Safe­ty con­cerns and man­u­fac­tur­ing short­com­ings aside, ex­ist­ing CAR-T ther­a­pies — No­var­tis’ Kym­ri­ah and Gilead’s Yescar­ta — sim­ply don’t work in 10% to 20% of pa­tients with B cell ma­lig­nan­cies. What fac­tors un­der­pin this re­sis­tance to CAR-T ther­a­py? The main cul­prit could be the can­cer cells them­selves, ac­cord­ing to a team of re­searchers at Penn.

CAR-T ther­a­pies are en­gi­neered to work in this way: Cells are ex­tract­ed from the pa­tient and then ma­nip­u­lat­ed in a lab where chimeric anti­gen re­cep­tors are added to di­rect the pa­tient’s own T cells to snuff out spe­cif­ic can­cer cells once re-in­fused back in­to the pa­tient. But in a frac­tion of pa­tients, the armed im­mune at­tack does not oblit­er­ate the dis­ease. By tar­get­ing CD19, a mark­er present on al­most all B cells, CAR-T ther­a­pies have shown re­mark­able po­ten­cy and dura­bil­i­ty in a num­ber of blood can­cers, in­clud­ing acute lym­phoblas­tic leukemia (ALL).

Re­search so far sug­gests that re­sis­tance to CAR-T ther­a­pies is re­lat­ed to the loss of CD19. When CD19 dis­ap­pears from leukemic cells, they be­come in­vis­i­ble to CAR-T ther­a­pies, not­ed the study’s co-se­nior au­thor Mar­co Ruel­la, an as­sis­tant pro­fes­sor of hema­tol­ogy-on­col­o­gy at the Uni­ver­si­ty of Penn­syl­va­nia, in an in­ter­view with End­points News.

“That ex­plains maybe half of the re­laps­es in leukemia and maybe a third in lym­phoma — so there is still a vast ma­jor­i­ty of pa­tients where we sim­ply don’t know what’s go­ing on,” he said.

An­oth­er fac­tor dri­ving re­sis­tance was dys­func­tion­al T cells, he added. “What we are hy­poth­e­siz­ing here is that there can be a third mech­a­nism…that even in the pres­ence of CD19 those leukemic cells are un­able to die when they are trig­gered by CAR-T.”

“The con­stant pres­ence of the leukemic cells that ba­si­cal­ly can­not die — they’re sort of high­landers — caus­es dys­func­tion in the T-cells. To start with — the CAR-T (cells) are okay — but then they keep try­ing to kill leukemic cells that in­trin­si­cal­ly can­not die, and then, over time, they be­come dys­func­tion­al.”

The find­ings were pub­lished on Thurs­day in Can­cer Dis­cov­ery, a jour­nal of the Amer­i­can As­so­ci­a­tion for Can­cer Re­search.

In the Penn study, re­searchers per­formed a genome-wide CRISPR/Cas9-based screen of an ALL cell line to iso­late path­ways as­so­ci­at­ed with re­sis­tance. Cells were edit­ed for loss of func­tion of sin­gle genes and com­bined with CAR-T cells for 24 hours to iden­ti­fy the path­way dri­ving the pri­ma­ry re­sis­tance. The in vit­ro da­ta showed that in the ALL cells that re­sist­ed the CAR-T at­tack, there was a short­age of genes in­volved in ac­ti­vat­ing the cell death path­way and a spike in genes nec­es­sary for evad­ing the cell death path­way.

In­stead of in­ter­ro­gat­ing sam­ples from pa­tients that have failed to ben­e­fit from CAR-T ther­a­pies, the plan was to mod­el a genome-wide re­sis­tance mech­a­nism and then con­firm it in pa­tients. Many pa­tients are now be­ing treat­ed with CAR-Ts, but still, the num­bers are lim­it­ed — so this ap­proach was used to dis­cov­er aber­ra­tions that the lim­it­ed num­ber of pa­tient sam­ples would not be pow­ered to iden­ti­fy, Ruel­la said.

“We start­ed with an un­bi­ased genome-wide ap­proach to study re­sis­tance and we saw that the new CRISPR/Cas9 genome knock­out li­braries were per­fect be­cause they would al­low you to ex­plore knock­outs in the whole genome and in­ter­ro­gate it for re­sis­tance to CAR-T.”

