Darrell Irvine. MIT

Su­per­charg­ing CAR-T with can­cer vac­cine, MIT team spot­lights some new tech un­der­pin­ning Dar­rell Irvine's start­up

Many of the ef­forts to im­prove on the first gen­er­a­tion of CAR-T ther­a­pies such that they can reach sol­id tu­mors had fo­cused on tweaks in­her­ent to the can­cer killing agent — specif­i­cal­ly, uti­liz­ing more po­tent T cells as their base, from stem mem­o­ry T cells to vi­ral­ly as­so­ci­at­ed T cells to mar­row in­fil­trat­ing lym­pho­cytes. But what if just am­pli­fy­ing CAR-T cells can do the job? Dar­rell Irvine and his team at MIT have some in­trigu­ing mouse da­ta for one such tech.

Leyuan Ma Irvine Lab

Writ­ing in Sci­ence, Irvine — an in­ves­ti­ga­tor at the Koch In­sti­tute for In­te­gra­tive Can­cer Re­search — and his post­doc Leyuan Ma de­scribe “am­phiphile CAR-T lig­ands (amph-lig­ands) that, up­on in­jec­tion, traf­ficked to lymph nodes and dec­o­rat­ed the sur­faces of anti­gen-pre­sent­ing cells, there­by prim­ing CAR-Ts in the na­tive lymph node mi­croen­vi­ron­ment.” Among mice giv­en the boost­er shot af­ter CAR-T in­fu­sion, 60% ex­pe­ri­enced a com­plete re­sponse for a va­ri­ety of tu­mors in­clud­ing glioblas­toma, breast and melanoma. In con­trast, bare­ly any­thing hap­pened to those giv­en just the cell ther­a­py.

It rep­re­sents a twist to the once-hot — but elu­sive — can­cer vac­cine ap­proach, whose premise is to in­duce an im­mune at­tack on tu­mor cells. It al­so promis­es to solve the dura­bil­i­ty prob­lem of CAR-T that many re­searchers have high­light­ed.

“This is a strat­e­gy that can be as­signed to any CAR-T cell and po­ten­tial­ly en­hance its func­tion,” he tells me, ren­der­ing it ex­po­nen­tial­ly more po­tent. “So what­ev­er oth­er strat­e­gy they might be tak­ing en­gi­neer­ing bet­ter CARs, build­ing in oth­er ge­net­ic pay­loads in­to the T cells, this would be a way to make those cells more func­tion­al in vi­vo.”

By send­ing a vac­cine di­rect­ly to the lymph nodes to stim­u­late CAR-T cells, he ex­plains, they hit two birds with one stone: Pre­vent­ing vac­cines from get­ting de­grad­ed and CAR-T cells from re­leas­ing tox­ic cy­tokines — both of which hap­pen in blood­streams. And it com­bines the promis­es of both ther­a­pies.

“If we take the an­i­mals that ap­pear to be cured and we rechal­lenge them with tu­mor cells, they will re­ject all of them,” Irvine said in an in­ter­view with MIT News. “That is an­oth­er ex­cit­ing as­pect of this strat­e­gy. You need to have T cells at­tack­ing many dif­fer­ent anti­gens to suc­ceed, be­cause if you have a CAR-T cell that sees on­ly one anti­gen, then the tu­mor on­ly has to mu­tate that one anti­gen to es­cape im­mune at­tack. If the ther­a­py in­duces new T-cell prim­ing, this kind of es­cape mech­a­nism be­comes much more dif­fi­cult.”

To de­liv­er the amph-lig­ands, the sci­en­tists tagged on a lipid tail that binds to al­bu­min in the blood­stream and fol­lows it to the lymph nodes. Once there, the anti­gen in­side the vac­cine — ei­ther the same one the CAR-T is orig­i­nal­ly en­gi­neered to rec­og­nize or an­oth­er, they test­ed both — su­per­charges T cells and spurs their pro­lif­er­a­tion.

Irvine is hope­ful about con­duct­ing first-in-hu­man tri­als with­in one to two years through Eli­cio Ther­a­peu­tics, the sec­ond biotech he co-found­ed. In ad­di­tion to go­ing af­ter sol­id tu­mor in­di­ca­tions, he al­so sees ap­pli­ca­tion of his am­pli­fied CAR-T in the more tra­di­tion­al CD19 and BC­MA set­tings, as well as de­ploy­ing the vac­cine can­di­date alone for KRAS-mu­tant can­cers.

Eli­cio launched ear­li­er this year with $30 mil­lion in fund­ing, Robert Con­nel­ly (old timers may re­mem­ber him as found­ing CEO of Do­man­tis) as chief and Gami­da Cells’ Ju­lian Adams as ex­ec­u­tive chair­man. The com­pa­ny is in talks with part­ners that might bring their own CAR-T to the ta­ble.

“Part of the beau­ty of this is,” he adds, “in the grand scheme of things, it will add noth­ing to the cost of CAR-T cell ther­a­py be­cause [it’s] es­sen­tial­ly a de­fined mol­e­c­u­lar en­ti­ty that can be made at scale pret­ty sim­ply.”

