De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on de­vel­op­ing and de­liv­er­ing a CAR T-cell ther­a­py with mul­ti-tu­mor speci­fici­ty com­bined with cell man­u­fac­tur­ing suc­cess

Overview

Tran­si­tion­ing po­ten­tial ther­a­peu­tic as­sets from acad­e­mia in­to the com­mer­cial en­vi­ron­ment is an ex­er­cise that is large­ly un­der­ap­pre­ci­at­ed by stake­hold­ers, ex­cept for drug de­vel­op­ers them­selves. The promise of pre­clin­i­cal or ear­ly clin­i­cal re­sults dri­ves en­thu­si­asm, but the prag­mat­ic de­liv­ery of a ther­a­py out­side of small, lo­cal test­ing is most of­ten a ma­jor chal­lenge for drug de­vel­op­ers es­pe­cial­ly, in­clud­ing among oth­er things, the man­u­fac­tur­ing chal­lenges that sur­round the pro­duc­tion of just-in-time and per­son­al­ized au­tol­o­gous cell ther­a­py prod­ucts.

While de­vel­op­ing a se­ries of NKG2D chimeric anti­gen re­cep­tors (CARs), which Celyad be­lieves car­ry enor­mous po­ten­tial through their breadth of po­ten­tial tu­mor tar­get­ing, cre­at­ing so­lu­tions to en­sure the man­u­fac­tura­bil­i­ty and sta­bil­i­ty has re­quired fur­ther ex­am­i­na­tion of the ba­sic bi­ol­o­gy around the CAR and its tar­gets. This de­tailed knowl­edge has giv­en rise se­quen­tial­ly to sev­er­al po­ten­tial man­u­fac­tur­ing so­lu­tions with­in a few months. The hur­dles of low yield and lack of prod­uct sta­bil­i­ty fol­low­ing cry­op­reser­va­tion were ma­jor chal­lenges that Celyad has over­come to gen­er­ate what it be­lieves is a ro­bust man­u­fac­tur­ing process for its se­ries of NKG2D-based CAR prod­uct can­di­dates. Con­tin­u­ing in-house re­search has sought fur­ther im­prove­ments to the process, es­pe­cial­ly fo­cus­ing on gen­er­at­ing less dif­fer­en­ti­at­ed T-cells which are cur­rent­ly con­sid­ered to be op­ti­mal for gen­er­at­ing an adop­tive CAR T-cell ther­a­py with po­ten­tial long-last­ing im­pact. This ad­vance­ment led rapid­ly to our cur­rent pro­pri­etary man­u­fac­tur­ing process called ‘Op­ti­mAb’, which is now im­ple­ment­ed in the com­pa­ny’s two dif­fer­ent clin­i­cal au­tol­o­gous NKG2D-based CAR prod­uct can­di­dates, CYAD 01 and CYAD-02.

CAR T-cell Ther­a­py

Ear­ly be­gin­nings and lim­i­ta­tions of the sin­gle tar­get­ing clas­si­cal con­struct

The con­cept of the chimeric anti­gen re­cep­tor (CAR) was de­vel­oped by Zelig Es­h­har at the Weiz­mann In­sti­tute, Is­rael dur­ing the late 1980s and ear­ly 1990s. The CAR ap­proach was de­vel­oped specif­i­cal­ly in re­sponse to ob­ser­va­tions that tu­mor cells ac­tive­ly avoid im­mune-me­di­at­ed elim­i­na­tion by the spe­cif­ic down­reg­u­la­tion of cru­cial mol­e­cules that me­di­ate im­mune recog­ni­tion. T-cells are key ef­fec­tors of the im­mune sys­tem that use a ‘T-cell re­cep­tor’ to bind to the ma­jor his­to­com­pat­i­bil­i­ty com­plex (MHC) present on every nu­cle­at­ed cell. Tu­mor cells ac­tive­ly in­ter­fere with MHC which, in ef­fect, re­sults in the tu­mors be­com­ing in­vis­i­ble to T-cell sur­veil­lance. This is a ma­jor rea­son why tu­mors can grow de­spite the pres­ence of T-cells that could read­i­ly elim­i­nate the tu­mor.

