U technology is key to potent drug to treat blood cancer

An ancient snippet of salmon DNA resurrected as a result of an aborted University of Minnesota program to restock lakes with larger walleye has become a potent tool in one of the hottest areas of human cancer research.

U researchers, led by genetics Prof. Perry Hackett, ultimately lost their state funding to create genetically modified sport fish in the late 1980s. But the geneticists could not ignore the tantalizing possibilities raised by what they'd seen in the salmon DNA.

"We believed in what we were doing," Hackett said. "We believed so strongly that the world would need our technology. It sounds hokey, but seriously, that was it. If people didn't know then that they were going to be needing it, they would years later."

In January, biotech companies Intrexon Corp. and Ziopharm Oncology paid $100 million to license a cancer-drug made using the technology.

Two months later, drugmaker Merck agreed to pay the firms nearly $1 billion, plus royalties for it.

But not to treat fish. Merck is working with the companies to develop human immune cells genetically engineered to detect and kill blood cancer, using the U's gene-transfer method, known as "the Sleeping Beauty system."

Only a few dozen patients have been treated with cells developed using the Sleeping Beauty system, and many of them ultimately died from their advanced-stage leukemias and lymphomas. But the early trials proved that indeed a reconstructed gene from salmon DNA could be used to modify human immune cells to kill cancer.

The Sleeping Beauty system is just one of the technologies used to turn immune cells into a potent type of drug called a CAR-T, which hunts and kills specific late-stage blood cancers. But the Minnesota innovation is a key feature distinguishing Merck's therapy from the pack.

Major drugmakers like Novartis and Pfizer have struck massive deals with organizations like the University of Pennsylvania and private company Cellectis to develop their own CAR-T drugs.

But all the other publicly announced CAR-T drugs under development use genetically engineered viruses to manipulate genetic code, which is costly, difficult and prone to causing mutations in the host DNA. Sleeping Beauty is a transposon gene, not a virus, acting like a molecular scalpel to cut-and-paste itself into the host DNA, along with additional genetic instructions to kill cancer.

It's supposed to be faster, cheaper, and potentially safer, though the research is ongoing. For cancer, the transposon is engineered to implant instructions for finding blood cancer cells in a patient's immune cells. Potential future applications include treatments for eye disorders and rare genetic diseases, according to news accounts and interviews.

The drug companies also hope to expand their work in cancer to solid tumors. So far, the early work has focused on blood cancers that bear a biological marker called CD19, which makes them easier to target than other ­malignancies.

Blood cancers have been "a good test bed," said Cooper, who is a former researcher at Houston's MD Anderson Cancer Center. "I think it's really moved the needle, because we are doing something not just for CD19, but how you undertake gene therapy per se. The question is, can you move this to a point where you can treat solid tumors, and can you do it so nimbly, cost-effectively, and in a way that allows them to get at these cells almost on a worldwide basis?"

Interest in CAR-T drugs has driven rapid growth at companies like Ziopharm, directly benefiting the University of Minnesota, which agreed to share in an unusual upfront licensing payment of $100 million in stock from Boston-based Ziopharm and synthetic biology company Intrexon, based in Germantown, Md.

The value of that stock has grown 70 percent since the license was struck in January. The growth spiked in March after Merck's biotech division announced its $1 billion investment in the effort.

So far, the significant corporate interest is correlating with huge costs to the health care system. CAR-T therapies are among the burgeoning wave of personalized oncology drugs whose eye-popping six-figure price tags create a risk of what one California biotech executive has called "fiscal toxicity."

"Is this a scalable, customizable drug for our future?" asked Robert Pierce, chief scientific officer at San Diego-based oncology biotech firm OncoSec Medical. "With CAR-T, is it going to bring enough benefit to warrant the cost of these ultra-personalized therapies? I don't know the answer."

The basic idea is to extract human T cells and insert a code that causes them to develop the ability to detect proteins called "chimeric antigens" like SB19 that are found on the surface of cancer cells. The cells are then multiplied in a lab until they number in the billions, and then precisely reinfused in the patient.

Transposons were famously discovered in the 1950s as the cause of multicolored corn. In 1997, Hackett's U lab discovered in its fish research that they could reconstruct an ancient transposon that was still present in the dormant DNA. What's more, it appeared to be able to modify vertebrate DNA, including in humans.

Hackett said the team called it Sleeping Beauty because "they brought something from a very long evolutionary sleep back into life."

In 2005, Cooper reached out to Hackett to explore the idea of using Sleeping Beauty in humans, as a non-viral method of inserting the CAR genetic instructions he was designing for T cells, work that was eventually performed at Houston's MD Anderson.

Ten years later, in January, the combination of Cooper and Hackett's work yielded strong-enough results in late-stage blood cancer patients that Intrexon and Ziopharm offered $100 million for exclusive rights to it.

"You don't see this commonly done," Udupa said. "The broader vision was, this can be translated in the clinic to help patients. Why don't we come together and find a way to work together?"

Ziopharm, meanwhile, touted its exclusive license to the technology in a $75 million stock offering last February:

"Non-viral gene transfer using the SB system is unique in the field of oncology," the prospectus filed with the Securities and Exchange Commission says. "Our non-viral methods, which we believe are nimble, fast and less costly than other approaches, together with our industrialized, scalable engineering approach, are expected to enable highly efficient and less costly manufacturing approaches to gene engineered cell-based therapy."

In March, Merck offered to pay Intrexon and Ziopharm an upfront payment of $115 million and up to $826 million once certain milestones are hit in development and commercialization, plus royalties on net sales.

"There is so much energy going into this field right now … that I am confident that the repertoire of cancers are going to move beyond blood cancers," said Dan Voytas, director of the Center for Genome Engineering at the U. "There may be differences in effectiveness, but I feel pretty good that this technology is going to be quite transformative in terms of how a diverse array of cancers are treated."