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.

Introduction

Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in patients (pts) with an inadequate response to UDCA or as monotherapy in pts unable to tolerate UDCA. RESPONSE was a Phase 3, randomised, placebo-controlled clinical trial of seladelpar in pts with inadequate response/intolerance to UDCA. Pts completing RESPONSE were eligible to roll over into ASSURE (NCT03301506), an ongoing, open-label, long-term, Phase 3 safety trial. Here, we describe data from month 18 (month 6 of ASSURE) in pts with or without prior use of fibrates or obeticholic acid (OCA) who rolled over from RESPONSE into ASSURE.

Aims & Methods

Pts received 10 mg seladelpar orally daily or placebo in RESPONSE; pts received open-label 10 mg seladelpar in ASSURE. Fibrates and OCA were prohibited during the study period and a 6-week washout was required prior to entry in RESPONSE. Data were described for pts in ASSURE with or without prior use of fibrates/OCA and based on whether they received seladelpar (continuous seladelpar pts) or placebo (crossover pts) in RESPONSE. Efficacy included the percentage of pts achieving a composite biochemical response (CBR; alkaline phosphatase [ALP] < 1.67 × upper limit of normal [ULN], ALP decrease ≥ 15%, and total bilirubin ≤ ULN). Safety assessments included adverse events (AEs) and laboratory parameters.

Results

Among pts who continued into ASSURE from RESPONSE (158), 16 continuous seladelpar and 11 crossover pts reported prior use of fibrates/OCA (total, n=27; 17%); 88 continuous seladelpar and 43 crossover pts reported no prior use of fibrates/OCA (total, n=131; 83%). At month 18, among continuous seladelpar pts, 9/15 (60%) pts with prior fibrate/OCA use achieved a CBR vs 54/87 (62%) pts without prior fibrate/OCA use. Among crossover pts, 7/11 (64%) pts with prior fibrate/OCA use vs 32/41 (78%) pts without prior fibrate/OCA use achieved a CBR at month 6 of ASSURE. From ASSURE initiation to month 6, incidence of AEs was similar across continuous seladelpar and crossover pts, regardless of prior OCA/fibrate use; no treatment-related serious AEs were reported.

Conclusion

In this interim analysis of continuous seladelpar and crossover pts from ASSURE, pts who reported prior use of fibrates/OCA achieved a similar sustained biochemical response with seladelpar compared with pts who reported no prior use. Seladelpar appeared safe and well tolerated in this subgroup.

Disclosure

AV reports receiving speaker fees from Intercept Pharmaceuticals and participation on an advisory board with Novartis. DP reports receiving consulting fees from Mediar Therapeutics. AEK reports receiving grants or contracts from Gilead Sciences, Inc., Intercept Pharmaceuticals and Roche; consulting fees from AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; Astellas; AstraZeneca; Attovia Therapeutics; Avior Bio; Bayer; Bristol Myers Squibb; Böhringer-Ingelheim; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Rectify Pharma; Roche; and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Advanz Pharma; AOP Orphan Pharmaceuticals; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Johnson & Johnson; Medscape; Merck Sharp & Dohme; Mirum Pharma; NewBridge Pharmaceuticals; Novartis; Roche; Vertex Pharmaceuticals; and Viofor; support for attending meetings and/or travel from Gilead Sciences, Inc.; participation on a data safety monitoring board with AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; AstraZeneca; Avior Bio; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Roche; and Takeda; and a leadership or fiduciary role in other board, society, committee, or advocacy groups (paid or unpaid) with PBC Foundation, Swiss Association for the Study of the Liver (SASL), Swiss Gastroenterology Society (SGG), Swiss Hepa, and Swiss Transplant Society (STS). VC reports receiving speaker fees from AbbVie; Advanz Pharma; Echosens; Gilead Sciences, Inc.; Ipsen; and Roche; and participation on an advisory board with Advanz Pharma; Gilead Sciences, Inc.; Ipsen; and Roche. EGD reports receiving consulting fees from Ipsen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen; support for attending meetings and/or travel from Advanz Pharma; and participation on a data safety monitoring board or advisory board for GSK. CH, XQ, SP, WTB, and TRW are employees of Gilead Sciences, Inc., and may own stock in Gilead Sciences, Inc. SCG reports receiving grants or contracts from AbbVie, Arbutus Biopharma, CymaBay Therapeutics, GSK, Ipsen, and Mirum Pharma; and participation on a data safety monitoring board or advisory board with CymaBay Therapeutics, GSK, and Ipsen.

Introduction

Immune checkpoint inhibitors (ICIs), a new class of immunotherapeutic agents, are the first-line treatment for many advanced epithelial cancers. Gastrointestinal irAEs, particularly diarrhea and colitis, affect approximately 40% of ICI-treated patients and often lead to therapy discontinuation.¹ High-dose corticosteroids represent the first-line treatment, but about one-third of patients show inadequate response and require second-line immunosuppressants such as Infliximab or Vedolizumab.² As the body of evidence about the role of gut microbiota in the pathogenesis of GI irAE grows, fecal microbiota transplantation (FMT) is emerging as a potential treatment for steroid- and biologic-refractory ICI-induced colitis.³ Although data are still preliminary, FMT represents a promising therapeutic strategy in this setting.

