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

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.

Mer­ck is tak­ing the ax to its US op­er­a­tions, cut­ting 500 jobs in its lat­est re­or­ga­ni­za­tion

Merck is cutting 500 jobs in its US sales and headquarters commercial teams in its latest effort to find new ways to streamline the operation.

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Alice Shaw, Lung Cancer Foundation of America

Top ALK ex­pert and can­cer drug re­searcher Al­ice Shaw bids adieu to acad­e­mia, hel­lo to No­var­tis

Jay Bradner has recruited a marquee oncology drug researcher into the ranks of the Novartis Institutes for BioMedical Research. Alice Shaw is jumping from prestigious posts intertwined through Mass General, Harvard and Dana-Farber to take the lead of NIBR’s translational clinical oncology group.

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Mi­rati preps its first look at their KRAS G12C con­tender, and they have to clear a high bar for suc­cess

If you’re a big KRAS G12C fan, mark your calendars for October 28 at 4:20 pm EDT.

That’s when Mirati $MRTX will unveil its first peek at the early clinical data available on MRTX849 in presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Mirati has been experiencing the full effect of a rival’s initial success at targeting the G12C pocket found on KRAS, offering the biotech some support on the concept they’re after — and biotech fans a race to the top. Amgen made a big splash with its first positive snapshot on lung cancer, but deflated sky-high expectations as it proved harder to find similar benefits in other types of cancers.

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Sean Parker, AP

Sean Park­er helps cre­ate a CRISPRed cell ther­a­py 2.0 play — and he’s got a high-pro­file set of lead­ers on the team

You can rack up one more high-profile debut effort in the wave of activity forming around cell therapy 2.0. It’s another appealing Bay Area group that’s attracted some of the top hands in the business to a multi-year effort to create a breakthrough. And they have $85 million in hand to make that first big step to the clinic.

Today it’s Ken Drazan and the team at South San Francisco-based ArsenalBio that are coming from behind the curtain for a public bow, backed by billionaire Sean Parker and a collection of investors that includes Beth Seidenberg’s new venture investment operation based in LA.
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Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
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Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Flu Virus (Source: CDC)

FDA ex­pands Xofluza ap­proval as Roche strug­gles to catch loom­ing flu mar­ket

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Xofluza (baloxavir marboxil) was approved last October in the US, the first landmark flu drug approval in 20 years and a much-needed green light for a company that had watched its leading flu drug Tamiflu get eaten alive by generics. Like its predecessor, the pill offered a reduction in flu symptoms but not a cure.

EMA backs sev­en ther­a­pies, in­clud­ing Mer­ck­'s Ebo­la vac­cine

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The drugmaker $MRK began developing the vaccine, christened Ervebo, during the West African outbreak that occurred between 2014 and 2016, killing more than 11,000.

The current outbreak in the Democratic Republic of Congo (DRC) has shown case fatality rates of approximately 67%, the agency estimated. Earlier this year, the WHO declared the outbreak — which so far has infected more than 3,000 people — a public health emergency of international concern.