The CAR ap­proach in­volves en­graft­ing T-cells with a nov­el cell sur­face re­cep­tor that pro­vides a tu­mor speci­fici­ty and is in­de­pen­dent of the usu­al T-cell recog­ni­tion sys­tem. In the most com­mon it­er­a­tion, this re­cep­tor is based on an an­ti­body which can di­rect­ly rec­og­nize tar­get pro­teins on the cell sur­face in the ab­sence of MHC, and thus re­move the cloak of in­vis­i­bil­i­ty from the tu­mor and ex­pose them to T-cell me­di­at­ed killing.

CAR T-cell ther­a­py is now a clin­i­cal re­al­i­ty hav­ing moved from ear­ly con­cept to clin­i­cal proof of prin­ci­ple and, in 2017, to the U.S. li­cens­ing of two CAR T-cell prod­ucts for the treat­ment of B-cell ma­lig­nan­cies. The rapid ap­proval of the two prod­ucts Yescar­ta™ and Kym­ri­ah™ were based on clin­i­cal re­spons­es in pa­tients for whom there were lit­tle, if any, ther­a­peu­tic op­tion that could dri­ve long-term ben­e­fit. These ap­provals were ground­break­ing for the in­dus­try and for the treat­ment of can­cer. How­ev­er, the ex­pec­ta­tion of a flood of CAR T-cell ther­a­pies be­yond B-cell ma­lig­nan­cies de­liv­er­ing sim­i­lar lev­els of clin­i­cal ef­fi­ca­cy has not yet been ful­filled. We be­lieve this is large­ly due to sev­er­al is­sues, which in­clude suit­abil­i­ty of tar­gets with which to aim the CAR T cell to tu­mors and the chal­lenge of man­u­fac­tur­ing CAR T-cells in a com­mer­cial­ly vi­able man­ner that is able to sup­ply the need of the world­wide ad­dress­able pa­tient pop­u­la­tion.

The po­ten­tial ad­van­tage of us­ing an­ti­bod­ies for CAR T-cell ther­a­py is their ex­quis­ite speci­fici­ty for a sin­gle tar­get. The tar­get typ­i­cal­ly de­ter­mines the in­di­ca­tion for which the CAR T-cell ther­a­py can be used. Yescar­ta™ and Kym­ri­ah™ both use an an­ti­body spe­cif­ic for the CD19 pro­tein present on B-cell leukemias and lym­phomas. Since CD19 is ab­sent on non-B-cells, these two prod­ucts can­not be ef­fec­tive­ly used be­yond treat­ing B-cell ma­lig­nan­cies. Out­side of B-cell tu­mors, there are un­for­tu­nate­ly very few ide­al tar­gets sim­i­lar in pro­file to CD19. The ad­van­tage of mono-tar­get speci­fici­ty of an­ti­bod­ies is al­so po­ten­tial­ly a dis­ad­van­tage since the tu­mor may lose the spe­cif­ic tar­get (a process called ‘anti­gen loss’) and hence be­come ef­fec­tive­ly in­vis­i­ble to the CAR T-cell ther­a­py. This is in­deed a phe­nom­e­non ap­pear­ing with­in CD19 CAR T-cell prod­uct can­di­dates, where pa­tients are suc­cumb­ing to B-cell leukemias and lym­phomas de­spite the pres­ence of CD19 CAR T-cells in their blood, as the tu­mor blasts have lost the CD19 pro­tein.

Find­ing a sys­tem that pro­vides tu­mor speci­fici­ty and over­comes tu­mor anti­gen es­cape by tar­get­ing mul­ti­ple tu­mor spe­cif­ic epi­topes may be a suc­cess­ful com­bi­na­tion to de­liv­er a broad CAR T-cell ther­a­py ap­proach.

