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.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

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Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Facing the big dogs in the PD-(L)1 space, AstraZeneca has taken its own contender Imfinzi into blockbuster territory in its four years on the market but sees even bigger things for the drug. Combinations could be the key, and early results from a mid-stage test are adding some fuel to that strategy.

Imfinzi combined with one of two investigational immunotherapies — a CD73 antibody dubbed oleclumab or an anti-NGK2a named monalizumab — topped Imfinzi alone in terms of overall response and progression-free survival in patients with stage III non-small cell lung cancer whose tumors had not worsened during concurrent chemoradiation, according to interim data from the Phase II COAST trial set to be presented at #ESMO21.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Eu­ro­pean study finds that Gilead­'s Covid-19 an­tivi­ral remde­sivir shows no clin­i­cal ben­e­fit

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Grifols is now the largest shareholder of Biotest, a company valued at more than $1.8 billion. By teaming up, the two will try to increase the number of plasma therapies available and increase patient access around the world, Grifols said in a press release.

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