Khalid Shah from the Harvard Stem Cell Institute (HSCI) has designed a new way to genetically engineered stem cells to secrete tumor-killing toxins. In collaboration with colleagues from the HSCI and Massachusetts General Hospital, Shah and his team have shown that their toxin-secreting stem cells can be used to eradicate cancer cells in the brains of mice after the main tumor has been removed.
Shah and his coworkers used the toxin produced by a bacterium called “Pseudomonas.” This soil bacterium secretes a powerful exotoxin that blocks protein synthesis in cells. This Pseudomonas exotoxin or PE has the capability to kill tumor cells. Unfortunately, this powerful toxin will also kill any other cell it comes into contact with. Therefore, the administration of PE is a very delicate and precise enterprise. Therefore, Shah and his collaborators modified PE so that it bound to specific receptors that are found on the surfaces of particular brain tumors. This way. the toxin was only taken up by cells that expressed these particular receptors. Shah and others also engineered the stem cells to harbor a mutation in the gene that encodes the target for PE (EF-2) that renders this target protein resistant to the effects of PE (for those who are interested, a G‐to‐A transition in the first nucleotide of
codon 717 that is known to confer toxin resistance).
Next, Shah and others embedded the toxin-secreting stem cells into biodegradable hydrogels that were implanted at the site of the tumor. This way, the toxin-secreting cells are near the site of the tumor and only secrete the toxin where it is needed. Any toxin that escapes from this site undergoes rapid degradation, which prevents it from causing any systemic side effects or toxicities.
Shah and his colleagues are pursuing FDA approval to bring this and other stem cell-based technologies to clinical trials.
“A few years ago recognized hat stem cells could be used to continuously deliver these therapeutic toxins in the brain, but first we needed to genetically engineer the stem cells that could resist being killed themselves by the toxins,” said Shah.
Shah continued: “Cancer-killing toxins have been used with great success in a variety of blood cancers, but they didn’t work as well in solid tumors because the cancers aren’t as accessible and the toxins have a short half-life.”
“We tested these stem cells in a clinically relevant mouse model of brain cancer, where you resect the tumors [from patients] and implant the stem cells encapsulated in a gel into the resection cavity. After doing all of the molecular analysis and imaging to track the inhibition of protein synthesis within brain tumors, we do see the toxins kill the cancer cells and eventually prolong the survival in animal models of resected brain tumors.”
Shah next plans to combine his toxin-secreting stem cells with several different therapeutic stem cells developed by his team to further enhance their positive results in mouse models of glioblastoma, which is the most common brain tumor in human adults. Shah hopes that he will bring these therapies into clinical trials within the next five years.