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Atezolizumab; Isatuximab; Solid tumors Atezolizumab; Isatuximab; Tumores sólidos Atezolizumab; Isatuximab; Tumors sòlids Background The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients. This work was sponsored by Sanofi (no grant number).

Background: Cerebrovascular disease is one of the leading causes of death worldwide. Hepatitis C virus (HCV) infection, a well-accepted causal agent for liver-related diseases, has been reported to increase the risk for atherothrombosis. However, the association between HCV infection and cerebrovascular diseases remains inconclusive and the dose-response relationship between serum HCVRNA levels and cerebrovascular death has never been elucidated. Methods: This study enrolled 23,665 residents aged between 30–65 years in community during 1991–1992. They were personally interviewed using structured questionnaires and provided blood samples for various serological and biochemical testing at study entry. Those who were seropositive for antibodies against HCV (anti-HCV) were examined for serum HCVRNA levels. HCV genotypes were determined in participants who had detectable serum HCVRNA. Cerebrovascular deaths of participants during follow-up were ascertained by computerized linkage with National Death Certification profiles from 1991 to 2007 (ICD-9: 430–438). Person-years at risk were calculated for each person as time from enrollment date to either the date of death, or to the end of 2007, whichever came first. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for magnitude of HCV after adjustment of other risk factors. Results: There were 240 cerebrovascular deaths with 361,171 person-years of follow-up, giving a mortality of 66.5 per 100,000 person-years in this population. The cumulative risks for cerebrovascular death were 1.0% and 2.7% for anti-HCV seronegatives and anti-HCV seropositives (p < 0.001). Participants seropositive for anti-HCV had increased risk of cerebrovascular death, with a multivariate-adjusted relative risk (95% confidence interval) of 2.27 (1.56–3.30). Elevated serum HCVRNA levels increased the risk for cerebrovascular death with dose-response trend (p < 0.001). The adjusted relative risks were 1.52 (0.67– 3.44), 1.73 (0.43–6.98), 2.31 (1.25–4.25), and 3.45 (1.76– 6.75) in corresponding to participants with serum HCVRNA level

The transport of ATP out of mitochondria and uptake of ADP and Pi into the matrix are coupled to the uptake of one proton (Klingenberg, M., and Rottenberg, H. (1977) Eur. J. Biochem. 73, 125--130). According to the chemiosmotic hypothesis of oxidative phosphorylation this coupling of nucleotide and Pi transport to proton transport implies that the P/O ratio for the synthesis and transport of ATP to the external medium is less than the P/O ratio for the synthesis of ATP inside mitochondria. A survey of previous determinations of the P/O ratio of intact mitochondria showed little convincing evidence in support of the currently accepted values of 3 with NADH-linked substrates and 2 with succinate. We have measured P/O ratios in rat liver mitochondria by the ADP pulse method and by 32 Pi esterification, measuring oxygen uptake with an oxygen electrode, and find values close to 2 with beta-hydroxybutyrate as substrate and 1.3 with succinate as substrate in the presence of rotenone to inhibit NADH oxidation. These values were largely independent of pH, temperature, Mg2+ ion concentration, Pi concentration, ADP pulse size, or amount of mitochondria used. We suggest that these are the true values of the P/O ratio for ATP synthesis and transport by mitochondria, and that previously reported higher values resulted from errors in the determination of oxygen uptake and the use of substrates which lead to ATP synthesis by succinate thiokinase.