ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene ther­a­pies (C&GTs) has seen a re­nais­sance, with first gen­er­a­tion com­mer­cial ther­a­pies such as Kym­ri­ah, Yescar­ta, and Lux­tur­na lay­ing the ground­work for an in­com­ing wave of po­ten­tial­ly trans­for­ma­tive C&GTs that aim to ad­dress di­verse dis­ease ar­eas. With this re­nais­sance comes sev­er­al po­ten­tial op­por­tu­ni­ties, of which we dis­cuss three pre­dic­tions be­low.

Al­lo­genic Nat­ur­al Killer (NK) Cells have the po­ten­tial to dis­place cur­rent Cell Ther­a­pies in on­col­o­gy if proven durable.

De­spite be­ing ear­ly in de­vel­op­ment, Al­lo­genic NKs are prov­ing to be an at­trac­tive new treat­ment par­a­digm in on­col­o­gy. The ques­tion of dura­bil­i­ty of re­sponse with al­lo­genic ther­a­pies is still an un­known. Fate Ther­a­peu­tics’ re­cent phase 1 da­ta for FT516 showed rel­a­tive­ly quick­er re­laps­es vs al­ready ap­proved au­tol­o­gous CAR-Ts. How­ev­er, oth­er man­u­fac­tur­ers, like Al­lo­gene for their al­lo­genic CAR-T ther­a­py AL­LO-501A, are ex­plor­ing nov­el lym­phode­ple­tion ap­proach­es to im­prove per­sis­tence of al­lo­genic cells. Nev­er­the­less, al­lo­genic NKs demon­strate a strong val­ue propo­si­tion rel­a­tive to their T cell coun­ter­parts due to com­pa­ra­ble re­sponse rates (so far) com­bined with the added ad­van­tage of a sig­nif­i­cant­ly safer AE pro­file. Specif­i­cal­ly, lit­tle to no risk of graft ver­sus host dis­ease (GvHD), cy­to­tox­ic re­lease syn­drome (CRS), and neu­ro­tox­i­c­i­ty (NT) have been seen so far with al­lo­genic NK cells (Fig. 1). In ad­di­tion, be­ing able to har­ness an al­lo­genic cell source gives way to op­er­a­tional ad­van­tages as “off-the-shelf” prod­ucts pro­vide im­proved turn­around time (TAT), scal­a­bil­i­ty, and po­ten­tial­ly re­duced cost. NKs are cur­rent­ly in de­vel­op­ment for a va­ri­ety of over­lap­ping hema­to­log­i­cal in­di­ca­tions with chimeric anti­gen re­cep­tor T cells (CAR-Ts) to­day, and the ques­tion re­mains to what ex­tent they will dis­rupt the cur­rent cell ther­a­py land­scape. Click for more de­tails.

Fig­ure 1: Ef­fi­ca­cy and safe­ty da­ta for Au­tol­o­gous vs Al­lo­genic cell ther­a­pies in de­vel­op­ment. Sam­ple n sizes are pro­vid­ed for each point as N:x [1].

In-vi­vo gene ther­a­pies (vs cell-based ther­a­pies) could be the more promi­nent Cell & Gene tech­nol­o­gy in sol­id can­cers.

An in­creas­ing num­ber of in-vi­vo gene ther­a­pies are in clin­i­cal tri­als for sol­id can­cers (Fig. 2). Gene ther­a­pies are poised to make deep in­roads in­to sol­id tu­mor treat­ments with sev­er­al unique mech­a­nisms of ac­tion (MOAs) by which in-vi­vo gene ther­a­pies can tar­get can­cer rang­ing from ac­ti­vat­ing apop­to­sis and re­cruit­ing im­mune cells as well as di­rect on­colyt­ic ef­fects. Al­though many of the gene ther­a­pies in sol­id can­cer work in a more tan­gen­tial way to tu­mor killing, usu­al­ly re­cruit­ing oth­er can­cer killing cells, cell-based ther­a­pies are al­so fac­ing ef­fi­ca­cy strug­gles in over­com­ing the im­muno­sup­pres­sive tu­mor mi­croen­vi­ron­ment (TME) in sol­id can­cers. In-vi­vo gene ther­a­pies are bet­ter sit­u­at­ed to han­dle the TME and are ad­van­ta­geous vs au­tol­o­gous cell ther­a­pies as an “off-the-shelf” op­tion. While still ear­ly in de­vel­op­ment, the breadth of both the pipeline and pos­si­ble MOAs make in-vi­vo gene ther­a­pies an at­trac­tive po­ten­tial tech­nol­o­gy type for sol­id can­cers in the fu­ture.

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Fig­ure 2: Ph II+ C&GTs by tech­nolo­gies across sol­id tu­mors with the num­ber of unique as­sets by ther­a­py type [1].

While the first wave of C&GTs are sin­gle agents, the fu­ture may be in com­bi­na­tion.

