Boehringer Ingelheim (Switzerland)

Cigarette smoke contains over 5000 compounds, including polycyclic aromatic hydrocarbons, which induce cytochrome P450 (CYP) enzymes, particularly CYP1A1 and CYP1A2. Therefore, smoking significantly alters drug metabolism and can reduce therapeutic efficacy. To investigate tissue-specific CYP enzyme induction by cigarette smoke extract (CSE), a previously established hepatic in vitro smoke induction model was expanded to include human intestinal organoids and lung cell models. CYP1A1, CYP1A2, and CYP3A4 mRNA expression and CYP1A1 and CYP1A enzyme activity were quantified following CSE exposure. CYP1A1 mRNA expression and enzyme activity were robustly induced in all tissues and donors (up to 77-fold and 212-fold respectively). CYP1A2 mRNA and CYP1A enzyme activity were induced in liver and intestine (up to 13-fold) but were only weakly detectable in lung. CYP3A4 induction was exclusively observed in liver (up to 16-fold). Comparison of F2- and Emax-values of concentration-dependent induction across all models revealed that intestinal cells showed significantly lower values of CYP1A1 induction than liver cells. Other comparisons were non-significant. Inter-donor variability was visible across all cell models, CYP enzymes and tissue types (57-82% CV). This reflects physiological inter-individual variability, supporting the conclusion that these single-cell models capture donor-specific differences. Conclusively, it was shown that extrahepatic metabolism is altered by CSE and that considering tissue-specific CYP enzyme induction may be beneficial in clinical pharmacology to optimize drug efficacy and safety in smoking populations.

BackgroundKISIMATM platform-derived recombinant chimeric protein vaccines were shown to elicit both CD8 and CD4 T cell responses against model or tumor associated antigens, resulting in control of tumor growth in different preclinical models.1 Vesicular stomatitis virus (VSV)-GP is a chimeric variant of VSV modified to avoid neurotoxicity, which is exploited for cancer therapy thanks to its oncolytic activity and also as a potent vaccine vector for delivering of tumor associated antigen. Previously, we have shown that therapeutic heterologous prime-boost vaccination with KISIMA protein vaccine and a tumor-antigen armed VSV-GP (VSV-GP-TAg) oncolytic virus elicits a potent CD8 T cell response, enhances the infiltration and functionality of antigen-specific CD8 T cells, and inflames the tumor microenvironment in different mouse models, resulting in increased anti-tumoral efficacy.2 However, the efficacy of tumor-specific immune responses could be limited by intratumoral T cell exhaustion which can results in tumor escape and disease relapse. Immune check point inhibitors changed the landscape of cancer therapy, but their efficacy is often restricted to highly T cell infiltrated tumor, making them attractive for combination therapy with cancer vaccines.MethodsIn this study, we evaluate the combination of NKG2A blockade and KISIMA – VSV-GP-TAg heterologous prime-boost vaccination focusing on modulation of T cell phenotype and antitumoral efficacy in TC-1 tumor model, a lung epithelial cell line transfected with HPV16 E6/E7 and c-H ras oncogene.ResultsKISIMA – VSV-GP-TAg prime-boost vaccination strongly increased the expression of NKG2A on both circulating and tumor infiltrating antigen-specific CD8 T cells. Vaccination of TC-1 tumor-bearing mice in combination with NKG2A blocking antibody resulted in inhibition of tumor growth, induced complete tumor remission and prolonged survival. Mechanistically, NKG2A blockade did not enhance the infiltration nor the ability to secrete cytokine of antigen-specific CD8 T cells induced by heterologous prime-boost vaccination, but it significantly reduced exhaustion. Surprisingly, NKG2A blockade reduced the expansion and activation of circulating antigen-specific CD8 T cells elicited by KISIMA – VSV-GP-TAg vaccination. Consistently, combination treatment resulted in decreased number of long-lasting antigen-specific effector memory CD8 T cells in secondary lymphoid organs, while complete responders were only partially protected against homologous tumor rechallenge, highlighting a negative impact of NKG2A blockade on immune memory.ConclusionsTaken together, these data suggest a dual role of NKG2A blockade on cancer vaccine-induced T cells, increasing early antitumoral efficacy by reducing intratumoral T cell exhaustion but impairing the establishment of long-term immunity.ReferencesBelnoue E, Mayol JF, Carboni S, Di Berardino Besson W, Dupuychaffray E, Nelde A, Stevanovic S, Santiago-Raber ML, Walker PR, Derouazi M. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight. 2019 Apr 23;5(11):e127305. doi: 10.1172/jci.insight.127305. PMID: 31013258; PMCID: PMC6629093.Das K, Belnoue E, Rossi M, Hofer T, Danklmaier S, Nolden T, Schreiber LM, Angerer K, Kimpel J, Hoegler S, Spiesschaert B, Kenner L, von Laer D, Elbers K, Derouazi M, Wollmann G. A modular self-adjuvanting cancer vaccine combined with an oncolytic vaccine induces potent antitumor immunity. Nat Commun. 2021 Aug 31;12(1):5195. doi: 10.1038/s41467-021-25506-6. PMID: 34465781; PMCID: PMC8408233.Ethics ApprovalThis study has been approved by the Cantonal veterinary authority of Geneva, under the authorization number GE193.

