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 (Clin­i­cal­Tri­ 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.

Biogen CEO Michel Vounatsos (via Getty Images)

With ad­u­canum­ab caught on a cliff, Bio­gen’s Michel Vounatsos bets bil­lions on an­oth­er high-risk neu­ro play

With its FDA pitch on the Alzheimer’s drug aducanumab hanging perilously close to disaster, Biogen is rolling the dice on a $3.1 billion deal that brings in commercial rights to one of the other spotlight neuro drugs in late-stage development — after it already failed its first Phase III.

The big biotech has turned to Sage Therapeutics for its latest deal, close to a year after the crushing failure of Sage-217, now dubbed zuranolone, in the MOUNTAIN study.

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Pascal Soriot (AP Images)

As­traZeneca, Ox­ford on the de­fen­sive as skep­tics dis­miss 70% av­er­age ef­fi­ca­cy for Covid-19 vac­cine

On the third straight Monday that the world wakes up to positive vaccine news, AstraZeneca and Oxford are declaring a new Phase III milestone in the fight against the pandemic. Not everyone is convinced they will play a big part, though.

With an average efficacy of 70%, the headline number struck analysts as less impressive than the 95% and 94.5% protection that Pfizer/BioNTech and Moderna have boasted in the past two weeks, respectively. But the British partners say they have several other bright spots going for their candidate. One of the two dosing regimens tested in Phase III showed a better profile, bringing efficacy up to 90%; the adenovirus vector-based vaccine requires minimal refrigeration, which may mean easier distribution; and AstraZeneca has pledged to sell it at a fraction of the price that the other two vaccine developers are charging.

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Jason Kelly, Ginkgo Bioworks CEO (Kyle Grillot/Bloomberg via Getty Images)

Af­ter Ko­dak de­ba­cle, US lends $1.1B to a syn­thet­ic bi­ol­o­gy com­pa­ny and their big Covid-19, mR­NA plans

In mid-August, as Kodak’s $765 million government-backed push into drug manufacturing slowly fell apart in national headlines, Ginkgo Bioworks CEO Jason Kelly got a message from his company’s government liaison: HHS wanted to know if they, too, might want a loan.

The government’s decision to lend Kodak three quarters of a billion dollars raised eyebrows because Kodak had never made drugs before. But Ginkgo, while not a manufacturing company, had spent the last decade refining new ways to produce materials inside cells and building automated facilities across Boston.

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Bahija Jallal (file photo)

TCR pi­o­neer Im­muno­core scores a first with a land­mark PhI­II snap­shot on over­all sur­vival for a rare melanoma

Bahija Jallal’s crew at TCR pioneer Immunocore says they have nailed down a promising set of pivotal data for their lead drug in a frontline setting for a solid tumor. And they are framing this early interim readout as the convincing snapshot they need to prove that their platform can deliver on a string of breakthrough therapies now in the clinic or planned for it.

In advance of the Monday announcement, Jallal and R&D chief David Berman took some time to walk me through the first round of Phase III data for their lead TCR designed to treat rare, frontline cases of metastatic uveal melanoma that come with a grim set of survival expectations.

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Vivek Ramaswamy (Jeff Rumans/JPM 2020)

Urovan­t's lead drug dis­ap­points in mid-stage study as first big FDA de­ci­sion looms

Just as Urovant gets ready for its first big FDA decision on vibegron, the drug has flopped in what would’ve been a follow-on indication.

In a Phase IIa trial involving women with abdominal pain due to irritable bowel syndrome, vibegron failed to meet the bar on improving “average worst abdominal pain” over 12 weeks, compared to placebo, among IBS-D patients.

There were actually slightly more responders in the placebo group than in the drug arm, with only 40.9% of those randomized to vigebron achieving at least a 30% decrease in “worst abdominal pain” in the past 24 hours. The trial enrolled 222 women but only 189 completed the study.

Gen­mab ax­es an ADC de­vel­op­ment pro­gram af­ter the da­ta fail to im­press

Genmab $GMAB has opted to ax one of its antibody-drug conjugates after watching it flop in the clinic.

The Danish biotech reported Tuesday that it decided to kill their program for enapotamab vedotin after the data gathered from expansion cohorts failed to measure up. According to the company:

While enapotamab vedotin has shown some evidence of clinical activity, this was not optimized by different dose schedules and/or predictive biomarkers. Accordingly, the data from the expansion cohorts did not meet Genmab’s stringent criteria for proof-of-concept.

Vas Narasimhan, Novartis CEO (Jason Alden/Bloomberg via Getty Images)

Vas Narasimhan's 'Wild Card' drugs: No­var­tis CEO high­lights po­ten­tial jack­pots, as well as late-stage stars, in R&D pre­sen­ta­tion

Novartis is always one of the industry’s biggest R&D spenders. As they often do toward the end of each year, company execs are highlighting the drugs they expect will most likely be winners in 2021.

And they’re also dreaming about some potential big-time lottery tickets.

As part of its annual investor presentation Tuesday, where the company allows investors and analysts to virtually schmooze with the bigwigs, Novartis CEO Vas Narasimhan will outline what he thinks are the pharma’s “Wild Cards.” The slate of five experimental drugs are those that Novartis hopes can be high-risk, high-reward entrants into the market over the next half-decade or so, and cover a wide range of indications.

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The ad­u­canum­ab co­nun­drum: The PhI­II failed a clear reg­u­la­to­ry stan­dard, but no one is cer­tain what that means any­more at the FDA

Eighteen days ago, virtually all of the outside experts on an FDA adcomm got together to mug the agency’s Billy Dunn and the Biogen team when they presented their upbeat assessment on aducanumab. But here we are, more than 2 weeks later, and the ongoing debate over that Alzheimer’s drug’s fate continues unabated.

Instead of simply ruling out any chance of an approval, the logical conclusion based on what we heard during that session, a series of questionable approvals that preceded the controversy over the agency’s recent EUA decisions has come back to haunt the FDA, where the power of precedent is leaving an opening some experts believe can still be exploited by the big biotech.

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John Maraganore, Alnylam CEO (Scott Eisen/Bloomberg via Getty Images)

Al­ny­lam gets the green light from the FDA for drug #3 — and CEO John Maraganore is ready to roll

Score another early win at the FDA for Alnylam.

The FDA put out word today that the agency has approved its third drug, lumasiran, for primary hyperoxaluria type 1, better known as PH1. The news comes just 4 days after the European Commission took the lead in offering a green light.

An ultra rare genetic condition, Alnylam CEO John Maraganore says there are only some 1,000 to 1,700 patients in the US and Europe at any particular point. The patients, mostly kids, suffer from an overproduction of oxalate in the liver that spurs the development of kidney stones, right through to end stage kidney disease.

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