Re­sis­tant to CAR-T ther­a­pies? It's the can­cer, not your im­mune sys­tem — study

Safe­ty con­cerns and man­u­fac­tur­ing short­com­ings aside, ex­ist­ing CAR-T ther­a­pies — No­var­tis’ Kym­ri­ah and Gilead’s Yescar­ta — sim­ply don’t work in 10% to 20% of pa­tients with B cell ma­lig­nan­cies. What fac­tors un­der­pin this re­sis­tance to CAR-T ther­a­py? The main cul­prit could be the can­cer cells them­selves, ac­cord­ing to a team of re­searchers at Penn.

CAR-T ther­a­pies are en­gi­neered to work in this way: Cells are ex­tract­ed from the pa­tient and then ma­nip­u­lat­ed in a lab where chimeric anti­gen re­cep­tors are added to di­rect the pa­tient’s own T cells to snuff out spe­cif­ic can­cer cells once re-in­fused back in­to the pa­tient. But in a frac­tion of pa­tients, the armed im­mune at­tack does not oblit­er­ate the dis­ease. By tar­get­ing CD19, a mark­er present on al­most all B cells, CAR-T ther­a­pies have shown re­mark­able po­ten­cy and dura­bil­i­ty in a num­ber of blood can­cers, in­clud­ing acute lym­phoblas­tic leukemia (ALL).

Re­search so far sug­gests that re­sis­tance to CAR-T ther­a­pies is re­lat­ed to the loss of CD19. When CD19 dis­ap­pears from leukemic cells, they be­come in­vis­i­ble to CAR-T ther­a­pies, not­ed the study’s co-se­nior au­thor Mar­co Ruel­la, an as­sis­tant pro­fes­sor of hema­tol­ogy-on­col­o­gy at the Uni­ver­si­ty of Penn­syl­va­nia, in an in­ter­view with End­points News.

“That ex­plains maybe half of the re­laps­es in leukemia and maybe a third in lym­phoma — so there is still a vast ma­jor­i­ty of pa­tients where we sim­ply don’t know what’s go­ing on,” he said.

An­oth­er fac­tor dri­ving re­sis­tance was dys­func­tion­al T cells, he added. “What we are hy­poth­e­siz­ing here is that there can be a third mech­a­nism…that even in the pres­ence of CD19 those leukemic cells are un­able to die when they are trig­gered by CAR-T.”

“The con­stant pres­ence of the leukemic cells that ba­si­cal­ly can­not die — they’re sort of high­landers — caus­es dys­func­tion in the T-cells. To start with — the CAR-T (cells) are okay — but then they keep try­ing to kill leukemic cells that in­trin­si­cal­ly can­not die, and then, over time, they be­come dys­func­tion­al.”

The find­ings were pub­lished on Thurs­day in Can­cer Dis­cov­ery, a jour­nal of the Amer­i­can As­so­ci­a­tion for Can­cer Re­search.

In the Penn study, re­searchers per­formed a genome-wide CRISPR/Cas9-based screen of an ALL cell line to iso­late path­ways as­so­ci­at­ed with re­sis­tance. Cells were edit­ed for loss of func­tion of sin­gle genes and com­bined with CAR-T cells for 24 hours to iden­ti­fy the path­way dri­ving the pri­ma­ry re­sis­tance. The in vit­ro da­ta showed that in the ALL cells that re­sist­ed the CAR-T at­tack, there was a short­age of genes in­volved in ac­ti­vat­ing the cell death path­way and a spike in genes nec­es­sary for evad­ing the cell death path­way.

In­stead of in­ter­ro­gat­ing sam­ples from pa­tients that have failed to ben­e­fit from CAR-T ther­a­pies, the plan was to mod­el a genome-wide re­sis­tance mech­a­nism and then con­firm it in pa­tients. Many pa­tients are now be­ing treat­ed with CAR-Ts, but still, the num­bers are lim­it­ed — so this ap­proach was used to dis­cov­er aber­ra­tions that the lim­it­ed num­ber of pa­tient sam­ples would not be pow­ered to iden­ti­fy, Ruel­la said.

“We start­ed with an un­bi­ased genome-wide ap­proach to study re­sis­tance and we saw that the new CRISPR/Cas9 genome knock­out li­braries were per­fect be­cause they would al­low you to ex­plore knock­outs in the whole genome and in­ter­ro­gate it for re­sis­tance to CAR-T.”

