Introduction

There is an unmet need for adjunctive therapies for patients with celiac disease (CeD) who experience inadequate disease control while maintaining a gluten-free diet (GFD). The optimal trial design to assess CeD treatment efficacy is unclear and increased adherence to a GFD during trials may improve disease control. We assessed symptom severity changes during the screening and run-in periods (no treatment) of two phase 2b CeD trials, one using simulated inadvertent gluten exposure (SIGE) and one without.

Aims & Methods

In two concurrent ongoing phase 2 CeD trials (NCT05353985 and EudraCT2020-004612-97) daily gastrointestinal (GI) symptom severity was measured using the Celiac Disease Symptom Diary 2.1^© during the screening and run-in periods (4 weeks each in NCT05353985; 6 weeks and 5 weeks, respectively in EudraCT2020-004612-97) before any treatment administration. In both trials, eligible patients had biopsy-confirmed CeD and were experiencing CeD-related symptoms and enteropathy despite following a GFD. NCT05353985 included food bars containing ~500 mg gluten, consumed 3-times weekly after Week 2, for 2 weeks during the run-in period (post randomization). EudraCT2020-004612-97 did not include gluten exposure. Mean GI symptom severity scores were calculated each week during the screening and run-in periods.

Results

From the start of the screening period through to the end of the run-in period, mean GI symptom severity scores improved significantly in EudraCT2020-004612-97 (0.96 at Week 1 of screening, and 0.75 at Week 5 of run-in) whereas changes were non-significant in NCT05353985 (0.96 at Week 1 of screening and 0.92 at Week 4 of run-in).

Conclusion

Clinical trial participation may result in an improvement in CeD-related GI symptoms due to better GFD adherence. Administration of SIGE can minimize such trial effects and does not worsen symptoms in patients with CeD.

Disclosure

SB, NC, AH, DAL and QL are employees and shareholders of Takeda.
KH RM and RM are employees of Dr. Falk Pharma GmbH.
JM reports grants (to institution) from, National Institutes of Health, Immunogenix, Takeda Pharmaceutical, Allakos, ProventionBio, Oberkotter Foundation, and 9Meters, Inc.; contract (to institution) from Kanyos Bio (a wholly owned subsidiary of Anokion); and consultancy fees from Johnson and Johnson, Bristol Myers Squibb, Intrexon Corporation, Dren Bio, Neoleukin, Reistone pharma, GSK, Immunic Therapeutics, Brightseed Bio, Chugai Pharma, Alimentiv, Equillium, Ukko, Medibeacon, Israel Biotech Fund, Precigen, triangle insights group, Sanofi, Zag Bio, Loop bio and Orbimed; and has received royalties from Evelo. MS has no funding to disclose relating to this study and is the Principal Investigator in the EudraCT2020-004612-97 clinical trial.
MS has no funding to disclose relating to this study and is the Principal Investigator in the EudraCT2020-004612-97 clinical trial.
ML receives research funding from Takeda and Moderna, and has previously acted as a consultant for Anokion and Amgen.
JS reports grants (to institution) from Celiac Disease Foundation, National Institutes of Health, Takeda Pharmaceutical, Allan Foundation and consultancy fees from Alimentiv and Takeda Pharmaceuticals.
DS received study related management/advisory fees from Dr. Falk Pharma.

Introduction

Intestinal point-of-care ultrasound, as standardized by the International Bowel Ultrasound Group (IBUS), has emerged as a valuable tool for diagnosing, monitoring, and managing patients with Inflammatory Bowel Disease (IBD). While IBUS emphasizes a structured intestinal assessment, some European centers adopt a more comprehensive approach, combining intestinal ultrasound with a complete abdominal examination.
The Karolinska Centre for Digestive Health, a tertiary referral institution providing specialized care to approximately 4,500 patients with IBD, established a dedicated Gastrointestinal Ultrasound Unit in October 2023. This unit offers advanced diagnostic services to both hospitalized patients and those treated on an outpatient basis.

