PhD Candidate University of Houston Houston, Texas, United States
Disclosure(s):
Prashant Menon, BSc: No relevant disclosure to display
Introduction/Rationale: Despite the remarkable success of chimeric antigen receptor (CAR) T cell therapy in hematological cancers, the clinical experience with solid tumors has not been encouraging. Preclinical and clinical data support that the tumor-specific extracellular matrix (ECM) presents a physical barrier restricting the entry of immune cells like T cells into the tumor microenvironment (TME). ECM-degrading enzymes like heparanase and MMP7 have been explored; however, these enzymes are also associated with tumor growth, metastasis, and poor prognosis in several cancers. We focused on the collagenase MMP8 since it: (1) exhibits the best catalytic efficiency (kcat/KM) with the ability to degrade a broad range of collagens and also aggrecan, gelatins, fibronectin, and laminin, (2) MMP8 is secreted only by immune cells, and (3) MMP8 expression is not prognostic in any cancer.
Methods: Donor-derived T cells and second generation CAR T cells targeting CD19, HER2, and GD2 were engineered with and without MMP8. Proliferative and migratory exhaustion upon exposure to mechanical stress was evaluated in vitro. Matrigel-embedded tumor organospheroids were used to assess infiltration and cytotoxicity functions of the T cells. In vivo, xenograft models and immunohistochemistry evaluated safety, tumor rejection, and TME remodeling.
Results: T cells exposed to cross-linked ECM exhibited both proliferative and migratory exhaustion but this defect was rescued by secretion of MMP8. Parental T cells showed poor ECM penetration, while enzyme-expressing T cells demonstrated enhanced infiltration, migration, and tumor killing in vitro. MMP8-CAR T cells showed robust infiltration in multiple tumor models in vivo and eradicated HEY-A8 tumors and extended survival beyond 100 days, outperforming parental CAR T cells.
Conclusion: MMP8-engineered T cells offer a stoffer a promising strategy to overcome physical barriers in solid tumors, enhance infiltration, and unlock their full anti-tumor potential.
