Build­ing a bul­let­proof CAR? Sci­en­tists en­gi­neer a built-in PD-1 shield

CAR-Ts won’t be on the mar­ket be­fore next year, but the tech­nol­o­gy arms race in­spired by the prospect of a multi­bil­lion-dol­lar mar­ket has in­spired a group of promi­nent in­ves­ti­ga­tors to de­sign a new, 3.0 mod­el in the lab that in­cludes a built-in check­point mech­a­nism. And it worked like a charm in mouse mod­els of sol­id tu­mors—a crit­i­cal hur­dle that the key play­ers have been strug­gling to clear.

Pub­lish­ing in The Jour­nal of Clin­i­cal In­ves­ti­ga­tion, a group in­clud­ing Juno sci­en­tif­ic co-founder and Memo­r­i­al Sloan-Ket­ter­ing star Michel Sade­lain write about their lat­est ge­net­ic en­gi­neer­ing project with CAR-Ts, the in­di­vid­u­al­ly tai­lored T cells used to as­sault can­cer. The pa­per ex­plores how they tin­kered with var­i­ous as­pects of their third-gen­er­a­tion CAR-T. But the key de­vel­op­ment cen­tered on their use of a vi­ral vec­tor to de­sign a new ther­a­py with a built-in check­point mech­a­nism.

The check­point drugs—Op­di­vo and Keytru­da and Tecen­triq, which un­leash an im­mune sys­tem at­tack on can­cer cells—all present prob­lems of their own when used in com­bi­na­tion with CAR-T drugs, the re­searchers note. And that’s some­thing that can be skirt­ed with ge­net­ic reengi­neer­ing.

Ac­cord­ing to the sci­en­tists, this new mod­el CAR-T man­aged to work longer at a low­er dose in sol­id tu­mors in mice. Sev­er­al key el­e­ments—per­sis­tence, scor­ing a bet­ter hit on a sol­id tu­mor, low­er­ing the dose to achieve bet­ter safe­ty—are all in play. And the work promis­es to in­flu­ence the fran­tic race to dom­i­nate a new and com­pelling ther­a­peu­tic block­buster that can ul­ti­mate­ly eclipse the rel­a­tive­ly crude first-gen­er­a­tion treat­ments now in piv­otal stud­ies.

The study con­cludes:

“We demon­strate here that CAR T cell ther­a­py and PD-1 check­point block­ade are a ra­tio­nal com­bi­na­tion in a sol­id tu­mor mod­el. To di­rect­ly coun­ter­act PD-1–me­di­at­ed in­hi­bi­tion we used retro­vi­ral vec­tors to com­bine CAR-me­di­at­ed cos­tim­u­la­tion with a PD-1 (dom­i­nant neg­a­tive re­cep­tor). This com­bi­na­to­r­i­al strat­e­gy (cos­tim­u­la­tion and check­point block­ade) en­hanced T cell func­tion in the pres­ence of tu­mor PD-L1 ex­pres­sion, re­sult­ing in long-term tu­mor-free sur­vival fol­low­ing in­fu­sion of a sin­gle low dose of CAR T cells. Our study is rel­e­vant to the clin­i­cal prac­tice of adop­tive T cell ther­a­py and im­me­di­ate­ly trans­la­tion­al for the fol­low­ing rea­sons: (a) the cos­tim­u­la­to­ry sig­nal­ing do­mains test­ed—CD28 and 4-1BB—are the 2 cos­tim­u­la­to­ry do­mains used in on­go­ing clin­i­cal tri­als (Clin­i­cal­Tri­als.gov NCT02414269, NCT02159716, NCT01583686); (b) our mod­els of pleur­al mesothe­lioma re­ca­pit­u­late hu­man dis­ease and use large, clin­i­cal­ly rel­e­vant tu­mor bur­dens that elu­ci­date the rel­e­vance of T cell ex­haus­tion; and (c) our strat­e­gy of po­ten­ti­at­ing CAR T cells by ge­net­i­cal­ly en­cod­ed check­point block­ade us­es hu­man se­quences that can be read­i­ly ap­plied in the clin­ic.”

The in­ves­ti­ga­tors care­ful­ly note that this is not a mag­ic bul­let. Oth­er fac­tors are in play that will have to be ex­plored. And re­duc­ing a safe­ty threat on one side doesn’t mean that this tac­tic won’t back­fire.

“Be­cause it pro­vides block­ade of in­hibito­ry path­ways that is lim­it­ed to a tu­mor-tar­get­ed T cell reper­toire, adop­tive trans­fer of PD-1–in­sen­si­tive T cells may lim­it the au­toim­mu­ni­ty that re­sults from a more broad­ly ap­plied an­ti­body check­point block­ade,” they note. “Nonethe­less, ad­di­tion­al safe­ty strate­gies are nec­es­sary to lim­it or pre­vent po­ten­tial aug­ment­ed au­toim­mu­ni­ty of the ge­net­i­cal­ly mod­i­fied PD-1–in­sen­si­tive T cells.”

Of course, any mouse study is just the first step in a process that can lead to a long road of clin­i­cal work. Typ­i­cal­ly, they nev­er sur­vive that process. But this par­tic­u­lar project is ex­cep­tion­al, cen­ter­ing on promi­nent, well-con­nect­ed in­ves­ti­ga­tors like Sade­lain, who are al­ready close­ly in­volved in Juno’s de­vel­op­ment ef­fort.

As Kite’s move yes­ter­day to snag new tech un­der­scores, the lead­ers in the field are acute­ly aware of the fact that lim­i­ta­tions and threats—like the one that claimed the lives of four pa­tients in Juno’s work—have to be over­come be­fore CAR-Ts can reach their full po­ten­tial.