Aims & Methods

This retrospective study aimed to assess the prevalence of secondary extraintestinal findings in IBD patients undergoing comprehensive abdominal ultrasound between October 4, 2023, and March 4, 2025. All patients underwent ultrasound assessments that included both intestinal and abdominal imaging. Patients referred for indications unrelated to intestinal ultrasound (IUS), as well as those undergoing repeat examinations, were excluded from the analysis to ensure data consistency.
All examinations were performed by a single gastroenterologist with 25 years of ultrasound experience. In cases where secondary extraintestinal findings were identified, patients’ electronic medical records were reviewed to determine whether these findings represented new diagnoses or previously known conditions.

Results

The study included 348 patients with IBD, 201 (58%) females and 147 (42%) males, with a mean age of 42.4 years. Among these, 260 (75%) were referred internally by our IBD Outpatient Clinic, 47 (13%) by the Gastroenterology Ward, 33 (10%) by private outpatient clinics, and the remainder from other healthcare sites. IUS revealed evidence of intestinal inflammation in 144 patients (42%), while findings were normal in 204 patients (58%).
Furthermore, 150 patients presented with a total of 195 secondary extraintestinal findings, of which 113 (58%) represented newly identified pathologies. Among all secondary findings, the majority, 104 (53%), were related to the hepatobiliary system, including 33 newly diagnosed cases of hepatic steatosis and 17 new cases of cholecystolithiasis. One patient demonstrated ultrasound features suggestive of primary sclerosing cholangitis (PSC) and is currently undergoing further evaluation. Additional findings involved the reproductive system (29/15%), urinary system (15/7%), spleen (32/16%), and pancreas (5/2%). Various other intra-abdominal findings were also identified (37/18%). Notably, one patient presented with a suspicious mass in the right iliac fossa, and another demonstrated ultrasound findings suggestive of a prostatic tumor; both cases were referred for further oncologic evaluation. Additionally, three patients were newly diagnosed with intraductal papillary mucinous neoplasm (IPMN), which was subsequently confirmed via magnetic resonance imaging, and all were enrolled in the national IPMN surveillance protocol.

Conclusion

A considerable proportion of patients with IBD were found to have previously unknown extraintestinal abdominal pathologies, underscoring the essential role of comprehensive ultrasound examination that combines both intestinal and abdominal assessment. Fortunately, only a minority of these findings resulted in changes to patient management.

Disclosure

Francesca Bresso has acted as national and/or local principal investigator for clinical trials for Janssen, Ferring, and AbbVie. Charlotte Hedin served as a speaker and/or advisory board member for AstraZeneca, AbbVie, Dr. Falk Pharma and the Falk Foundation, Galapagos, Janssen, Pfizer, Ferring, Takeda, and Tillotts Pharma and received grant support from Tillotts Pharma and Takeda. Stephan L. Haas has served as a speaker for Takeda, Santax Medico, Tillotts Pharma, Johnson & Johnson, and Mediahuset. The rest of the authors have nothing to declare.

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a widespread chronic liver condition closely associated with obesity, insulin resistance, and dyslipidemia. Recent evidence points to gut microbiota dysbiosis as a key player in MASLD pathogenesis, affecting intestinal barrier function and systemic inflammation.

Aims & Methods

The aim was to investigate gut microbiota composition in patients with MASLD and assess its association with disease progression and gut barrier dysfunction. A total of 152 MASLD patients and 150 matched controls without liver pathology were examined. Diagnosis was confirmed by ultrasound and steatometry, alongside assessment of cardiometabolic risk factors. Gut microbiota composition was analyzed using real-time PCR, focusing on Bacteroidetes, Firmicutes, and Actinobacteria. Hydrogen breath testing was used to diagnose small intestinal bacterial overgrowth (SIBO), and the presence of Akkermansia muciniphila was evaluated as a marker of gut barrier integrity.

