Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. nlre admzdciia ras uhavne aeldt nices nsria aefo esthan less from rate survival in increase today an 90% to than led greater have to of advances 1960s Such cause chemotherapy the multiagent frequent of trials. in common most efficacy clinical 10% most the second randomized in the the improvements age large, progressive still it by of in is cancer making years with it patients year, 20 among therapies, each before survival excellent cancer diagnosed despite from are However, death leukemia children. childhood its among of including cancer cases B-ALL, r/r 3,500 with Approximately adults young Available Therapies and therapy challenges. and of children current refractory B-ALL lines in and two is effects, tisagenlecleucel after that side of lymphoma B-ALL common cell use efficacy, with B the clinical large old discuss refractory years will or 25 relapsed review Drug with first to and patients relapse Food the up adult the greater patients became by including or approved for tisagenlecleucel second be therapy indication to in therapy cell an or cell T with adoptive engineered (CAR) (FDA), genetically receptor Administration first antigen the vital. and chimeric with remains therapy patients autologous therapies gene for new the prognosis coupled of the 2017, development discovery but In Thus, well, of do dismal. The therapies pace remains B-ALL. conventional for B-ALL to The development (r/r) respond in relapsed/refractory who still kinases. patients the are of driver specific therapies majority creating identify of targeted large marrow, to other targeting remarkable scientists B-ALL, bone precise dur- positive been for the Philadelphia-chromosome gas has for ability in relevance current mustard blasts cells clinical the to leukemic hematopoietic with to exposed in way the given personnel lesions in great have naval changes genetic the chemotherapy, that toxic of of observations one experienced basis been Initial fundamental II has War patients, therapy. World younger cancer ing in of especially stories B-ALL, treating success in improvements iterative Rapid, in drug. tisagenlecleucel this of of efficacy potential maximum Introduction clinical barriers the as the well realize of as to strategies, summary order management updated associated in their addressed an immunobiology and be provide effects basic side to the will common remain on review B-ALL, that understanding r/r This with deeper lymphoblastic adults a drug. young acute gained and cell this have childhood we B of approval, relapsed/refractory efficacy its with clinical since adults years field and young three this and Now revolutionized children has B-ALL). genetically Administration, (r/r in first Drug leukemia the success and Tisagenlecleucel, clinical Food impressive States decade. United demonstrating past the the by by over approved drastically therapy changed cellular has adoptive therapy engineered cancer for landscape treatment The Abstract 2020 24, September 2 1 Si Stephanie leukemia lymphoblastic with acute adults cell young B and relapsed/refractory children of treatment for Tisagenlecleucel h hlrnsHsia fPhiladelphia of Hospital Children’s The Philadelphia of Hospital Children’s 1 tpa Grupp Stephan , 2 hrl fe,i a 08 eodidcto o ramn a added, was treatment for indication second a 2018, May in after, Shortly . 1 n mnaDiNofia Amanda and , 4-6 1 oee,wt h xeto ftrsn iaeihbtr in inhibitors kinase tyrosine of exception the with However, . eiti -L a rvddamdlfripoeetof improvement for model a provided has B-ALL Pediatric . 5,7 hr eaetdyhsbe rup fciia trial clinical of triumph a been has today are we Where . 1 2 3 This . Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. utdi h S[C0289] nteESG td,CL1 a rdcda h enGPfacility, con- GMP was Penn which U the trial, at ENSIGN produced Novartis-sponsored was CTL019 the study, was ENSIGN the product In T [NCT02228096]. CAR US a the in of ducted trial in multicenter remains first trial The that on treated patient years. 2 24 first 8 Phase in The at months) therapy persistence. (1-39 further assessment T without last CAR CR CTL019 continuous to functional CR up phenotype. for continued CD19-negative marker ongoing subsequently which patients a macodynamic with Twenty aplasia, patients with at cell months. 34 escape 12 B remission antigen of at at by complete 79% demonstrating 76% accompanied was was in (13) was survival (RFS) overall persistence majority were survival and the Relapse-free (93%) months, On- with 12 Clinical (88%). patients at relapsed patients of 55 55% 52 Society and demonstrated in American months MRD the 6 2016 negative at in with presented a post-infusion meeting (n=59) one-month with cohort annual publication pediatric one-month (ASCO) the of 90% cology months). on time was 1-24 focused CRi, at (range results months or remission Updated 7 CR continued of either demonstrated time as trials up (63%) defined follow two patients median rate, these Nineteen response from overall the reported post-infusion. The at were HSCT. Philadelphia B-ALL time allogeneic of CD19+ that undergone Hospital refractory at Children’s or (produced the studies relapsed tisagenlecleucel label at open of center, conducted single feasibility NCT01029366] arm, (CHOP) single and and 1/2a phase safety NCT01626495 were B-ALL [clinicaltrials.gov the in CTL019) determine as Pennsylvania to of University trials first The review. a 1 this B-ALL tisagenlecleucel, Phase calicheamicin-class of to in a approval focus tisagenlecleucel full the to of granted be efficacy conjugated FDA will Clinical the which antibody 2017, product, anti-CD22 August cell in T an prior recently, CAR the most ozogamicin, CD19-directed in and unprecedented Inotuzumab (3), was (2) drug that cells, feat cytotoxic cells, cancer a B-ALL, on T r/r immunotherapy antigens distinct of CD3+ of and treatment novel the targeting three years