Systemic Delivery of Fusogenic Membrane Glycoprotein-expressing Neural Stem Cells to Selectively Kill Tumor Cells

Abstract

Intravenously injected neural stem cells (NSCs) can infiltrate both primary and metastatic tumor sites; thus, they are attractive tumor-targeting vehicles for delivering anticancer agents. However, because the systemic distribution of the injected NSCs involves normal organs and might induce off-target actions leading to unintended side effects, clinical applications of this approach is impeded. Given that the vesicular stomatitis virus glycoprotein (VSV-G) can promote the formation of multinucleated syncytia to kill cells in a pH-dependent manner, we engineered a pH sensor of VSV-G and generated a novel VSV-G mutant that efficiently promotes syncytium formation at the tumor extracellular pH (pHe) but not at pH 7.4. Using transduced NSCs derived from induced pluripotent stem cells (iPSCs), the VSV-G mutant was delivered into mice with metastatic breast cancers in the lung through tail vein injection. Compared with the conventional stem cell-based gene therapy that uses the herpes simplex virus thymidine kinase (HSVtk) suicide gene, this treatment did not display toxicity to normal non-targeted organs while retaining therapeutic effects in tumor-bearing organs. Our findings demonstrate the effectiveness of a new approach for achieving tumor-selective killing effects following systemic stem cell administration. Its potential in stem cell-based gene therapy for metastatic cancer is worthy of further exploration.

Antitumor Effects of CD40 Ligand-Expressing Endothelial Progenitor Cells Derived From Human Induced Pluripotent Stem Cells in a Metastatic Breast Cancer Model

“…Comparable results were shown by Wei et al, who found that tail vein injection of mouse embryonic EPCs into C3H mice resulted in the injected cells that were sequestered in the lung and spleen predominantly [6]. Our previous biodistribution studies using human NSCs also showed a similar cell distribution pattern [17,34]. This distribution pattern is useful for eliminating metastatic cancer cells in the lungs, liver, and spleen and has provided a rationale for us to test the therapeutic effects of intravenously injected iPS-EPCs in the breast cancer lung metastasis model in the present study.…”

“…Given that the vesicular stomatitis virus glycoprotein (VSV-G) can promote the formation of multinucleated syncytia to kill cells in a pH-dependent manner, we have generated a VSV-G mutant that efficiently promotes syncytium formation at the tumor extracellular pH but not at pH 7.4. Using transduced NSCs derived from iPS cells to deliver the VSV-G mutant into mice with metastatic breast cancer in the lung through tail vein injection, we observed tumor-selective killing without obvious toxicity to normal nontargeted organs [34].…”

“…Other types of adult stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), as well as MSCs and NSCs derived from pluripotent stem cells, also show the ability to home to tumors [17,[32][33][34][35]. However, it has been noted that MSCs that reach tumor stroma can contribute to tumor development through the mechanisms of creating a niche to support cancer stem cells, promoting angiogenesis, and/or promoting cancer metastasis [36][37][38].…”

Targeted Inhibition of the miR‐199a/214 Cluster by CRISPR Interference Augments the Tumor Tropism of Human Induced Pluripotent Stem Cell‐Derived Neural Stem Cells under Hypoxic Condition

“…NSCs are able to home in on not only the brain tumors but also solid tumors of a nonneural origin [2, 11]. In animal tumor models, the tumor tropism of NSCs has been extensively explored for targeted delivery of anticancer agents to both original tumor masses and distant tumor metastases [6, 7]. A phase 1 clinical trial using a human NSC line to deliver a suicide gene into recurrent glioblastoma multiforme is currently ongoing at the City of Hope Medical Center in Duarte, California [1].…”

“…This tumor-tropic behavior has been reported to be stimulated by chemokines released from hypoxic tumors via signaling pathways such as SDF-1/CXCR4 and HGF/c-Met [3]. In animal tumor models, the innate tumor-tropic property of NSCs has been extensively exploited for targeted delivery of therapeutic genes not only to brain tumors [4, 5], but also to other disseminated metastatic solid tumors by systemic administration [6–8]. The availability of human induced pluripotent stem cell (hiPSC) technique has solved the ethical and allergic problems of NSCs in clinical applications [9, 10].…”