CAR-M era be­gins as Caris­ma dos­es first pa­tient

Last month, doc­tors at the Abram­son Can­cer Cen­ter in Philadel­phia in­sert­ed a nee­dle in­to a pa­tient with an un­treat­able tu­mor and be­gan draw­ing blood in­to a ma­chine.

The ma­chine fil­tered out every­thing but a spe­cif­ic set of im­mune cells that were then pack­aged, put on a plane and shipped, still warm, to a fa­cil­i­ty in Sun­ny­vale, CA. Over 24 days, tech­ni­cians ex­pand­ed the cells, armed them with a new kind of re­cep­tor and sent them back, now cryo­geni­cal­ly frozen, on a plane to Philadel­phia to be in­fused back in­to the pa­tient.

Saar Gill

It’s a fa­mil­iar process. A few de­tails aside, it’s played out thou­sands of times over the past half decade as pa­tients with dead­ly blood can­cers re­ceived CAR-T treat­ments, po­ten­tial­ly life-sav­ing in­fu­sions of ge­net­i­cal­ly tur­bocharged T cells. But for the first time, de­vel­op­ers used a dif­fer­ent im­mune cell, one they hope can un­lock a whole new set of pa­tients and in­cur­able tu­mors: macrophages.

Caris­ma Ther­a­peu­tics, the Uni­ver­si­ty of Penn­syl­va­nia spin­out, an­nounced to­day that they had dosed their first pa­tient with CAR-macrophages, or what they call CAR-M. Re­ly­ing on a bub­bly im­mune cell that eats pathogens and of­ten gath­ers around sol­id tu­mors, they hope it can bring the ben­e­fits of cell ther­a­py in­to places where CAR-T has con­sis­tent­ly failed.

Joshua Bauml

“CAR-T ther­a­pies have made huge ad­vances in the field of [blood can­cers], but there are ma­jor lim­i­ta­tions to uti­liz­ing the same tech­nol­o­gy in sol­id tu­mors,” Joshua Bauml, an on­col­o­gist at Penn Med­i­cine and lead in­ves­ti­ga­tor on the study, told End­points News. “And I think that this tri­al aims to over­come some of those in a very clever way.”

Biotechs and aca­d­e­m­ic re­searchers have man­aged to make CAR-Ts with re­cep­tors that go af­ter sev­er­al dif­fer­ent blood can­cers, in­clud­ing lym­phoma and mul­ti­ple myelo­ma. But ef­forts to ap­ply T cells in sol­id tu­mors have failed, in large part be­cause many such tu­mors have mech­a­nisms to keep T cells from in­fil­trat­ing their en­vi­ron­ment and de­stroy­ing can­cer cells.

Those en­vi­ron­ments, though, are of­ten swarm­ing with macrophages. That’s ac­tu­al­ly a bad thing: There are mul­ti­ple types of macrophages and tu­mors re­ly on ones that sup­press the im­mune sys­tem, ef­fec­tive­ly giv­ing the can­cer a walled-off com­pound in which to thrive.

Michael Klichin­sky

But near­ly a decade ago Uni­ver­si­ty of Penn­syl­va­nia hema­tol­o­gist Saar Gill and a grad­u­ate stu­dent, Michael Klichin­sky, fig­ured out that if you at­tached a CAR on­to a macrophage, those macrophages can en­ter the tu­mor’s en­vi­ron­ment like a Tro­jan horse. There it both di­rect­ly eats up the tu­mor and sends out sig­nals that turn bad macrophages in­to good macrophages that can kill can­cer cells and re­cruit oth­er im­mune cells to join the brigade.

Or at least it did in an­i­mal mod­els. The new tri­al is test­ing to see whether those re­sults can trans­late in­to hu­mans, be­gin­ning with 18 pa­tients who have can­cers that ex­press HER2 and have ex­haust­ed oth­er op­tions.

