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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UP­DAT­ED: Stay tuned: Bio­gen’s num­bers are great — it’s their wor­ri­some fu­ture that leaves an­a­lysts skit­tish

Biogen came out with an upbeat assessment of their Q2 numbers today, discounting the arrival of a key rival for its blockbuster Spinraza franchise. But the top execs remain grimly determined to not say much anything new about the sore points that have dragged down its stock, including the future of its big investment in Alzheimer’s or how it plans to invest the considerable cash that the big biotech continues to reap.

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Why wait? Cel­gene re­struc­tures a big Jounce pact — ze­ro­ing in on new I/O path­way with $530M deal and bump­ing ICOS

Celgene’s business team isn’t waiting for the big merger with Bristol-Myers Squibb to go through before syncing its strategy with the new mother ship.

Tuesday evening the big biotech unveiled a $530 million deal — $50 million in upfront cash — to amend their alliance with Jounce Therapeutics $JNCE to gain worldwide rights to JTX-8064, an antibody that targets the LILRB2 receptor on macrophages. Their old, $2.6 billion deal is being scrapped, leaving Jounce with a pipeline that includes the lead drug, the ICOS-targeting vopratelimab.

PACT Phar­ma says it's per­fect­ed the tech to se­lect neoanti­gens for per­son­al­ized ther­a­py — now on­to the clin­ic

At PACT Pharma, the lofty goal to unleash a “tsunami” of T cells personalized for each patient has hinged on the ability to correctly identify the neoantigens that form something of a fingerprint for each tumor, and extract the small group of T cells primed to attack the cancer. It still has a long way to go testing a treatment in humans, but the biotech says it has nailed that highly technical piece of the process.

UP­DAT­ED: My­ovan­t's uter­ine fi­broid drug looks com­pet­i­tive in PhI­II — but can they van­quish mighty Ab­b­Vie?

Vivek Ramaswamy’s Myovant $MYOV has closely matched its positive first round of Phase III data for their uterine fibroid drug relugolix, setting up a head-to-head rivalry with pharma giant AbbVie as the little biotech steers to the market with a planned filing in Q4.

Here’s how Myovant plans to prevail over the AbbVie $ABBV empire.

In the study, 71.2% of women receiving once-daily relugolix combination therapy achieved the clinical response they were looking for, compared to only 14.7% in the control arm. The data comfortably reflected the same outcomes in the first Phase III — 73.4% of women receiving once-daily oral relugolix combination therapy achieved the responder criteria compared with 18.9% of women receiving placebo — which will reassure regulators that they are getting the carefully randomized data that qualifies for the FDA’s gold standard for success.

Lit­tle Mar­i­nus sees its shares eclipsed as the Sage ri­val fails to com­pare on PPD in PhII

The executive team at Sage $SAGE have skirted another potential pitfall on its way to racking up a big future for its depression drug Zulresso.

Little Marinus Pharmaceuticals $MRNS had sought to challenge the Sage drug with an IV formulation — followed by an oral version — of ganaxolone for postpartum depression. But researchers say their Phase II study failed to positively differentiate itself from a placebo at 28 days — leaving them to hold up “clinically meaningful” data within the first day of administration compared to the control arm.

Roche cuts loose Tam­i­flu OTC rights, hand­ing Sanofi the keys as the phar­ma gi­ant dou­bles down on Xofluza

Roche set out to make a better flu medicine than Tamiflu as that franchise was headed to a generic showdown. Now they’ll see just how well Xofluza stacks up against the mainstay drug after handing off over-the-counter rights in the US to Sanofi.

Sanofi $SNY says it will now step in to negotiate a deal with the FDA to steer Tamiflu into the OTC market, a role that could well involve new studies to ease passage of the drug out of doctor’s hands and into the consumer end of the market. And the French pharma giant will have first dibs over “selected” OTC markets around the world as they push ahead.

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.