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 de­scribes “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.

BiTE® Plat­form and the Evo­lu­tion To­ward Off-The-Shelf Im­muno-On­col­o­gy Ap­proach­es

Despite rapid advances in the field of immuno-oncology that have transformed the cancer treatment landscape, many cancer patients are still left behind.1,2 Not every person has access to innovative therapies designed specifically to treat his or her disease. Many currently available immuno-oncology-based approaches and chemotherapies have brought long-term benefits to some patients — but many patients still need other therapeutic options.3

Gilead re­leas­es an­oth­er round of murky remde­sivir re­sults

A month after the NIH declared the first trial on remdesivir in Covid-19 a success, Gilead is out with new results on their antiviral. But although the study met one of its primary endpoints, the data are likely to only add to a growing debate over how effective the drug actually is.

In a Phase III trial, patients given a 5-day dose of remdesivir were 65% more likely to show “clinical improvement” compared to an arm given standard-of-care. The trial, though, gave little indication for whether the drug had an impact on key endpoints such as survival or time-to-recovery. And in a surprising twist, a 10-day dosing arm of remdesivir didn’t lead to a statistically significant improvement over standard of care.

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Fangliang Zhang (Imaginechina via AP Images)

The big mon­ey: Poised to make drug R&D his­to­ry, a Chi­na biotech un­veils uni­corn rac­ing am­bi­tions in a bid to raise $350M-plus on Nas­daq

Almost exactly three years after Shanghai-based Legend came out of nowhere to steal the show at ASCO with jaw-dropping data on their BCMA-targeted CAR-T for multiple myeloma, the little player with Big Pharma connections is taking a giant step toward making it big on Wall Street. And this time they want to seal the deal on a global rep after staking out a unicorn valuation in what’s turned out to be a bull market for biotech IPOs — in the middle of a pandemic.

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Federico Mingozzi (Spark)

Spark touts an­i­mal da­ta for a so­lu­tion to AAV gene ther­a­py's an­ti­body prob­lem

Among all the limitations of using an adeno-associated virus as a vector to deliver a gene — still the most established modality in gene therapy given years of trial and error and finally success — the presence of neutralizing antibodies, whether pre-existing or induced, looms large.

“When I think about the immune responses in AAV, I try to sort of layer them,” Federico Mingozzi, the CSO at Spark Therapeutics, told Endpoints News. “The antibody is the first layer. It’s the first block that you find when you’re trying to do gene transfer.”

Len Schleifer (left) and George Yancopoulos, Regeneron (Vimeo)

Eyes on he­mo­phil­ia prize, Re­gen­eron adds a $100M wa­ger on joint de­vel­op­ment cam­paign with In­tel­lia

When George Yancopoulos first signed up Intellia to be its CRISPR/Cas9 partner on gene editing projects 4 years ago, the upstart smartly ramped up its IPO at the same time. Today, Regeneron $REGN is coming back in, adding $100 million in an upfront fee and equity to significantly boot up a whole roster of new development projects.

And they’re highlighting some clinical hemophilia research plans in the process.

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Covid-19 roundup: Did in­sid­ers cash in on pos­i­tive news re­port about Gilead be­fore pub­li­ca­tion?

A series of bullish trades on Gilead options just before the release of a favorable news story is raising questions among regulatory experts, Reuters reported.

On April 16, just hours before STAT published anecdotes from a Chicago hospital that served as one of the clinical sites to test Gilead’s remdesivir in Covid-19 patients, the California-based company’s shares were trading at around $75. Four large blocks of options were purchased for about $1.5 million each, betting that the stock would rise beyond that to as much as $87.5 by mid-August.

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Jean-Jacques Bienaimé, BioMarin chairman and CEO

Bio­Marin holds the line on bleeds with 4-year val­rox up­date on he­mo­phil­ia A — but what's this about an­oth­er de­cline in Fac­tor 8 lev­els?

BioMarin has posted some top-line results for their 4-year followup on the most advanced gene therapy for hemophilia A — extending its streak on keeping a handful of patients free of bleeds and off Factor VIII therapy, but likely stirring fresh worries over a continued drop in Factor VIII levels.

We just don’t know how big a drop.

We’ll see more data when the results are presented at the World Federation of Hemophilia in a couple of weeks. But in a statement out Sunday night, BioMarin $BMRN reported that none of the patients required Factor VIII treatment, adding:

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As­traZeneca trum­pets the 'mo­men­tous' da­ta they found for Tagris­so in an ad­ju­vant set­ting for NSCLC — but many of the ex­perts aren’t cheer­ing along

AstraZeneca is rolling out the big guns this evening to provide a salute to their ADAURA data on Tagrisso at ASCO.

Cancer R&D chief José Baselga calls the disease-free survival data for their drug in an adjuvant setting of early stage, epidermal growth factor receptor-mutated NSCLC patients following surgery “momentous.” Roy Herbst, the principal investigator out of Yale, calls it “transformative.”

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Pablo Legorreta, founder and CEO of Royalty Pharma AG, speaks at the annual Milken Institute Global Conference in Beverly Hills, California (Patrick T. Fallon/Bloomberg via Getty Images)

Cap­i­tal­iz­ing Pablo: The world’s biggest drug roy­al­ty buy­er is go­ing pub­lic. And the low-key CEO di­vulges a few se­crets along the way

Pablo Legorreta is one of the most influential players in biopharma you likely never heard of.

Over the last 24 years, Legorreta’s Royalty Pharma group has become, by its own reckoning, the biggest buyer of drug royalties in the world. The CEO and founder has bought up a stake in a lengthy list of the world’s biggest drug franchises, spending $18 billion in the process — $2.2 billion last year alone. And he’s become one of the best-paid execs in the industry, reaping $28 million from the cash flow last year while reserving 20% of the cash flow, less expenses, for himself.

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