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.

Hal Barron, GSK

Break­ing the death spi­ral: Hal Bar­ron talks about trans­form­ing the mori­bund R&D cul­ture at GSK in a crit­i­cal year for the late-stage pipeline

Just ahead of GlaxoSmithKline’s Q2 update on Wednesday, science chief Hal Barron is making the rounds to talk up the pharma giant’s late-stage strategy as the top execs continue to woo back a deeply skeptical investor group while pushing through a whole new R&D culture.

And that’s not easy, Barron is quick to note. He told the Financial Times:

I think that culture, to some extent, is as hard, in fact even harder, than doing the science.

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Aca­dia is mak­ing the best of it, but their lat­est PhI­II Nu­plazid study is a bust

Acadia’s late-stage program to widen the commercial prospects for Nuplazid has hit a wall. The biotech reported that their Phase III ENHANCE trial flat failed. And while they $ACAD did their best to cherry pick positive data wherever they can be found, this is a clear setback for the biotech.

With close to 400 patients enrolled, researchers said the drug flunked the primary endpoint as an adjunctive therapy for patients with an inadequate response to antipsychotic therapy. The p-value was an ugly 0.0940 on the Positive and Negative Syndrome Scale, which the company called out as a positive trend.

Their shares slid 12% on the news, good for a $426 million hit on a $3.7 billion market cap at close.

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Some Big Phar­mas stepped up their game on da­ta trans­paren­cy — but which flunked the test?

The nonprofit Bioethics International has come out with their latest scorecard on data transparency among the big biopharmas in the industry — flagging a few standouts while spotlighting some laggards who are continuing to underperform.

Now in its third year, the nonprofit created a new set of standards with Yale School of Medicine and Stanford Law School to evaluate the track record on trial registration, results reporting, publication and data-sharing practice.

Busy Gilead crew throws strug­gling biotech a life­line, with some cash up­front and hun­dreds of mil­lions in biobucks for HIV deal

Durect $DRRX got a badly needed shot in the arm Monday morning as Gilead’s busy BD team lined up access to its extended-release platform tech for HIV and hepatitis B.

Gilead, a leader in the HIV sector, is paying a modest $25 million in cash for the right to jump on the platform at Durect, which has been using its technology to come up with an extended-release version of bupivacaine. The FDA rejected that in 2014, but Durect has been working on a comeback.

In­tec blitzed by PhI­II flop as lead pro­gram fails to beat Mer­ck­'s stan­dard com­bo for Parkin­son’s

Intec Pharma’s $NTEC lead drug slammed into a brick wall Monday morning. The small-cap Israeli biotech reported that its lead program — coming off a platform designed to produce a safer, more effective oral drug for Parkinson’s — failed the Phase III at the primary endpoint.

Researchers at Intec, which has already seen its share price collapse over the past few months, says that its Accordion Pill-Carbidopa/Levodopa failed to prove superior to Sinemet in reducing daily ‘off’ time. 

Cel­gene racks up third Ote­zla ap­proval, heat­ing up talks about who Bris­tol-My­ers will sell to

Whoever is taking Otezla off Bristol-Myers Squibb’s hands will have one more revenue stream to boast.

The drug — a rising star in Celgene’s pipeline that generated global sales of $1.6 billion last year — is now OK’d to treat oral ulcers associated with Behçet’s disease, a common symptom for a rare inflammatory disorder. This marks the third FDA approval for the PDE4 inhibitor since 2014, when it was greenlighted for plaque psoriasis and psoriatic arthritis.

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Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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Vlad Coric (Biohaven)

In an­oth­er dis­ap­point­ment for in­vestors, FDA slaps down Bio­haven’s re­vised ver­sion of an old ALS drug

Biohaven is at risk of making a habit of disappointing its investors.

Late Friday the biotech $BHVN reported that the FDA had rejected its application for riluzole, an old drug that they had made over into a sublingual formulation that dissolves under the tongue. According to Biohaven, the FDA had a problem with the active ingredient used in a bioequivalence study back in 2017, which they got from the Canadian drugmaker Apotex.

Apotex, though, has been a disaster ground. The manufacturer voluntarily yanked the ANDAs on 31 drugs — in late 2017 — after the FDA came across serious manufacturing deficiencies at their plants in India. A few days ago, the FDA made it official.

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