Park­er In­sti­tute sum­moned the neoanti­gen pi­o­neers to com­pare their pre­dic­tion al­go­rithms. And they have some sug­ges­tions for the field

What makes a good neoanti­gen?

For all the promis­es of the bold new ap­proach to can­cer vac­cines and ther­a­pies — ze­ro­ing in on spe­cif­ic mu­tat­ed anti­gens ex­pressed on­ly by tu­mors — com­pa­nies and aca­d­e­mics have lit­tle way of know­ing how good they are at pre­dict­ing which neoanti­gens rep­re­sent the best tar­gets. There’s no stan­dard or base­line for play­ers to stack them­selves against ri­vals in the nascent field, and by the time they find out, it could be too late.

No sin­gle group could re­al­ly build that bench­mark. Pre­cious pro­pri­etary in­for­ma­tion is at stake, not to men­tion tremen­dous re­sources re­quired.

Dan­ny Wells

But four years ago, just as the con­cept was tak­ing off, it struck the Park­er In­sti­tute for Can­cer Im­munother­a­py as the ex­act kind of prob­lem its col­lab­o­ra­tive mod­el was built to solve.

“We’re like Switzer­land of neoanti­gens,” Dan­ny Wells, the prin­ci­pal da­ta sci­en­tist at PI­CI, told End­points News.

So work­ing with the Can­cer Re­search In­sti­tute and a non­prof­it named Sage Bionet­works, it brought to­geth­er over 40 bio­phar­ma com­pa­nies and aca­d­e­m­ic labs, gave them the same melanoma and non-small cell lung can­cer tis­sue, and asked each team to sub­mit its most promis­ing neoanti­gen pre­dic­tions. PI­CI re­searchers then went in­to the lab and cross-com­pared the pre­dic­tions, check­ing whether the neoanti­gens were in­deed rec­og­nized by T cells. The re­sult is a base­line dataset that the ini­tia­tive — named TES­LA, short for Tu­mor Neoanti­gen Se­lec­tion Al­liance — is mak­ing pub­lic to the sci­en­tif­ic world to­day.

To the re­searchers’ sur­prise, the dif­fer­ences be­tween the pre­dic­tion al­go­rithms were “tremen­dous,” said Wells, a co-se­nior au­thor in the pa­per pub­lished in Cell. No team man­aged to iden­ti­fy every neoanti­gen or even a large ma­jor­i­ty of them: “The over­lap be­tween pre­dic­tions, no mat­ter how we sliced it, was re­al­ly low.”

It high­lights the need for new knowl­edge in the field, he added, and PI­CI be­lieves TES­LA has yield­ed some in­sights.

Na­dine De­fra­noux

A set of five dis­tinct fea­tures, it turned out, could pre­dict good neoanti­gens with high ac­cu­ra­cy and speci­fici­ty when in­te­grat­ed in­to a mod­el. They are bind­ing affin­i­ty, tu­mor abun­dance and bind­ing sta­bil­i­ty, which has to do with how the neoanti­gens are pre­sent­ed; as well as agre­topic­i­ty and for­eign­ness, which re­lates to their recog­ni­tion by im­mune cells.

“These are all fea­tures that had been talked about, but I think we were sur­prised that just by in­te­grat­ing them to­geth­er in­to this sin­gle mod­el that it works so well,” Wells said.

When par­tic­i­pat­ing teams reap­plied these char­ac­ter­is­tics in­to their al­go­rithms, PI­CI re­port­ed, the pre­dic­tions im­proved. A da­ta mod­el em­pha­siz­ing all five fea­tures came out of a test against an­oth­er set of can­cer sam­ples ac­cu­rate­ly pre­dict­ing 75% of ef­fec­tive neoanti­gen tar­gets and fil­ter­ing out 98% of in­ef­fec­tive ones. De­pend­ing on the ther­a­peu­tic strat­e­gy drug de­vel­op­ers may cal­i­brate their al­go­rithms dif­fer­ent­ly, Wells said. But the hope he and co-se­nior au­thor Na­dine De­fra­noux have is that they can pro­vide a com­mon base­line both for those al­ready in the field and oth­ers look­ing to jump in.

Lisa But­ter­field

“This re­search has the po­ten­tial to im­prove drug mak­ers’ and re­searchers’ math­e­mat­i­cal al­go­rithms,” Lisa But­ter­field, vice pres­i­dent of re­search and de­vel­op­ment at PI­CI, said in a state­ment. “It can pri­or­i­tize anti­gens most like­ly to be present on each pa­tient’s can­cer and most vis­i­ble to the im­mune sys­tem while de­pri­or­i­tiz­ing the ones that aren’t.”

Robert Schreiber

While TES­LA won’t be mon­i­tor­ing the space lon­gi­tu­di­nal­ly to see how com­pa­nies com­pare over time, Wells does en­vi­sion new evo­lu­tions for the coali­tion. Many ques­tions still need to be an­swered; for in­stance, while they fo­cused on class 1 pre­dic­tion, or how CD8+ T cells see the tu­mor, co-se­nior au­thor Robert Schreiber’s re­search has sug­gest­ed that class 2, or how CD4+ T cells see the tu­mor, are just as im­por­tant.

“Un­til now, neoanti­gen pre­dic­tion has been a black box,” said Schreiber, a pro­fes­sor at the Wash­ing­ton Uni­ver­si­ty School of Med­i­cine in St. Louis. TES­LA has be­gun shed­ding light on it, and it in­tends to con­tin­ue.