for selective 2017, FDA 25 T, to the 2014 CAR by an From approved provide of effects. were Immunotherapies case side drugs and immunotherapy. target” therapy, the “off added: radiation in unwanted surgery, be limiting and, now often therapy: action can cancer of pillar of mechanism fourth pillars alternative a established list, three this respectively been To and have 2012, chemotherapy. clofarabine there and 1950s, with 2004 the 30% B-ALL, in Since to FDA relapsed 20 the for of by FDA-approved rates approved CNS remission been as injection complete have malignancy, universally liposomal agents used secondary chemotherapy, sulfate new intrathecal for vincristine Few of risk effects increased exists. cognitive systems long-term obesity, prophylaxis, nervous the peripheral and on and significant, syndrome information cerebrovascular, are relapse cardiovascular, limited metabolic regimens who of treatment patients impairment to, such for long-term from limited regimens and Toxicities into not (CNS). those incorporated system but for nervous often chemotherapy central including, is of the Radiation years in features. 2 leukemia trans- approximately risk with cell and standard stem high-risk, or haemopoietic as lower by 10-20% stratified with followed only patients chemotherapy of for multi-agent rate (HSCT) survival include plantation overall has B-ALL including 5-year progress relapsed relapse, a for after less with algorithms prognosis prognosis B-ALL, relapse the worst of diagnosed to the contribute site portends newly factors and nosis with Several immunophenotype, B-ALL. patients relapse, r/r to of but, of time treatment outcome abroad, the improved in and steadily made US been the the patients to in of contrast 15-20% both By in groups, occurs cooperative relapse by improvements, these enrollment despite patient multicenter and development 17 18 1 lntmmb iseicTcl nae BT)dsge oln D9 el with cells B CD19+ link to designed (BiTE) engager cell T bi-specific a Blinatumomab, (1) . n h nvriyo enyvna( en.I 04 0ptet 2 hlrn dls with adults) 5 children, (25 patients 30 2014, In Penn). (U Pennsylvania of University the and 20 hwn htBcl pai ol eue sawdl vial phar- available widely a as used be could aplasia cell B that showing , 14-16 . 2 5 eulr eas ihn3 otso nta diag- initial of months 36 within relapse Medullary . 8 . 19 8ptet a previously had patients 18 ; 9-11 eea treatment General . 12,13 5 naddition, In . ae on based , Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. iaeihbtr o ainsrfatr osadr R ramn yptnl n eesbyinhibiting reversibly and potently study by active treatment multityrosine of CRS a area standard dasatinib, important to of an activity refractory now, remains potential patients For demonstrated CRS for by care. also of of inhibitor, required have management standard is kinase studies remains the therapy pre-clinical and in cell recent product, siltuximab undergoing the addition, of patients for (REMS) for place strategy CRS pharmacy the mitigation COVID-19 and the evaluation treat in risk available to the tocilizumab off-label Having used supply. being is a tocilizumab are siltuximab, which and continues, steroids CRS high-dose where 28 as cases such In publication interventions one support. other pressor corticosteroids, indicated antagonist manage, for as adding IL-6 to controlled, need direct then challenging is no doses, most CRS to two severe the minimal is or most and generally tisagenlecleucel interventions, one fever from these of in CRS After resolution Severe tocilizumab by dose. function with management. tocilizumab the first-line starting another as jeopardize by fashion, avoided can followed stepwise be doses a to prolonged driver in cells, therapy and key T managed anti-cytokine high CAR a at targeted of is and persistence as (IL-6) lympholytic and CRS, 6 are for which interleukin therapy corticosteroids, that allowed severe FDA-approved patients only of initial is the management our 3-4) reaction currently The in (grade CRS observation CRS insufficiency. the the Severe respiratory of by hypoxia. significant revolutionized and or was includes tachypnea, management hypotension CRS hypotension, symptoms, unstable CRS for moderate by monitoring to characterized mild close with and patients compromising pediatric care For without toxicity supportive function. organ life-threatening cell avoid toxicity T and multiorgan CAR symptoms tumor the and/or minimize hypoxia, to and is therapies hypotension, activation, CRS to anti-CD19 of system management progress to immune can from restricted and resulting proliferation, not myalgias symptoms expansion, and is inflammatory cell and of toxicities constellation T elimination a treatment-related cell with describes similar associated CRS report elevations CRS. tisagenlecleucel, being cytokine common including most products, the cell with T CAR CD19-directed (CRS) syndrome release months Cytokine 63-86) 24 CI (95% at 76% 54-76) Effects of CI, patients Side infused (95% Common all reconstitution 66% among cell of OS B an and by early showed driven months of 2018 evidence largely 12 in with was ASH at patients at it 2 presented relapse, months and data tisagenlecleucel-induced a MRD+ 12 trial in were experienced Updated at while who who 52-77) HSCT patients patients 2 allogeneic CI those underwent including (95% In patients remission, 66% Eight months. was variants. 