The re­search pub­lished to­day was par­tial­ly fund­ed by J&J — along­side the NIH, the Mar­ble Cen­ter for Can­cer Nanomed­i­cine and the Na­tion­al In­sti­tute of Gen­er­al Med­ical Sci­ences. Irvine said the phar­ma gi­ant is not cur­rent­ly an in­vestor, though it has been in touch.

Vlad Coric (Biohaven)

In an­oth­er dis­ap­point­ment for in­vestors, FDA slaps down Bio­haven’s re­vised ver­sion of an old ALS drug

Biohaven is at risk of making a habit of disappointing its investors. 

Late Friday the biotech $BHVN reported that the FDA had rejected its application for riluzole, an old drug that they had made over into a sublingual formulation that dissolves under the tongue. According to Biohaven, the FDA had a problem with the active ingredient used in a bioequivalence study back in 2017, which they got from the Canadian drugmaker Apotex.

Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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Chas­ing Roche's ag­ing block­buster fran­chise, Am­gen/Al­ler­gan roll out Avastin, Her­ceptin knock­offs at dis­count

Let the long battle for biosimilars in the cancer space begin.

Amgen has launched its Avastin and Herceptin copycats — licensed from the predecessors of Allergan — almost two years after the FDA had stamped its approval on Mvasi (bevacizumab-awwb) and three months after the Kanjinti OK (trastuzumab-anns). While the biotech had been fielding biosimilars in Europe, this marks their first foray in the US — and the first oncology biosimilars in the country.

Seer adds ex-FDA chief Mark Mc­Clel­lan to the board; Her­cules Cap­i­tal makes it of­fi­cial for new CEO Scott Bluestein

→ On the same day it announced a $17.5 million Series C, life sciences and health data company Seer unveiled that it had lured former FDA commissioner and ex-CMS administrator Mark McClellan on to its board. “Mark’s deep understanding of the health care ecosystem and visionary insights on policy reform will be crucial in informing our thinking as we work to bring our liquid biopsy and life sciences products to market,” said Seer chief and founder Omid Farokhzad in a statement.

Daniel O'Day

No­var­tis hands off 3 pre­clin­i­cal pro­grams to the an­tivi­ral R&D mas­ters at Gilead

Gilead CEO Daniel O’Day’s new task hunting up a CSO for the company isn’t stopping the industry’s dominant antiviral player from doing pipeline deals.

The big biotech today snapped up 3 preclinical antiviral programs from pharma giant Novartis, with drugs promising to treat human rhinovirus, influenza and herpes viruses. We don’t know what the upfront is, but the back end has $291 million in milestones baked in.

Vas Narasimhan, AP Images

On a hot streak, No­var­tis ex­ecs run the odds on their two most im­por­tant PhI­II read­outs. Which is 0.01% more like­ly to suc­ceed?

Novartis CEO Vas Narasimhan is living in the sweet spot right now.

The numbers are running a bit better than expected, the pipeline — which he assembled as development chief — is performing and the stock popped more than 4% on Thursday as the executive team ran through their assessment of Q2 performance.

Year-to-date the stock is up 28%, so the investors will be beaming. Anyone looking for chinks in their armor — and there are plenty giving it a shot — right now focus on payer acceptance of their $2.1 million gene therapy Zolgensma, where it’s early days. And CAR-T continues to underperform, but Novartis doesn’t appear to be suffering from it.

So what could go wrong?

Actually, not much. But Tim Anderson at Wolfe pressed Narasimhan and his development chief John Tsai to pick which of two looming Phase III readouts with blockbuster implication had the better odds of success.

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H1 analy­sis: The high-stakes ta­ble in the biotech deals casi­no is pay­ing out some record-set­ting win­nings

For years the big trend among dealmakers at the major players has been centered on ratcheting down upfront payments in favor of bigger milestones. Better known as biobucks for some. But with the top 15 companies competing for the kind of “transformative” pacts that can whip up some excitement on Wall Street, with some big biotechs like Regeneron now weighing in as well, cash is king at the high stakes table.

We asked Chris Dokomajilar, the head of DealForma, to crunch the numbers for us, looking over the top 20 deals for the past decade and breaking it all down into the top alliances already created in 2019. Gilead has clearly tipped the scales in terms of the coin of the bio-realm, with its record-setting $5 billion upfront to tie up to Galapagos’ entire pipeline.

Dokomajilar notes:

We’re going to need a ‘three comma club’ for the deals with over $1 billion in total upfront cash and equity. The $100 million-plus club is getting crowded at 164 deals in the last decade with new deals being added towards the top of the chart. 2019 already has 14 deals with at least $100 million in upfront cash and equity for a total year-to-date of over $9 billion. That beats last year’s $8 billion and sets a record.

Add upfronts and equity payments and you get $11.5 billion for the year, just shy of last year’s record-setting $11.8 billion.

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Part club, part guide, part land­lord: Arie Bellde­grun is blue­print­ing a string of be­spoke biotech com­plex­es in glob­al boom­towns — start­ing with Boston

The biotech industry is getting a landlord, unlike anything it’s ever known before.

Inspired by his recent experiences scrounging for space in Boston and the Bay Area, master biotech builder, investor, and global dealmaker Arie Belldegrun has organized a new venture to build a new, 250,000 square foot biopharma building in Boston’s Seaport district — home to Vertex and a number of up-and-coming biotech players.

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