This project was initiated in April of 2010, and was for comparing
• three types of stem cells
• two distinct therapeutic gene modifications of stem cells, and
• intravascular administration vs. direct tumor injection of stem cells
in order to identify the most efficacious stem cell + therapeutic gene + route of administration for treating patients with recurrent glioblastoma (GBM), a brain tumor that has a dismal prognosis, and that badly needs innovative approaches for improving treatment outcomes.
Major conclusions from this project, as concerns the objectives indicated above, are:
1. Stem cells administered by the vascular route do not reach brain tumors established in rodent subjects, to an extent which demonstrable therapeutic stem cell anti-tumor activity should be anticipated. In most instances, intravascular administration results in no detectable stem cells in intracranial tumor in rodent models. Therefore, therapeutic stem cells need to be administered direct into brain tumors in order to achieve a sufficient number and concentration of stem cells for observing anti-tumor effect.
2. Neural stem cells and mesenchymal stem cells delivered directly into intracranial tumor display similar extents of dispersion in tumor, indicating these stem cell types should perform comparably as concerns their ability to disseminate within, and deliver therapy to tumor.
3. However, unmodified (non-immortalized) neural stem cells, derived from single adult or fetal sources, have insufficient proliferative capacity for production as therapeutic stem cells to be used in clinical trials that enroll multiple patients. Because of the ready availability of mesenchymal stem cells (MSCs), from many donors, combined with the proliferative capacity of MSCs, MSCs were determined as the preferred candidate for developing therapeutic stem cells to treat patients with recurrent GBM.
4. Studies conducted with therapeutic stem cell + tumor cell mixtures indicated superior anti-tumor activity of cytosine deaminase modified stem cells + 5-fluorocytosine (FC), relative to secretable TRAIL modified stem cells, when anti-tumor activity is examined in liquid media (cell culture). The two types of therapeutic stem cells showed comparable anti-tumor activities when administered directly into brain tumor in animal (rodent) subjects.
5. In relation to other types of therapies (e.g., chemotherapeutics, antibodies, liposomal drugs) being tested by members of this disease team, manufactured therapeutic stem cells displayed low (modest) anti-tumor activity in animal subjects with brain tumor.
Technical advances, discovery, and products developed in association this project, and that can be shared/transferred in support of other CIRM funded research, include:
• Development of approaches for delivering stem cells through distinct routes of administration in rodent subjects.
• Development of a method, based on the use of polymerase chain reaction, for detecting human cells in rodent tissues, with a sensitivity of detection of one human cell per 100,000 mouse cells.
• Development of a cell labeling approach that enables tracking of stem cell migration in rodent subjects.
• Development of a histochemical method for detection of labeled human cells in rodent tissues.
• Development and characterization of multiple, tumorigenic human glioblastoma xenograft models for use in therapeutic testing.