Abstract LB-423: A first in class novel cell therapy (PVS-30200) for the treatment and prevention of metastatic cancer by regulating the tumor microenvironment

Abstract

Abstract Cancer metastases have been difficult to treat and to control. The nature of tumor growth and metastases depends on many elements including the tumor microenvironment and cellular and vascular components to sustain viability and dissemination of cancer cells. Tumors themselves release signals that can alter resident endothelial cells (ECs) to form aberrant vessels to sustain tumor growth. Here we report the use of a novel, endothelial cell therapy (PVS-30200) that is delivered locally and able to control tumor growth and inhibit metastases. It promotes homeostasis and acts as a paracrine regulator of the tumor and its microenvironment to prevent growth and limit cancer invasion and metastasis. PVS-30200 comprises allogeneic ECs cultured on a gelatin substrate; this unique setting maintains the quiescent nature of the ECs and resists tumor alteration of the quiescent endothelial phenotype. A similar local EC therapy is entering a Phase 3 clinical trial for enhancing blood vessel repair and promoting vascular health in hemodialysis patients and has demonstrated a safe and tolerant profile.In vitro proliferation assays that cultured MDA-MB-231 breast and A549 lung carcinoma cells with EC-conditioned media reduced growth by approximately 40% (p < 0.001 for both cell lines). Migration and invasion were measured in a dual chamber culture system. Culture in EC-conditioned media significantly reduced in vitro invasiveness of both cancer lines. Analysis of the conditioned media showed the presence of anti-inflammatory, and anti-tumorigenic factors, such as TGF-β1, heparan sulfate proteoglycan and tissue inhibitors of matrix metalloproteinases. In vivo studies were performed to confirm the anti-proliferative and invasiveness activity. A spontaneously metastasizing orthotopic prostate (PC-3M-Luc) tumor model was utilized to determine the therapeutic potential of this treatment. Progression of the tumor and distant metastases were monitored using bioluminescent in vivo imaging (BLI). These studies demonstrated that a single injection of 500 μL PVS-30200 to the area surrounding the tumor prevented distant chest metastases and inhibited primary tumor growth. Twenty-nine days after tumor inoculation and 15 days post PVS-30200 treatment, the metastatic BLI measurements were 2.1-, 8.8-, and 11.8-fold greater than the initial day 0 BLI measurements for PVS-30200, vehicle, and untreated groups, respectively. Statistical significance was observed using a Kruskal-Wallis comparison of the group median BLI measurements for primary tumor growth (p=0.0386) and distant chest metastases (p=0.0387). This safe and novel cell therapy has demonstrated promising utility in the treatment of local cancers and in the reduction of metastases. This therapy is being explored in other in vivo solid tumor models to further assess the effects on tumor growth and metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-423. doi:10.1158/1538-7445.AM2011-LB-423