Biomarker analysis of VT1021, a first-in-class therapeutic agent that stimulates Thrombospondin-1 and reprograms the tumor microenvironment

Abstract

Abstract VT1021 is a first-in-class therapeutic agent which has been tested in a phase I/II clinical study in solid tumors (NCT03364400) and has advanced to a phase II/III clinical study in glioblastoma (NCT03970447). Preclinical studies demonstrated that VT1021 inhibited tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprogramming the tumor microenvironment. We sought to confirm the mechanism of action (MOA) of VT1021 in a clinical setting and identify biomarkers for VT1021 in future clinical studies. Accordingly, we evaluated potential biomarkers from peripheral blood samples and available paired biopsy samples from evaluable subjects enrolled in the phase I/II expansion study. Here, we report the clinical confirmation of TSP-1 induction by VT1021 in peripheral blood and tumor biopsy samples. Moreover, we observed that treatment with VT1021 resulted in the remodeling of the TME from one that was immunosuppressive and tumor-promoting to one that is immune active and tumor-inhibiting. The modifications were characterized by an increased ratio of CD8+ T cells (cytotoxic T lymphocytes, or CTLs) to T Regulatory (Treg) cells, increased Tumor-infiltrating lymphocytes (TIL), decreased T cell exhaustion, increased M1:M2 macrophage ratio and decreased microvascular density. To identify non-invasive biomarkers for VT1021, we analyzed plasmatic cytokines and identified four cytokines as potential predictive biomarkers for VT1021 activity, including matrix metallopeptidase 9 (MMP9), plasminogen activator inhibitor-1 (PAI-1), chitinase 3 like protein 1 (CHI3L1), and C-C Motif Chemokine Ligand 5 (CCL5). In addition, we found that macrophage migration inhibitory factor (MIF), Interleukin-18 binding protein alpha (IL-18 Bpa), CHI3L and CCL5 could be potential pharmacodynamic biomarkers for VT1021.