortality (OR 3.29 - CI 95% [1.42-7.63], p = 0.005) as well as day 90 (OR 2.65 - CI 95% [1.19-5.88], p = 0.02), without impact on the delirium measured by CAM-ICU (OR 1.8 - CI 95% [0.68-4.77], p = 0.023). After adjustment with SAPS II, FOUR and RASS, difference in mortality was not any more different.It is also noted that patients with BRASS ≥ 3 are more sedated (RASS: -5 [-5 - -5] vs -4 [-5 - -3], p < 0.0001) and more comatose (FOUR: 2 [1-4] vs 6 [4-9], p < 0.0001), and have higher doses of midazolam (10 mg/h [5-15] vs 7.5 mg/h [5-10], p = 0.02) and sufentanil (20 µg/h [15-22.5] vs 10 [10-12.5], p = 0.01).Conclusions: The early alteration of brainstem reflexes measured by the BRASS score was not independently predictable in terms of mortality in the non-neurological ICU patients, admitted under sedation and mechanical ventilation.Trial registration: ClinicalTrials.gov Identifier: NCT03835091,Registered 8 February 2019 - prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03835091.

Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers.

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.