447. Mesenchymal Stem Cells as Delivery Systems for Cancer Therapy: Evaluation of Tropism and Efficacy

Abstract

Top of pageAbstract We have previously demonstrated that bone marrow-derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements following intravenous injection (JNCI 96(21):1593, 2004, Cancer Res 62:3603, 2002). These finding suggests the development of novel anti-cancer therapies based on the local production of biological agents by gene-manipulated MSC. However, no direct evidence has demonstrated this migration and incorporation into the tumor microenvironment. To this end, we utilized noninvasive imaging of migrating MSC in animal models. MSC were labeled by a fiber modified Ad vector expressing firefly luciferase (AdLux-F/RGD) and these MSC-Lux were injected into normal (healthy) SCID mice or mice bearing established metastatic breast or ovarian tumors. Biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS detection system. In normal mice, human MSC (hMSC) migrated to the lungs where they remained resident for 7-10 days. In animals bearing established metastatic lung tumors, IV injected hMSC again migrated to the lungs. However, in contrast to control mice, the Lux signal remained strong over a 15 day period with only a slight decrease over the first 10 days. After IP injection, hMSC-LUX were detected in the peritoneum, and after 7 days, no hMSC-LUX was detected in normal animals, while strong punctate regions of LUX-activity were observed in ovarian tumors. In contrast to SCID mice injected with hMSC, healthy Balb/C mice injected with Balb/C derived MSC-LUX initially migrated to the lungs and within 2.5 hrs had exited the lungs to remain liver and spleen resident for 5-7 days. We then examined whether hMSC producing interferon-beta (MSC-IFNb) can inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 10E6 MSC/week) into SCID mice bearing pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared to untreated or vector-control MSC controls (p= 0.007), while recombinant IFNb protein (50,000 IU qod) was ineffective (p=0.14). IV injected MSC-IFNb prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001) Intraperitoneal (IP) injections of MSC-IFNb into mice carrying ovarian carcinomas resulted in doubling of survival in SKOV-3, and cures in 70% of mice carrying OVAR-3 tumors. These data suggest that systemically administered gene-modified MSC selectively engraft into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-b inhibit the growth of metastatic breast cancer, and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Clinical trials are in preparation.