Stem Cells as Potential Vehicles for Drug Delivery


Stem Cells as Potential Vehicles for Drug Delivery

California researchers are set to begin the first clinical trial of souped-up stem cells that seek and destroy brain cancer by delivering the means to make a potent chemotherapeutic.

The scientists, at City of Hope Comprehensive Cancer Center in Duarte, received the FDA green light on May 18. This Phase I study will include about 15 patients with recurrent, high-grade glioma, said principal investigator Jana Portnow. Participants will receive neural stem cells (NSCs) engineered to produce an enzyme that converts a low-toxicity antifungal drug into a molecule that is poison to dividing cells.

This is the first human study using stem cells not to rebuild diseased tissue, but to deliver a medical “payload,” said Karen Aboody of the City of Hope National Medical Center, who did the preclinical research and will provide the stem cells. Therefore, other researchers are watching to see whether the treatment will prove safe and effective. The primary goal for this Phase I study is to show that the therapy lacks dangerous side effects. The researchers are not quite ready to enroll patients, Portnow said, but hope to commence the trial this summer.

The doctors intend to take advantage of a convenient property of stem cells: they are attracted to tumors and damaged tissue. Aboody is one of a small cadre of scientists hoping to make use of this homing ability. The idea is that the cells can act like multiple cellular syringes, said Jeanne Loring of The Scripps Research Institute in La Jolla, California. In animal studies, stem cells can deliver enzymes, growth factors, antibodies, or even therapeutic viruses to where they’re needed (reviewed in Menon et al., 2009 and Aboody et al., 2008: PMID18369324). Cancer is one of the first diseases that these scientists have set their sights upon, but other conditions, such as Alzheimer disease, are also potential targets.

In recurrent glioma, tumor cells migrate throughout the brain. Surgeons can remove the main cancerous mass, but “you’re going to miss all the cells that have already infiltrated,” Aboody said. Behind the blood-brain barrier that surrounds the spinal cord and brain, intravenous chemo cannot easily reach these cells. The upcoming trial will run concurrently with surgery. When doctors remove the tumor, they’ll leave NSCs behind in its place.

These cells will carry a little something extra, an enzyme called cytosine deaminase. Cytosine deaminase turns the antifungal 5-FC into 5-FU, a chemotherapeutic that attacks dividing cells. The stem cells, Aboody and Portnoy hope, will seek out the tumor cells. When the patient takes 5-FC, which can reach the brain, the new cells should secrete 5-FU right on top of the tumor. “You’re making localized chemotherapy,” Aboody said.

Aboody and colleagues have tested their concept in animal models of brain cancer. In one published study, they used a similar approach to treat mice carrying human neuroblastoma, a childhood cancer of the peripheral nervous system. They treated the animals with the prodrug CPT-11, plus neural stem cells carrying the enzyme to convert CPT-11 into toxic SN-38. Ninety percent of treated animals survived for a year, with no detectable tumors, compared to 30 percent of animals treated with CTP-11 alone. None of the untreated control animals lived (Danks et al., 2007: PMID17210679).

Naturally, there are safety concerns when injecting people with genetically engineered, immortalized stem cells. That is part of the reason to go after deadly brain cancer, Aboody said: “We have to start with the worst-case scenario—where there are no effective options available.” With glioma, once the tumor recurs people typically have six months to live, she said, and there is no standard therapy. The grim prognosis means that trying a new therapeutic on brain cancer has the best risk-to-benefit ratio, Aboody wrote in an e-mail to StemBook.

Animal studies indicate the NSC treatment is safe, and the cells do not become a permanent brain fixture. Even if the cells do cause problems, the same enzyme-prodrug combination that allows them to kill cancer should cause them to self-destruct if they begin to divide.

Other scientists are eagerly awaiting results from the City of Hope trial. “I think that Karen’s work is going to be the path-finding part of the entire idea,” said Loring, who is interested in using stem cells to deliver therapeutics for Alzheimer disease. “We’re hoping that Karen goes through the entire process so we can follow.”

Other researchers keeping an eye on City of Hope are Rona Carroll and Lata Menon of Harvard Medical School and Brigham and Women’s Hospital in Boston. They are taking aim at recurrent glioblastoma, the most aggressive glioma subtype. These researchers hope to use stem cells to deliver a natural molecule, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis specifically in tumor cells. When they treated mice carrying human glioma with mesenchymal stem cells expressing secretable TRAIL, the treated animals lived more than two weeks longer than control, buffer-treated mice (Menon et al., 2009: PMID19544410).

Loring, for her part, hopes to use NSCs to treat Alzheimer disease. Simply rebuilding the damaged tissue with stem cells is not an option, she said: “You can’t make them turn into all the cell types lost in the disease.” But NSCs migrate to damaged, inflamed tissue, where they might be able to deliver a payload that helps the remaining cells. Loring and colleagues transplanted NSCs into Alzheimer’s model mice, and found an increase the density of synapses linking neurons. “This means the neurons are happier connecting with each other,” Loring said; those connections are the basis for memory. The mice with the stem cell treatment also did better on memory tests than untreated animals (Blurton-Jones et al., 2009: PMID19633196).

NSCs produce plenty of a growth factor called brain-derived neurotrophic factor (BDNF). In further experiments, Loring and colleagues found that BDNF treatment affected synaptic density much like the stem cells did. Loring’s project is still in very early stages, but she hypothesizes that by genetically ramping up the BDNF made by NSCs, she could deliver more of this memory-booster to the sites that need it most. Ideally, she said, the cells would remain in the brain as benign growth factor factories. In a clinical setting they would also include a suicide gene, similar to Aboody’s enzymes, so doctors could destroy the implanted cells via a prodrug if necessary.

“The key issue here is stem cells will go somewhere and stay there,” Loring said. Should these cellular delivery boys prove to be a safe and effective approach, scientists suspect they could provide medicines for a variety of conditions. Beyond the brain, other cancers such as breast and lung cancer might find themselves in the crosshairs. Perhaps, Loring speculated, stem cells could deliver growth factors to damaged tissue such as burns.


Aboody, K.S., Najbauer, J., and Danks, M.K. (2008). Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther., 739-752.

Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N.A., Müller, F.J., Loring, J.F., Yamasaki, T.R., Poon, W.W., Green, K.N., and LaFerla, F.M. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc. Natl. Acad. Sci. U S A, 13594-13599.

Danks, M.K., Yoon, K.J., Bush, R.A., Remack, J.S., Wierdl, M., Tsurkan, L., Kim, S.U., Garcia, E., Metz, M.Z., and Najbauer, J., et al. (2007). Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res., 22-25.

Menon, L.G., Kelly, K., Yang, H.W., Kim, S.K., Black, P.M., and Carroll, R.S. (2009). Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. Stem Cells, 2320-2330.

Menon, L.G., Shi, V.J., and Carroll, R.S., Mesenchymal stromal cells as a drug delivery system (January 15, 2009), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.35.1, .