Engineering Stem Cells to Fight Cancer


Advanced brain tumors are typically treated by surgical removal. However, it is difficult in the extreme to extirpate an entire tumor and therefore, tumor relapse is a perennial problem. A special group of small proteins known as ‘cytotoxic proteins” can target and destroy remaining cancer cells, but these proteins have short half-lives in the body and recent clinical trial called the PRECISE trial was not able to demonstrate that administered cytotoxic proteins had any efficacy against glioblastoma multiforme (GBM) brain tumors.

A new study, however, published online from the journal Stem Cells, a research group led by Khakid Shah from the Harvard Stem Cells Institute, have devised a new strategy designed around these engineered cytotoxic proteins has shown that neural stem cells (NSCs) can be genetically engineered to express these proteins and help treat GBM tumors.

So how did Shah and his colleagues design this novel strategy? They engineered NSCs to not only express specific cancer cell-killing toxins, but also have resistance to these toxins. Secondly, they designed cytotoxins that have the ability to enter cancer cells and target proteins known to be over-expressed by GBM tumors. Then these neural stem cells were encapsulated, they were transplanted into the space left after the bulk of the tumor was surgically removed.

In a mouse model of GMB, the implanted engineered stem cells survived and mediated an increase in long-term survival. This therapy was also effective against multiple patient-derived GBM cancer cell lines, which demonstrated their potential clinical relevance and applicability.

Shah and his coworkers want to bring these results to human trials within the next five years. They hope that this strategy can be successfully deployed in combination with surgical removal of the tumor mass. Shah also hopes that this approach can be adapted to treat other tumor types by using tissue-specific stem cells that express tumor-specific cytotoxins.

See Stuckey DW, Hingtgen SD, Karakas N, et al. Engineering toxin-resistant therapeutic stem cells to treat brain tumors. Stem Cells 2014.

Stem Cell-Conventional Treatment Combo Offers New Hope in Fighting Deadly Brain Cancer


A new type of treatment that combines neural stem cells with conventional cancer fighting therapies shows promise in animal studies for the most common and deadliest form of adult brain cancer — glioblastoma multiforme (GBM). The details are revealed in a groundbreaking study led by Maciej Lesniak, M.D., that appeared in the journal STEM CELLS Translational Medicine.

“In this work, we describe a highly innovative gene therapy approach, which is being developed along with the NIH and the FDA. Specifically, our group has developed an allogeneic neural stem cell line that is a carrier for a virus that can selectively infect and break down cancer cells,” explained Dr. Lesniak, the University of Chicago’s director of neurosurgical oncology and neuro-oncology research at the Brain Tumor Center.

The stem cell line used is a neural stem cell line called HB1.F3 NSC. The US Food and Drug Administration has recently approved this cell line for use in a phase I human clinical trial.

Glioblastoma multiforme remains fatal despite intensive treatment with surgery, radiation and chemotherapy. Cancer-killing viruses have been used in clinical trials to treat those tumors that resist treatment with other therapies and infiltrate throughout the brain. Unfortunately, according to Lesniak, this therapy was subject to some “major drawbacks.”

“When you inject a virus into a tumor alone (without a carrier, like NSC), the virus stays at the site of the injection, and does not spread. Moreover, our immune system clears it. By using NSCs, we can achieve a widespread distribution of the virus throughout the tumor mass, since the NSC travel. Also, they act like a stealth fighter, hiding the virus from the immune system.” Lesniak and his co-workers used NSCs loaded with a novel oncolytic adenovirus. This virus selectively targets glioblastoma multiforme in combination with chemo-radiotherapy. Using this strategy, Lesniak’s team was able to overcome the limitations associated with anticancer viral therapies.

Using mice that had glioblastoma multiforme, the research team showed that their neural stem cell line, which is derived from human fetal cells, significantly increased the median survival time of the mice beyond conventional treatments alone. The addition of chemo-radiotherapy further enhanced the benefits of this novel stem cell-based gene therapy approach.

“Our study argues in favor of using stem cells for delivery of oncolytic viruses along with multimodal chemo-radiotherapy for the treatment of patients with glioblastoma multiforme, and this is something that we believe warrants further clinical investigation,” Dr. Lesniak concluded.

Lesniak’s team is completing final FDA-directed studies. He expects to start a human clinical trial, in which a novel oncolytic virus will be delivered via NSCs to patients with newly diagnosed glioblastoma multiforme, early in 2014.

Treatment of glioblastoma multiforme depends on novel therapies,” said Anthony Atala, M.D., Editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “This study establishes that a combination of conventional and gene therapies may be most effective and suggests a protocol for a future clinical investigation.”