Block­ing PD-L1 pro­duc­tion in mice, UCSF team spot­lights pre­clin­i­cal promise of a Pfiz­er-backed I/O drug

The check­point fren­zy in the im­muno-on­col­o­gy sphere has large­ly fo­cused on block­ing the lig­and-re­cep­tor duo of PD-L1 and PD-1, which can­cer cells use to shield them­selves from the im­mune sys­tem. Dis­sat­is­fied by the abil­i­ty of PD-L1 agents to go af­ter ag­gres­sive, metasta­t­ic can­cers, a group of UCSF re­searchers are chart­ing a new path: What if the pro­duc­tion of check­point pro­teins could be stopped from the out­set?

Da­vide Rug­gero

In a mice tri­al, the re­searchers found that they could pull back the “ro­bust PD-L1 in­vis­i­bil­i­ty cloak” used by can­cer cells, in­creas­ing sur­vival rates by dis­rupt­ing the trans­la­tion of RNA in­to pro­teins — us­ing a mol­e­cule de­vel­oped by eF­FEC­TOR Ther­a­peu­tics, a biotech co-found­ed by the study’s se­nior au­thor, Da­vide Rug­gero.

The ap­proach stems from Rug­gero’s ob­ser­va­tion that ag­gres­sive types of liv­er can­cer are dri­ven by onco­genes that can hi­jack pro­tein trans­la­tion — in which ri­bo­somes as­sem­ble pro­teins at the di­rec­tion of RNA — to boost pro­duc­tion of pro­teins that help the tu­mor skirt an im­mune at­tack.

“If ag­gres­sive liv­er can­cer de­pends on this in­creased trans­la­tion, it may die if you hit it with a trans­la­tion in­hibitor,” said Rug­gero in a state­ment. “This is the ba­sis of an emerg­ing move­ment in can­cer ther­a­py.”

Yichen Xu

Rug­gero and his team took in­to a pre­clin­i­cal tri­al a com­pound known as eFT508 — now in Phase II as both a monother­a­py and an add-on to check­points — which in­hibits eIF4E, a cel­lu­lar “trans­la­tion fac­tor” they say is re­spon­si­ble for pair­ing RNA with ri­bo­somes. The drug did what it was sup­posed to do, halv­ing PD-L1 pro­tein lev­els and in­creas­ing sur­vival rates in mice with tu­mors dri­ven by both the MYC and KRAS genes, but not so much among mice car­ry­ing KRAS tu­mors.

That’s in line with the sci­en­tists’ the­o­ry that a high­er lev­el of PD-L1 trans­la­tion and pro­duc­tion ex­plains why MYC/KRAS tu­mors grow more ag­gres­sive­ly, metas­ta­size more of­ten and are gen­er­al­ly dead­lier than KRAS tu­mors.

It’s not just PD-L1, ei­ther. MYC/KRAS is al­so re­spon­si­ble for el­e­vat­ed lev­els of oth­er pro­teins that can­cer cells re­ly on to re­pro­duce, evade the im­mune sys­tem and spread be­tween or­gans, sug­gest­ed Yichen Xu, a post­doc in Rug­gero’s lab who served as a lead au­thor of the study.

Pub­lished in Na­ture Med­i­cine, the pa­per of­fers val­i­da­tion for eF­FEC­TOR’s stat­ed aim to “trans­la­tion­al­ly reg­u­late gene ex­pres­sion” — an ap­proach that has con­vinced Pfiz­er and Mer­ck KGaA to bankroll a col­lab­o­ra­tion test­ing a com­bo in hopes of boost­ing the ef­fec­tive­ness of its PD-L1 ther­a­py Baven­cio, hav­ing had to con­tend with mul­ti­ple flops. Mer­ck is al­so in for a Keytru­da/eFT508 com­bo slat­ed to be­gin Phase II in the com­ing months.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

Eu­ro­pean study finds that Gilead­'s Covid-19 an­tivi­ral remde­sivir shows no clin­i­cal ben­e­fit

Gilead’s remdesivir — or Veklury, as it’s marketed in the US — raked in around $2.8 billion last year as the only FDA-approved antiviral to treat Covid-19. But new data from a European study suggest the drug, which has been given to about half of hospitalized Covid patients in the country, has no actual benefit.