Caris­ma chose to start with HER2 be­cause there’s al­ready a swath of treat­ments that tar­get the re­cep­tor, CMO Deb­o­ra Bar­ton said. It helps stan­dard­ize an oth­er­wise high­ly ex­per­i­men­tal pro­ce­dure.

Deb­o­ra Bar­ton

“We don’t want to add any vari­abil­i­ty,” she told End­points.

The first group of pa­tients will re­ceive 5 bil­lion cells in 3 dif­fer­ent in­fu­sions over 5 days to en­sure noth­ing goes wrong. If that goes well, the sec­ond group will re­ceive all the cells at once. Bar­ton, though, said they have good ev­i­dence to sug­gest the ther­a­py is safe. It doesn’t re­quire the same in­tense con­di­tion­ing reg­i­men that CAR-T ther­a­pies do, and they don’t think it will trig­ger the cy­tokine re­lease syn­drome, the dan­ger­ous im­mune over-re­ac­tion that CAR-T can stim­u­late.

Bar­ton isn’t promis­ing the near-cu­ra­tive im­pact that the first CAR-T stud­ies showed. In­stead, they’re hop­ing to sim­ply show that it’s safe, that the CAR-Ms are get­ting in­to the en­vi­ron­ment around the tu­mor and that they’re hav­ing some ef­fect.

The study al­so serves as a test run for the month-long, cross-coun­try process man­u­fac­tur­ing need­ed to make the CAR-Ms. Caris­ma has checked all the lo­gis­ti­cal box­es, she said, but mak­ing a cell ther­a­py is nev­er an easy task. If it runs smooth­ly and proves safe, Caris­ma hope to move for­ward with a swath of CAR-M ther­a­pies for oth­er tu­mors and oth­er anti­gens.

“It’s a whole world of lo­gis­tics that we need to get in place, and we have it in place, but you know there are snow­storms and every­thing can hap­pen,” Bar­ton said. “Every­thing can go wrong and we’re tak­ing all mea­sures.”

Qual­i­ty Con­trol in Cell and Gene Ther­a­py – What’s Re­al­ly at Stake?

In early 2021, Bluebird Bio was forced to suspend clinical trials of its gene therapy for sickle cell disease after two patients in the trial developed cancer. As company scientists rushed to assess whether there was any causal link between the therapy and the cancer cases, Bluebird’s stock value plummeted – as did those of multiple other biopharma companies developing similar therapies.

While investigations concluded that the gene therapy was unlikely to have caused cancer, investors and the public may be more skittish regarding the safety of gene and cell therapies after this episode. This recent example highlights how delicate the fields of cell and gene therapy remain today, even as they show great promise.

Law pro­fes­sors call for FDA to dis­close all safe­ty and ef­fi­ca­cy da­ta for drugs

Back in early 2018 when Scott Gottlieb led the FDA, there was a moment when the agency seemed poised to release redacted complete response letters and other previously undisclosed data. But that initiative never gained steam.

Now, a growing chorus of researchers are finding that a dearth of public data on clinical trials and pharmaceuticals means industry and the FDA cannot be held accountable, two law professors from Yale and New York University write in an article published Wednesday in the California Law Review.

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Novavax CEO Stanley Erck at the White House in 2020 (Andrew Harnik, AP Images)

As fears mount over J&J and As­traZeneca, No­vavax en­ters a shaky spot­light

As concerns rise around the J&J and AstraZeneca vaccines, global attention is increasingly turning to the little, 33-year-old, productless, bankruptcy-flirting biotech that could: Novavax.

In the now 16-month race to develop and deploy Covid-19 vaccines, Novavax has at times seemed like the pandemic’s most unsuspecting frontrunner and at times like an overhyped also-ran. Although they started the pandemic with only enough cash to last 6 months, they leveraged old connections and believers into $2 billion and emerged last summer with data experts said surpassed Pfizer and Moderna. They unveiled plans to quickly scale to 2 billion doses. Then they couldn’t even make enough material to run their US trial and watched four other companies beat them to the finish line.

