Knipp, G. T. | bioRxiv Science

bioRxiv2026

TRPV4 antagonist efficacy in a post-hemorrhagic hydrocephalus pig model

Hydrocephalus occurs across the age spectrum but is particularly prevalent in young and old individuals. One form of this disease is post-hemorrhagic hydrocephalus (PHH), which is a life-threatening sequela of intraventricular hemorrhage (IVH). There are no effective non-surgical interventions for the treatment of PHH or other forms of hydrocephalus. Progress has been limited by the lack of gyrencephalic animal models that exhibit high fidelity to human conditions. Here, we establish a pathophysiologically relevant novel swine model of IVH that recapitulates key features of severe PHH, including sustained ventriculomegaly, elevated intracranial pressure (ICP), neuroinflammation and white matter injury. Using this model, we test the therapeutic potential of pharmacologic inhibition of the transient receptor potential vanilloid 4 (TRPV4) non-specific cationic channel. The orally bioavailable TRPV4 antagonist GSK2789917 penetrates the blood-brain barrier, and prevents progression to PHH when administered 2 days after IVH. Specifically, GSK2789917 prevents the development of ventriculomegaly, suppresses early ICP elevations and prevents or reverses inflammasome activation. These findings establish a clinically relevant large-animal model of PHH and identify TRPV4 antagonism as a promising treatment for hydrocephalus.

neuroscience↗

bioRxiv2020

Tumor-responsive, multifunctional CAR-NK cells cooperate with impaired autophagy to infiltrate and target glioblastoma

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking have rendered glioblastoma (GBM) highly resistant to therapy. As a result, GBM immunotherapies have failed to demonstrate sustained clinical improvements in patient overall survival (OS). To overcome these obstacles, here we describe a novel, sophisticated combinatorial platform for GBM: the first multifunctional immunotherapy based on genetically-engineered, human NK cells bearing multiple anti-tumor functions, including local tumor responsiveness, that addresses key drivers of GBM resistance to therapy: antigen escape, poor immune cell homing, and immunometabolic reprogramming of immune responses. We engineered dual-specific CAR-NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally-released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site specific activity in the tissue and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells, but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising new NK cell-based combinatorial strategy that can target multiple clinically-recognized mechanisms of GBM progression simultaneously.

immunology↗