Roche (Czechia)

The effects of gastrointestinal tract microbiota (GTM) on host physiology and health have been the subject of considerable interest in recent years. While a variety of captive bred species have been used in experiments, the extent to which GTM of captive and/or inbred individuals resembles natural composition and variation in wild populations is poorly understood. Using 454 pyrosequencing, we performed 16S rDNA GTM barcoding for 30 wild house mice (Mus musculus) and wild-derived inbred strain mice belonging to two subspecies (M. m. musculus and M. m. domesticus). Sequenced individuals were selected according to a 2 × 2 experimental design: wild (14) vs. inbred origin (16) and M. m. musculus (15) vs. M. m. domesticus (15). We compared alpha diversity (i.e. number of operational taxonomic units - OTUs), beta diversity (i.e. interindividual variability) and microbiota composition across the four groups. We found no difference between M. m. musculus and M. m. domesticus subspecies, suggesting low effect of genetic differentiation between these two subspecies on GTM structure. Both inbred and wild populations showed the same level of microbial alpha and beta diversity; however, we found strong differentiation in microbiota composition between wild and inbred populations. Relative abundance of ~ 16% of OTUs differed significantly between wild and inbred individuals. As laboratory mice represent the most abundant model for studying the effects of gut microbiota on host metabolism, immunity and neurology, we suggest that the distinctness of laboratory-kept mouse microbiota, which differs from wild mouse microbiota, needs to be considered in future biomedical research.

OBJECTIVE: To evaluate the clinical and economic impact of adopting noninvasive prenatal testing (NIPT) using circulating cell-free DNA as a first-line screening method for trisomy 21, 18, and 13 in the general pregnancy population. METHODS: A decision-analytical model was developed to assess the impact of adopting NIPT as a primary screening test compared to conventional screening methods. The model takes the Belgium perspective and includes only the direct medical cost of screening, diagnosis, and procedure-related complications. NIPT costs are EUR 260. Clinical outcomes and the cost per trisomy detected were assessed. Sensitivity analysis measured the impact of NIPT false-positive rate (FPR) on modelled results. RESULTS: The cost per trisomy detected was EUR 63,016 for conventional screening versus EUR 66,633 for NIPT, with a difference of EUR 3,617. NIPT reduced unnecessary invasive tests by 94.8%, decreased procedure-related miscarriages by 90.8%, and increased trisomies detected by 29.1%. Increasing the FPR of NIPT (from < 0.01 to 1.0%) increased the average number of invasive procedures required to diagnose a trisomy from 2.2 to 4.5, respectively. CONCLUSION: NIPT first-line screening at a reasonable cost is cost-effective and provides better clinical outcomes. However, modelled results are dependent on the adoption of an NIPT with a low FPR.

BACKGROUND AND AIMS: Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma. METHODS: A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up. RESULTS: The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)-positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels <1500, 1500-20,000, and >20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a <10% decline in HBsAg at Week 12 was associated with HBsAg clearance rates of 16% vs 4%. Hepatocellular carcinoma incidence was lower than REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) model predictions. CONCLUSIONS: Sustained off-treatment immune control is achieved with peginterferon alfa-2a in a real-world setting. HBsAg clearance 3 years after completion of peginterferon alfa-2a can be predicted on the basis of on-treatment HBsAg kinetics.

Abstract Understanding the adaptive immune system is integral to disease progression studies, development of diagnostic biomarkers, identification of therapeutic targets, and discerning varied treatment responses. Despite growing interest in profiling B and T cells in cancer research, the interaction between these cells and also the crucial roles of γδ T cells often go overlooked. In this research project, we explored the role of crucial yet frequently ignored γδ T cells in cancer research, using immune repertoire data from bladder cancer patients. We also studied the synergy between B and T cells in the immune repertoires of COVID-19 patients.Roche has developed immunoPETE (immune repertoire Primer Extension Target Enrichment), a DNA- based target enrichment assay to capture adaptive immune repertoire data*. immunoPETE efficiently identifies the heavy chains of B cells, alongside αβ and γδ T cells in one reaction, facilitating normalized clone counts across the adaptive immune system. To explore the significance of γδ T cells, we profiled the immune repertoires of 24 Non-Muscle Invasive Bladder Cancer patients treated with Bacillus Calmette-Guerin (BCG). Additionally, we evaluated the interplay between B and T cells in 117 peripheral blood immune repertoire from healthy and COVID-19 afflicted individuals, ranging from mild to severe cases.Immune repertoire data analysis indicates that underrepresentation of T cell receptor delta locus (TRD) is associated with higher risk of bladder cancer recurrence or progress. Urine pellet DNA was available for a subset of the patients in this study. Comparing immune repertoires from PBMC and urine revealed that urine repertoires represent the tumor repertoire more accurately than PBMC. Analysis of the immune repertoires from the COVID-19 patients linked disease severity with immune repertoire measures across all three cell types, highlighting the importance of multiple lymphocyte classes in disease progression. Using immunoPETE technology, which is capable of capturing the heavy chain of multiple immune cell types simultaneously in a single reaction, we have demonstrated that both B cell and T cell compartments provide distinct and valuable information in cancer and infectious diseases, each responding uniquely to the disease. Additionally, we emphasized the significance of γδ T cells in predicting cancer prognosis. Note: immunoPETE is for Research Use Only. Not for use in diagnostic procedures. Citation Format: Hossein Asgharian, Hamid Mirebrahim, Dilduz Telman, Hahn Zhao, Ulrich Schlecht, Sylvie McNamara, Rajiv Dua, Jan Berka, Patrick Bogard, Dinesh Kumar. Adaptive immune receptor repertoire characterization highlights the importance of interplay between B and T cells in disease progression [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A008.

