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.

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; and more

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Re­searchers move clos­er to de­ci­pher­ing blood clots from As­traZeneca, J&J's Covid-19 vac­cines

Researchers may be nearing an answer for the mysterious and life-threatening blood clots that appeared on very rare occasions in people who received the J&J or AstraZeneca Covid-19 vaccine.

The new work builds on an early hypothesis researchers in Norway put forward last spring, when the cases first cropped up. They proposed the events were similar to blood clots that can occur in a small subset of patients who receive heparin, one of the most commonly used blood thinners.

Lisa Deschamps, AviadoBio CEO

Ex-No­var­tis busi­ness head hops over to a gene ther­a­py start­up — and she's reeled in $80M for a dash to the clin­ic

Neurologist and King’s College London professor Christopher Shaw has been researching neurodegenerative diseases like ALS and collaborating with drugmakers for the last 25 years in the hopes of pushing new therapies forward. But unfortunately, none of those efforts have come anywhere close to fruition.

“So, you know, after 20 years in the game, I said, ‘Let’s try and do it ourselves,’” he told Endpoints News. 

Glax­o­SmithK­line, Ox­ford un­veil new part­ner­ship pit­ting buzzy R&D ad­vances against neu­ro­log­i­cal dis­ease

When GlaxoSmithKline trumpeted its return to neuroscience with a $700 million upfront deal with Alector this summer, it touted its early investments in functional genomics as a key guidepost for that deal. Now, the drug giant has partnered up with Oxford to hopefully add jet fuel to its hunt for breakthroughs in the brain.

GSK and Oxford have kickstarted a five-year collaboration aimed at spurring R&D breakthroughs across a range of hard-to-treat diseases like Alzheimer’s and Parkinson’s through the use of genomic testing and machine learning, the partners said Wednesday.

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In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.

Ab­b­Vie tacks on a new warn­ing to Rin­voq la­bel as safe­ty frets crimp JAK class

The safety problems that continue to plague the JAK class as new data highlight some severe side effects are casting a large shadow over AbbVie’s Rinvoq.

As a result of a recent readout highlighting major adverse cardiac events (MACE), malignancy, mortality and thrombosis with Xeljanz a couple of months ago, AbbVie put out a notice late Friday afternoon that it is adding the new class risks to its label for their rival drug.

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Biospec­i­men M&A: Dis­cov­ery ac­quires Al­bert Li's he­pa­to­cyte project; PhI­II tri­al on Bay­er's Nube­qa reached pri­ma­ry end­point

Discovery Life Sciences has acquired what claims to be the Maryland-based host of the world’s largest hepatocyte inventory, known as IVAL, to help researchers select more effective and safer drug candidates in the future.

The combined companies will now serve a wider range of drug research and development scientists, according to Albert Li, who founded IVAL in 2004 and is set to join the Discovery leadership team as the CSO of pharmacology and toxicology.