The open-label DisCoVeRy trial enrolled Covid-19 patients across 48 sites in Europe to test a handful of treatments, including remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, and hydroxychloroquine. To participate, patients had to show symptoms for seven days and require oxygen support. A total of 429 patients were randomized to receive remdesivir plus standard of care, while 428 were assigned to standard of care alone.

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Gri­fols drops $1B on Ger­man hold­ing com­pa­ny in con­tin­ued plas­ma push

One Spanish biotech is beefing up its plasma therapy operations, and on Friday, it announced that it’s doing so in a billion-dollar deal.

Grifols is now the largest shareholder of Biotest, a company valued at more than $1.8 billion. By teaming up, the two will try to increase the number of plasma therapies available and increase patient access around the world, Grifols said in a press release.

The company did so by acquiring holding company Tiancheng Pharmaceutical, the Germany-based owner of nearly 90% of Biotest shares, for nearly $1.27 billion. Grifols now owns nearly 90% of Biotest voting rights and almost 45% of the total share capital of Biotest.

Amgen VP of R&D David Reese

Am­gen rolls out da­ta for KRAS in­hibitor com­bo study in col­orec­tal can­cer, hop­ing to move on from ug­ly ear­ly re­sults

With the first win for its KRAS inhibitor sotorasib in hand, Amgen is pushing ahead with an aggressive clinical plan to capitalize on its first-to-market standing. The drugmaker thinks combinations — in-house or otherwise — could offer a path forward, and one early readout from that strategy is bearing fruit.

A combination of Amgen’s sotorasib and its EGFR inhibitor Vectibix posted an overall response rate of 27% in 26 patients with advanced colorectal cancer (CRC) with the KRAS-G12C mutation, according to data from the larger Phase Ib/II CODEBREAK 101 study set to present at this weekend’s virtual ESMO Congress.

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Multiple antibiotic resistant Pseudomonas aeruginosa bacterium

A new way to in­fil­trate (and de­stroy) some of the dead­liest drug-re­sis­tant bugs

About four years ago, Ruben Tommasi, the gregarious scientific chief of antibiotics startup Entasis, walked into a meeting with his top chemist and top biologist to chew over another batch of unchanging results.

“It felt like we were running the same experiment over and over,” Tommasi told Endpoints News. “We had all sort of come to that point in time where we felt like we were banging our heads against the wall.”

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Covid-19 roundup: FDA re­veals boost­er ad­comm ques­tion; Eli Lil­ly's an­ti­body cock­tail cleared for pre­ven­tion

The FDA released briefing documents this week from the agency and Pfizer each outlining their arguments for today’s Covid-19 booster shot adcomm, but one thing conspicuously missing was the question on which panel members would be voting. But late Thursday night, regulators published that question.

Adcomm members will be asked whether or not the safety and efficacy data from Pfizer/BioNTech’s original Phase III study “support approval” of a booster shot at least six months after the second dose in individuals older than 16. The question notably excludes the real-world data from Israel and other analyses that Pfizer and the Biden administration had said would be a centerpiece of their arguments for boosters.

A Pfiz­er part­ner wel­comes ex-ADC Ther­a­peu­tics CMO Jay Fein­gold to the team; Amid tough sled­ding, Im­muno­vant choos­es Eli Lil­ly alum as CFO

→ Last week we told you about the CMO revolving door at ADC Therapeutics, as Joseph Camardo replaced the departing Jay Feingold. The next opportunity for Feingold in the CMO slot has opened up at antibody-drug conjugate and mAb developer Pyxis Oncology, which has added several new execs and scientific advisory board members in recent months, including ex-Immunovant CFO Pamela Yanchik Connealy. Before his tenure at ADC, Feingold was Daiichi Sankyo’s VP of US medical affairs and chairman of the Global Medical Affairs Oversight Committee. Within weeks in March, Pyxis struck a licensing deal with Pfizer for two of its ADCs and raked in $152 million from a Series B round.

Carl Hansen, AbCellera CEO

Look­ing for the next mR­NA break­through, Mod­er­na taps Ab­Cellera in mys­te­ri­ous an­ti­body dis­cov­ery deal

Moderna’s success with its Covid-19 vaccine has busted the dam open on a range of potential mRNA therapeutics — and now the biotech is pushing to keep the cutting edge in-house. A new partnership with standout antibody discovery outfit AbCellera could help keep the ball in the competition’s court.

Moderna will partner with antibody player AbCellera on up to six undisclosed targets for a range of mRNA-encoded drugs harvested from AbCellera’s bustling discovery platform, the companies said Wednesday.