1008

The formation of stroma is essential for tumor growth and involves complex interactions between a variety of cell types, including malignant tumor cells, and non-tumor stromal cells. Stroma provides structural support for malignant cells, modulates the tumor microenvironment, and influences the phenotypic behavior of the malignancy. Therefore, targeting tumor stromal cells could uncover new therapeutic opportunities in the control of neoplasms and their metastases. Stromal cells are thought to derive from fibroblasts localized at the site of cancer. However, we have demonstrated that bone marrow-derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements following intravenous injection (Cancer Res 62:3603, 2002). This finding suggests the development of novel anti-cancer therapies based on the local production of biological agents by gene-manipulated MSC. We examined whether MSC producing interferon-beta (IFNβ-MSC) could selectively incorporate into the tumor architecture and the resultant production of IFNβ inhibit the growth of metastatic tumors in the lungs of SCID mice. When 4 doses of 106 MSC/week injected IV into SCID mice bearing established pulmonary metastases of breast carcinomas or melanomas, the tumor growth was significantly inhibited as compared to untreated or vector-control (MSC-expressing GFP (p=0.007), while recombinant IFNβ protein (50,000 IU qod) was ineffective (p=0.14). IV injected IFNβ-MSC prolonged the survival of mice bearing metastatic breast carcinomas or melanomas (p=0.001) [JNCI 96(21):1593, 2004]. To investigate an alternative mode of delivery, intraperitoneal (IP) injections of IFNβ-MSC into mice carrying established ovarian carcinomas resulted in doubling of survival in SKOV-3, and cures in 70% of mice bearing OVAR-3 tumors. Furthermore, we demonstrate the capacity of MSC to deliver biological payloads to tumors by delivering an oncolytic, tumor selective replicating adenovirus (delta24RGD) via MSC. Five weekly IP injections of MSC-delta24RGD significantly prolonged survival in mice bearing established ovarian cancers with a noted reduction in non-target tissue transduction by delta24RGD. In a model of CML-blast crisis (KBM5), interferon-alpha (IFNα) was delivered by MSC using mifepristone (RU486) to turn on IFNα production. Remarkable anti-leukemic effects and increased survival of KBM5-bearing mice was observed. Infection of MSC with luciferase constructs and in vivo imaging confirmed homing of MSC to tumor sites. These data suggest that systemically administered gene-modified MSC can inhibit the growth of metastatic breast cancer, melanomas, ovarian cancers, and myeloid leukemias. The biological basis is the integration of MSC into the tumor stroma and the in situ production of therapeutic agents. Clinical trials are in preparation.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]