Grigor Andreev

Severe immune-related adverse events (irAE) in cancer patients receiving immune checkpoint inhibitors (ICI) require treatment interruption and immunosuppression. Based on prior preclinical data, in this prospective, single arm, non-randomized phase-Ib/II clinical trial we test the activity of Extracorporeal Photopheresis (ECP) against steroid-refractory irAEs in 30 patients (EudraCT-No.:2021-002073-26). The primary endpoint is the evaluation of the safety of ECP treatment for patients with ICI-induced irAEs. The study meets its pre-specified primary endpoint of less than 50% of patients developing ECP-related severe adverse events (SAE). No ECP-related SAE is observed and ECP-related AEs are reported in 20% (6/30) of patients. Overall response rate for all irAEs is 96.3% (CI 81.0–99.91). Colitis-, hepatitis- and dermatitis-specific response rates are 100% (13/13), 86.7% (13/15) and 100% (3/3), respectively. Secondary endpoints include the assessment of response rate of irAE and overall survival. ECP therapy is associated with reduced granzyme-A/B/K, T-bet, interferon-γ and TNF in peripheral T cells and pro-inflammatory gene-expression in the intestinal tract. The 12-month overall survival rate is 84.3% (CI 63.4%-93.8%). Response correlates with a decrease in inflammatory gene expression in the intestinal tract. These results suggest that ECP is a safe treatment option for SR-irAEs and warrant further investigation in subsequent randomized clinical trials.

Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation, and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 has tissue regenerative activity in the lower gastrointestinal tract in mice and patients with steroid-refractory aGVHD. Here, we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase in pH in the stomach, and allogeneic T cells had infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Compared with wild-type mice, Gast−/− mice experienced more severe aGVHD in the intestine and liver, which was rescued by pentagastrin treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for the therapeutic use of pentagastrin in a clinical trial of patients with aGVHD.

Proteinuric kidney disease substantially affects renal tubules through incompletely understood mechanisms. We identify elongation of primary cilia in distal renal tubules in the context of glomerular nephropathy. In renal biopsies and mouse models, tubular injury correlates with ciliary elongation, tubule dilation, and disruption of the cortical actin cytoskeleton. In vitro studies implicate biophysical cues of the glomerular filtrate and subsequent dysregulation of the actin cytoskeleton as contributing factors, confirmed by conditional deletion of N-WASP and Arp2/3 in vivo and in vitro. Electron and fluorescence microscopy revealed enlarged ciliary pockets, basal body mislocalization, and intracellular cilia formation in Arp3 knockout conditions. Transcriptome analysis identifies the essential role of cilia in maintaining adaptive tubular cell states, while persistent activation leads to disease progression through extracellular matrix remodeling, exemplified by Tenascin-C. Our findings establish cilia as central mediators of tubular adaptation to injury and identify the Arp2/3-dependent actin cytoskeleton as a critical regulator, providing essential insights into the pathogenesis of chronic kidney disease.