NKG2D

A pos­si­ble an­swer to the broad CAR T-cell ther­a­py co­nun­drum

An ob­vi­ous an­swer to mul­ti­ple tu­mor tar­get­ing for CAR T-cells is to use mul­ti­ple an­ti­bod­ies and re­cep­tors (Springuel et al. 2019)¹. This some­what man­u­al ap­proach is in­deed be­ing ex­plored ex­ten­sive­ly in the CD19 CAR T-cell space in re­sponse to anti­gen-loss vari­ants seen af­ter CAR T-cell ther­a­py. How­ev­er, a po­ten­tial­ly more ex­quis­ite ap­proach would be to use mul­ti-tar­get speci­fici­ty de­signed by na­ture it­self. Nat­ur­al killer (NK) cells are a part of the in­nate im­mune sys­tem that has evolved to pro­vide an im­me­di­ate re­sponse to in­fec­tion by pathogens such as virus­es. One spe­cif­ic mech­a­nism em­ployed by NK cells is through the Nat­ur­al Killer Group 2D (NKG2D) re­cep­tor which binds to eight known tar­gets in hu­mans. These tar­gets are ‘stress lig­ands’ that are dis­played by cells rapid­ly af­ter mi­cro­bial in­fec­tion, among oth­ers. Thus, this sin­gle NKG2D re­cep­tor en­ables NK cells to rec­og­nize any of the eight tar­gets dis­played by in­fect­ed cells and ini­ti­ate a killing re­sponse. In this man­ner, es­cape of NKG2D-me­di­at­ed sur­veil­lance would like­ly re­quire loss of all eight tar­gets (Fig­ure 1).

Im­por­tant­ly, many tu­mors (both hema­to­log­i­cal and sol­id) dis­play these NKG2D tar­gets main­ly as a re­sult of genome in­sta­bil­i­ty. How­ev­er, tu­mors avoid NK cell me­di­at­ed killing by many fac­tors in­clud­ing the fact that NK cells are on­ly rarely found with­in the tu­mor en­vi­ron­ment. Pro­fes­sor Charles Sent­man² con­ceived the idea of us­ing the NKG2D re­cep­tor fused to a T-cell ac­ti­va­tion do­main to form a CAR. When ex­pressed in a T-cell, this re­cep­tor could po­ten­tial­ly pro­vide an ap­proach that is tru­ly broad (in tar­get­ing a wide ar­ray of tu­mors) and aimed at mul­ti­ple tar­gets (there­by po­ten­tial­ly re­duc­ing anti­gen-es­cape vari­ants to de­vel­op).

Fig­ure 1: Com­par­i­son of sin­gle-tar­get and mul­ti-tar­get CAR T ap­proach­es

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Ex­ten­sive pre­clin­i­cal stud­ies ob­served the po­ten­tial of a NKG2D-based CAR T-cell in­ves­ti­ga­tion­al ther­a­py, which pro­gressed in­to ini­tial Phase 1 clin­i­cal test­ing at the Dana Far­ber Can­cer In­sti­tute in 2015. The aca­d­e­m­ic mono-cen­tric CM-CS1 tri­al used low dos­es of fresh NKG2D CAR T-cells pro­duced at an on-site cell pro­duc­tion fa­cil­i­ty. Twelve pa­tients with ad­vanced mul­ti­ple myelo­ma or acute myeloid leukemia re­ceived NKG2D CAR T-cells in this dose-es­ca­la­tion safe­ty tri­al. Giv­en the breadth of tar­get bind­ing, the key read­out from this tri­al was that the CAR T-cell in­ves­ti­ga­tion­al ther­a­py was well tol­er­at­ed with no ev­i­dence of on-tar­get, off-tis­sue tox­i­c­i­ty (Baumeis­ter et al. 2019)³.