Aims & Methods

The aim of this study is to evaluate the safety and efficacy of FMT in patients referred to our Microbiome clinic for steroid- and biologic-refractory ICI-induced colitis. After clinical evaluation, patients were treated with FMT via colonoscopy from healthy donors. FMT was performed as already described, following international clinical guidelines.^4,5 Following the endoscopic procedure, patients were evaluated at 1, 4, 8, and 12 weeks. We collected data on: patient characteristics, cancer type, cancer treatment and its suspension, severity of diarrhea before FMT (graded via CTCAE)⁶, time in weeks from initiation of cancer therapy to onset of diarrhea, grade of diarrhea following treatment and resumption of ICI.

Results

Our cohort included 7 patients with steroid- and biologic-refractory ICI-induced colitis (grade 1: n=0 ; grade 2: n=1 ; grade 3: 5=x; grade 4: n=1). Four patients were affected by renal cell carcinoma, 2 by melanoma, 1 by pulmonary cancer. All patients were treated with PD-1/PDL-1 inhibitors or CTLA-4 ( Nivolumab: n= 3; Nivolumab and Ipilimumab: n=2; Durvalumab: n= 1; Pembrolizumab: n= 1) and 6 patients interrupted ICI due to gastrointestinal irAEs. All patients received single FMT from healthy donors via colonoscopy. Following FMT, diarrhea improved to grade ≤ 1 in 6 patients (85%) at week 1, 4, 8, and 12 after the procedure, suggesting a sustained effect of microbiome modulation in the medium term. One patient died during follow-up for reasons other than ICI-colitis.

Conclusion

Our preliminary findings suggest that FMT may be a promising therapeutic strategy for refractory ICI-colitis. Further, larger and randomized studies are warranted to confirm our data.

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. 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
3. 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
4. Cammarota G, Ianiro G, Kelly CR, et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019;68(12):2111-2121. doi:10.1136/gutjnl-2019-319548
5. Ianiro G, Rossi E, Thomas AM, et al. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat Commun. 2020;11(1):4333. doi:10.1038/s41467-020-18127-y
6. 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

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.

Introduction

Barrier healing (BH) has emerged as a novel treatment target in Inflammatory Bowel disease (IBD). Persistence of barrier impairment despite endoscopic and histological remission has been associated with worse long-term outcomes. However, accurate real-time assessment of intestinal barriers remains challenging in clinical practice. This study explores the role of advanced endoscopy (ultra-high magnification endocytoscopy [ECS] and confocal laser endomicroscopy [CLE]) for real-time, in vivo, structural and functional assessment of epithelial and vascular intestinal barrier. Further, we aim to investigate their correlation with automated barrier protein expression and clinical outcomes in IBD.

Aims & Methods

IBD patients undergoing endoscopic evaluation and healthy controls (HC) were recruited from two tertiary university centres.
The intestinal mucosa was assessed with ECS or CLE by novel scoring systems including epithelial and vascular features. BH was defined as ECS score ≤1 or CLE score ≤4, with preserved villi/crypt architecture, normal vessels, and, for CLE, absence of fluorescein leakage.
Biopsies were collected from both inflamed and non-inflamed areas. Epithelial (ZO-1, Claudin-2, E-cadherin) and vascular (PV-1 and CD-31) barrier markers were analysed through confocal microscopy, and their mean expression was automatically quantified using QuPath (v0.5.1). A biopsy-wise analysis assessed the correlation between endoscopic and histopathological evaluation. Moreover, occurrence of clinical outcomes at 6-month follow-up according to imaging-detected barrier impairment was evaluated.

Results

A total of 74 IBD patients (39 Crohn’s disease [CD], 35 Ulcerative colitis [UC]) and 9 HC) were considered. 46% (34/74) and 42% (30/74) IBD patients were in endoscopic and histological remission, respectively, while advanced imaging-defined BH was present in 24.3% (18/74) patients (Table 1). Barrier impairment was significantly associated with clinical outcomes at 6-month follow-up (p<0.01).
Mean expression of Claudin-2 was significantly higher in UC with ECS-based barrier impairment (85.5 vs 175.1, p 0.02), while PV1 expression was elevated in CD with CLE-based barrier dysfunction (362.1 vs 442.2, p 0.1). Significant correlations were found between ECS/CLE scores and epithelial and vascular barrier proteins.
In UC, Claudin-2 showed a moderate correlation with altered crypt architecture, goblet cell depletion and ECS total score (r 0.5), while PV-1 was moderately associated with altered vascular pattern and ECS total score (r -0.4).
In CD, Claudin-2 demonstrated a moderate correlation with crypt distortion, goblet cell depletion and total CLE scores (r 0.5), while PV-1 moderately correlated with fluorescein leakage, altered vessel architecture and total CLE score (r 0.4).

Conclusion

pCLE and ECS enable real-time intestinal barrier assessment in IBD, showing good correlation with epithelial and vascular barrier proteins and predicting clinical outcomes. This approach shows promise for targeting BH, guiding early and long-term disease management, and enabling flare-up prediction.