Results

MASLD patients demonstrated a significant increase in Firmicutes (50.3%) and Actinobacteria (15.3%) proportions compared to controls, with a higher Firmicutes/Bacteroidetes (F/B) ratio. SIBO was detected in 52% of MASLD patients versus 40.5% in controls (p<0.05). The presence of Akkermansia muciniphila was notably lower in MASLD patients (33%) compared to controls (63%), suggesting impaired gut barrier function. Strong positive correlations were observed between Actinobacteria abundance and the F/B index (r=0.75, p<0.05), while Akkermansia muciniphila presence negatively correlated with MASLD development (r=–0.69, p<0.05).

Conclusion

Gut microbiota dysbiosis, characterized by elevated Firmicutes and Actinobacteria and reduced Akkermansia muciniphila, is closely associated with MASLD pathogenesis. The findings highlight the potential of microbiota-targeted interventions for improving gut barrier function and modifying disease progression in MASLD patients.

Introduction

Chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in hematological malignancies, but remain largely ineffective in solid tumors such as pancreatic ductal adenocarcinoma (PDAC). Major barriers include CAR-T cell dysfunction, poor infiltration, and limited persistence within the immunosuppressive tumor microenvironment. STING (stimulator of interferon genes) activation can remodel this environment by inducing inflammation and reversing cancer immune privilege. However, the use of STING agonists in combination with CAR-T cells is hampered by T cell-intrinsic STING signaling, which induces T cell dysfunction and apoptosis.

Aims & Methods

To overcome these limitations, we investigated the therapeutic potential of combining STING agonists with CAR-T cells genetically ablated for STING for the treatment of PDAC. Using CRISPR-Cas9-edited CAR-T cells and the STING agonist diABZI, we assessed antitumor activity in vitro using a CAR-T cell exhaustion model and in vivo using both a cell line-derived xenograft and a syngeneic mouse model.

Results

The combination of STING^KO CAR-T cells and diABZI substantially enhanced CAR-T cell function. In vitro, we observed improved tumor cell killing, increased CAR-T cell proliferation, reduced expression of exhaustion markers, and expansion of an effector-memory phenotype. These effects required genetic deletion of STING in CAR-T cells and were dependent on cancer cell-intrinsic STING signaling. Mechanistically, we identified a synergistic feedback loop, in which CAR-T cell-derived IFN-γ and TNF-α enhanced STING signaling in cancer cells, further promoting beneficial CAR-T cell states. In vivo, this combination achieved superior tumor control in both xenograft and syngeneic mouse models.

Conclusion

Our findings demonstrate that STING^KO CAR-T cells can be effectively combined with STING agonists to enhance therapeutic efficacy in immune-cold tumors such as PDAC. This strategy represents a promising approach to overcoming current barriers in CAR-T cell therapy for solid tumors.

Disclosure

I.P. reports reimbursement of travel expenses from Roche and received third-party funding for scientific research from Novartis. A.G. received research support from Tabby Therapeutics and from Nanogami for work unrelated to the paper. M.S. has received research funding from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi Biotech, Molecular Partners, Novartis, Roche, Seagen and Takeda, honoraria from AbbVie, Amgen, AvenCell, BMS, CanCell Therapeutics, Gilead, Janssen, Miltenyi Biomedicine, Molecular Partners, Pfizer and Roche and was invited as speaker by AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche and Springer Healthcare. S. K. has received honoraria from Cymab, Plectonic, TCR2 Inc., Miltenyi, Galapagos, Novartis, BMS and GSK. S. K. is an inventor of several patents in the field of immuno-oncology. S. K. received license fees from TCR2 Inc and Carina Biotech. S.K. received research support from TCR2 Inc., Tabby Therapeutics, Catalym GmBH, Plectonic GmBH and Arcus Bioscience for work unrelated to the manuscript. The other authors have no competing interests to declare.