Armed with ini­tial clin­i­cal safe­ty da­ta and the ther­a­peu­tic po­ten­tial of the NKG2D-based CAR T-cell in­ves­ti­ga­tion­al ther­a­py, Celyad de­cid­ed to ac­tive­ly pur­sue the ap­proach in­to larg­er scale, in­dus­try-spon­sored clin­i­cal tri­als to in­ves­ti­gate the safe­ty pro­file of the in­ves­ti­ga­tion­al cell ther­a­py and to as­sess the clin­i­cal ac­tiv­i­ty of the NKG2D-based ap­proach.

Tran­si­tion­ing from Aca­d­e­m­ic to Larg­er Cell Ther­a­py Tri­als

Lo­gis­tics and man­u­fac­tur­ing chal­lenges

One im­por­tant chal­lenge fac­ing Celyad was re­lat­ed to mov­ing in­to mul­ti­cen­ter, multi­na­tion­al clin­i­cal tri­als for the NKG2D CAR T-cell in­ves­ti­ga­tion­al ther­a­py that em­ployed mul­ti­ple dos­es of au­tol­o­gous pa­tient’s T-cells pro­duced from a sin­gle aphere­sis. This re­quired the cell prod­uct to be frozen at the end of the man­u­fac­tur­ing process, for ship­ment of the sev­er­al dos­es to the treat­ing cen­ters all around the world. The cells are then stored frozen and thawed just be­fore the pa­tient is treat­ed (Fig­ure 2). The com­pa­ny strong­ly ben­e­fit­ed from its his­to­ry in cell ther­a­py man­u­fac­tur­ing and ex­per­tise gained from its own be­spoke cell man­u­fac­tur­ing fa­cil­i­ty. More­over, the com­pa­ny al­so pos­sessed in-house ex­pe­ri­ence in pro­duc­ing cell ther­a­py prod­uct can­di­dates for large mul­ti­cen­ter clin­i­cal tri­als, mean­ing that many of the lo­gis­ti­cal hur­dles that hin­der cell ther­a­py, in­clud­ing in­ter­na­tion­al (and in­deed, in­ter­con­ti­nen­tal) cold-chain de­liv­ery, had al­ready been ad­dressed by the com­pa­ny.

Fig­ure 2: Schemat­ic rep­re­sen­ta­tion of the man­u­fac­tur­ing process of a fresh or frozen CAR T-cell prod­uct.

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How­ev­er, while the fun­da­men­tals of de­liv­er­ing an in­ves­ti­ga­tion­al cell ther­a­py to clin­i­cal sites was large­ly al­ready es­tab­lished in-house, it was clear at a very ear­ly stage that the aca­d­e­m­ic man­u­fac­tur­ing process em­ployed for the CM CS1 clin­i­cal tri­al to de­liv­er a fresh dose of NKG2D CAR T-cells should be adapt­ed for the pro­duc­tion of mul­ti­ple dos­es of frozen CAR T-cells. First­ly, the num­ber of cells that could be pro­duced was lim­it­ed and, sec­ond­ly, the freez­ing of cells (cry­op­reser­va­tion) re­sult­ed in a sig­nif­i­cant loss of liv­ing NKG2D-based CAR T-cells. Both are ma­jor re­stric­tions to de­liv­er­ing a ro­bust just-in-time man­u­fac­tur­ing so­lu­tion for pa­tients with ad­vanced can­cer.