The purpose of this study was to elucidate the absolute abundance of transporters, enzymes, receptors, and tight junction and marker proteins at human blood-arachnoid barrier (BAB) and compare with those of dogs and pigs. Protein expression levels in plasma membrane fractions of brain leptomeninges were determined by quantitative targeted absolute proteomics. To realistically compare the absolute abundance of target molecules at the BAB among humans, dogs, and pigs, the unit was converted from fmol/μg-protein to pmol/cm2 -leptomeninges. Of a total of 70 proteins, 52 were detected. OAT1, OAT3, GLUT1, 4F2hc, EAAT1, EAAT2, MCT8, SMVT, CTL2, GFAP, Claudin-5, Na+ /K+ -ATPase, COMT, GSTP1, and CES1 were abundantly expressed at the human BAB (>1pmol/cm2 ). The protein expression levels were within a 3-fold difference for 16 out of 33 proteins between humans and dogs and for 13 out of 28 proteins between humans and pigs. Both human-dog and human-pig differences in protein expression levels were within 3-fold for OAT1, OAT3, 4F2hc, xCT, OCT2, MDR1, BCRP, PEPT2, SYP, and MCT1. In contrast, OCT3, MCT4, and OATP1A2 were detected in humans but not in dogs or pigs. MRP3 was detected in dogs and pigs but not in humans. The absolute level of GLUT1 in humans was nearly the same as that in dogs but was 6.14-fold greater in pigs. No significant differences in the levels were observed between male and female dogs for nearly all molecules. These results should be helpful in understanding the physiological roles of BAB and cerebrospinal fluid pharmacokinetics in humans and their differences from dogs and pigs.

Health-related quality of life (HRQoL) in patients with moderate to severe chronic obstructive pulmonary disease (COPD) is often reduced by high symptom burden and frequent exacerbations. So far, data on therapeutic success in Swiss COPD patients receiving dual bronchodilation therapy as COPD maintenance treatment are limited. Data from a recently published, non-interventional study on clinical benefit after the start of combined tiotropium–olodaterol treatment were analyzed focusing on Swiss patients compared to the overall cohort including patients from various European countries. Demographic data on the changes in Clinical COPD Questionnaire (CCQ) for the assessment of HRQoL in correlation to symptoms and the number of exacerbations, as well as physician’s global assessment (PGE), were evaluated 6 weeks after treatment start. In Switzerland (n = 61), significantly more patients had comorbidities and exacerbations but showed less symptoms compared to the overall cohort (n = 4639). HRQoL improved in both cohorts, with a negative correlation to symptom burden and number of exacerbations in the overall cohort. PGE scores improved after 6 weeks with a better general condition at baseline in Swiss patients (PGE score 4/5: 68.9% [Swiss cohort] vs. 49.0% [overall cohort]. Despite significant differences regarding the presence of symptoms and exacerbations, therapeutic success was similar in both patient groups. Highly symptomatic patients benefited mostly from tiotropium–olodaterol treatment.

AimsTo evaluate the safety, pharmacokinetics and pharmacodynamics of BI 655064 in healthy Chinese and Japanese subjects after administration of single doses of 80‐240 mg and multiple dosing of 240 mg once weekly over 4 weeks.MethodsTwo phase 1, double‐blind, placebo‐controlled studies were conducted (single‐rising doses of BI 655064 in Chinese/Japanese male subjects [n = 12 per BI 655064 dose group] or repeated 240 mg BI 655064 in Chinese male subjects [n = 9]). Plasma samples were collected to investigate BI 655064 pharmacokinetics, pharmacodynamics (CD40 receptor occupancy [RO]) and immunogenicity, along with the safety and tolerability of BI 655064.ResultsBI 655064 showed good overall tolerability following single‐dose administration of 80‐240 mg and repeated administration of 240 mg BI 655064 over 4 weeks. More Chinese subjects reported adverse events compared with Japanese subjects following single‐dose administration (59.4% vs 3.1%). BI 655064 exhibited nonlinear, saturable kinetics, with higher doses resulting in slower apparent clearance (0.514‐0.713 mL min−1), and disproportionately higher total exposure (AUC0‐inf; 5610‐7780 μg·h mL−1) and maximum plasma concentration (15 700‐21 300 ng mL−1) with 240 mg BI 655064. Ninety percent inhibition of CD40 RO was achieved with doses ≥120 mg, and a direct relationship between BI 655064 plasma concentration and inhibition of CD40 RO was observed. Most subjects had a positive treatment‐emergent antidrug antibody response.ConclusionsBI 655064 pharmacokinetic and safety profiles in East Asian male subjects were consistent with those observed in a Western population. No adjustments in the BI 655064 dosing recommendations are warranted for future clinical trials.

Objective We examined the efficacy and safety of nintedanib in Japanese patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the global Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial. Methods Randomised patients received oral nintedanib 150 mg (N = 34) twice daily or placebo (N = 36) until the last patient reached 52 weeks of treatment (up to 100 weeks). Data were analysed using a subgroup analysis model with Japanese and non-Japanese patients as subgroup variables. Results In Japanese patients, the adjusted annual rate of forced vital capacity (FVC) decline over 52 weeks was –86.2 mL/year (nintedanib) and –90.9 mL/year (placebo); treatment difference, 4.67 mL/year (95% confidence interval, −103.28, 112.63). Treatment effect heterogeneity between Japanese and non-Japanese patients was not detected (treatment-by-visit-by-subgroup interaction; p = .49). FVC decline was smaller for nintedanib versus placebo through 100 weeks in Japanese patients. The most commonly reported adverse events with nintedanib were gastrointestinal and liver disorder events; most were mild-to-moderate in severity. Conclusion In both Japanese and non-Japanese patients with SSc-ILD, nintedanib slowed the progression of ILD, with no heterogeneity detected between the subgroups. The safety profile for nintedanib in Japanese patients was similar to that observed in patients with idiopathic pulmonary fibrosis (ClinicalTrials.gov: NCT02597933).

Background: In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks vs. placebo (primary endpoint).