Introduction

There is an unmet need for new therapies to promote mucosal healing and restoration of epithelial barrier function in the inflammatory bowel diseases (IBD). The development of novel approaches to specifically deliver a therapy to the gut has the theoretical advantage of optimizing benefit while limiting side effects. Adenoviral (Ad) gene therapy has been successful in treating cancer and has recently been used in clinical trials as a vaccine for SARS-Cov2. Ad vectors can be modified to target specific tissues and therefore may be more effective vehicles for gene therapy for diseases like IBD than other systemic therapeutics. We propose that gene therapy using adenovirus has promise to achieve these goals in IBD. As a proof of concept, we developed an approach to deliver IL-22 via Ad gene therapy. IL-22 plays an important role in maintaining the epithelial barrier at mucosal sites like the skin, airway, and intestine. Epithelial cells are the primary target of IL-22 signaling, where it activates transcription of genes involved in cell proliferation and promotes antimicrobial functions.

Aims & Methods

We hypothesize that gene therapy with Ad vectors to deliver IL22 directly to the intestine could be an effective therapeutic for IBD by promoting intestinal wound healing and microbial homeostasis. To test this hypothesis, we injected human adenovirus serotype 5 (huAd5) expressing Il22 (Ad-CMV-Il22) intravenously into 6-week-old C57BL/6 mice.

Results

IL-22 protein levels in the serum, liver, ileum, and colon were increased with Ad-CMV-Il22 compared to the empty vector control (Ad-CMV-GFP). We analyzed transcription of genes downstream of IL-22 signaling and found Ad-CMV-Il22 increased relative expression of Lcn2 in the liver, ileum, and colon, as well as increased expression of Mt1 and Mt2 in the liver and colon. Ad-CMV-Il22 induced increased crypt depth and goblet cell count in the ileum and colon, and increased villus length in the ileum compared to Ad-CMV-GFP. Changes to the stool microbiome included increased abundance of the pro-tolerogenic family Lachnospiraceae-Ruminococcaceae with Ad-CMV-Il22 in both colon and ileum. It is known that huAd5 has liver tropism and gene therapy with hAdv5 has been associated with liver toxicity. We also observed higher levels of IL-22 in the liver than in the serum, ileum, or colon after Ad-CMV-Il22 treatment. To reduce liver tropism, we modified the vector to incorporate myeloid-binding peptide (MBP) on the virus fiber, which re-targets the virus to the intestine and vascular endothelium. Incorporation of MBP significantly reduced IL-22 protein levels in the liver by nearly 10-fold. The ratio of IL-22 protein levels in the ileum and colon was 1.35 and 1.81 times higher with the targeted vector compared to untargeted virus. Increased colon and ileal crypt depth (45%) as well as villus length (9%) were seen with Ad-CMV-MBP-Il22 as compared to the untargeted virus.

Conclusion

Together, these data suggest that IL-22 gene therapy in the intestine can promote cell proliferation and microbial homeostasis. In the future, this adenoviral gene therapy could be modified further to increase Il22 gene delivery specifically to intestinal tissues.

Disclosure

D.T.C. is a consultant for Ocugen, Circero, Asgard, Accession and Tome Biosciences.

Introduction

The advent of biologics and small molecule inhibitors targeting immunologic mechanisms has revolutionized the landscape of inflammatory bowel diseases (IBD) treatment. However, a significant proportion of patients remain primary non-responders and initial responders can relapse over time. Combining treatments with different mechanisms of action holds potential to increase the clinical response rates in IBD patients. The aim of this study was to examine the potential utility of combining distinct anti-inflammatory mechanism(s) with α4β7 integrin inhibition in IBD. We utilized the clinically relevant CD4⁺CD45RB^hi T cell transfer (TCT) colitis mouse model, which has been used to validate the preclinical monotherapy efficacy of these agents for IBD.

Aims & Methods

At initiation of TCT colitis, Rag2^-/- mice received anti-α4β7 monoclonal antibody (mAb) alone, or in combination with subtherapeutic doses of an anti-IL12p40 mAb, an anti-IL23p19 mAb, or a small molecule inhibitor (SMi) of TYK2 (deucravacitinib, BMS-986165) for 7 weeks. Colitis development was evaluated via readouts including body weights, gross colon weight by length ratios, transcriptomic analysis of the colonic tissue, and histopathological scores.

Results

In monotherapy settings, treatment with anti-α4β7 significantly inhibited the development of moderate to severe colitis in mice. This was reflected by improved body weights, gross colon weight/length ratios, and histopathology scores (sum of inflammation, erosion, hyperplasia, and gland loss scores) compared to vehicle controls. The combination treatment of anti-α4β7/IL12p40 was the most robust, indicated in part by a highly consistent therapeutic response across study animals, surpassing the therapeutic efficacy of both anti-α4β7 monotherapy and other combination treatments with anti-IL23p19 or TYK2 SMi. On the other hand, anti-α4β7/IL23p19 and anti-α4β7/Tyk2 SMi showed only moderately improved efficacy, compared to anti-α4β7 monotherapy. Finally, tissue transcriptomic analysis revealed involvement of mechanistic pathways related to efficacy, including T cell activation/differentiation for all groups with inhibitors but to different degrees. Additionally, combination treatments showed differences focused within cytokine signaling, innate immune receptor signaling, and antigen presentation pathways.

