Introduction

Celiac disease (CD) is an autoimmune disorder triggered by gluten ingestion in genetically predisposed individuals, leading to chronic intestinal inflammation. It affects about 1% of the global population and is often undiagnosed in childhood due to the absence of symptoms, with around 65% of cases in Italy going unnoticed. Early screening is a key tool for timely diagnosis and preventing long-term complications. In this perspective, the D1Ce Screen pilot study follows Italian Republic Law 130/2023, which mandates screening for pre-symptomatic CD and type 1 diabetes (T1D) in the general paediatric population through autoantibody measurements in capillary blood. Paediatric screening is a key tool for early detection and the prevention of long-term complications, associated with late or missed diagnosis. Individuals who tested positive for CD and T1D -specific autoantibodies will undergo further clinical evaluation at the regional specialized center to confirm the diagnosis

Aims & Methods

Primary objective of D1Ce Screen study is to assess, feasibility, acceptability and sustainability of a nationwide screening program, for the evaluation of undiagnosed CD cases and presymptomatic T1D. To assess operational aspects D1Ce Screen evaluates the involvement of primary care pediatricians (PCPs), blood sample collection accuracy and acceptability for families measuring anxiety, depression and quality of life through 3 validated questionnaires.
This is an observational multicenter study to screen 5,363 children in four Italian regions (Lombardy, Marche, Campania, Sardinia), distributed into three classes of age (2-2.9, 6-6.9, and 10-10.9 years), corresponding to peaks of seroconversion for these diseases. For eligibility, the inclusion criterion is age. T1D is the exclusion criterion. Voluntary PCPs were responsible for recruitment of participants, administration of informed consents and questionnaires, execution of blood drawing by finger prick, capillary blood collection and sample shipment. Specific T1D and CD autoantibodies are measured by ELISA in capillary samples. In addition, HLA DQ2 and DQ8 HLA typing is performed on dried blood spot (DBS).

Results

PCPs initially accepting to participate were 565, with 428 (75,7%) completing the study. Enrolled children were 5534, with 91,1% within the target age. The gender distribution was 49.4% females, 50.6% males. Samples suitable for analysis (adequacy for at least one assay) were 89% of the total collected. Most of DBS samples were suitable for HLA typing. The target of families undergoing questionnaire evaluation of 2% has been exceeded.

Conclusion

The D1Ce Screen pilot study provides evidence supporting the feasibility of a nationwide screening initiative. The active collaboration of PCPs, the high level of participation from families, and the efficient implementation of capillary blood sampling procedures were key contributors to its success. These findings confirm the potential for scalability of a paediatric screening program for T1D and CD within the framework of the Italian National Health Service. Early detection and timely initiation of a gluten-free diet in children diagnosed with CD are essential to preventing long-term complications and improving health outcomes.

References

Bosi E, Catassi C. Screening type 1 diabetes and celiac disease by law. Lancet Diabetes Endocrinol. 2024 Jan;12(1):12-14. doi: 10.1016/S2213-8587(23)00354-6

Introduction

TPM502 is a mixture of three distinct nanoparticles, each coupled with one celiac disease (CeD)-relevant gluten peptide, representing immunodominant and deamidated CD4⁺ T cell epitopes. TPM502 targets liver sinusoidal endothelial cells, which are unconventional antigen-presenting cells capable of inducing antigen-specific tolerance.

Aims & Methods

TCeD21 (NCT00565136) was a phase 2a double-blind, randomized, placebo-controlled study in HLA-DQ2.5-positive adults with confirmed CeD on a gluten-free diet. Patients achieving a predefined IL-2 response to a single dose (6 g) gluten challenge (GC1) were randomized into four cohorts to receive two intravenous infusions with escalating doses of TPM502 or placebo on day (D) 1 and D15. The GC was repeated 7 days after the second TPM502 dose (GC2). Peripheral blood mononuclear cells collected from each patient at predefined timepoints were analyzed by high-dimensional (30-color) flow cytometry, before and after HLA-DQ2.5-gliadin-specific tetramer (tet) enrichment, using surface staining for various phenotypic markers. The study aimed to characterize the phenotypes of gluten-specific T cells in CeD patients before and after TPM502 treatment to assess its immunomodulatory effects.

Results

Samples from 36 patients completing the study (12 placebo, 24 TPM502) were analyzed across five timepoints. In the placebo group, tet⁺ CD45RA^-CD62L^-CD4⁺ T (Ttet) cells increased after both GCs. By contrast, the TPM502 cohorts exhibited elevated Ttet cell numbers before GC2 (D22) but showed limited expansion afterward (D29), suggesting that TPM502 treatment may prevent further activation-induced expansion. Moreover, the frequency of activated Ttetcells—indicated by activation markers CD38, ICOS, and OX40—significantly decreased across all TPM502 dose levels after GC2 compared to the placebo group (fold change D22 vs D29, all p < 0.0001 by Kruskal-Wallis test). Notably, the diminished gluten response of Ttet cells post-treatment was accompanied by enhanced expression of co-inhibitory receptors TIGIT and PD-1 (D-21 vs D29, p < 0.0001), along with reduced CD127 expression (p < 0.01), indicative of decreased cell survival. These phenotypic changes, consistent with T cell exhaustion or anergy, persisted until study end and were visibly distinct from those in the placebo group, as illustrated by the heatmap of delta log-transformed flow cytometry data of Ttet cells across timepoints, clustered hierarchically. Gliadin-specific CD4⁺ regulatory T cells (CD25⁺CD127^- Ttet) and CD39⁺ Ttet cells increased post-treatment at the highest TPM502 dose, suggesting the induction of regulatory states in these T cells. Moreover, pre-enriched samples showed reduced activation of αEβ7⁺ γδ⁺ and CD8⁺ Tcells after GC2 at the highest TPM502 dose, suggesting potential bystander effects.

