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.

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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