This is one step that will be close­ly fol­lowed by all.

In­side Track: Be­hind the Scenes of a Ma­jor Biotech SPAC

Dr. David Hung and Michelle Doig are no strangers to the SPAC phenomenon. As Founder and CEO of Nuvation Bio, a biotech company tackling some of the greatest unmet needs in oncology, Dr. Hung recently took the company public in one of this year’s biggest SPAC related deals. And as Partner at Omega Funds, Doig not only led and syndicated Nuvation Bio’s Series A, but is now also President of the newly formed, Omega-sponsored, Omega Alpha SPAC (Nasdaq: OMEG; oversubscribed $138m IPO priced January 6, 2021).

Hal Barron, GSK R&D chief (Endpoints News)

Hal Bar­ron gam­bles $625M cash on high-wire TIG­IT act, throw­ing Glax­o­SmithK­line in­to heat­ed race and com­plet­ing next-gen I/O trin­i­ty

Count Hal Barron and GlaxoSmithKline in for the TIGIT fight.

The stakes are as high as the risks: While a growing pack of Big Pharma rivals is lending credence to the hypothesis that TIGIT will be the next big immune checkpoint and cancer drug target, the first clinical trials have shown response rates that can be described as modest at best. But Barron’s bet is on the whole “axis” that the receptor sits on, with an eye on testing its new anti-TIGIT antibody not just in combo with PD-1 but also in triplets.

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As Covid-19 shifts the world's at­ten­tion to biotech, Noubar Afeyan's Flag­ship builds $3.4B fund to fu­el new in­ven­tions. Here's the plan

A little more than a year ago, Flagship Pioneering rolled out a monster fund with $1.1 billion in it to bankroll the platform companies they were creating inside their own labs. But it turns out, that was just the prelude to a much, much larger raise, as both current investors — who’ve been reaping the rewards of some booming biotech stocks — join in with new investors betting on more in the years to come.

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Bio­gen sig­nals a big PhI­II fail­ure as the lead gene ther­a­py in their $800M Night­star buy­out goes down in flames

That $800 million buyout of Nightstar has turned into a bust for Biogen as the lead therapy in the deal failed a pivotal study, signaling a severe setback for the biotech’s ambitions in gene therapies.

The big biotech put out the word after the market closed on Monday that the gene therapy they picked up in the deal for a degenerative blindness called choroideremia failed the Phase III study, just a month after their #2 drug in the deal also flopped in a mid-stage study.

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Geoffrey Porges, SVB Leerink

Top an­a­lyst maps a rocky road for Ver­tex — un­less they adopt a $10B M&A cam­paign to save the pipeline

After repeatedly poking Vertex $VRTX execs with pointed criticism of their R&D strategy, top SVB Leerink analyst Geoffrey Porges is now turning up the heat to a full-scale roasting.

In a note out early Monday morning, Porges spotlights the impact of Vertex’s recent follow-up failure on AATD — their treatment hit the endpoint but missed on commercial prospects — rewriting his recommended scenario for CEO Reshma Kewalramani as she grapples with the setback.

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Stephen Hahn (AP Images)

UP­DAT­ED: Ex-FDA com­mish Stephen Hahn joins Flag­ship, a ven­ture group that spawned Covid-19 vac­cine mak­er Mod­er­na

That revolving door between the FDA and industry is spinning even faster than usual.

Former FDA commissioner Stephen Hahn is joining Flagship Pioneering, the venture outfit that founded Moderna — which raced its way to an FDA EUA for a Covid-19 vaccine that is making billions of dollars– as the new CMO of its Preemptive Medicine and Health Security initiative.

Flagship confirmed the hire — first reported in The Washington Post — in a statement out late Monday.

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Patrizia Cavazzoni, CDER

FDA’s Cavaz­zoni calls for ad­comms to ‘get back to the sub­stance’

While her comments were recorded prior to the FDA’s recent approval of Biogen’s controversial Alzheimer’s drug, CDER Director Patrizia Cavazzoni presciently called for substantiating reforms to the advisory committee process at the agency.

Short on examples, Cavazzoni said at a BIO event aired on Monday that some recent adcomms show “how they can be swayed by emotion in the face of hard facts,” but they need to “get back to the fundamentals, which is listening to thoughtful input from experts in response to thoughtful questions that we ask them.”

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Terns Phar­ma­ceu­ti­cals touts safe­ty da­ta from an ex-Eli Lil­ly can­di­date in the hunt for NASH treat­ment

While many others have tried — and failed — to get a NASH candidate across the finish line, Terns Pharmaceuticals thinks its FXR agonist will eventually earn its wings without the safety issues that have slowed others down. Now, a mid-stage safety readout could help add some validity to those hopes.

No patients in the Phase IIa LIFT study discontinued TERN-101 due to side effects, CMO Erin Quirk said during a call with investors on Monday morning. That includes pruritus, an uncomfortable itching sensation that frequently leads patients to drop out of other FXR agonist studies.

Paul Burton, incoming Moderna CMO (J&J/file photo)

Look­ing be­yond the pan­dem­ic, Mod­er­na ap­points J&J vet­er­an Paul Bur­ton as new CMO

Moderna is turning to one of its Covid-19 vaccine competitors to fill its open CMO slot, but this time, it’s not the vaccine experience they’re after.

Paul Burton, who’s spent 16 years at J&J, most recently as chief global medical affairs officer of Janssen, will take over as Moderna CMO on July 6.

With an eye toward a future beyond the pandemic, the mRNA biotech went with Burton, who earned his MD and PhD degrees in London, as he offers experience on a range of therapeutic areas, as well as work as a cardiothoracic surgeon and leading tech projects with Apple.

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