FDA of­fers scathing re­view of Emer­gent plan­t's san­i­tary con­di­tions, em­ploy­ee train­ing af­ter halt­ing pro­duc­tion

The FDA wrapped up its inspection of Emergent’s troubled vaccine manufacturing plant in Baltimore on Tuesday, after halting production there on Monday. By Wednesday morning, the agency already released a series of scathing observations on the cross contamination, sanitary issues and lack of staff training that caused the contract manufacturer to dispose of millions of AstraZeneca and J&J vaccine doses.

Brad Bolzon (Versant)

Ver­sant pulls the wraps off of near­ly $1B in 3 new funds out to build the next fleet of biotech star­tups. And this new gen­er­a­tion is built for speed

Brad Bolzon has an apology to offer by way of introducing a set of 3 new funds that together pack a $950 million wallop in new biotech creation and growth.

“I want to apologize,” says the Versant chairman and managing partner, laughing a little in the intro, “that we don’t have anything fancy or flashy to tell you about our new fund. Same team, around the same amount of capital, same investment strategy. If it ain’t broke, don’t fix it.”

But then there’s the flip side, where everything has changed. Or at least speeded into a relative blur. Here’s Bolzon:

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From left: James Brown, Michael Chambers, John Ballantyne

Alde­vron founders back a biotech start­up that's look­ing to end the moral de­bate over cell lines once and for all

For millions of Catholics around the world, the development of new vaccines to combat Covid-19 has sparked a moral dilemma. All the approved vaccines in use relied — in some fashion — on cell lines that were derived from aborted fetal tissue.

While church leaders accepted the vaccines and recommended their use to end the pandemic, a number also highlighted their preference for the mRNA vaccines from Pfizer/BioNTech and Moderna over the J&J and AstraZeneca shots, which they noted were more heavily dependent on cell lines that they found morally objectionable.

Sen. Patty Murray (D-WA) (Graeme Sloan/Sipa USA/Sipa via AP Images)

Sen­a­tors to NIH: Do more to pro­tect US bio­med­ical re­search from for­eign in­flu­ence

Although Thursday’s Senate health committee hearing was focused on how foreign countries and adversaries might be trying to steal or negatively influence biomedical research in the US, the only country mentioned by the senators and expert witnesses was China.

Committee chair Patty Murray (D-WA) made clear in her opening remarks that the US cannot “let the few instances of bad actors” overshadow the hard work of the many immigrant researchers in the US, many of which have won Nobel prizes for their work. But she also said, “There is more the NIH can be doing here.”

Jenny Rooke (Genoa Ventures)

Ear­ly Zymer­gen in­vestor Jen­ny Rooke re­flects on 'chimeras' in biotech, what it takes to spot a $500M gem

When Jenny Rooke first heard of Zymergen back in 2014, she knew she was looking at something different and exciting. The Emeryville, CA biotech held the promise of blending biology and technology to solve a huge unmet need for cost-effective chemicals — of all things — and a stellar founding team to boot.

But back then, West Coast venture capitalists didn’t see in Zymergen the one thing they were looking for in a winning biotech: therapeutic potential. Rooke, however, saw an opportunity and made her bets. Seven years later, that bet is paying off in a big way.

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Saurabh Saha at Endpoints News' #BIO19

On the heels of $250M launch, Centes­sa barges ahead with an IPO to fu­el its 10-in-1 Medicxi pipeline

Francesco De Rubertis made no secret of IPO plans for Centessa, his 10-in-1 legacy play. Barely two months later, the S-1 is in.

The hot-off-the-press filing depicts the same grand vision that the longtime VC touted when he did the rounds in February: Take the asset-centric mindset that he’s been preaching at Medicxi over the years, and roll up a bunch of biotech upstarts, with unrelated risk profiles, into 1 pharma company that can carry on the development at scale.