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.

Paul Hudson, Sanofi CEO (Getty Images)

Sanofi CEO Paul Hud­son has $23B burn­ing a hole in his pock­et. And here are some hints on how he plans to spend that

Sanofi has reaped $11.1 billion after selling off a big chunk of its Regeneron stock at $515 a share. And now everyone on the M&A side of the business is focused on how CEO Paul Hudson plans to spend it.

After getting stung in France for some awkward politicking — suggesting the US was in the front of the line for Sanofi’s vaccines given American financial support for their work, versus little help from European powers — Hudson now has the much more popular task of managing a major cash cache to pull off something in the order of a big bolt-on. Or two.

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As­traZeneca trum­pets the good da­ta they found for Tagris­so in an ad­ju­vant set­ting for NSCLC — but many of the ex­perts aren’t cheer­ing along

AstraZeneca is rolling out the big guns this evening to provide a salute to their ADAURA data on Tagrisso at ASCO.

Cancer R&D chief José Baselga calls the disease-free survival data for their drug in an adjuvant setting of early stage, epidermal growth factor receptor-mutated NSCLC patients following surgery “momentous.” Roy Herbst, the principal investigator out of Yale, calls it “transformative.”

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The Avance Clinical leadership team: CEO Yvonne Lungershausen, Sandrien Louwaars - Director Business Development Operations, Gabriel Kremmidiotis - Chief Scientific Officer, Ben Edwards - Chief Strategy Officer

How Aus­tralia De­liv­ers Rapid Start-up and 43.5% Re­bate for Ear­ly Phase On­col­o­gy Tri­als

About Avance Clinical

Avance Clinical is an Australian owned Contract Research Organisation that has been providing high-quality clinical research services to the local and international drug development industry for 20 years. They specialise in working with biotech companies to execute Phase 1 and Phase 2 clinical trials to deliver high-quality outcomes fit for global regulatory standards.

As oncology sponsors look internationally to speed-up trials after unprecedented COVID-19 suspensions and delays, Australia, which has led the world in minimizing the pandemic’s impact, stands out as an attractive destination for early phase trials. This in combination with the streamlined regulatory system and the financial benefits including a very favourable exchange rate and the R & D cash rebate makes Australia the perfect location for accelerating biotech clinical programs.

Iron­wood kicks de­layed-re­lease Linzess for­mu­la­tion to the curb af­ter tri­al fail­ure

The delayed-release formulation of Ironwood and Allergan’s bowel drug Linzess will not see the light of day.

The experimental drug, MD-7246, failed to help patients with abdominal pain associated with irritable bowel syndrome with diarrhea (IBS-D) in a mid-stage study, prompting the partners to abandon the therapy.

First approved in 2012, Linzess (known chemically as linaclotide) enhances the activity of the intestinal enzyme guanylate cyclase-C to increase the secretion of intestinal fluid and then transit through the intestinal tract, as well as reduce visceral pain, to relieve pain and constipation associated with IBS.

Pablo Legorreta, founder and CEO of Royalty Pharma AG, speaks at the annual Milken Institute Global Conference in Beverly Hills, California (Patrick T. Fallon/Bloomberg via Getty Images)

Cap­i­tal­iz­ing Pablo: The world’s biggest drug roy­al­ty buy­er is go­ing pub­lic. And the low-key CEO di­vulges a few se­crets along the way

Pablo Legorreta is one of the most influential players in biopharma you likely never heard of.

Over the last 24 years, Legorreta’s Royalty Pharma group has become, by its own reckoning, the biggest buyer of drug royalties in the world. The CEO and founder has bought up a stake in a lengthy list of the world’s biggest drug franchises, spending $18 billion in the process — $2.2 billion last year alone. And he’s become one of the best-paid execs in the industry, reaping $28 million from the cash flow last year while reserving 20% of the cash flow, less expenses, for himself.

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Dan O'Day, Gilead CEO (Andrew Harnik, AP Images)

UP­DAT­ED: Gilead leas­es part­ner rights to TIG­IT, PD-1 in a $2B deal with Ar­cus. Now comes the hard part

Gilead CEO Dan O’Day has brokered his way to a PD-1 and lined up a front row seat in the TIGIT arena, inking a deal worth close to $2 billion to align the big biotech closely with Terry Rosen’s Arcus. And $375 million of that comes upfront, with cash for the buy-in plus equity, along with $400 million for R&D and $1.22 billion in reserve to cover opt-in payments and milestones..

Hotly rumored for weeks, the 2 players have formalized a 10-year alliance that starts with rights to the PD-1, zimberelimab. O’Day also has first dibs on TIGIT and 2 other leading programs, agreeing to an opt-in fee ranging from $200 million to $275 million on each. There’s $500 million in potential TIGIT milestones on US regulatory events — likely capped by an approval — if Gilead partners on it and the stars align on the data. And there’s another $150 million opt-in payments for the rest of the Arcus pipeline.

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Roger Perlmutter, Merck R&D chief (YouTube)

UP­DAT­ED: Backed by BAR­DA, Mer­ck jumps in­to Covid-19: buy­ing out a vac­cine, part­ner­ing on an­oth­er and adding an­tivi­ral to the mix

Merck execs are making a triple play in a sudden leap into the R&D campaign against Covid-19. And they have more BARDA cash backing them up on the move.

Tuesday morning the pharma giant simultaneously announced plans to buy an Austrian biotech that has been working on a preclinical vaccine candidate, added a collaboration on another vaccine with the nonprofit IAVI and inked a deal with Ridgeback Biotherapeutics on an early-stage antiviral.

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Bryan Roberts, Venrock

Ven­rock sur­vey shows grow­ing recog­ni­tion of coro­n­avirus toll, wan­ing con­fi­dence in ar­rival of vac­cines and treat­ments

When Venrock partner Bryan Roberts went to check the results from their annual survey of healthcare leaders, what he found was an imprint of the pandemic’s slow arrival in America.

The venture firm had sent their form out to hundreds of insurance and health tech executives, investors, officials and academics on February 24 and gave them two weeks to fill it out. No Americans had died at that point but the coronavirus had become enough of a global crisis that they included two questions about the virus, including “Total U.S. deaths in 2020 from the novel coronavirus will be:”.

David Hoey (Vaxxas)

In for the long vac­cine game, Mer­ck buys in­to patch de­liv­ery tech with pan­dem­ic po­ten­tial

When Merck dived into the R&D fray for a Covid-19 vaccine earlier this week, execs made it clear that they’re not necessarily looking to be first — with CEO Ken Frazier throwing cold water on the hotly-discussed 12- to 18-month timelines. But when it does emerge from behind, the pharma giant clearly expects to play a significant part.

Part of that will depend on next-generation delivery technology that reshapes the world’s imagination of a vaccine.