Abstract 4273: Genetically engineered mesenchymal stromal cells degrade hyaluronic acid to disrupt the ECM and enhance cancer therapy outcomes

Abstract The extracellular matrix (ECM) is a vital component of cancer pathophysiology. However, little is known about how to modulate the ECM for therapeutic benefit effectively. Hyaluronic acid (HA) is a polysaccharide component of the ECM with increased deposition during tissue injury or inflammation. HA in the tumor microenvironment (TME) has been linked to aggressive cancer progression. We have found enhanced ECM remodeling behavior linked to pre-metastatic niche formation and metastatic progression. To remodel this ECM-enriched microenvironment, we developed HA-targeting genetically engineered mesenchymal stromal cells (GEMesys) expressing hyaluronidase (Hyal), the enzyme responsible for HA degradation. We examined the impact of Hyal-GEMesys in osteosarcoma (F42010), rhabdomyosarcoma (M-3-9M), and pancreatic cancer (Panc02) syngeneic murine models. Hyal-GEMesys delivered to tumor-bearing mice homed to primary tumor sites and successfully degraded HA in the TME. The degradation of HA also resulted in a significant remodeling of collagen. T cells in Hyal-GEMesy treated tumors display an activated CD4+CD44+ phenotype with a reduction of LAG3+PD1+ exhaustion markers. Additionally, Hyal-GEMesy treatment results in a significant decrease in hypoxic regions within tumors and reorganization of the tumor vasculature to a more normalized phenotype, marked by diminished CD31 expression. Hyal-GEMesy treatment reduces tumor volumes in osteosarcoma, rhabdomyosarcoma, and pancreatic cancer models and enhances chemotherapeutic efficacy. These findings suggest that reorganizing the tumor ECM with Hyal-GEMesys holds the potential to dismantle the protective stroma of the tumor, which often shields malignant cells from therapeutic reach, and combining anti-cancer and anti-stroma agents can enhance anti-tumor efficacy and patient outcomes. Citation Format: Alice T. Browne, Miranda Clements, Wei Ju, Rosandra Kaplan. Genetically engineered mesenchymal stromal cells degrade hyaluronic acid to disrupt the ECM and enhance cancer therapy outcomes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4273.