24 achieving RFS at (98%) escape responders, responders CD19-negative 47-75) tis- For the CI received receive of flow. (95% had who majority not multiparameter 62% vast patients (61%) by did the and for with state patients them months, negative rate 3 3 of MRD at response patients; a 712-90) majority overall CI of The (95% A 96% 82% therapies was leukopenia. in agenlecleucel enrollment. previous to infusion at 3 due tisagenlecleucel cy- chemotherapy 74% of to and lymphodepleting fludarabine of prior median dose given percentage a (moderate was chemotherapy blast undergone clophosphamide) Lymphodepleting excluded marrow had HSCT. were allogeneic bone tisagenlecleucel undergone 18 tisagenlecleucel median received previously and precluded a who that infused, conducted commercial events had patients were was adverse for and 79 79 and other used enrolled, The or countries, currently were death, 11 is issues, patients infusion. in which product-related 97 facility, centers tisagenlecleucel analysis, GMP 25 ELIANA to Novartis’s primary at due B-ALL. in the patients refractory on manufactured In enrolling or based cells study, relapsed manufacturing. was using cell safety with entirety tisagenlecleucel T the adults its test CAR of young to in global approval and study multicenter first cryopreserved children FDA cohort, the shipping for the single was tisagenlecleucel for a Subsequently, was of chain” to which efficacy infrastructure “cold center. [NCT02435849], the and study logistics treating developed ELIANA a the the study creating of This to results including core. and therapy, vector from cell CHOP cells T the at CAR made multicenter was do vector lentiviral GMP and h tlt fsluia sa seilyipratqeto uigteCVD1 admc where pandemic, COVID-19 the during question important especially an is siltuximab of utility The . 25 ociia xeineo ulse aaeit ospotisuea rtln management first-line as use its support to exists data published or experience clinical no , 18,27 25 a ecniee.Atog itxmbhsbe rpsda rtln gn in agent first-line a as proposed been has siltuximab Although considered. be may , eeeCSi rae ihteI- eetrihbtrtclzmb hc is which tocilizumab, inhibitor receptor IL-6 the with treated is CRS Severe . 3 22 . 23,24 29 n hr a ecnen bu drug about concerns be may there and , R siiilycaatrzdb fevers by characterized initially is CRS . 25,26 23 h vrl olof goal overall The . oiiua has Tocilizumab . 30,31 In . 21 . Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. go oywih o ains5k rls,o . o25x10 2.5 to 0.1 or less, or x10 50kg 5.0 patients to 50kg for than 0.2 weight contains body tisagenlecleucel malignancies. of of cell kg dose B beyond recommended therapy current manufacturing cell The cell powerful T this T CAR of CAR of benefit and application potential leukapheresis leuka- the the toxicity Successful maximize extending unique successful to treatment of its ensuring us goal managing anti-cancer allow as and the will relapse, of with barriers such disease therapy these landscape remain, and into insights non-response challenges the Continued manufacturing, many cell profile. revolutionizing therapy, T in CAR cellular and made of pheresis development been the has through progress including impressive separately not graded Although while is which edema, hemorrhage, cerebral CNS challenges or or Current seizures CRS), as mild event. 43 such even bleeding of events with a 12 patients major as to in other compared common paper as (very disease consensus 95% well headache CNS ASTCT 7%; as the with trial in encephalopathy (18%) 50% CTL019 presented patients vs. for resolved, in been 17 (32% encephalopathy that also of developed now 3 episodes 3 disease has days neurologic through as CNS 18 3 involvement, without 0 grade within CNS (28%) grade patients Among resolved with with 75% correlated points)). those be and percentage neurologic to among days, after 50 Severe 10 than to weeks within -1 CRS resolution. more 8 resolved difference, occurred 4 its events within the after neurologic grade for (40%) 3 shortly with (grade CI reported. patients or CRS were patients higher-grade edema 75 CRS in with cerebral patients during of or frequently in events occurred frequently 30 4 more events grade was occurred no neurologic events but trial of events, neurologic ELIANA majority 3 the The grade had in patients Ten neurotoxicity infusion. of symptoms incidence of causes The potential exists trial other correlation 2 out symptoms clear phase ruling of no in after severity Neurotoxicity months, care known and for supportive is CNS on persist it the focused can although antibodies in blockade, Furthermore, mainly and tisagenlecleucel monoclonal receptor is cytokines. barrier of most IL-6 other brain presence (as of by the blood involvement CNS between ameliorated role the the the or or crosses a into barrier), tisagenlecleucel reversed play distribution brain that may inefficient readily blood IL-6, cells cross be of not T the to do upregulation through engineered appear to cytokines the not inflammatory due by of does possibly toxicity diffusion ICANS the CNS data, suggest direct seizures available to and/or and evidence barrier deficits; some with focal blood-brain toxicity agitation; off-target and an tremor, be hallucination, confusion, aphasia, include 19,21,35 CRS can syn- from which neurotoxicity distinct thy, therapy-associated pathophysiologically (IEC) cell is of cells. effector (ICANS), severity immune positive drome as the CD3 known with also and neurotoxicity, correlated CD8 T-related CAR positive infusion, CAR before of marrow levels bone higher received had in Neurotoxicity patients also cells of CRS blast reversible severe percent were of with Thirty-nine CRS ex- percentage Patients of patients CRS. the dialysis. cases of by required All percent defined patients corticosteroids. Fifty-three as received of percent (77%). 20% Fifteen 10% and patients vasopressors. and 65 high-dose tocilizumab. intubated, required of were 24% 50 patient and in intervention, of occurring required that CRS hypotension ELIANA, 1) perienced (Table trial CRS global for the scale In grading trial ASTCT 2 the phase producing in products, CRS T CAR commercial and trials function across cell T CAR hl h ahpyilg fnuooiiyrmist eflyeuiae,i shpteie to hypothesized is it elucidated, fully be to remains neurotoxicity of pathophysiology the While . 