The find­ings were am­pli­fied in an­i­mal mod­els. The re­searchers then tried to make sense of the re­sults by us­ing pe­di­atric pa­tient sam­ples from pre­vi­ous CAR-T tri­als by an­a­lyz­ing the genes in leukemia cells and in T cells — pre- and post-in­fu­sion — from re­spon­ders and non-re­spon­ders. The da­ta were stark: pre­vi­ous­ly iden­ti­fied sig­nal­ing path­ways in can­cer cells were di­rect­ly as­so­ci­at­ed with re­spons­es to CAR ther­a­py, sug­gest­ing that death re­cep­tor sig­nal­ing is a key reg­u­la­tor of pri­ma­ry re­sis­tance to CAR T cell ther­a­py in ALL, the au­thors con­clud­ed.

“This mech­a­nism ap­pears to re­ly on two phas­es: an ini­tial re­sis­tance to death re­cep­tor-dri­ven killing, fol­lowed by an anti­gen-dri­ven, pro­gres­sive im­pair­ment in CAR-T cell func­tion. To­geth­er this leads to CAR T cell fail­ure that per­pet­u­ates dis­ease pro­gres­sion,” they wrote.

De­spite their abun­dant promise, the adop­tion of CAR-T ther­a­pies — No­var­tis’ Kym­ri­ah and Gilead’s Yescar­ta — has un­der­whelmed ini­tial ex­pec­ta­tions.

The up­take of Kym­ri­ah was plagued by man­u­fac­tur­ing prob­lems, and de­spite No­var­tis’ at­tempt to ex­pand its ca­pac­i­ty, sales con­tin­ue to dis­ap­point com­mer­cial­ly, giv­ing Yescar­ta an edge in the mar­ket. Mean­while, big side ef­fects — no­tably life-threat­en­ing episodes of cy­tokine re­lease syn­drome and neu­ro­tox­i­c­i­ty — as well as the ther­a­pies’ ex­pen­sive price tags have al­so lim­it­ed their use. Oth­er drug de­vel­op­ers have tak­en note of these con­straints and are de­vel­op­ing off-the-shelf CAR-T ther­a­pies, de­signed to smoothen man­u­fac­tur­ing com­plex­i­ties by us­ing healthy donor cells.

But the team at Penn cau­tioned that the prac­tice may not nec­es­sar­i­ly help the sub­set of pa­tients whose can­cer cells car­ry this pro­por­tion of un­fa­vor­able genes.

“A pos­si­ble im­pli­ca­tion of our ob­ser­va­tions is that the use of healthy donor (i.e. al­lo­gene­ic donor or “uni­ver­sal” donor) T cells as a sub­strate for CAR T cell man­u­fac­tur­ing may face the same bar­ri­ers as au­tol­o­gous prod­ucts,” the au­thors wrote. “Un­der­stand­ing how in­trin­sic and ac­quired T cell dys­func­tion co­op­er­ate to cause ther­a­peu­tic fail­ure will be crit­i­cal to the de­sign of the next gen­er­a­tion of cel­lu­lar ther­a­pies.”

The top 100 bio­phar­ma VCs, Bob Brad­way places $2B bet in can­cer, gene edit­ing pi­o­neer's new big idea, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Before diving in, we had some news to share: Endpoints is launching a premium weekly report focusing on all things regulatory. Coverage will be led by our new senior editor, Zachary Brennan, who joins us from POLITICO. Arsalan Arif has more details in his Publisher’s Note.

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Robert Bradway (Photographer: Scott Eisen/Bloomberg via Getty Images)

UP­DAT­ED: Am­gen snaps up can­cer drug play­er Five Prime, adding PhI­II-ready FGFR2b drug in $2B M&A play

Amgen is making a long-awaited move on the M&A side, buying South San Francisco-based Five Prime $FPRX for close to $2 billion and adding a slate of new cancer drugs to the pipeline.

Amgen is paying $38 a share, putting the deal value at $1.9 billion. The stock closed at $21.26 last night, giving investors a 78% premium.

The jewel in the crown of this deal is bemarituzumab, which Amgen describes as a first-in-class, Phase III-ready anti-FGFR2b antibody. Amgen was drawn to the bargaining table by Five Prime’s mid-stage data on gastric cancer, satisfied by PFS and OS data helping to validate FGFR2b as a target. Amgen researchers will now expand on the R&D program in other epithelial cancers, including lung, breast, ovarian and other cancers.

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David Liu (Casey Atkins Photography courtesy Broad Institute)

David Liu has a new big idea: pro­teome edit­ing. It could one day shred tau, RAS and some of the worst dis­ease-caus­ing pro­teins

Before David Liu became famous for inventing new forms of gene editing, he was known around academia in part for a more obscure innovation: a Rube Goldberg-esque system that uses bacteria-infecting viruses to take one protein and turn it into another.