Fig­ure 3: Frat­ri­cide ef­fect af­ter thaw­ing of NKG2D CAR T cells

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The rea­sons for low cell num­ber and poor vi­a­bil­i­ty af­ter cry­op­reser­va­tion ap­peared linked. Our re­search showed that the tar­gets for the NKG2D CAR are tran­sient­ly ex­pressed on the ac­ti­vat­ed T-cells mean­ing that that T-cells armed with the NKG2D CAR could po­ten­tial­ly kill oth­er T cells, and pos­si­bly them­selves, dur­ing the cul­ture pe­ri­od (termed frat­ri­cide). More con­cern­ing, these NKG2D tar­gets are in­creased dur­ing cel­lu­lar stress and the freeze-thaw process in­duces stress that re­sults in the ma­jor up­reg­u­la­tion of NKG2D tar­gets and thus ex­plains the rapid loss of vi­able T-cells af­ter thaw­ing through frat­ri­cide (Fig­ure 3). Deal­ing with these two is­sues has been a chal­lenge for the com­pa­ny to over­come over the past few years. Dur­ing that time our man­u­fac­tur­ing has been through dif­fer­ent it­er­a­tions re­sult­ing in a process that is able to sup­ply all cur­rent clin­i­cal ac­tiv­i­ty with high man­u­fac­tur­ing suc­cess rates in a com­mer­cial­ly rel­e­vant con­text.

Process De­vel­op­ment

An es­sen­tial, con­tin­u­ing im­prove­ment ex­er­cise

An­oth­er of­ten over­looked con­cern is the fact that some as­sets brought in­to the com­pa­ny come with fun­da­men­tal is­sues around man­u­fac­ture. How­ev­er, rather than shy away from the chal­lenge, the re­search teams at Celyad fo­cused up­on ex­plor­ing prag­mat­ic an­swers to the is­sues. The first so­lu­tion fo­cused up­on cry­op­reser­va­tion and the serendip­i­tous ob­ser­va­tion that cer­tain ki­nase in­hibitors could en­hance the re­cov­ery of NKG2D CAR T-cells af­ter thaw­ing. The in­clu­sion of a phos­phatidyli­nos­i­tol 3-ki­nase (PI3K) in­hibitor (LY294002, re­ferred to as LY) in­to the man­u­fac­tur­ing process sig­nif­i­cant­ly en­hanced cell yield (Fig­ure 4). The first clin­i­cal tri­al ini­ti­at­ed by Celyad (THINK tri­al, NCT03018405), aimed to eval­u­ate the frozen NKG2D CAR prod­uct can­di­date (CYAD-01) in a mul­ti­ple in­fu­sion sched­ule with no pri­or pre­con­di­tion­ing (three to six dos­es of cells with up to 3 bil­lion cells per in­fu­sion). All dos­es for a spe­cif­ic pa­tient were pro­duced from a sin­gle aphere­sis and were then frozen and de­liv­ered to the clin­i­cal site for in­fu­sion over a one-month pe­ri­od. The in­clu­sion of LY proved to be a rel­a­tive­ly mi­nor ad­di­tion to the aca­d­e­m­ic man­u­fac­tur­ing process but one that en­abled the ini­ti­a­tion of the THINK clin­i­cal tri­al in clin­i­cal cen­ters in the EU and U.S. in ear­ly 2016.

Fig­ure 4: Re­duc­tion of the frat­ri­cide ef­fect through im­ple­men­ta­tion of the LY and mAb process­es

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As the tri­al pro­gressed, the is­sue of cell yield be­came more press­ing. Pro­duc­ing enough cells from pa­tients with ad­vanced hema­to­log­i­cal ma­lig­nan­cies was prob­lem­at­ic. We be­lieve the rea­sons for this poor yield were again like­ly due to the frat­ri­cide is­sue. Our con­tin­ued re­search iden­ti­fied that the in­clu­sion of a NKG2D-block­ing mon­o­clon­al an­ti­body (an­ti-CD314) to block the frat­ri­cide ef­fect re­sult­ed in high cell yields and much im­proved con­sis­ten­cy of pro­duc­tion. The in­clu­sion of the mon­o­clon­al an­ti­body in­to the man­u­fac­tur­ing process (com­mon­ly re­ferred to as the mAb process, Fig­ure 4) again was a fair­ly min­i­mal amend­ment but re­sult­ed in a high­ly re­pro­ducible and ro­bust process that, since in­tro­duc­tion in Jan­u­ary 2018, has re­sult­ed in a greater than 94% man­u­fac­tur­ing suc­cess rate for the just-in-time au­tol­o­gous ap­proach.

