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CRISPR Helps Fight Cancer... With Cancer

News   Jul 12, 2018

by Ruairi J Mackenzie, Science Editor, Technology Networks

In this image, CRISPR-engineered therapeutic cancer cells (green) track primary cancer cells (red) in the brain. Credit: CSTI/Khalid Shah lab

Ruairi MacKenzie
Science Writer

@rjmsci

Whilst the phrase “fight fire with fire” might not make much sense in practical terms, a recent study has shown that science really can fight cancer with cancer.

A study in mice has exploited the power and potential of the CRISPR gene editing technique to develop cancer cells that hunt down and attack their tumor of origin. The research could lead to promising therapies for different types of cancer.

The work, published in Science Translational Medicine was led by Khalid Shah, director of the Center for Stem Cell Therapeutics and Imaging at Brigham and Women’s Hospital (BWH). Shah and his team demonstrated that their technique was able to improve survival in mouse models of multiple types of cancer.

Cancer research has advanced massively in recent years, with initiatives like the Cancer Moonshot giving funding to innovative projects to accelerate the development of effective therapies. Shah and his team had noted that tumor cells show a rather unusual self-homing ability naturally; cells that metastasize and travel around a patient’s body return to their tumor of origin. Previous research that has tried to exploit this ability by attaching therapeutics to these emigrant cancer cells has been impaired by the concern that these cells might form outpost tumors and spread the cancer further, or that the cells would be killed by their own therapeutic payload, a process known as autocrine toxicity.

Shah and his colleagues decided to circumvent this risk by developing two classes of cancer cell that would be able to effectively turn on their former companions. The first type, so-called “off the shelf” cells, were engineered to secrete molecules that target a surface region on other cancer cells rather ominously called the “death receptor (DR)”. When the DR was targeted by these molecules, the target tumor cells stopped multiplying and instead started dying out. The “off the shelf” cells were also engineered to be resistant to DR-mediated death, meaning they could avoid the same fate as the tumor cells they were targeting. The cells chosen were specialized to match the mouse’s HLA phenotype, essentially a personalized signature of the immune system, to avoid the mouse rejecting the cells. 

The team then decided to try and top this research with a second, even more ingenious technique, which exploited the current golden child of genetics, the CRISPR gene editing technique. CRISPR, a set of genomic tools derived originally from pathogenic bacteria, has shown immense promise in several fields, including correcting errors in the human genome, acting as a diagnostic tool, and even saving the world’s supply of chocolate.

Here, CRISPR was used to edit tumor cells taken directly from the mice tested in the study, first by inducing the cells to produce therapeutic molecules, and then by making the cells resistant to those molecules, enabling them to handle and deliver the therapy back to their home tumor. Finally, the therapeutic cancer cells were engineered with a prodrug-activated “kill-switch”, which destroyed them once they had successfully attacked the other tumor cells, reducing the risk that they might form additional tumors. Ultimately, the technique killed 90% of vulnerable tumor cells within 72 hours.

Whilst this is a small, introductory study, and questions inevitably remain about the treatment translation to humans (and that’s not an insubstantial point), In a press release from BWH, Shah was unfazed about the task ahead: “This is just the tip of the iceberg," said Shah. "Cell-based therapies hold tremendous promise for delivering therapeutic agents to tumors and may provide treatment options where standard therapy has failed. With our technique, we show it is possible to reverse-engineer a patient's own cancer cells and use them to treat cancer. We think this has many implications and could be applicable across all cancer cell types."

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