Conclusion

Data from the first longitudinal tetramer-based flow cytometry analysis in CeD patients provide evidence that TPM502 induces antigen-specific tolerance through T-cell immunomodulation. These results corroborate other pharmacodynamic outcomes generated in this study, including a significant and dose-dependent reduction in ex vivo IL-2 and IFN-γ secretion by gluten-specific T cells after treatment. In addition to a good safety and tolerability profile of TPM502, this nanoparticle-mediated induction of antigen-specific tolerance may provide a novel therapeutic avenue to treat celiac disease.

Introduction

Prospective evidence of the long-term efficacy of endoscopic submucosal dissection (ESD) for T1 colorectal cancer (CRC) is insufficient.

Aims & Methods

We aimed to evaluate long-term ESD outcomes for T1 CRC, focusing on the risk stratification criteria and necessity of additional surgery.
This large-scale, multicenter, prospective cohort study was conducted by Hiroshima GI Endoscopy Research Group. All consecutive patients who underwent colorectal ESD between January 2014 and December 2018 were included, and those with pathologically confirmed T1 CRC were analyzed. Patients were classified into low-risk and high-risk groups based on histopathological risk factors for lymph node metastasis in JSCCR guidelines. High-risk patients were categorized into those who underwent additional surgery (surgery group) and those who were followed up without surgery (follow-up group).

Results

Among 2357 patients who underwent ESD for 2478 early colorectal neoplasms, 431 were diagnosed with T1 CRC. Ten recurrences (2.6%) and five T1 CRC-associated deaths (1.3%) occurred in the high-risk group, with none in the low-risk group. Five-year cumulative overall and local recurrence rates were significantly higher in the follow-up versus surgery group (7.7% and 1.9%; P=0.019 versus 6.4% and 0%; P<0.001), with no local recurrence in the surgery group. Five-year overall survival was significantly worse in the follow-up group (79.5% and 95.2%; P<0.001), while no significant difference was found in 5-y disease-specific survival (98.5% and 98.5%; P=0.447).

Conclusion

No recurrence or mortality occurred in the low-risk group, suggesting that intensive surveillance may be unnecessary for these patients after curative ESD. Additional surgery could prevent local recurrence for high-risk T1 CRC, supporting a risk-based treatment approach.

Introduction

Immune checkpoint inhibitors (ICIs) have marked a breakthrough in the management of a wide range of cancer types, leading to increased overall survival. However, this treatment is frequently associated with the onset of various immune-related adverse events (irAEs), including ICI-related diarrhea and colitis.¹ Current recommendations for patients with diarrhea or colitis grade 2 or higher (graded via CTCAE)² include the discontinuation of ICI and administration of immune suppressants (e.g. steroids or biologics), which may lead to worse outcomes in these patients.³ Therefore, alternative therapeutic strategies to manage irAEs are needed. The gut microbiota plays a pivotal role in the onset of gastrointestinal irAEs, but the role of its therapeutic modulation on these disorders is mostly unknown. ^4,5

Aims & Methods

Our aim was to evaluate the efficacy and safety of therapeutic microbiome modulation for gastrointestinal irAEs in cancer patients. We enrolled cancer patients affected by ICI-related diarrhea/colitis referred to our Microbiome Clinic from January 2023 to March 2025. After clinical evaluation, patients were stratified according to severity of diarrhea (graded via CTCAE)² and then received a microbiome-modulating therapy. Patients were followed-up for at least 8 week after the initiation of therapy. We collected data about patient demographics (age and gender), patient’s overall health status as assessed by the the Charlson Comorbidity Index (CCI)⁶, type of cancer, oncological therapy and its suspension, time in weeks from initiation of cancer therapy to onset of diarrhea, severity of diarrhea (graded via CTCAE)², time in weeks until resolution of diarrhea and resumption of oncological therapy

Results

We enrolled 42 patients in the study period (8 males, 34 females, mean age 58,3 years-old, mean CCI-index 5.8). All patients were treated with ICI (Pembrolizumab: n=25 , Dostarlimab: n=4, Nivolumab: n=4; Atezolizumab: n=3; Novulumab and Ipilumab: n=2, Cemiplimab: n=2; Mogamulizumab: n=1; Pertuzumab: n=1). Ten patients experienced G1 diarrhea (23,8%), 16 (38,1) G2, 15 (35,7%) G3 and one G4 (2,4%). As indicated by current European Guidelines³, 30 patients (71,4%) had to interrupt ICI due to diarrhea. Multi-strain probiotics were administered to 27 (64.3% ) patients, rifaximin to 22 (52,4%). Overall, 21 patients (50%) needed therapy with systemic steroids. Seven patients who experienced ICI-related colitis refractory to steroids and biologics were successfully treated with FMT. Twenty-eight patients (66.7% ) had a resolution of the diarrhea (G0) and 11 patients (26.2%) had diarrhea G1 at a mean time of 8 weeks. Upon resolution of diarrhea, nine of the 30 patients who had interrupted ICI (30%) were able to resume the treatment. None of the patients experienced any adverse event related to gut microbiota modulation as defined by CTCAE².

Conclusion

Therapeutic modulation of gut microbiota appears to be a promising safe and effective approach for treating ICI-related diarrhea and colitis. However, these preliminary findings need confirmation through more consolidated and well-designed studies.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009
3. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
5. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.01235
6. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.