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.

Introduction

Ulcerative colitis (UC) has increasingly been recognized as a progressive disease. However, the benefit of starting early biologic therapy (BT) has not been established, contrary to Crohn´s disease. We aimed to assess if early intervention improves UC outcomes, particularly in preventing disease progression.

Aims & Methods

We conducted a retrospective multicenter study (11 centers) including adult UC patients who initiated BT until 2019 (minimum follow-up [FU]: 5 years). Early intervention was defined as BT initiation within ≤12 months of diagnosis. The primary outcome was UC progression at 5 and 10 years, defined as a composite of proximal extension, colonic structural changes (stenosis/ tubularization) and dysplasia/cancer. Secondary outcomes included clinical endpoints: hospitalizations, colectomy and corticosteroid use. Multivariate analysis was performed, adjusted for disease severity, extent, and prior activity.

Results

A total of 236 patients were included, with 28.8% (n=68) initiating BT within ≤12 months (mean FU after BT initiation: 8.06 ± 4.12 years).
Early intervention was associated with a reduced risk of proximal extension after BT initiation (p=0.012). In multivariable Cox regression, later BT initiation was an independent predictor of colonic structural changes at 10 years (HR 8.54; 95% CI 1.15-62.63; p=0.036). Later BT initiation independently predicted the composite outcome of progression (23.2% vs 5.9%) at 5 years (HR 5.97; 95% CI 1.42-25.13; p=0.015) and 10 years (HR 4.58; 95% CI 1.41-14.88; p=0.011). No differences in clinical outcomes were observed.
Longer disease activity before BT was also a predictor of the primary outcome at 5 years (HR 4.20; 95% CI 1.27–13.82; p=0.018) and 10 years (HR 3.60; 95% CI 1.28–10.12; p=0.015).

Conclusion

Starting BT early in the disease course may reduce the long-term risk of disease progression, reshaping the window of opportunity in UC.

References

Lujan, Rona, et al. "Early initiation of biologics and disease outcomes in adults and children with inflammatory bowel diseases: results from the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort." Gastroenterology 166.5 (2024): 815-825.

Introduction

Endoscopic submucosal dissection (ESD) is a valuable technique for the en-bloc resection of superficial neoplasms in the anal canal. However, its safety and efficacy in patients who have previously undergone transanal endoscopic surgery (TES) —such as transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery (TEM)—remain unclear.

Aims & Methods

To assess the safety and outcomes of ESD in the anal canal for patients with a history of TES compared to naïve patients.
A retrospective analysis was conducted at our tertiary center on 51 patients who underwent ESD in the anal canal between March 2010 and November 2024. Patients with a history of transanal endoscopic surgery were compared to those undergoing ESD as their primary treatment. Key parameters, including resection speed, perforation rates, coagrasper usage, inpatient status, late hemorrhage, and recurrence, were evaluated. Statistical analysis was performed to determine significant differences between groups.

Results

Histological examination confirmed the following cases: 3 adenocarcinomas (including 1 non-curative ESD), 15 adenomas with high-grade dysplasia, 11 adenomas with low-grade dysplasia, 2 sessile serrated lesions, 15 sessile serrated lesions with dysplasia, 2 high-grade intraepithelial lesions, 2 low-grade intraepithelial lesions.
The median resection velocity was slightly lower in patients with recurrence (16.01 mm²/min) compared to those without recurrence (25.56 mm²/min), though this difference did not reach statistical significance (p = 0.062). Perforation occurred in 9.62% of cases, with similar rates between groups (p = 0.58), suggesting that prior TEM does not significantly increase the risk of this complication. Late hemorrhage was observed in 7.84% of patients, again without a significant difference between groups (p = 0.29).
The only statistically significant finding was the smaller lesion size in patients with recurrence (1,162 mm² vs. 2,250 mm², p = 0.045). This is likely due to intensive post-TEM surveillance, which allowed for early detection of recurrence before lesions could grow larger. Other factors, including sex, age, use of coagrasper during the procedure, en-bloc resection, R0 status, and inpatient admission rates, showed no significant differences between groups.

Conclusion

ESD in the anal canal after prior TES appears to be a safe and feasible procedure, with outcomes statistically comparable to those in naïve patients. Although absolute numbers suggest differences, particularly in lesion size, these findings may be influenced by the small sample size. Larger studies are needed to confirm these results and further evaluate long-term efficacy.