Abstract Background Data regarding the experience and unmet needs of individuals enrolled to IBD clinical trials are limited, and challenges to participation are underexplored. To address this knowledge gap, a non-interventional study was conducted utilising qualitative interviews of individuals who participated or declined to participate in a phase 2/3 clinical trial of moderate-to-severe ulcerative colitis (UC) or Crohn’s disease (CD). Methods Semi-structured, 30- to 60- minute telephone interviews were conducted with individuals who were screened for or took part in a clinical trial up to two years prior. The primary objective was to capture the clinical trial experience of people living with IBD, identifying unmet needs and key challenges that impact trial participation. Topics covered motivations, expectations and experiences related to trial participation. Reasons for declining were discussed with those who did not participate in a clinical trial. Results From May to October 2023, 35 individuals were enrolled (n = 30 Poland; n = 4 Germany; n = 1 USA); 27 had completed a clinical trial, two had withdrawn and six declined to participate. Mean age was 37 years and 71% were female. The main concern prior to trial enrolment was potential side effects, as cited by 45% of trial participants and all those who declined to participate. Other concerns were potential lack of drug efficacy, time commitment, and the possibility of receiving placebo (Table). In total, 58% of trial participants identified restrictions around pregnancy as a potential barrier to participation; the most commonly perceived (≥15%) barriers to participation were side effects, travel considerations, frequency of assessments and study procedures. The most cited reasons for declining trial participation were side effects, opinions of family and/or friends, and time commitment (Table). Common suggestions (≥15%) from participants to improve trial experience included reducing study visit length, providing access to study results and permitting self-administration of medication at home. Further suggestions for improvement are described in the Table. Conclusion Our findings highlight the importance of early communication between clinicians, trial participants and their families regarding concerns such as potential side effects and restrictions around pregnancy. More convenient study visits and improving access to open-label extension programmes could make IBD trials more participant-inclusive, reduce trial burden and improve recruitment and retention. The results of this study have informed the trial design for four ongoing phase 3 clinical trials of afimkibart for people with UC (AMETRINE-1 [NCT06589986], AMETRINE-2 [NCT06588855]) and CD (SIBERITE-1 [NCT06819878] and SIBERITE-2 [NCT06819891]). Conflict of interest: Saldaña, Roberto: Logistic expenses coverage to attend scientific congresses from AbbVie. Atreya, Raja: Honoraria from AbbVie, Abivax, AlfaSigma, AstraZeneca, Boehringer, Bristol Myers Squibb, Celltrion Healthcare, Galapagos, InDex Pharmaceuticals, Johnson &amp; Johnson, Lilly, MSD, Pfizer and Takeda consulting or advisory role/board from AbbVie, Abivax, AstraZeneca, Boehringer, Bristol Myers Squibb, Celltrion Healthcare, Galapagos, Johnson &amp; Johnson, Lilly, MSD, Pfizer, F. Hoffmann-La Roche Ltd and Takeda speakers’ bureau from AbbVie, Abivax, AlfaSigma, AstraZeneca, Bristol Myers Squibb, Celltrion Healthcare, Galapagos, Johnson &amp; Johnson, Lilly, MSD, Pfizer and Takeda research funding from AbbVie, Takeda, InDex Pharmaceuticals. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI. Low, Jason: Employment at Genentech, Inc. stock or other ownership interests from F. Hoffmann-La Roche Ltd. Mr. Eisner, Tomáš: Employment and stocks from F. Hoffmann-La Roche Ltd. Meyer, Ina: Employment and stock or other ownership interests from F. Hoffmann-La Roche AG. Philpott, Stephanie: Employment from IQVIA and conducted work as an employee of IQVIA for a project funded by F. Hoffmann-La Roche Ltd. Kierkuś, Jarosław: Speakers’ Bureau from Nestle, Ferring and Danone. Grant from Nestle.