Conclusion

Inhibition of cytokines IL12/IL23, which drive effector Th1 and Th17 responses, and regulate innate and Jak-STAT signaling, in combination with blockade of the cell trafficking integrin α4β7, resulted in significantly increased protection from colitis compared to monotherapy groups. Combining these agents with different mechanisms of action offers a rational approach to test these combinations for potential increased therapeutic activity in patients with IBD.

Disclosure

All authors are employees and shareholders of Morphic Therapeutic, Waltham, MA, USA.

Introduction

Chronic inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are associated with an increased risk of various cancers, particularly colorectal cancer, but also other types, such as small intestine, biliary tract, or liver cancers. Additionally, certain extra-digestive cancers may also occur in patients with these conditions. These risks vary depending on the duration and severity of inflammation, as well as other factors such as family history or exposure to certain treatments. This work explores the diversity of cancers associated with IBD, their prevalence, and their clinical characteristics, highlighting the importance of considering these risks in the medical management of patients.

Aims & Methods

This is a retrospective and descriptive single-center study conducted within a hepatogastroenterology department, focusing on patients followed for inflammatory bowel diseases (IBD) who developed cancer. The study covers the period from 1990 to 2025.

Results

Out of a total of 1,795 patients followed for IBD (1,200 for Crohn's disease and 595 for ulcerative colitis), 2% (36 patients) developed cancer. The male-to-female sex ratio was 0.38, with a clear female predominance. Among the patients, 69.4% (25) had Crohn's disease, and 30.55% (11) had ulcerative colitis.
The most common location of Crohn's disease was colonic involvement (44%, 11 cases),the predominant phenotype was inflammatory (52%, 13 cases) ,for ulcerative colitis the most frequent location was left-sided colitis (54%, 6 cases) ,the median disease duration before the onset of cancer was 60 months.
Digestive cancers were the most commonly associated with IBD (38.8%, 14 cases), followed by breast cancer in women (30.5%, 11 cases), gynecological cancers (11.1%, 4 cases), prostate adenocarcinoma (5%, 2 cases), skin cancers (5%, 2 cases), and other cancers (5%, 2 cases).
Only 30.5% (11 patients) had risk factors (chronic smoking, family history of cancer, etc.).
Regarding treatment, 33% (12 patients) were on biologic therapy , 30.5% (11) were on azathioprin , 16.6% (6) were on therapeutic abstention , 8.3% (3) were on aminosalicylates, and 5.5% (2) were on corticosteroids.
Treatment was discontinued in 63.8% (23) of patients after the discovery of cancer, and 22% (8) experienced a flare-up which was successfully managed with corticosteroid therapy.
Eighty-three point three percent (83.3%, 30 patients) underwent surgical treatment alone or in combination with radiochemotherapy. Sixteen point six percent (16.6%, 6 patients) were at an advanced stage and had metastases, so they received palliative treatment.
Thirty-six percent (36%, 13 patients) had a good outcome, 30.5% (11) were lost to follow-up, and 2.7% (1) died.

Conclusion

The study shows a 2% cancer incidence in IBD patients, slightly higher than the general population's risk (0.3–0.5% annually), likely due to prolonged inflammation and disease duration. These findings highlight the need for enhanced cancer surveillance and preventive strategies, especially for patients with colonic involvement.

Introduction

Inflammatory bowel disease (IBD) is a chronic multi-factorial disease characterized by inflammation of the gastrointestinal tract. Currently, the mechanisms underlying the disease are far from being elucidated. Thus, the study of proteins involved in its pathogenesis would allow further insights into the molecular mechanisms underlying IBD.

Aims & Methods

The serum and intestinal mucosa (ileum and left colon) proteomic profiles of patients with Crohn´s disease (CD) and ulcerative colitis (UC) and healthy controls (HC) were analyzed through label-free relative quantitative proteomic profiling using nLC MS/MS. Data mining and pattern recognition techniques were performed to identify hidden relationships that are not detectable using classical linear classifiers, and thus identify potential markers able to discriminate between the different study groups. Six candidate biomarkers were selected for further validation using enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in serum and intestinal tissue samples, respectively.

Results

Comparison of serum proteins between UC patients and HC revealed statistically lower levels of protein 1 and 2 and higher levels of protein 3. The comparison of potential biomarkers between CD and HC group showed lower levels of protein 1 and higher levels of protein 3. In addition, protein 4 was differentially upregulated in CD patients compared to UC. Regarding the intestinal biopsies, protein 5 showed higher intensity in the IHC staining of ileum from CD patients compared to HC, whereas protein 6 was significantly decreased in left colon and ileum from CD and UC patients compared to HC. These proteins are involved in thyroxine transport, regulation of chemotactic chemokine activity, inflammatory processes, triglyceride homeostasis, oxidative stress and regulation of NF-kappa-B activation in the cytosol.

Conclusion

In this study, we have identified a panel of six potential biomarkers that could help to elucidate mechanisms involved in IBD pathogenesis. Their roles in the pathophysiology need to be clarified in further experiments.