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.”

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; 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.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

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No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'


Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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Tillman Gerngross, Adagio CEO

Q&A: Till­man Gern­gross ex­plains why his Covid mAb will have an edge over an al­ready crowd­ed field

If anyone knows about monoclonal antibodies, it’s serial entrepreneur, Adimab CEO, and Dartmouth professor of bioengineering Tillman Gerngross.

Even the name of Gerngross’ new antibody startup Adagio Therapeutics is meant to reflect his vision behind the development of his Covid-19 mAb: slowly, he said, explaining that “everyone else, whether it’s Regeneron, Lilly, or AstraZeneca, Vir, they all valued speed over everything.”

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Susan Galbraith speaking at Endpoints News' virtual EUBIO21 summit

Imfinzi/treme­li­mum­ab com­bo scores As­traZeneca an­oth­er OS win — this time in liv­er can­cer

Is the tide turning on AstraZeneca’s battered PD-L1/CTLA4 combo?

A single priming dose of the experimental tremelimumab, followed by Imfinzi every four weeks, beat Nexavar (sorafenib) in helping a group of liver cancer patients live longer in a Phase III study, the company reported, meeting the primary endpoint.

Specifically, the two drugs extended overall survival for patients with unresectable hepatocellular carcinoma who had not received prior systemic therapy and were not eligible for localized treatment.

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FDA's vac­cine ad­comm unan­i­mous­ly sup­ports Mod­er­na's boost­er in same pop­u­la­tions as Pfiz­er's boost­er

The FDA’s vaccine advisory committee on Thursday voted 19-0 in support of expanding Moderna’s Covid-19 vaccine EUA for booster doses for certain high-risk individuals. FDA is expected to authorize the Moderna booster shortly.

Similarly to the Pfizer booster shot, Moderna’s will likely be authorized for those older than 65, adults at high risk of severe Covid-19, and adults whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of Covid-19. But unlike the Pfizer adcomm, where FDA had to scramble to get the committee to vote in favor of a booster, this committee was unanimous with the Moderna shot.