Targeting the Physicochemical, Cellular, and Immunosuppressive Properties of the Tumor Microenvironment by Depletion of Hyaluronan to Treat Cancer

Hyaluronan (HA) is a megadalton, polymeric glycosaminoglycan that forms highly extended, random conformations, occupying large volumes in the extracellular matrix. HA is found in high concentrations in skin tissue, where it maintains tissue hydrationand viscoelasticity, and promotes transport of biomolecules, and in joint fluid, where it serves as a lubricant, space filler, and shock absorber. Many types of solid tumors abnormally accumulate high amounts of HA in the tumor microenvironment (TME). Post hoc analyses from biopsied tumor specimens have revealed that a HA-high status is linked to poor prognosis. This is most likely due to multifactorial contributions, including HA-mediated facilitation of tumor-stroma interactions, which leads to tumor progression, promotion of the epithelial-mesenchymal transition(EMT), physicochemical alterations of TME ( desmoplasia, increased tumor interstitial fluid interstitial fluidpressure (IFP), reduced perfusion, increased hypoxia), enhanced metastasis, tumor cell cloakingfrom immune cells, and immune system dysregulation. Experimental studies with PEGPH20, an investigational drug candidate currently in clinical development, have demonstrated that enzymatic degradation of HA significantly improves the access of therapeutics to HA-high tumors, through the reduction of tumor interstitial fluidpressure, increased vascular patency, and improved perfusion. As a result of this unique mechanism of action, PEGPH20 holds promise as a future treatment strategy for combination therapy with chemotherapeutics, precision therapies, immune checkpointinhibitors, and next-generation cellular immunotherapies.