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Scientist behind key CAR-T advances co-founds new biotech

There are two things Phil Greenberg, the head of immunology at Seattle’s Fred Hutchinson Cancer Research Center, is especially well known for: a characteristic wiry gray mop of hair and a rock-solid reputation as one of the leading researchers in cancer immunotherapy.

Greenberg was behind some of the key scientific advances that led to breakthrough CAR-T cell therapies, and cofounded Juno Therapeutics, a biotech that helped launch one of the first of those treatments. Now, he’s cofounding a new venture called Affini-T Therapeutics, a Seattle- and Massachusetts-based company that hopes to eliminate cancers by targeting the source of cancer cells. The budding biotech, unveiled this week at the JPM Health Care Conference, will use a relatively new technology known as engineered T-cell receptors, or TCRs, to target oncogenic driver mutations, errors in key genes that cause cells to revolt and turn malignant in the first place.

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“Greenberg really knows TCRs,” said Marcela Maus, a cellular therapist at Mass General Hospital Cancer Center who is not involved with Affini-T, adding that it bodes well for the biotech that he’s involved.

The company’s approach aims to sidestep a key obstacle in CAR-T cell therapy, which uses a synthetic receptor called a CAR to weaponize immune T-cells against cancer. CAR-T cells will recognize and kill any cell carrying a certain target protein on its surface membrane, so researchers choose targets that commonly appear on the cancer cells they want to treat. The issue is that normal tissues usually carry the same targets, and the CAR-T cells will kill them, too. That’s one of the reasons why CAR-T has only been used successfully in B-cell cancers like myeloma or leukemia so far, Greenberg said; humans can survive without B-cells if they’re a casualty of CAR-T therapy.

“That the CAR-T cells eliminate normal B-cells is tolerable. But there are not many normal cells that you can delete that [it’s] tolerable,” he said. “It’s really different if you’re saying, ‘I’m treating your lung cancer, but I’m also going to get rid of your lung.’ ”

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But engineered TCRs have the potential to pick out malignant cells from healthy ones, since they have the ability to detect mutated genes — not just surface membrane proteins — that only cancer cells may have. All proteins inside a cell eventually get digested and chopped up into pieces called peptides. Those pieces will glob together in a kind of trash pile, called an MHC, that eventually migrates to the cell’s surface membrane, making it available to T-cell sensing.

“Since most of those are derived from normal proteins, T-cells are naturally trained to say, ‘That’s normal. That’s OK,’ ” Greenberg said. “Now when you have one that’s different from a normal cell, the T-cell says, ‘Oh, that’s different.’ ”

A number of issues can produce unusual peptides: a virus, perhaps, or a genetic mutation in cancerous cells. If the T-cell’s receptor can latch onto the junk pile, it’ll kill the abnormal cell. In cancerous cells with many mutations, the immune system is usually adept at doing this to prevent cancer naturally — or the process can be encouraged using drugs called checkpoint blockades.

“But the problem is in cancers with only a few mutations, it is a lot harder for the immune system to see and stop it,” Greenberg said.

If Affini-T can get the right TCR to detect key oncogenic driver mutations based on the MHCs decorating cell surfaces, in theory, their engineered T-cells carrying the TCR should be able to find and kill even cancer cells that have just one mutation, while leaving normal cells unscathed.

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“You’re dealing with a mutation that makes it a cancer,” Greenberg said. “So, you’ve got a cell that’s already malignant or becoming malignant.” That would also open up a lot more cancers that could be treated with this technology.

But finding the perfect TCR that can do this is a monumental task, said Charles Nicolette, the cofounder of CoImmune, a biotech focusing on cancer immunotherapy.

That’s because the MHC — or protein fragment complexes that TCR is looking for — may take different forms. Because the protein fragments can clump together in different configurations, even MHCs including fragments from the same mutated gene can look different on the surface of the cell in different people. Affini-T will need to create new TCRs for those different forms to be able to treat more of the population.

“That’s the problem,” Nicolette said. “[The TCR] will be binding to a very specific MHC molecule, and your T-cell must be compatible with that.”

And once solid tumors have formed, they have means of fending off attacks by the immune system, including those spurred by engineered CAR-T cells or TCR T-cells. Many tumors change their surrounding environment, like starving it of oxygen, to make it more hostile to the immune system. Some release signals that shut down immune T-cells that might attack it. Affini-T plans to overcome this by further engineering their TCR T-cells with genes that are more resistant to those signals or even become more activated by typically suppressive signals.

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That introduces a huge amount of engineering, though, and currently, scientists can only change a cell so much before it starts to get more difficult and much more expensive, MGH’s Maus pointed out.

“There is a cargo limit to how much you can put into one vector,” she said.

Right now, the company is using a virus to deliver the engineered genes into T-cells, which does put a size restraint on how much engineering they can do at one time, Greenberg admitted.

“We can have about five to six genes we can add at once, then it’s too large,” he said. “But we’re moving to new systems like CRISPR-Cas9 for gene editing that will be cheaper overall and allow us to do more editing.”

Company executives are also confident that they’ll be able to discover and engineer the perfect TCR for their first targets, which are mutations in the genes KRAS and P53 that can cause a cell to divide uncontrollably and turn into cancer.

“The first thing we do in selecting a TCR is doing an affinity screen [for the mutation],” said Jak Knowles, the company’s CEO. “That’s the start of our process,” and why they named the company Affini-T.

Knowles said that the company is starting to grow rapidly, hiring dozens of employees in the last year and acquiring hundreds of thousands of square feet in lab and office space. The new labs, he said, are already churning out exciting data.

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