Neural Stem Cells as a Novel Platform for Tumor-Specific Delivery of Therapeutic Antibodies

Abstract

BackgroundRecombinant monoclonal antibodies have emerged as important tools for cancer therapy. Despite the promise shown by antibody-based therapies, the large molecular size of antibodies limits their ability to efficiently penetrate solid tumors and precludes efficient crossing of the blood-brain-barrier into the central nervous system (CNS). Consequently, poorly vascularized solid tumors and CNS metastases cannot be effectively treated by intravenously-injected antibodies. The inherent tumor-tropic properties of human neural stem cells (NSCs) can potentially be harnessed to overcome these obstacles and significantly improve cancer immunotherapy. Intravenously-delivered NSCs preferentially migrate to primary and metastatic tumor sites within and outside the CNS. Therefore, we hypothesized that NSCs could serve as an ideal cellular delivery platform for targeting antibodies to malignant tumors.Methods and FindingsAs proof-of-concept, we selected Herceptin™ (trastuzumab), a monoclonal antibody widely used to treat HER2-overexpressing breast cancer. HER2 overexpression in breast cancer is highly correlated with CNS metastases, which are inaccessible to trastuzumab therapy. Therefore, NSC-mediated delivery of trastuzumab may improve its therapeutic efficacy. Here we report, for the first time, that human NSCs can be genetically modified to secrete anti-HER2 immunoglobulin molecules. These NSC-secreted antibodies assemble properly, possess tumor cell-binding affinity and specificity, and can effectively inhibit the proliferation of HER2-overexpressing breast cancer cells in vitro. We also demonstrate that immunoglobulin-secreting NSCs exhibit preferential tropism to tumor cells in vivo, and can deliver antibodies to human breast cancer xenografts in mice.ConclusionsTaken together, these results suggest that NSCs modified to secrete HER2-targeting antibodies constitute a promising novel platform for targeted cancer immunotherapy. Specifically, this NSC-mediated antibody delivery system has the potential to significantly improve clinical outcome for patients with HER2-overexpressing breast cancer.

Cells As Delivery Vehicles for Cancer Therapeutics

“…For example, NSCs expressing variants of EGFR-specific nanobodies reduced glioma growth and invasiveness [14]. NSCs secreting an anti-HER2 antibody inhibited breast cancer growth in vitro and although an anti-tumor effect wasn't shown, migrated successfully to in vivo to breast cancer xenografts [15].…”

Wharton's Jelly Stem Cells as Agents for Cancer Therapy

“…Hypoxic conditions may be one way in which tumor tissue provides a niche for stem cells. The tumor tropic properties of UCMSC and other MSC is apparently not disturbed by loading of various therapeutic genes [29,[42][43][44][45], drugs [46,47], and nanoparticles into the cells. Thus, it is possible to utilize UCMSC as tumor or inflammatory tissue-targeted delivery vehicles for various therapeutics.…”

Non-hematopoietic stem cells as factories for in vivo therapeutic protein production

“…Frank et al 39 tested the ability of NSCs to deliver intact anti-Human Epidermal growth factor Receptor 2 antibodies to human breast cancer foci inoculated in the mammary fat pad. Four days later, mice were euthanized and tumors were harvested.…”