Since 2011, Liu’s lab has used the system, called PACE, to dream up fantastical new proteins: DNA base editors far more powerful than the original; more versatile forms of the gene editor Cas9; insecticides that kill insecticide-resistant bugs; enzymes that slide synthetic amino acids into living organisms. But they struggled throughout to master one of the most common and powerful proteins in the biological world: proteases, a set of Swiss army knife enzymes that cut, cleave or shred other proteins in everything from viruses to humans.

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The 2021 top 100 bio­phar­ma in­vestors: As the pan­dem­ic hit and IPOs boomed, VCs swung in­to ac­tion like nev­er be­fore

The global pandemic may have roiled economies, killed hundreds of thousands and throttled entire industries, but the only effect it had on biopharma venture investing was to help turbocharge the field to giddy new heights.

Below you’ll find the new top 100 venture investors in the industry, ranked by the number of deals they were publicly involved in, as tracked by DealForma chief Chris Dokomajilar. The numbers master then calculated the estimated amount of money they put into each deal — divvying up the cash by the number of players — to indicate how they managed their syndicates.

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Bruce Cozadd, Jazz CEO (Jazz Pharmaceuticals)

Jazz CEO Bruce Cozadd cam­paigned for 6 months to buy GW Phar­ma. A 90% pre­mi­um sealed the deal — along with $17.6M in ‘re­ten­tion’ in­cen­tives

Jazz CEO Bruce Cozadd didn’t beat around the bush.

In his first video meeting with GW Pharma chief Justin Gover last July 8, he offered to pay $172 a share to get the company, which had beaten the odds in getting its remarkable cannabinoid drug Epidiolex across the regulatory finish line for epilepsy. GW’s stock closed at $129 that day.

Cozadd had already done his homework on the financing to make sure he could swing it the way he wanted. He just needed to do some due diligence before making the non-binding bid firm.

UP­DAT­ED: Not 3 weeks af­ter tak­ing Hu­ma­cyte pub­lic, Ra­jiv Shuk­la launch­es an­oth­er blank check com­pa­ny

One of biotech’s earliest SPAC investors is back with another blank-check company, less than a month after his last effort announced its intent to merge.

Rajiv Shukla is intending to take a third lucky winner public with Alpha Healthcare Acquisition III, filing to go public Thursday with a $150 million raise penciled in. The move comes just a couple of weeks after Shukla’s second SPAC said it would jump to Nasdaq in tandem with Laura Niklason’s Humacyte in a $255 million new investment.

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Paul Hudson, Getty Images

How does Paul Hud­son's $13.5M comp pack­age stack up against oth­er CEOs? He's in the 'first quar­tile'

Paul Hudson arrived at Sanofi like a hurricane, chopping off duds in the pipeline, shaking up the C-suite, striking big M&A deals and jumping into the Covid-19 vaccine race — all in an attempt to reboot a pharma giant notorious for its setbacks.

Now, we’re getting a look at what the CEO brought home in his first year on the job.

When all is said and done, Hudson will have made about $6.7 million in 2020, about $2.5 million of which has already been paid. The bigger figure includes a $2.3 million bonus that’s subject to approval at an April meeting, and another $1.8 million in variable compensation that has yet to be paid.

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Ab­b­Vie of­floads UK site for $119M in sale to Chi­nese cell and gene ther­a­py play­er Phar­maron

With its Allergan buyout now long in the books, AbbVie has been taking a hard look at its suddenly expansive global ops to find space for a deal. Now, working with a Chinese cell and gene therapy player hungry for more elbow room abroad, AbbVie has taken one UK facility off its books.

AbbVie has offloaded its Liverpool manufacturing site as part of a $118.7 million sale to Chinese cell and gene therapy player Pharmaron, which is pitching the purchase as the next step in its global expansion plans, the companies said last week.

Af­ter three years of courtship (and turn­downs), Mer­ck pounced on the first glance of clin­i­cal da­ta in $1.85B Pan­dion takeover

It’s almost become cliché for biotech executives to talk about the importance of keeping your options open and being prepared to go all the way. But when it comes to negotiating with a giant like Merck, a little patience can indeed go a long way.

Just ask Pandion Therapeutics.

Days ago we already learned that Merck is shelling out $1.85 billion to pick up the biotech and its slate of autoimmune hopefuls. What we didn’t know until the SEC disclosure dropped Thursday is that the deal comes after Pandion turned down two other proposals from Merck over the past three years and held out until the last minute for a sweetened deal.

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