PHILADELPHIA—Refuge Biotech isn’t the first company to edit T cells with CRISPR to fight disease. But the Bay Area biotech is looking to separate itself from the pack with its CRISPR interference technology that allows it to modify multiple genes in one go.
The Menlo Park, California-based company is advancing “intelligent” T cell therapies that can “think for themselves and react to their environment,” Refuge Chief Business Officer Jing Zhao told FierceBiotech. “The cell therapy, when it comes in contact with the tumor cell, will have an arsenal of mechanisms to essentially effect treatment... With CRISPR interference, we regulate different genes within the T cell to express different things on its surface, allowing it to react differently in its external environment.”
The hope is, these T cells would be fitter and persist in their environment, compared to conventional CAR-T treatments, he said.
Refuge’s technology uses dead Cas9 technology licensed from Stanford University. Instead of cutting DNA, it switches genes on and off.
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“It borrows the original homing mechanism for CRISPR together with the ability to switch the gene on and off, but not just in a digital manner. If you cut the gene out, it’s a one-and-zero effect. With our technology, we can to a certain extent tune the response. We can downregulate a gene by 80% or 50%, for example,” he said.
The tech also allows Refuge to “multiplex” its treatments, that is, to make multiple edits to the T cell at once.
“When we multiplex, we essentially add more guide RNA to the mix. It’s like a recipe—just like in the kitchen, we just add more ingredients. For many of the competing technologies out there, they would have to do this in a sequential manner and within cell therapy, that starts to get difficult,” Zhao said.
It would mean using a virus to deliver each package to the cell, he said. The amount of virus used would quickly add up—it gets expensive and inefficient. When material is transferred from virus to cell, some of it gets lost. Doing this for multiple ingredients means “you start to get an exponential loss of cells” and may result in not enough viable cells at the end of the process.
Last year, Refuge raised $25 million in its series B to advance a pipeline led by a CD19-targeting CAR-T for diffused large B-cell lymphoma.
“CD19 is very much involved in bloodborne cancers and that’s where the [CAR-T] product is today with Novartis and Gilead,” Zhao said. But as Refuge moved its pipeline forward, it saw promise in HER2-based CAR-T in solid tumors, with some “exciting data in ovarian cancer. Despite its success in some blood cancers, CAR-T's success has been limited in solid tumors.
Refuge is going full steam ahead with its ovarian cancer program, with it’s “pre-pre-IND" meeting with the FDA coming in July. It wants to start human trials in the second half of 2020, if not sooner. As it proceeds, the company will be looking to fundraise again, with a potential listing to come next year, or the year after. But the goal posts could always change, Zhao said.