CAR-T, Startups

UCSF scientist rolls out a new blueprint for programming T cells, the 2.0 way

Wendell Lim

Wendell Lim

While analysts debate about whether or not the FDA will be willing to hand out the first CAR-T approval to Kite, the scientists in this burgeoning field have been laboring in the lab on next-gen T cell therapy models that have a lot more built-in safety and efficacy features. One of the top cell therapy engineers is Wendell Lim at UC San Francisco, the scientific founder of Cell Design Labs. And he’s just come out with a new paper on his work featuring some of the cool new technologies that he’s been using on T cells 2.0.

The Howard Hughes Medical Institute investigator has his sights set on a very high bar. Building on earlier work on synthetic Notch (synNotch) — where he tinkered with the Notch sensor so it could program a cell therapy to go after a particular cancer cell target and then issue instructions to turn genes on or off — Lim believes you can use synNotch to essentially create a cell bot that can be mustered into armies of patrolling therapeutics.

In what amounts to developing living micro devices, Lim believes the technology can be used to program T cells to produce checkpoint inhibitors, bispecific antibodies and customizable cytokines, among other things. And it can also all be integrated into CAR-T with a suicide switch.

“The way I view the last couple of years and months” of CAR-T work, says Cell Design CEO and co-founder Brian Atwood, “these are a first-generation cruise missile. They went to an address and blew up. The products in the clinic today are pretty crude. For ALL and CLL patients, they’re pretty amazing, but there’s no controllability. That’s Wendell’s thing.”

True, it’s all preclinical right now, involving mouse models. But Cell Design has already signed up Kite as a partner and an investor, working on an on/off switch for CAR-T, which would have a major impact on safety, reining them in if they start to run out of control.

“I think that’s a really important thing,” Lim tells me, “enhancing T cell function” and moving beyond the relatively limited applications of today’s CAR-T therapies now in late-stage development.

Lim says he’s been working on a systematic tool kit to engineer what a cell senses and responds to. And if he can begin to apply what he’s done in mice to humans, reprogramming cells could become a radical new approach for cancer as well as autoimmune diseases.

By equipping their synNotch receptor with a component that can be switched out to customize it for each disease, the UCSF team believe they have a universal approach with wide functionality. In their work published in Cell today, the team not only used it to produce checkpoint inhibitors, they also developed a treatment that drops a Bispecific T Cell Engager (BiTE) payload that left normal cells in mice unmolested.

Lim isn’t talking blue sky theory. He believes that Cell Design is a couple of years out from the clinic, starting out with the autologous cells extracted from the human body to make personalized therapies and then moving to off-the-shelf autologous cells.

Cell Design has gathered $34.4 million in backing, says Atwood. “Kite’s project adds to that, with milestones and research support” to carry the company into the clinic. The fledgling company has 18 staffers, while Lim’s lab includes 20 investigators. A year from now, the CEO expects to have 50 staffers on board.

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