Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM.

Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma.

Non-invasive evaluation of endothelial function, arterial mechanics and nitric oxide levels in children of hypertensive parents.

OBJECTIVE: To evaluate endothelial function, arterial mechanics and nitric oxide levels in apparently healthy children of hypertensive parents. DESIGN: Analytical observational study. SETTING: Tertiary Care hospital. MATERIAL: The group comprised 40 non-obese normotensives (11-18 years). Out of these, 20 were children of parents (one or both) with hypertension (systolic >140 mm Hg, diastolic > 90 mm Hg) while the rest were children of normotensive parents (controls). High resolution ultrasonography was performed to measure flow mediated and glyceryltrinitrate induced dilatation in the brachial artery and arterial mechanics in the common carotid artery. Fasting blood was assayed for nitric oxide by the Griess method. RESULTS: Flow mediated dilatation (FMD) was decreased in children of hypertensive parents as compared to controls (0.016 + 0.007 cm vs 0.075 vs 0.075 7plus; 0.130 cm, p < 0.05) the difference being statistically significant. But subsequently, the post glyceryl-trinitrate (GTN) dilation was comparable in both with no statistical significant difference being noted. Arterial mechanics (carotid intima-media thickness-C-IMT) were comparable in both the groups. Similarly nitric oxide levels estimated in platelet rich and platelet poor plasma were comparable in both the groups, with no statistical significance. CONCLUSIONS: Flow mediated vasodilatation (FMD) in the brachial artery was decreased in children of hypertensive parents as compared to controls. Subsequent post GTN vasodilatation was comparable in both the groups because, GTN acts directly on vascular muscle and not on endothelium. Similarly, arterial mechanics (C-IMT) and nitric oxide estimation in platelet rich and platelet poor plasma were comparable in both the groups. It is, therefore, concluded that children of hypertensive parents have evidence of endothelial dysfunction, as shown by the decrease in flow mediated dilatation, which could be an early marker for the development of coronary artery disease.