Op­ti­mAb Process

Mov­ing process de­vel­op­ment be­yond in­creas­ing the yield

The gen­er­a­tion of a ro­bust man­u­fac­tur­ing process that over­comes the chal­lenges of frat­ri­cide is de­signed to en­able the pro­duc­tion of suf­fi­cient num­bers of cells for all of Celyad’s NKG2D CAR T-cell tri­als. How­ev­er, re­search con­tin­ues and, re­cent­ly, rather than deal­ing with over­com­ing prag­mat­ic is­sues, has fo­cused on ef­forts to gen­er­ate cells that may have in­creased an­ti-tu­mor ac­tiv­i­ty in the pa­tient. This is of im­por­tance to Celyad giv­en the com­pa­ny’s cur­rent fo­cus on the high­ly chal­leng­ing clin­i­cal in­di­ca­tions of ad­vanced acute myeloid leukemia and metasta­t­ic col­orec­tal can­cer.

There is an emerg­ing view in the cell ther­a­py field that T-cells that dis­play fea­tures as­so­ci­at­ed with re­duced dif­fer­en­ti­a­tion may be more ac­tive in the ther­a­peu­tic set­ting. Ma­ture T-cells are de­rived from prog­en­i­tor cells that are pro­duced in the bone mar­row and ma­ture through a process of ‘ed­u­ca­tion’ in the thy­mus. The T-cell that emerges from the thy­mus is known as a naïve T-cell and cir­cu­lates the body look­ing for ac­tion. This ac­tion takes place in sec­ondary lym­phoid struc­tures such as lymph nodes and it is here where the naïve T-cell meets its tar­get and be­comes li­censed to go out and kill. Even­tu­al­ly, the T-cell leaves the lymph node to do its busi­ness of chas­ing in­fect­ed and can­cer cells around the body. As it does this, the T-cell be­comes more dif­fer­en­ti­at­ed – in short, the T-cell when first made is naïve or de-dif­fer­en­ti­at­ed and de­signed to move around the body in or­der to go to the cor­rect struc­tures to be­come ed­u­cat­ed. As the T-cell emerges to deal with chal­lenges around the body, it be­comes more ma­ture and set in its ways – this is dif­fer­en­ti­a­tion. As T-cells be­come more dif­fer­en­ti­at­ed, they are bet­ter able to kill tar­get cells, but this is al­so as­so­ci­at­ed with a short­ened life span – they tend to die dur­ing the process of killing. This is a nat­ur­al mech­a­nism used to en­sure that high­ly pow­er­ful and de­struc­tive T-cells do not per­sist for ex­ces­sive­ly long pe­ri­ods of time which could re­sult in tox­i­c­i­ty.

With re­spect to CAR T-cell in­ves­ti­ga­tion­al ther­a­py, the man­u­fac­tur­ing process­es used to date tend to pro­duce more dif­fer­en­ti­at­ed T-cells that are high­ly ac­tive in killing but less able to per­sist. Stud­ies in mouse mod­els sug­gest that gen­er­at­ing less dif­fer­en­ti­at­ed T-cells may de­liv­er a stronger an­ti-tu­mor ef­fect. This is a lit­tle counter-in­tu­itive since less dif­fer­en­ti­at­ed T-cells pos­sess less di­rect can­cer cell killing ac­tiv­i­ty, but this can be coun­ter­bal­anced by the fact that this less ac­tive killing per­sists for long pe­ri­ods.