5AM Ven­tures: Fu­el­ing the Next Gen­er­a­tion of In­no­va­tors

By RBC Capital Markets
With Andy Schwab, Co-Founder and Managing Partner at 5AM Ventures

Key Points

Prescription Digital Therapeutics, cell therapy technologies, and in silico medicines will be a vital part of future treatment modalities.
Unlocking the potential of the microbiome could be the missing link to better disease diagnosis.
Growing links between academia, industry, and venture capital are spinning out more innovative biotech companies.
Biotech is now seen by investors as a growth space as well as a safe haven, fuelling the recent IPO boom.

Hal Barron, GSK via YouTube

What does $29B buy you in Big Phar­ma? In Glax­o­SmithK­line’s case, a whole lot of un­com­fort­able ques­tions about the pipeline

Talk about your bad timing.

A little over a week ago, GSK R&D chief Hal Barron marked his third anniversary at the research helm by taking a turn at the virtual podium during JP Morgan to make the case that he and his team had built a valuable late-stage pipeline capable of churning out more than 10 blockbusters in the next 5 years.

And then, just days later, one of the cancer drugs he bet big on as a top prospect — bintrafusp, partnered with Merck KGaA — failed its first pivotal test in non-small cell lung cancer.

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Janet Woodcock (AP Images)

End­points poll: Janet Wood­cock takes the (in­ter­im) helm at the FDA. And a large ma­jor­i­ty of our read­ers want her to stay there

It’s official: Janet Woodcock is now the acting chief of the FDA.

And — according to an Endpoints poll — most industry readers would like her to stay there, although a significant minority is strongly opposed.

To recap: Joe Biden is reportedly choosing between Woodcock and former deputy FDA commissioner Joshua Sharfstein as his nominee for the permanent position. Given their respective track records, the decision is set to determine the agency’s lodestar for years to come.

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What’s next for End­points — and how to sup­port our in­de­pen­dent bio­phar­ma news mis­sion

The firehose of biopharma news is gushing these days.

That’s why broader and deeper is the theme for 2021 at Endpoints. You can expect new coverage outside our core R&D focus, with deeper reporting in some key areas. When John Carroll and I launched Endpoints nearly five years ago, we were wading in waist-high waters. Now we’re a team of 25 full-time staffers (and growing) with plans to cover the flood of biopharma news, Endpoints-style.

Jonathan Weissman (MIT)

Can a new CRISPR tech­nique un­lock the se­crets of how can­cer spreads?

Jonathan Weissman’s team watched the cancer cells spread across the doomed mouse. Engineered with a bioluminescent enzyme, they appeared in scans first as a small navy blue diamond lodged near the heart; a week later, as a triangle splayed across the mouse’s upper body, with streaks of green and two distinct bright red hubs of activity. By day 54, the mouse resembled a lava lamp.

The images would have been familiar to any cancer biologist, but they didn’t actually tell you much about what was going on: why the cancer was metastasizing or which cells were responsible. For that, Weissman’s team had designed a new tool. Inside the original navy blue diamond, they had engineered the microbiological equivalent of an airplane’s black box — a “molecular recorder” that, after the mouse’s death, could allow them to extract the cells and wind back intimate footage of a single cancer’s ascent.

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Janet Woodcock and Joshua Sharfstein (AP, Images)

Poll: Should Joshua Sharf­stein or Janet Wood­cock lead the FDA from here?

It’s time for a new FDA commissioner to come on board, a rite of passage for Joe Biden’s administration that should help seal the new president’s rep on seeking out the experts to lead the government over the next 4 years.

As of now, the competition for the top job appears to have narrowed down to 2 people: The longtime CDER chief Janet Woodcock and Joshua Sharfstein, the former principal deputy at the FDA under Peggy Hamburg. Both were appointed by Barack Obama.

Fast on Glax­o­SmithK­line's heels, Au­rinia wins OK to steer a sec­ond lu­pus nephri­tis drug straight to the mar­ket

GlaxoSmithKline’s Benlysta isn’t alone in the small circle of approved lupus nephritis drugs anymore.

Little Aurinia Pharmaceuticals has gotten the green light from the FDA to start marketing its first and only program, voclosporin, under the brand name Lupkynis — something CEO Peter Greenleaf says it’s been ready to do since December.

Regulators went right down to the wire on the decision, keeping the company and the entire salesforce it’s already assembled on its toes.

Charlie Fuchs, Roche and Genentech global head of product development for oncology and hematology (Yale Cancer Center)

Yale can­cer spe­cial­ist Char­lie Fuchs tapped as new glob­al de­vel­op­ment chief for Roche/Genen­tech

Roche and their big sub Genentech have just recruited a top cancer specialist at Yale to head up global product development in oncology and hematology.

I just got word that the pharma giant, which leads one of the most active cancer research operations in the world, recruited Charlie Fuchs, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital. He’ll join the global operation March 1 and will be based in South San Francisco, where Genentech is based.

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Kimberly Smith, ViiV R&D chief (ViiV Healthcare)

Af­ter sting­ing FDA set­back, Glax­o­SmithK­line's Vi­iV fi­nal­ly notch­es US ap­proval for long-act­ing HIV in­jec­tion

GlaxoSmithKline’s HIV unit ViiV was dealt a stinging loss back in late 2019 when the FDA slammed the brakes on its application for a once-monthly injection based on manufacturing issues. Now, with that roadblock in the rearview, ViiV has finally made good on its promise to change the HIV game.

The FDA on Thursday approved ViiV’s Cabenuva (cabotegravir and rilpivirine) as a long acting, once-monthly therapy for HIV-positive adults who are virologically suppressed and on a stable antiviral regimen.