Introduction

Endoscopic submucosal dissection (ESD) is the technique of choice for treating early gastric cancer deemed to have very low risk of lymph node metastasis based on endoscopic evaluation. However, currently, up to 20% of ressected lesions do not meet curative criteria, underlining the importance of patient selection.

Aims & Methods

We aimed to evaluate predictive factors for non curative ressection. We conducted a retrospective cohort study including consecutive gastric epithelial lesions removed by ESD between January of 2005 and June of 2024. Incomplete ESD were excluded. Non curative resection was defined using the high-risk resection criteria from the European Society of Gastrointestinal Endoscopy guidelines. Univariate and multivariate analysis were used to identify predictive factors.

Results

From 990 ESD, 974 were included in the final analysis: median size of lesion 19mm (P25-P75: 15-25), presence of ulceration in 25 (2.8%), deep submucosal invasion in 74 (7.6%), en bloc resection in 944 (96.9%), R0 resection in 901 (92.5%) and non curative resection in 116 (11.9%). In this sample, the following independent predictive factors for non curative resection were identified: location on the superior third of the stomach [adjusted Odds Ratio (aOR) 2.275; IC95% 1.248-4.148], lesion size > 20mm (aOR 4.212; IC95% 2.618-6.775), depressed/ulcerated lesion (aOR 2.394; IC95% 1.328-4.315) or sessile/pedunculated lesion (aOR 4.186; IC95% 2.083-8.411), presence of high-grade dysplasia (aOR 4.372; IC95% 2.139-8.939) or carcinoma (aOR 12.484; IC95% 5.995-25.998) in previous biopsies.

Conclusion

Location, size and morphology of lesion, as well as previous biopsy results are predictive factors for non curative resection, and may assist in decision-making regarding treatment alocation of gastric superficial lesions.

References

Dinis-Ribeiro M, et al. Management of epithelial precancerous conditions and early neoplasia of the stomach (MAPS III): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG) and European Society of Pathology (ESP) Guideline update 2025. Endoscopy, 2025 May;57(5):504-554. doi: 10.1055/a-2529-5025.
Vasconcelos AC, et al. Endoscopic Resection of Early Gastric Cancer and Pre-malignant Gastric Lesions. Cancers, 2023 Jun 7;15(12):3084. doi: 10.3390/cancers15123084.

Introduction

Haematochezia is a common adverse event after endoscopic submucosal dissection (ESD) of colorectal tumours, but the need for endoscopic intervention remain unclear.

Aims & Methods

This study aimed to verify the feasibility and safety of watchful waiting for the development of haematochezia after colorectal ESD. This multicentre, prospective, single-arm validation study was conducted at 15 hospitals in Japan. Patients planned to undergo colorectal ESD, ≥18 years of age, and with an Eastern Cooperative Group performance status of 0–1 were enrolled. Haematochezia was evaluated onsite for at least 48 hours after ESD and then managed according to a watchful waiting strategy (Table 1). The co-primary endpoints were the proportion of patients who avoided emergency colonoscopy and blood transfusion for haematochezia within 48 hours after ESD. The thresholds were set at 80% for emergency colonoscopy and 90% for blood transfusions.

Results

Between May 2023 and December 2024, 515 patients were enrolled. ESD was performed in 482 patients, and haematochezia occurred in 121 patients within 48 hours after ESD. Emergent colonoscopy was avoided in 120 of 121 patients (99.2%; 95% confidence interval [CI], 95.5–100%), and blood transfusion was avoided in all 121 patients (100%; 95% CI, 97.0–100%). Of the 482 patients who underwent ESD, four (0.8%; 95% CI, 0.2–2.1%) underwent emergent colonoscopy, two (0.4%; 95% CI, 0.1–1.5%) required endoscopic haemostasis, and one received blood transfusion (0.2%; 95% CI, 0–1.2%), within 28 days after ESD.

Conclusion

Haematochezia after colorectal ESD can be safely observed with minimal endoscopic intervention by following a watchful waiting strategy when certain conditions are met.

Disclosure

Takashi Kanesaka received honoraria for lectures from Olympus Marketing, Inc. The other authors have no financial relationships to declare.