The poor prognosis for patients with metastatic cancer and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Dosage of systemically administered chemotherapeutic agents is limited by the toxicity to normal tissues, often precluding achievement of therapeutic indices of sufficient levels to affect complete cures. Malignant brain tumors pose further limitations to available therapies due to the infiltrative nature of the tumor cells throughout the brain and the presence of the blood–brain barrier. Novel anti-cancer treatment approaches must be more tumor-localized and tumor cell-selective to improve effectiveness and clinical outcome.
Neural stem (and/or progenitor) cells (NSCs) display inherent tumor-tropic properties that can be exploited for targeted delivery of anti-cancer agents to invasive and metastatic tumors. We and others have previously demonstrated that NSCs can deliver bioactive therapeutic agents to elicit a significant anti-tumor response in animal models of intracranial glioma, medulloblastoma and melanoma brain metastases. Recent studies demonstrate retention of tumor-tropic properties when NSCs are injected into the peripheral vasculature, localizing to multiple tumor sites in animal models of disseminated neuroblastoma and orthotopic breast carcinoma, with little accumulation in normal tissues. We postulate that this NSC-mediated, tumor-selective approach can maximize local concentrations of anti-cancer agents to tumor foci, while minimizing toxicity to normal tissues. This would potentially achieve therapeutic indices sufficient to eradicate invasive tumors that are otherwise lethal.
Several well-characterized immortalized murine and human NSC lines have been extensively studied for the determination of their therapeutic potential in animal tumor models of glioblastoma, melanoma brain metastases, medulloblastoma, and disseminated neuroblastoma. In all invasive and metastatic solid tumor models, 70–90% therapeutic efficacy was achieved as measured by increased long-term survival or decreased tumor burden. Other studies in the literature demonstrated the achievement of similar results with nonimmortalized NSC pools modified with various therapeutic genes, further verifying the NSC tumor tropism phenomenon. However, these pools are more difficult to keep consistent over time and passage, adding more variability to pre-clinical trials and more difficulty in creating uniform master cell banks for clinical trials.
We suggest that using a stable, sustainable and easily expandable clonal NSC line will circumvent the problems associated with characterization, senescence, and replenishment sources of primary stem cell pools. It would also allow for cost-effective and accessible patient trials. At the very least, such NSC lines can serve in proof-of-concept pre-clinical studies, where tumor types and therapeutic regimens are being tested. Preliminary biodistribution studies indicate that one such immortalized human NSC line (HB1.F3) is safe, non-immunogenic and non-tumorigenic. Furthermore, these cells retain their tumor-tropic property when modified to express therapeutic transgenes. Genomic stability and retention of tumor-tropic properties over time and passage has also been confirmed, making it a very promising line for clinical trials.
Regardless of which NSCs move towards therapeutic cancer trials, safety and feasibility would be best assessed first in patients with no alternative treatments, such as recurrent high-grade gliomas. These aggressive tumor cells infiltrate normal brain, and are not readily treatable by resection, irradiation, chemotherapy or gene therapy. In rodent models of orthotopic human brain tumors, it has been demonstrated that HB1.F3 NSCs can selectively target invasive tumor cells and distant micro tumor foci, achieving therapeutic efficacy with an enzyme/prodrug strategy. This serves as one example of many different anti-cancer agents that could be similarly delivered to tumor sites throughout the body.