Mesenchymal stem cells as delivery systems for cancer and leukemia gene therapy

Abstract

3194 Background: We previously demonstrated that intravenously (IV) injected bone marrow-derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal fibroblasts and proliferate selectively in situ. We here propose a novel cancer therapy concept based on the intratumoral drug production by gene-modified MSC. Methods: MSC were transduced with adeno (AdV)- or adeno-associated (AAV) virus carrying marker- or therapeutic genes. Gene-modified MSC were injected IV into mice carrying cancer xenografts. Results: MSC were found only in tumors, where they proliferate not in normal tissues. MSC producing human interferon-beta (IFNβ-MSC) directly inhibited the growth of metastatic A375 melanoma and MDA 231 breast carcinoma following IV injection (p=0.0073), while recombinant IFNβ protein injected subcutaneously (SC) did not (p=0.14). IFNβ-MSC doubled the survival of tumor-bearing mice (p=0.001) while SC injected IFNβ was ineffective (p=0.021 vs p=0.4). Intraperitoneal (IP) injections of IFNβ-MSC into mice with ovarian carcinomas doubled their survival (SKOV-3) and cured 70% of OVAR-3 mice. IP administration of MSC carrying a replication competent oncolytic adenovirus prolonged survival. MSC injected into the carotid artery (IA) of mice with gliomas selectively proliferated in gliomas, not in normal brain tissues. Intratumoral injection of IFNβ-MSC in vivo significantly inhibited tumor growth. In a model of chronic myelogenous leukemia in blast crisis (KBM5), interferon α (IFNα) produced in vivo by MSC induced tumor regressions and doubled the survival of mice. The melanoma differentiation-associated gene 7 (MDA7) produced by MSC, preferentially inhibited Gleevec resistant KBM5 CML blast crisis cells. Conclusions: Results suggest that gene-modified MSC selectively grow in tumors and inhibit the growth of leukemias, and metastatic cancers. Tumor inhibition required spatial proximity of MSC to the malignant cells. The findings suggest that therapeutic proteins or oncolytic replicating adenovirus have potent anti-tumor effects when produced in situ and suggest the use of MSC as tumor-selective gene therapy delivery systems. No significant financial relationships to disclose.