Trans­lat­ing the ob­ser­va­tions made in mice to hu­man clin­i­cal stud­ies is not straight­for­ward. How­ev­er, our in-house re­search sug­gest­ed that swap­ping the in­hibitor used in our man­u­fac­tur­ing process for a dif­fer­ent, more spe­cif­ic in­hibitor and re­duc­ing the length of cul­ture from ten to eight days pro­duced cells that had a high­er fre­quen­cy of a pro­tein on their cell sur­face that in­di­cat­ed the cells were less dif­fer­en­ti­at­ed. In more de­tail, this al­tered process (now called Op­ti­mAb) gen­er­at­ed a NKG2D CAR T-cell pop­u­la­tion with a high­er fre­quen­cy of CD62L (or L-se­lectin) on the cell sur­face as com­pared to those gen­er­at­ed by the mAb process (Fig­ure 5). CD62L is a pro­tein used by T-cells to traf­fic to lymph nodes; thus, this pro­tein is present on cells that are less dif­fer­en­ti­at­ed and track­ing to lymph nodes. Con­se­quent­ly, T-cells that ex­press CD62L are like­ly to be less dif­fer­en­ti­at­ed. How­ev­er, we have al­so ob­served in mouse mod­els that Op­ti­mAb T-cells al­so pro­duce high­er lev­el of in­ter­fer­on gam­ma up­on chal­lenge with tu­mor cells, a cy­tokine which plays an im­por­tant role in dri­ving an­ti-tu­mor ef­fect.

Fig­ure 5: Com­par­i­son of the mAb and Op­ti­mAb man­u­fac­tur­ing process­es

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In a stress-test mouse mod­el, when com­par­ing mAb-pro­duced NKG2D CAR T-cells (at a re­duced dose to achieve a min­i­mal lev­el of an­ti-tu­mor ac­tiv­i­ty), the Op­ti­mAb NKG2D CAR T-cells showed much im­proved an­ti-tu­mor ac­tiv­i­ty at the same dose. Tak­en to­geth­er with oth­er in­ter­nal da­ta, these ob­ser­va­tions sug­gest­ed that through an­oth­er rel­a­tive­ly small change of the man­u­fac­tur­ing process, NKG2D CAR T-cells with po­ten­tial­ly in­creased po­ten­cy could be pro­duced. This Op­ti­mAb man­u­fac­tur­ing ap­proach is sup­port­ed by the clin­i­cal tol­er­a­bil­i­ty of NKG2D CAR T-cells ob­served in sev­er­al Phase I clin­i­cal tri­als. There­fore, the de­ci­sion to pro­duce T cells with the same speci­fici­ty pro­file but like­ly im­proved func­tion in line with the cur­rent lit­er­a­ture was strong­ly war­rant­ed.

Our pro­pri­etary Op­ti­mAb process was ac­cept­ed by both the U.S. Food and Drug Ad­min­is­tra­tion (FDA) and the Fed­er­al Agency for Med­i­cines and Health Prod­ucts (FAMHP) of Bel­gium as an amend­ment to the man­u­fac­tur­ing process for cur­rent clin­i­cal tri­als of in­ves­ti­ga­tion­al NKG2D CAR T cells.

“We ea­ger­ly await the trans­la­tion­al out­comes of our ef­forts to con­trol and now im­prove the man­u­fac­tur­ing of in­ves­ti­ga­tion­al NKG2D CAR T-cells.”

David Gilham, VP Re­search & De­vel­op­ment, Celyad


¹ Springuel et al. 2019. “Chimeric Anti­gen Re­cep­tor-T-cells for Tar­get­ing Sol­id Tu­mors: Cur­rent Chal­lenges and Ex­ist­ing Strate­gies.” Bio­Drugs. https://doi.org/10.1007/s40259-019-00368-z.

² Sent­man and Mee­han. 2014. Can­cer J. 2014 Mar-Apr;20(2):156-9.

³ Baumeis­ter et al. 2019. “Phase I Tri­al of Au­tol­o­gous CAR T-cells Tar­get­ing NKG2D Lig­ands in Pa­tients with AML/MDS and Mul­ti­ple Myelo­ma.” Can­cer Im­munol­o­gy Re­search 7 (1): 100–112.

AUTHOR

David Gilham

VP of R&D, Celyad