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Re­searchers in biotech, acad­e­mia and Big Phar­ma are of­fer­ing puz­zle pieces to crack CAR-T for sol­id tu­mors. Will they ever snap to­geth­er?

The idea seemed promis­ing enough.

By the time a group of sci­en­tists re­port­ed an at­tempt to treat colon can­cer with en­gi­neered T cells drawn from pa­tients, ex­pand­ed and armed with ar­ti­fi­cial sur­face pro­teins in 2010, the ex­per­i­men­tal ther­a­py — known as CAR-T, short for chimeric anti­gen re­cep­tor trans­duced T cells — had turned from an ec­cen­tric ther­a­peu­tic pro­pos­al to a some­what vi­able ap­proach be­ing test­ed in the clin­ic. The tar­get, HER2, was one of the most ex­ten­sive­ly stud­ied tar­gets in can­cer, im­pli­cat­ed in can­cers of breast, blad­der, ovary, pan­creas, and more. A “next-gen­er­a­tion” con­struct con­tain­ing a frag­ment of a well-known an­ti­body, de­ployed along­side ad­di­tion­al tried and true tweaks, looked like a promis­ing next step.

That’s not to men­tion the study was be­ing con­duct­ed by Steve Rosen­berg’s lab — the famed Na­tion­al Can­cer In­sti­tute group that had pro­duced some of the ear­li­est da­ta that con­vinced sci­en­tists of T cells’ abil­i­ty to at­tack sol­id tu­mors.

Yet the tri­al took a shock­ing and trag­ic turn. With­in 15 min­utes of re­ceiv­ing the in­fu­sion, the first pa­tient had se­ri­ous trou­ble breath­ing. She was sent to the hos­pi­tal, in­tu­bat­ed, and died five days lat­er.

“I think it shut every CAR-T cell ther­a­py study down which tar­get­ed HER2 at the time,” re­called Stephen Gottschalk, who was work­ing on a dif­fer­ent HER2 pro­gram him­self at Bay­lor Col­lege of Med­i­cine. “We spent quite a lot of time with the FDA com­ing up with an ap­proach that would al­low us to do it safe­ly.”

While CAR-Ts for hema­to­log­i­cal ma­lig­nan­cies have large­ly sailed through those ear­ly safe­ty scares — a group at Memo­r­i­al Sloan Ket­ter­ing had dis­closed an­oth­er death in a hema­tol­ogy tri­al that same year — and im­pressed the bio­phar­ma world with as­ton­ish­ing re­sponse rates, the same can’t be said about sol­id tu­mor ef­forts. Ear­ly clin­i­cal tri­als that didn’t turn up se­ri­ous side ef­fects al­so failed to demon­strate near­ly the same lev­el of ef­fi­ca­cy seen in acute lym­phoblas­tic leukemia and non-Hodgkin lym­phoma.

Rather than giv­ing up, both aca­d­e­m­ic and in­dus­try re­searchers are dou­bling down, thanks in part to the big suc­cess in the hema­to­log­ic space and the large mar­ket that awaits any­one who can fi­nal­ly un­lock any kind of sol­id tu­mors with CAR-T.

The few skep­tics haven’t stopped a tor­rent of ven­ture dol­lars from pro­pelling these ef­forts, most still pre­clin­i­cal, that promise to tear down the well-doc­u­ment­ed road­blocks now shield­ing many can­cers from these po­tent killing cells. The ques­tion boils down to how you choose among them — and who will be the last ones stand­ing.

Defin­ing the chal­lenge

Mar­tin Pule re­mem­bers the ear­ly days when every­thing was hard­er in CAR-T.

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