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.

UP­DAT­ED: Roche bags 'break­through' an­ti-fi­bro­sis drug in $1.4B biotech buy­out deal

Roche is snapping up a “breakthrough” anti-fibrotic drug in a $1.4 billion buyout.

The pharma giant announced Friday that it is acquiring Promedior, primarily to get its hands on PRM-151, a recombinant form of human pentraxin-2 (PTX-2) protein that has nailed down mid-stage clinical data on idiopathic pulmonary fibrosis and demonstrating its potential for a range of fibrotic conditions.

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Amarin emerges from an ex­pert pan­el re­view with a clear en­dorse­ment for Vas­cepa and high odds of suc­cess when the FDA weighs in for­mal­ly

Several FDA experts who gathered Thursday to consider the landmark approval of Vascepa to reduce cardio events in an at-risk population voiced their unease about various aspects of the efficacy and safety data, or ultimately the population it should be used to treat. But the overwhelming belief that the data pointed to the drug’s benefit and clearly outweighed risks carried the day for Amarin.

The panel voted unanimously (16 to 0) to support the company’s positive data presentation — backing an OK for expanding the label to include reducing cardio risk. The vote points Amarin $AMRN down a short path to a formal decision by the FDA, with the odds heavily in its favor. Chances are the rest of the questions about the future of this drug will be hashed out in the label’s small print.

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No­var­tis spin­out’s first an­ti-ag­ing PhI­II is a flop, so now they’ll turn to Parkin­son’s chal­lenge as shares wilt

Novartis spinout resTORbio is grappling with the collapse of its lead clinical program this morning — an anti-aging R&D failure that will badly damage their rep in the field.

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No­var­tis scores its lat­est FDA OK — this time for a new sick­le cell dis­ease drug picked up in a $665M deal

Novartis’ decision to buy Oklahoma-based biotech Selexys 3 years ago for up to $665 million has paid off with an FDA approval today.

Blessed with the FDA’s breakthrough drug designation for a speedy review, the pharma giant has pinned down an approval for crizanlizumab, a new therapy designed to reduce the frequency of painful incidents of vaso-occlusive crises among sickle cell disease patients 16 or older.

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As­traZeneca gains EU nod for di­a­betes triple; Am­gen and Duke launch re­al-world PC­SK9 ob­ser­va­tion­al study

→ Weeks after winning EU approval to start marketing dapagliflozin as Forxiga, AstraZeneca has racked up another OK for a triplet combo involving the SGLT2 diabetes drug. Named Qtrilmet, the pill combines Forxiga with the DPP-4 inhibitor Onglyza (saxagliptin) and the bedrock drug metformin in a modified-release format. That 3-in-1 approach proved superior in reducing average blood glucose levels to a number of other dual combinations across 5 Phase III trials, including Forxiga plus metformin, Onglyza with metformin, or glimepiride with metformin.

Five drugs, in­clud­ing two No­var­tis ther­a­pies, win EMA en­dorse­ment

As is custom, an EMA panel on Friday issued its weekly recommendations on marketing applications submitted by drug developers. This week, the agency backed the use of five new therapies — including two Novartis drugs — but issued no negative reviews.

Novartis’ S1P drug for relapsing forms of multiple sclerosis (MS) drug, Mayzent (known chemically as siponimod), which was approved by the FDA in March — has been given the nod by the EMA. The Swiss drugmaker already sells its other MS drug, Gilenya, in both regions.

Atom­wise's X-37 spin­out gets $14.5 mil­lion to launch AI dis­cov­ery ef­forts

The folks behind Atomwise’s spinout X-37 like to think in cosmological metaphors, and you can think of their AI drug development model as probes sent into space from a central station. That station just got $14.5 million in Series A funding from DCVC Bio, Alpha Intelligence Capital and Hemi Ventures to back those missions.

X-37 uses Atomwise’s AI platform to identify drug targets and – unlike the parent company, which largely sticks to computers  – bring those into a wet lab and preclinical testing.  In addition to AI professionals, it’s led in by part by drug developers from Velocity Pharmaceutical Development.

Ab­bott Lab­o­ra­to­ries CEO Miles White pass­es ba­ton down to suc­ces­sor; Lon­za CEO Marc Funk hits the ex­it

→ Abbott Laboratories has named a successor to CEO Miles White after he announced that he was stepping down in March after 21 years of service. Robert Ford, the company’s COO and president, will take the helm. Ford is known for his work in the $25 billion merger between St. Jude Medical into Abbott in January 2017. White will remain with the company as executive chairman of the board. 

→ After snapping up Novartis’ Swiss facility, Novartis Center of Excellence, in July, Lonza has announced that their CEO, Marc Funk, is hitting the exit for “personal reasons.” Funk has been the CEO of the company for less than a year — brought onto the company back in March. In the meantime, chairman Albert Baehny will serve as interim CEO. 

UCB adds on more pos­i­tive PhI­II da­ta for IL-17A/17F in­hibitor bimek­izum­ab, clear­ing a path to the FDA

A month after posting positive top-line data from their first Phase III trial of the IL-17A/17F inhibitor bimekizumab, Belgium’s UCB says they’ve added more upbeat results from their second late-stage test in moderate-to-severe plaque psoriasis.

That leaves the company on track for regulatory submissions in the middle of next year, says CMO Iris Loew-Friedrich.
Their drug beat out a placebo on the co-primaries — a 90% improvement in PASI 90 (the Psoriasis Area and Severity Index) and Investigator Global Assessment (IGA) response of clear or almost clear (IGA 0/1) at week 16, compared to placebo. Investigators also boasted of hitting some key secondaries.
UCB is angling to enter an increasingly crowded market space.
In their first of 3 Phase III studies for bimekizumab, researchers touted top-line wins on statistically significant results on clearing plaque psoriasis, including a victory over J&J’s IL-23 contender Stelara on key endpoints. The drug targets both IL-17A and IL-17F, a modification on the IL-17A strategy laid out for Taltz (Eli Lilly) and Cosentyx (Novartis). And the new group also includes J&J’s Tremfya and AbbVie’s Skyrizi.

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