Ally Therapeutics (United States)

Abstract Glioblastoma (GBM) is widely considered unresponsive to immunotherapy due to its immunosuppressive microenvironment and limited immune cell infiltration. However, recent single-cell transcriptomic studies reveal the presence of exhausted, potentially antigen-specific T cells in human GBM. We have developed a locally administered, brain-confined cytokine therapy with minimal systemic exposure using an engineered, neonatal Fc receptor (FcRn)-silenced, Compartment-Locked (CL) IL-12Fc fusion protein. This approach thus relies on presence and reactivation of tumor-resident, IL-12-responsive cells. In syngeneic, preclinical GBM models, intratumorally administered CL IL-12Fc induces robust antitumor efficacy, also under conditions of peripheral lymphopenia (induced via systemic temozolomide) or when T cell influx was pharmacologically inhibited. In 3D-perfused, patient-derived GBM explant cultures—with a largely preserved native tumor microenvironment and without addition of autologous peripheral immune cells—CL IL-12Fc triggered pro-inflammatory reprogramming. Proteomics-based secretome analysis revealed significant upregulation of interferon-gamma (IFNγ) pathway signatures. Single-cell RNA sequencing of GBM tissues prior to culture setup confirmed the presence of resident memory T cells in most patients. Notably, single cell transcriptome analysis of post-treatment explants demonstrated a robust IFNγ response in both tumor-associated macrophages, microglia and tumor cells. Our findings demonstrate that CL IL-12Fc can activate local immune responses within human GBM samples, independent of peripheral immune cell recruitment. This localized immune activation is an important prerequisite for the clinical translation of locally confined cytokine therapy. We aim to validate these findings using spatially resolved multiplex immunofluorescence histology. In summary we provide evidence that CL IL-12Fc can facilitate local immune activation without peripheral immune cell requirement.

Antibiotic resistance is a worsening public health threat. One poorly understood aspect of this problem is unexpected antibiotic treatment failure; when an infecting isolate is deemed susceptible to a given antibiotic, yet treatment with that drug fails. It has been proposed that heteroresistance may be an explanation for at least some unexplained treatment failures. Heteroresistance occurs when a bacterial isolate harbors a minor subpopulation of resistant cells which coexists with a majority susceptible population. The clinical relevance of heteroresistance is not clear. We obtained 291 index isolates from 288 unique patients in the piperacillin/tazobactam arm of the ALLIUM phase 3 clinical trial for the treatment of Gram-negative pathogens causing complicated urinary tract infections. The MIC for all isolates was below the piperacillin/tazobactam resistance breakpoint according to standard antimicrobial susceptibility testing. We performed population analysis profiles on these isolates to detect piperacillin/tazobactam heteroresistance and conducted a post hoc analysis to examine the impact of heteroresistance on clinical outcomes. We observed that 33/288 (11.5%) of the patients were infected with isolates that were heteroresistant to piperacillin/tazobactam and that patients infected with heteroresistant isolates had an increased rate of treatment failure when compared to patients infected with a non-heteroresistant isolate (odds ratio [OR] 2.13, 95% CI 1.02, 4.41; adjusted OR 1.74, 95% CI 0.82, 3.71). Further, patients without a removable catheter were at particular risk of treatment failure from infection with heteroresistant isolates. These data demonstrate that patients infected with a piperacillin/tazobactam heteroresistant isolate are at an increased risk for piperacillin/tazobactam treatment failure. The results help contextualize commonly observed unexpected antibiotic treatment failure and highlight heteroresistance as a potential cause.

Implantation of cardiovascular stents has surfaced as a forefront to treat coronary artery diseases through Percutaneous Coronary Intervention (PCI). However, stent migration is a significant complication that arises in a subset of patients, potentially leading to fatal outcomes. Current strategies including self-expanding stents, drug-eluting coatings, and imaging-guided placement are evaluated alongside emerging innovations like high-density lipoprotein (HDL)-infused coatings, 3D printing, and biodegradable stent materials. This review examines underlying mechanisms of stent migration, focusing on patient-specific, procedural, and design-related factors. By addressing stent migration, this research aims to enhance patient outcomes and advance the efficacy of PCI interventions.