It comes as no sur­prise that man­u­fac­tur­ers are be­gin­ning to con­sid­er com­bi­na­to­r­i­al ap­proach­es, lever­ag­ing the strengths of var­i­ous tech­nolo­gies to pro­vide rev­o­lu­tion­ary out­comes in high un­met need dis­ease ar­eas. Check­point in­hibitor and CAR-T com­bi­na­tions are al­ready in de­vel­op­ment while many oth­er cell and gene ther­a­py ap­proach­es are un­der­way that can al­so be com­ple­men­tary in func­tion (Fig. 3). How­ev­er, the ben­e­fits need to be weighed against the risks as com­bin­ing these po­tent ther­a­pies could ex­ac­er­bate po­ten­tial­ly fa­tal AEs, like CRS and NT. The pur­suit of nov­el C&GT com­bi­na­tions is like­ly to con­tin­ue the grow­ing trend of iden­ti­fy­ing sub­sets of pa­tients who are more like­ly to re­spond or at greater risk for se­vere AEs to bet­ter in­form treat­ment de­ci­sions.

Fig­ure 3: Overview of monother­a­py vs. com­bi­na­tion C&GT tri­als to date, il­lus­trat­ing that ap­prox­i­mate­ly 30% of cell and gene ther­a­pies are be­ing stud­ied in com­bi­na­tion with var­i­ous ther­a­pies, in­clud­ing im­muno-rheum ther­a­pies, chemother­a­py, tar­get­ed ther­a­py, ra­di­a­tion ther­a­py, in-vi­vo gene ther­a­py, and oth­er cell ther­a­pies [1].

The C&GT land­scape is rapid­ly evolv­ing

In just a short pe­ri­od from March 2021 to No­vem­ber 2021 we have ob­served a sub­stan­tial fluc­tu­a­tion in as­sets en­ter­ing / ex­it­ing clin­i­cal tri­als. 73  cell (61)  and gene (12) ther­a­py tri­als have paused or been ter­mi­nat­ed while 68 new cell (62) and gene (6) tri­als have been iden­ti­fied. Nav­i­gat­ing this ever-chang­ing C&GT land­scape re­quires a com­pre­hen­sive un­der­stand­ing of C&GT and how the field will con­tin­ue to change from man­u­fac­tur­ing, sup­ply chain lo­gis­tic, to pric­ing strate­gies and ac­cess is­sues. Here at ZS we have a team of ex­perts who seek to com­pre­hen­sive­ly un­der­stand the com­plex C&GT land­scape and these pre­dic­tions are an ex­cerpt from our broad­er e-book, read more here.

About ZS

ZS Emerg­ing Biotech and Phar­ma Space: ZS is the leader in “first launch”, part­ner­ing with 200+ unique pre- and ear­ly-com­mer­cial bio­phar­ma com­pa­nies on 1,000+ projects in just the last 5 years. ZS has a ro­bust un­der­stand­ing of com­mon chal­lenges of de­vel­op­ment-stage emerg­ing phar­ma, which con­sists of a grow­ing num­ber of C&GT man­u­fac­tur­ers. With deep ex­pe­ri­ence in ar­eas such as port­fo­lio and pipeline strat­e­gy, busi­ness de­vel­op­ment and li­cens­ing, pipeline as­set strat­e­gy and launch strat­e­gy and readi­ness, ZS can help en­sure that you re­al­ize the full po­ten­tial of your pipeline and achieve com­mer­cial suc­cess be­yond ap­proval. Click here to stay up-to-date on ZS’s “First Launch” thought lead­er­ship and here to find out more about our Pipeline & Launch Strat­e­gy ca­pa­bil­i­ties.

Cell and Gene Ther­a­py Space: ZS has been a part of every US cell & gene ther­a­py launch to date and most launch­es in the EU. In 2021, we part­nered with 35+ man­u­fac­tur­ers on 200+ projects in both the clin­i­cal and com­mer­cial set­tings. ZS’s C&GT space fo­cus­es on Dis­cov­ery, De­vel­op­ment and De­liv­ery to help man­u­fac­tur­ers jump­start their C&GT port­fo­lio, im­prove their man­u­fac­tur­ing and sourc­ing strat­e­gy, de­vel­op end-to-end da­ta strate­gies, and craft suc­cess­ful com­mer­cial, launch, ac­cess and ex­pan­sion strate­gies – all while look­ing ahead to the rapid­ly evolv­ing mar­ket space. ZS can help you pre­pare for a suc­cess­ful launch, es­pe­cial­ly in on­col­o­gy and rare dis­ease in­di­ca­tions where we see the most C&GT de­vel­op­ment to­day. Find out more on ZS.com here.

Fig­ure 4: ZS is the leader in “first launch”, part­ner­ing with Emerg­ing Bio­phar­ma and Cell & Gene Ther­a­py com­pa­nies on ear­ly strat­e­gy and plan­ning through to ex­e­cu­tion phas­es.

Ref­er­ences: 

[1] List of ref­er­ences can be found in the full e-book or up­on re­quest.