The find­ings were am­pli­fied in an­i­mal mod­els. The re­searchers then tried to make sense of the re­sults by us­ing pe­di­atric pa­tient sam­ples from pre­vi­ous CAR-T tri­als by an­a­lyz­ing the genes in leukemia cells and in T cells — pre- and post-in­fu­sion — from re­spon­ders and non-re­spon­ders. The da­ta were stark: pre­vi­ous­ly iden­ti­fied sig­nal­ing path­ways in can­cer cells were di­rect­ly as­so­ci­at­ed with re­spons­es to CAR ther­a­py, sug­gest­ing that death re­cep­tor sig­nal­ing is a key reg­u­la­tor of pri­ma­ry re­sis­tance to CAR T cell ther­a­py in ALL, the au­thors con­clud­ed.

“This mech­a­nism ap­pears to re­ly on two phas­es: an ini­tial re­sis­tance to death re­cep­tor-dri­ven killing, fol­lowed by an anti­gen-dri­ven, pro­gres­sive im­pair­ment in CAR-T cell func­tion. To­geth­er this leads to CAR T cell fail­ure that per­pet­u­ates dis­ease pro­gres­sion,” they wrote.

De­spite their abun­dant promise, the adop­tion of CAR-T ther­a­pies — No­var­tis’ Kym­ri­ah and Gilead’s Yescar­ta — has un­der­whelmed ini­tial ex­pec­ta­tions.

The up­take of Kym­ri­ah was plagued by man­u­fac­tur­ing prob­lems, and de­spite No­var­tis’ at­tempt to ex­pand its ca­pac­i­ty, sales con­tin­ue to dis­ap­point com­mer­cial­ly, giv­ing Yescar­ta an edge in the mar­ket. Mean­while, big side ef­fects — no­tably life-threat­en­ing episodes of cy­tokine re­lease syn­drome and neu­ro­tox­i­c­i­ty — as well as the ther­a­pies’ ex­pen­sive price tags have al­so lim­it­ed their use. Oth­er drug de­vel­op­ers have tak­en note of these con­straints and are de­vel­op­ing off-the-shelf CAR-T ther­a­pies, de­signed to smoothen man­u­fac­tur­ing com­plex­i­ties by us­ing healthy donor cells.

But the team at Penn cau­tioned that the prac­tice may not nec­es­sar­i­ly help the sub­set of pa­tients whose can­cer cells car­ry this pro­por­tion of un­fa­vor­able genes.

“A pos­si­ble im­pli­ca­tion of our ob­ser­va­tions is that the use of healthy donor (i.e. al­lo­gene­ic donor or “uni­ver­sal” donor) T cells as a sub­strate for CAR T cell man­u­fac­tur­ing may face the same bar­ri­ers as au­tol­o­gous prod­ucts,” the au­thors wrote. “Un­der­stand­ing how in­trin­sic and ac­quired T cell dys­func­tion co­op­er­ate to cause ther­a­peu­tic fail­ure will be crit­i­cal to the de­sign of the next gen­er­a­tion of cel­lu­lar ther­a­pies.”

Jazz CEO Bruce Cozadd didn’t beat around the bush.

In his first video meeting with GW Pharma chief Justin Gover last July 8, he offered to pay $172 a share to get the company, which had beaten the odds in getting its remarkable cannabinoid drug Epidiolex across the regulatory finish line for epilepsy. GW’s stock closed at $129 that day.

Cozadd had already done his homework on the financing to make sure he could swing it the way he wanted. He just needed to do some due diligence before making the non-binding bid firm.

With its Allergan buyout now long in the books, AbbVie has been taking a hard look at its suddenly expansive global ops to find space for a deal. Now, working with a Chinese cell and gene therapy player hungry for more elbow room abroad, AbbVie has taken one UK facility off its books.

AbbVie has offloaded its Liverpool manufacturing site as part of a $118.7 million sale to Chinese cell and gene therapy player Pharmaron, which is pitching the purchase as the next step in its global expansion plans, the companies said last week.