Introduction

Immune checkpoint inhibitors (ICIs), alone or in combination with tyrosine-kinase inhibitors (TKIs), have changed the therapeutic landscape of several cancers, but response is still unsatisfactory in a considerable (>30%) rate of patients. Increasing evidence shows that gut microbiome composition associates with response to ICIs in patients with epithelial cancers. Preliminary evaluations also suggest that fecal microbiota transplantation (FMT) may enhance response to ICIs in patients with melanoma, but randomized studies to confirm these results, as well as findings from other epithelial cancers, are still unavailable.

Aims & Methods

Our aim is to investigate, by a randomized, double-blind, placebo-controlled trial (TACITO trial - NCT04758507), whether targeted FMT (from donors who respond to ICIs) is effective in improving response to combined ICIs/TKIs first-line therapy in patients with advanced renal cell carcinoma (aRCC).
Fifty patients with aRCC, who were starting, or have started no earlier than 8 weeks, treatment with axitinib+pembrolizumab as first-line therapy, were randomized 1:1 to receive donor FMT (d-FMT) or placebo FMT (p-FMT) for three times in six months. Both groups underwent the first procedure by colonoscopy, followed by capsulized FMT after 90 and 180 days, respectively. Patients in the d-FMT arm received feces from a patient with mRCC who had achieved a complete and long-lasting response to ICIs, selected by following protocols recommended by international guidelines.
Patients were followed up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of biological samples. The primary endpoint was the progression-free survival (PFS) at 12 months. Secondary endpoints were: median PFS, overall survival (OS), objective response rate (ORR), adverse events after FMT, microbiome changes after FMT.
Sample size calculation was based on the hypothesis that FMT can provide a 20% improvement of the 12-month PFS rate when associated to standard of care (SOC) - from 60%, that is the reported 12-month PFS for SOC- to 80%.

Results

Fifty patients were randomized to d-FMT (International mRCC Database Consortium[IMDC] risk: 28% favorable, 72% intermediate-poor) or p-FMT (32% favorable, 68% intermediate-poor). At August 2024, 44 of them completed the follow-up and were evaluated for the primary endpoint (24 in the d-FMT arm and 20 in the p-FMT arm). The 12-month PFS rate was 66.7% in the d-FMT arm vs. 35.0% in the p-FMT arm (p=0.036). In the overall population, after a median follow-up of 28.0 months, the median PFS was 14.2 months (95%CI, 0.9–27.6) in the d-FMT arm vs. 9.2 months (95% CI, 3.0–15.4) in the p-FMT arm, and the median OS were not reached vs. 25.3 (95%CI, 17.1–33.6) months with d-FMT and p-FMT, respectively. The ORR was 54% in the d-FMT arm vs. 28% in the p-FMT arm. Stable disease (SD) was found in 38% of the d-FMT arm vs. 44% of the p-FMT arm. Disease progression (PD) was observed in 8% of the d-FMT arm vs. 28% of the p-FMT arm. Only one patient in the p-FMT arm reported a procedure-related adverse event (grade 3 oral mucositis) and discontinued capsules assumption.

Conclusion

The preliminary results of this unprecedented randomized controlled trial suggest that responder-derived FMT may improve the efficacy of ICIs+TKIs in patients with aRCC.

Supplementary Infographic ↗

Introduction

Diagnosis of celiac disease (CeD) is dependent on serological markers like IgA antibodies against transglutaminase 2 (TG2) and IgG antibodies against deamidated gluten peptides (DGP) caused by dietary gluten. The underlying immunological drivers of antibody response are however still poorly characterized. Clarifying these drivers may improve serology-based diagnostics and offer valuable immunobiological insight for CeD.

Aims & Methods

In this project, we aimed to identify new serum factors that are associated with celiac disease and serological response. A total of 224 serum samples (161 untreated and 63 treated) from patients with CeD were selected from Oslo University Hospital’s Intestinal Disease Biobank collected between 2018 to 2024. Data on serological response and treatment status were collected and the samples were compared with 40 healthy individuals. Serum samples from treated CeD were paired samples of untreated CeD. Serum was analyzed using the Olink® Target 96 Inflammation panel, which uses PCR-amplified dual-antibody proximity extension. Analyses were performed at the Proteomic Core Facility at Oslo University Hospital and statistics were performed in R-based with the OlinkAnalyze package.

Results

Thirty-one proteins differed significantly across all comparisons (p < 0.05) and were more abundant in CeD than in healthy controls. When untreated CeD was compared with controls, 24 proteins were elevated, namely CXCL9, CXCL10, CXCL11 (all ligands for CXCR3), CCL25 (ligand for CCR9), IFN-gamma, IL12B, IL17A, IL7, IL8, IL10, IL15RA, LIF, CCL11, CCL20, CCL28, PD-L1, TNFRSF9, CD40, VEGFA, ARTN, MMP10, ADA, ST1A1 and STAMBP. In treated CeD, 9 proteins were elevated compared to controls, namely CXCL10, CXCL11, IL12B, IL7, CD40, TNFRSF9, CSF1, VEGFA and ST1A1. Paired comparisons of treated and untreated samples showed that CXCL9, CXCL11, CCL11, CCL25, IL17A, TNFRSF9 and ADA were significantly higher in the untreated group. The proteins CXCL11 and TNFRSF9 were significant in all 3 comparisons. No significant differences were noted when comparing IgA-TG2 and IgG-DGP responses; however, IL-17A and CXCL11 were significantly lower among those with only a TG2 response compared to double positives.

Conclusion

We here report that multiple serum proteins are significantly elevated in untreated and treated CeD patients compared to healthy individuals. Many of the same serum proteins have previously been reported in serum taken hours after gluten challenge. Of particular interest, IL7, which is upregulated in intestinal CeD mucosa, was significantly upregulated in serum compared to controls. Both CXCL11 and TNFRSF9 which were found to be significant in all comparisons are immunological proteins relevant for T-cell activation and regulations. Future analyses will incorporate clinical data, including Marsh grades and serological levels, to deepen our understanding of the immunological landscape in CeD.