40 nodrt civ hsds,a dqaeqatt fTclsms rtb olce rmthe from collected be first must cells T of quantity adequate an dose, this achieve to order In . 32,33 netgtr rmmlil etr eetycnee ouiyCSgrading CRS unify to convened recently centers multiple from Investigators . 4 21 34 8 neetnl,nuooiiyde o appear not does neurotoxicity Interestingly, . 34 ypososre r lblencephalopa- global are observed Symptoms . A-oiieval el o ainsmore patients for cells T viable CAR-positive hssaenwpoie ossetgrading consistent provides now scale This . 6 A-oiieval el per cells T viable CAR-positive 37,38 22 39 aeiedsaeburden, disease Baseline . h rdn o ICANS for grading The . ramn o ICANS for Treatment . 31 . 36 nlimited In . 34 . Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. ihu ute niluei hrp.Ti soito shre odseni ypoaptet treated patients lymphoma ALL relapse in in disease remission discern and durable Non-response to domain a harder 4-1BB achieving is in a factor by association date important for mediated This an to propensity therapy. is is reduced anti-leukemia co-stimulation the persistence median when further to CAR due signaling a without that likely CAR suggests for is far tonic persistence thus blood by longer Data induced This the years. exhaustion domains, in 5-10 cell co-stimulatory for months persist CD28 T cells 2 using to T to constructs CAR shown CAR 1 persistent to with been approximately compared is has in days) persistence 20-167 and role (range whose domain important days 168 co-stimulatory efficacy an shown of products based have play duration generation that second 4-1BB also products are cell a tisagenlecleucel, may T including CAR utilizes point, processes product. this T manufacturing to CAR trials final and clinical or the in of design relapse performance CAR clinical of resultant the the the risk predicting thus, in high and, product a differences apheresis regimens Finally, having the intensive as of to product. quality prior cell identified the cells T patients improve T CAR may of in manufactured which collection disease, considered Early relapsed collected. be with cells should those cell T T chemotherapy of CAR quality cytotoxic productive the of with on associated impact cyclophospha- are direct that a with have cells treatment T prior lineage that early suggest expansion reduces selectively data products cytarabine clinical and Additionally, cell in mide collection). T implicated to chemotherapy CAR been exposed prior has poor-quality previously clofarabine doxorubicin and the or in insufficient clofarabine lies quantitatively containing fitness both cell regimens T chemotherapy in example, differences diseases. For to regimen. other contribute to can collection that applied at may factor are phenotype Another biology developmental cells disease cell T T that CAR patients’ indicating as the successful thus practices altering more cancers, collection in a pediatric role mediate a different can play across which further varied longer, samples persist blood cells peripheral T vivo memory in central response potential more expansion clinical contain cell that T with products successful correlates cell of directly biomarker cells a memory significant B-ALL CAR with central with correlate a stem na¨ıve pediatric cells to and predicting in T found in memory was performance role early na¨ıve product CAR and important of pre-manufactured the presence an in The to plays potenital activity. order phenotype proliferative clinical cell in subsequent T product product’s that cell cell demonstrated T T have the studies of recent drug. First, persistence this and of patients expansion in property in anti-leukemic expressed poor 301,000 the as behind patients and maximize mechanisms non-responding 28 response in the day days mean a understanding 13 to with geometric to to 0 patients compared the days in time as 11 315,000 from of (measured was expansion blood expansion days) response peripheral trial, times a in DNA ELIANA without curve of the concentration-time microgram Expansion In the per persistence. copies cell under response. T into area disease CAR infusion and the after to cell proliferation assessed T of element vivo best CAR in is vital of response, performance directly a performance disease time, may of this the is at metrics Predicting product so the leukapheresis testing, product. using vitro patient the cell in the T of using CAR characteristics difficult the quite collected, is of is an products performance attractive of cells and/or is quality prospect T investigation, the the of clinical affect patients, quantity early these peripheral adequate For in minimal to an B-ALL. remain these Once leading refractory which achieve highly disease product, to their cell able leukemic of never T progressive nature are CAR the or patients allogeneic to therapy count Some due cell cytotoxic cells. parameters CD3+ proximal cancer blood of a of apheresis replacement and timing starting marrow cells/uL include to bone ˜500 count prior of recommended cell (ALC) is CD3+ count cells/uL lymphocyte ˜150 absolute of minimum a therefore, patient; 53 . 43 hrfr,i sipratt nesadhwdffrn hmteaisaetTclsa tcan it as cells T affect chemotherapies different how understand to important is it Therefore, . 45,46 21 nadto,rsodr otsgnelue aeasotrmda iet maximum to time median shorter a have tisagenlecleucel to responders addition, In . neetnl,i a lobe eetysonta h itiuino elsbesin subsets cell T of distribution the that shown recently been also has it Interestingly, . 43 eihrlbodsmlsta otie ihrpretg of percentage higher a contained that samples blood Peripheral . 21,47,51 5 hr r ainsfo h rtCO studies CHOP first the from patients are There . 41 atr htwudaetbt L and ALC both affect would that Factors . 21,37 44,47 uhrsac a endedicated been has research Much . w togydsorg s of use discourage strongly (we 48-50 44 42 hc a inform can which , Tisagenlecleucel . . 44 n A T CAR and , 52 . Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. oso A ucin iko eas scniee ihrwt al elrcvr u ofailure recovery to cell due activity, B cell recovery T early cell CAR after augment B to offered early therapy therapies additional with without Current higher or cells. considered with cells, T indicates. is T which CAR relapse CAR infusion, of circulating with of months retreatment by six Risk include within surveillance recovery function. cell disease T B of as CAR recovery cell of B Loss early population. defined relapse this has positive group in antigen Our remission CD19 second of and recovery of potential inotuzumab achievement curative cell using after the B therapy on CD22 Early definitive data as for no option such but needed only options, antigens are the viable studies other as are prospective the further product of case, and T single targeting exist CAR either this relapse, CD22-directed analysis In relapse, a integration negative protein. the or site antigen CRA in ozogamicin by the cell shown with resulted but as gene B patients masked cell CAR leukemic For was ALL the single single molecule leukemia whether a CD19 negative a from unclear the CD19 into resulted was with that gene relapse relapsed It was studies CAR hypothesis tisagenlecleucel. our Lastly, one the received on infusion. but he of treated tisagenlecleucel after patient introduction ALL months for showed infusion An contraindication 9 tisagenlecleucel reported manufacturing. of A cell to recently presence as. T prior the was therapy during cytometry with case CD19-directed flow associated unique prior by not a regard events was that not negative escape CD19 do antigen we rare negative prior with MRD or achieve that remission to CD19 CAR demonstrating of failure dim of by after loss rate suspicion subsequent evasion higher significantly this or immune a confirmed remission with of with associated tisagenlecleucel trial was treatment received risk ELIANA blinatumomab concerns, the with who increased therapy in these patients criterion the to 166 exclusion Due an to of was cells. analysis blinatumomab contribute B-ALL malignant as CD19-negative relapsed/refractory may such therapy for with use anti-CD19 pressure prior in prior selection control to to its disease due response disease. therapy in in of effective plasticity Though levels is exceptional overemphasized. blinatumomab MRD be show cannot of may variants use escape cytogenetics for the certain monitoring careful with blinatumomab therefore, as blasts microenvironment; such their therapy, leukemic rearrangement directed that CD19 KMT2A other concept of with regardless the seen subtypes been traditionally leukemic also is myeloid has it to phenomenon Although lymphoid loss. from CD19 switch subtypes CD19 for lineage leukemic more mechanism KMT2A-rearranged with another infant heterogeneity with is tumor associated switch inherent lineage of Thirdly, occurrences subclones. higher of negative with emergence associated for are allows cytogenetics cells which certain precursor diagnosis, malignant negative at CD19 present harbor are blasts of subclones leukemic loss negative negative CD19 the CD19 to pre-existing leading that CD19 skipping) mutations pathways possible pre-existing 2 to modulation, with (exon and due heterogeneity loss splicing surface tumor antigen alternate hypotheses inherent In mechanistic includes modulation, switching. Three CD19 or lineage relapse. and loss CD19-negative antigen subclones, experience negative in: may suggested cells been T cell have CAR T CD19 CAR treated CD19 Patients other with institutions relapse Other rates negative escape. relapse antigen CD19 negative CD19 months of antigen 24 evidence within similar showed relapse reported (74%) to also 14 on constructs have timeframe, when country infusion that the cell in across T relapsed CAR disease who infusion after cell -negative patients of CR or cell T 19 year antigen-positive a T CAR achieved either 1 CAR long-term have initially anti-CD19 within achieve will who receiving who remission majority after achieve B-ALL the remission who r/r enter patients tisagenlecleucel relapse, with to of Although patients 30-50% fail remission. for and patients sustained therapy, the therapy of a in definitive 10-20% maintain lies challenge approximately to be another persistence, or to tisagenlecleucel, remission offers potential achieve that the institution either an has to at them treated be for to failure able is patient a When 47,51,55,56 . 58 rmttosi h D9caeoepoenCD81 protein chaperone CD19 the in mutations or , 60 pcfial,ptet ihBRAL oiieBALhv ensonto shown been have B-ALL positive BCR-ABL1 with patients Specifically, . 61 21,51,54 lhuh ute tde r eddt eemn whether determine to needed are studies further although, ; 6 57 68,69 pcfial,i h LAAtil 8 fpatients of 38% trial, ELIANA the in Specifically, . nerpini h rnpr fC1 otecell the to CD19 of transport the in interruption , hrfr,a hstm,algni STremains HSCT allogeneic time, this at Therefore, . 62 A elciia rashv loreported also have trials clinical cell T CAR , 67 . 59 eody ti also is it Secondly, . 64 hc highlights which , 65 221 22 21 seilyat especially , 66 Subsequent . However, . 56,63 fthose Of . This . Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. ocriotrisfrsvr erlgctxcte oaodfae eerleea lhuh hscomplication this tisagenlecleucel revert although, with often strong edema; treatment clinicians a cerebral after and is feared reported effective, avoid there been to been these although not toxicities neurotoxicity, not in neurologic has of has severe 1/3) severity tocilizumab for (by or with corticosteroids Treatment development reduction to CRS. the CRS severe for 4 with models grade correlation predictive for no management. endpoint are CRS standard the There received met they which tocilizumab after patients fever, pre-emptive high-risk ( of testing time burden the trial at disease tocilizumab This high attempt of of an dose with administration in single Patients burden a early disease receive CRS. high of severe with efficacy patients effect mitigate pediatric the an of in to evaluate without tisagenlecleucel use with CRS to treatment on severe later conducted after in reported tocilizumab was predicted decrease second cells NCT02906371] strongly modest T 4-1BB al. a [clinicaltrials.gov, CAR IL1RA, a et of of CHOP with + data persistence Gardner treatment encouraging and IFN-g after with engraftment explored. + dexamethasone product on cell without being sgp130 T and also incorporating CAR with is generation model tocilizumab infusion strategies development of a after treatment with administration as early prophylactic early associated biomarkers such of predictive strongly hours, Use as are 72 CRS. useful all first group not ferritin the Our are CRS and ill. in but controlling critically CRP CRS, become better in IL6, severe patients for that lies of allow before demonstrated may treatments management symptoms of CHOP/UPenn morbidity toxicity CRS implementation at of of in through cause recognition symptoms significant challenge Early of a efficacy. The control be clinical tisagenlecleucel. to compromising continues without with it symptoms CRS, treated T of patients CAR management and to in knowledge inhibitor in checkpoint advances a Despite immune-mediated of of addition management responses mechanism the toxicity complete possible in testing 2 Advances a data and partial suggest early constructs, therapy 2 patients very CAR in T different such In resulted the CAR in dosing. therapy Despite CD19 CAR. responses repeat humanized prior cell upon a by T after rejection alleviated CAR-specific relapse be still might of for which is lack events, CAR such antigen CTL119 in CD19 role response with a the treated objective endodomain CR CD28 negative patients an since a MRD 6/9 had with achieved possible, product none trial, is CAR but scFv) of T re-infusion disease, CD19 received CAR CD19+ who patients recurrent further 3 ongoing for described with with al. aplasia relapse et cell Lee positive B B expressed. early antigen persistent for had for patients pembrolizumab Treatment these received patients Fourteen of who results. Two patients encouraging aplasia. six therapy with shown cell pembrolizumab has of those B therapy three in re-established cell recovery and inhibitor T cell nivolumab, checkpoint CAR CARs. or to (PD-1) anti-CD19 response pembrolizumab death-1 murine-derived loss/no received programmed cell of with T rejection such treatment CAR experienced constructs immune-mediation early concurrent one CAR overcome center, different and patients to of our infusion, 7 infusion CARs At initial of and CD19 after 6 inhibitor months humanized checkpoint while recovery, 24 PD-1 as cell to with treatment B 9 concurrent repeat for remission after include treated in months children 21 remained relapse to 7 negative 6 six of CD19 aplasia group, Reinfusion cell 1 this infusion. B in preparatory continued Of initial time demonstrated after lymphodepleting infusion. hematogones months second standard positive 6 a re-infusion CD19 and/or the for for 3 the reinfused be at aplasia to persistence to cell had respond poor now two B for not consider induced only CTL019 retreatment murine did patients, most of eight their who what infusion the patients receive to repeat Of T six not prior loss. CAR cell the did regimen anti-CD19 engraftment however, B cells chemotherapy of of re-infusion; T early infusion evidence after CAR second for had expansion of a who re-infusion cell administered B-ALL on al. T with exists et CAR patients Gardner data 8 product. to published CAR cells Limited same transplant. the with cell recovery stem hematopoietic and/or 74,75 ial,orudrtnigo h ehnssudryn ertxct ean poor. remains neurotoxicity underlying mechanisms the of understanding our Finally, . 70 71 ehd en etdt mrv ucs ae fCRpritneatrre-infusion after persistence CAR of rates success improve to tested being Methods . . 72 oki non oass hte muoeiiyo h uieCRplays CAR murine the of immunogenicity whether assess to ongoing is Work . 74 ciiatil.r C0085] iia lncltilat trial clinical similar A NCT02028455]. [clinicaltrials.org 54 nteCL1 ra,1 f5 ainswr received were patients 55 of 17 trial, CTL019 the In . 7 71 . 76 > . 0 Mbat)o a- eealctdto allocated were day-1 on blasts) BM 40% 47 ntepae1CL1 (humanized CTL119 1 phase the In . 73 te nltscollected analytes Other . Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. 0 gynK eia ,CegS,e l atr nunigsria fe eas rmauelym- acute lymphoblastic from acute childhood relapse in failure after induction after survival Outcomes influencing al. et Factors CH, Pui leukemia. SP, Hunger al. M, et Schrappe B study. 11. SC, Group of Oncology treatment Cheng Children’s the M, a for Devidas leukemia: Tisagenlecleucel phoblastic K, DT. Nguyen Teachey SL, 10. Maude lymphoblastic SA, acute leukemia. Grupp childhood lymphoblastic CW, relapsed acute Elgarten treat cell AB, I Leahy How S. 9. Rutella ME, Bernardo M, Schrappe leukemia. F, Locatelli leukaemia. 8. lymphoblastic acute childhood challenges Relapsed cancer: CH. with 217. Pui adolescents D, and children Bhojwani for 7. Outcomes al. et century. (1992-2004). SF, twenty-first lym- Altekruse the U.S. NL, for Seibel Novar- B-cell the MA, Smith in 6. large from incidence Children. in cancer with therapy Leukemia Lymphoblastic childhood Acute 1552. patients CG. CAR-T in Mullighan SP, Trends Hunger r/r 5. first-in-class JA. Ross appropriate syn- the AM, treat 2008;112(2):416-432. Linabery release (tisagenlecleucel), to cytokine 4. Kymriah approval for FDA tocilizumab from-novartis-receives-second-fda-approval-treat-appropriate-rr-patients-large-b-cell-lymphoma. https://www.novartis.com/news/media-releases/kymriah-tisagenlecleucel-first-class-car-t-therapy- second and Novartis. phoma. receives ALL B-cell tis, for 3. tisagenlecleucel https://www.cancer.org/cancer/cancer- approves 2014; cell-all-and-tocilizumab-cytokine-release-syndrome. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b- Chemotherapy. drome. Treatments: 2. 2020. Cancer 2020, 1st, of May Accessed Evolution basics/history-of-cancer/cancer-treatment-chemo.html. sickest our in 1. therapy curative continue for that opportunity therapy the cellular immunology, References offer in basic advances and into patients. more B-ALL understanding would refractory in childhood Continued cells of most result r/r HSCT. end T and surely in avoid the CAR will outcomes to at of improve biology ability positive administration evaluatingto ALL the MRD earlier is and and are B-ALL if (AALLL1721) engineering, EFS who determine r/r genetic trial B-ALL on to beyond high-risk impact II tisagenlecleucel with an tisagenlecleucel phase patients receive have of Group in then other Oncology success rate to and Children’s survival the tumors consolidation harness free The expand solid to disease to to therapy. 5-year order ALL underway in the in B are earlier in therapies studies life-threatening patients successes cellular potentially addition, to these of managing translating In utility agents, and these the relapse, diseases. to disease optimize preventing accessibility to effects, Cellular increasing done side including B-ALL. decades. be potential, refractory few to full treatment past their remains with the patients work over in much promise significantly However, tremendous evolved offer has tisagenlecleucel, therapy as cancer such for therapies, landscape treatment The advance clinical further of to Conclusion reporting order and in and directions CRS forward Future assessment of going objective management constructs an cell and T for understanding CAR allow current and our will trials system clinical grading different between single severity a into unification The nlJMed. J Engl N Blood. 2012;120(14):2807-2816. 2012;366(15):1371-1381. lnOncol. Clin J xetRvAtcne Ther. Anticancer Rev Expert 2010;28(15):2625-2634. 17,24,25,77-82 8 Leukemia. . 2018. 2008;22(12):2142-2150. nlJMed. J Engl N actOncol. Lancet 2015;373(16):1541- 2013;14(6):e205- Cancer. Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 ahnv ,Bso R aiP ta.Ciei nie eetrTCl hrp uigthe During Therapy Cell T Receptor Antigen Chimeric al. et P, Dahi MR, Bishop Pandemic. V, COVID-19 ’ALL’. Bachanova receptor fit antigen not chimeric 29. does after management size Toxicity one SA. Grupp therapy: Leukemia. Release DG, cell Maloney Lymphoblastic Cytokine T MR, for Acute Bishop Biomarkers DT, for Teachey Predictive Therapy 28. of cell Identification T al. Receptor et Antigen PA, discovery. Chimeric manage- Shaw and SF, after recognition Lacey Syndrome DT, cells: Teachey T receptor 27. and antigen assessment chimeric - of Toxicities therapy JN. T-cell Kochenderfer ment. receptor JN, antigen Brudno Chimeric 26. al. et P, with Kebriaei toxicities. associated S, of syndrome Tummala management release SS, cytokine Neelapu of Grading 25. SA. tisagenlecleucel. with Grupp therapy associated Y, cell Weng syndrome T PA, Wood release CAR N, the cytokine Frey Managing D, Porter SA. 24. Grupp in DT, Tisagenlecleucel Teachey therapies. of D, cell-engaging Safety T Barrett and novel SL, Efficacy the Maude of Leukemia. 23. Analysis Lymphoblastic Updated Acute Meeting. (r/r) al. ASH Relapsed/Refractory et 895, with Patients S, 2019;abstract B-Cell Adult Rives with Young Adults S, and Young Maude Pediatric and S, Children Grupp in Tisagenlecleucel 22. al. et J, Buechner Leukemia. TW, in Lymphoblastic Laetsch SL, remissions ALL. Maude antigen sustained chimeric relapsed/refractory 21. for CD19-specific with with cells children remissions T Sustained in receptor al. cells 2016;34(15 et antigen T SR, Chimeric (CAR)-modified Rheingold DT, receptor Teachey al. SL, lymphoid Maude et acute PA, 20. for Shaw cells N, T Frey receptor-modified SL, antigen leukemia. Chimeric Maude al. 19. et the D, takes Barrett ALL M, for Kalos leukemia. Immunotherapy SA, Grupp 2017: in 18. leukaemia lym- lymphoblastic acute Acute Ph-negative storm. SP. refractory by Hunger world or DT, relapsed Teachey for vincristine 17. literature. Liposomal of refractory review MA. with Weiss a patients R, leukemia: pediatric Hess phoblastic issues. in P, clofarabine and of Pathak study findings II 16. current Phase leukemia. al. leukemia: lymphoblastic et acute acute BI, relapsed Razzouk pediatric PS, or Gaynon in S, Jeha Clofarabine 15. RJ. Arceci Tumors E, Solid Cancer. Barry Refractory Blood With Pediatr N, Marqibo(R)): Adults Hijiya (VSLI, Young Injection and 14. Liposomes Adolescents, Sulfate Children, Vincristine in al. Study Leukemias. et I or DE, Phase Cole a From MS, SFCE Merchant Results French in Chemotherapy NN, the Multiagent Shah of With Study Clofarabine 13. (VANDEVOL of Leukemia Study Lymphoblastic I Phase Acute Committee). A Leukemia of Acute al. Relapse et Risk G, High Leverger H, Childhood Cave B, Nelken 12. Blood. nlJMed. J Engl N Med. J Engl N 2016. suppl):3011-3011. 2016;127(26):3321-3330. eit lo Cancer. Blood Pediatr a e lnOncol. Clin Rev Nat 2012;59(3):417-422. ilBodMro Transplant. Marrow Blood Biol 2014;371(16):1507-1517. 2013;368(16):1509-1518. a e lnOncol. Clin Rev Nat nlJMed. J Engl N eit lo Cancer. Blood Pediatr acrJ. Cancer 2016;63(6):997-1005. 2018;15(2):69-70. eao Oncol. Hematol J 2018;378(5):439-448. lnOncol. Clin J 2014;20(2):119-122. a e lnOncol. Clin Rev Nat hrAvHematol. Adv Ther 2018;15(1):47-62. 9 2016;63(2):270-275. 2020. 2006;24(12):1917-1923. 2018;11(1):35. 2014;5(1):18-24. 2018;15(4):218. ora fCiia Oncology. Clinical of Journal Cancer Blood. Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 ueC,Sdli .Ciei nie eetrTherapy. Receptor Specific Antigen Regulates Chimeric Coreceptors M. of Sadelain Cells. Signaling CH, T Distinct June CAR trial. in 49. al. Development dose-escalation et Memory 1 JA, Impacts Fraietta phase and RS, Pathways a Metabolism O’Connor OU, adults: Kawalekar young 48. and receptors antigen children chimeric chimeric CD19 in CD19 expressing to cells leukaemia 2015;385(9967):517-528. T resistance lymphoblastic al. and et acute M, response Stetler-Stevenson for leukemia. of JN, Kochenderfer lymphocytic Determinants DW, antitumor chronic Lee potent al. of 47. have therapy et receptors cell EJ, antigen T Orlando chimeric (CAR) SF, receptor with Lacey antigen cells leukemia. JA, advanced T Fraietta with chemotherapy patients al. 46. after in et memory and DL, establish diagnosis Porter can at BL, and deficits Levine effects cell M, T Kalos Naive in cancers. DM. 45. proliferation pediatric Barrett in cell SA, potential T Grupp therapy drive L, cell phenotypes Vernau impair memory RK, Early Das DM. 44. Barrett SA, malignancies. Grupp pediatric J, development with Perazzelli patients cells: N, T CAR Singh allogeneic ’Off-the-shelf’ 43. L. Poirot G, Mufti SA, challenges. and Grupp P, and relapsed Duchateau for S, therapy Depil CAR-T 42. (tisagenlecleucel): CTL019 leukemia. H. lymphoblastic Bittencourt acute P, Teira B-cell JL, refractory Garcia https://www.fda.gov/media/107296/download. S, 2017; (CTL019) Vairy Information. cells 41. Prescribing T of (CAR)-modified Canada. Relapsed/Refractory Highlights Quebec, Receptor CNS Kymriah: Montreal, Antigen and 40. 2017; Marrow Chimeric ASPHO; Bone Leukemia. CNS/Combined al. Lymphoblastic with et Acut Children S, CD19+ in Maude Remissions G, Durable Hucks Cell-Associated Induce T M, CAR Talekar of Driver 39. a as Emerges Activation Cell acute Endothelial B-cell CNS Neurotoxicity. DB. relapsed/refractory Miklos in CL, CTL019 in Mackall of kinetics 38. Disruption leukemia. Cellular Barrier lymphocytic al. chronic et Blood-Brain and DL, and leukemia Porter SL, lymphoblastic Activation Maude KT, Endothelial Mueller Cells. 37. al. CAR-T et CD19 LA, with Hanafi Immunotherapy 1419. adult KA, Adoptive young Hay and after pediatric J, Neurotoxicity a Gust in CTL019 Syn- after 36. Neurotoxicity Release al. Cytokine et for DT, Teachey Grading PA, cohort. Shaw Consensus JS, Cells. ASTCT Gofshteyn Effector 35. Immune al. et with pharma- FL, Associated a Toxicity Locke as 2019;25(4):625-638. acts Neurologic BD, dasatinib Santomasso and inhibitor cell DW, drome kinase CAR-T Lee tyrosine of The cells. control 34. al. T Pharmacologic et CAR J, for CL. Weber switch Mackall T, on/off P, Giavridis cologic Xu K, J, Mestermann Lattin 33. E, Sotillo treated RC, dasatinib. patients using Lynn from function EW, serum Weber 2018. in Algorithm. sIL-6R Treatment 32. and Syndrome Release IL-6 therapy. Cytokine Measuring cell Novartis. T al. 31. CAR et following E, siltuximab Pequignot and/or DT, tocilizumab Teachey with F, Chen 30. n Neurol. Ann acrDiscov. Cancer a e rgDiscov. Drug Rev Nat 2018;84(4):537-546. lo Adv. Blood 2017;7(12):1371-1373. 2019;3(5):711-717. c rnlMed. Transl Sci c rnlMed. Transl Sci 2020;19(3):185-199. rgDsDvlTher. Devel Des Drug acrDiscov. Cancer 10 2016;8(320):320ra323. 2019;11(499). Blood. nlJMed. J Engl N 2019. 2017;130(21):2317-2325. muo Methods. Immunol J 2018;12:3885-3898. c rnlMed. Transl Sci a Med. Nat ilBodMro Transplant. Marrow Blood Biol acrDiscov. Cancer Immunity. 2018;379(1):64-73. 2018;24(5):563-571. 2011;3(95):95ra73. 2016;44(2):380-390. 2016;434:1-8. 2017;7(12):1404- Lancet. Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. 8 hjaiD psoR hhN,e l ntzmbooaii npdarcptet ihre- lymphoblastic with acute B patients relapsed or pediatric refractory in in therapy ozogamicin T-cell CAR Inotuzumab CD22 al. et al. B, Deng et Q, leukemia. Niu NN, J, therapy Pan Shah cell 69. R, T receptor Sposto leukemia. antigen lymphoblastic chimeric D, acute to lapsed/refractory Bhojwani resistance of cell. Induction B 68. al. leukemic et single DM, a Barrett of B-lymphoblastic J, transduction CD19-dim by Xu for M, effective is Ruella therapy. therapy blinatumomab T-cell 67. prior Acute CAR by Advanced al. impacted et for is W, Chemotherapy Meng but versus K, leukemia Muralidharan Blinatumomab V, Pillai al. 66. et N, Gokbuget A, Leukemia. Stein Lymphoblastic H, lineage a Kantarjian of reversion 65. Spontaneous ALL. infant PG. MLL-rearranged Schlegel in D, switch Reinhardt ALL-to-AML R, Adv. blinatumomab-induced Schmid initial M, an Eyrich following M, switch Rasche leukemia. receptor M, B-lymphoblastic Wolfl antigen chimeric fusion-positive 64. following TCF3-ZNF384 switch lineage with Myeloid patient al. a Cancer. et D, in Bhojwani therapy PS, T-cell Gaynon abnormali- MJ, MLL Oberley of significance 63. clinical as and ALL malignancies. biological BCR-ABL1-positive haematological The in in C. involvement ties Mannhalter cell G, stem therapy. Mitterbauer-Hohendanner Hematopoietic blinatumomab 62. al. to et resistance Immunotherapy J, of CART-19 mechanism Duell to potential M, Resistance a Bartels Enabling I, Isoforms Diagnosis. Nagel CD19 Initial formation 61. al. at complex et Patients CD19 K, B-ALL disrupts Malki in humans El Expressed in C, Are lymphoblastic defect Paret gene acute J, CD81 Fischer in al. 60. BiTE et deficiency. anti-CD19/CD3 B, antibody to Adams to J, Resistance leads Smet and MC, al. trafficking. Zelm membrane van et CD19 59. M, disrupted by Goebeler of mediated A, Splicing be Brandt Alternative may and leukemia F, Mutations Braig Acquired of Convergence 58. Immunotherapy. al. CART-19 immune et to allows KL, Resistance phenotype Black Enables myeloid DM, CD19-negative CD19 Barrett a E, therapy. of Sotillo CAR-T-cell Acquisition 57. CD19 al. from adult et B-ALL in S, MLL-rearranged composition Cherian of CD4+:CD8+ D, defined escape Wu of R, cells Gardner CAR-T 56. of CD19 cells al. T et patients. CAR C, ALL Berger CD19 cell B-Cell LA, by B Hanafi remission Refractory adults. CJ, leukemia young in Turtle Intent-to-treat and Cells 55. al. children T et in Receptor C, dose and Annesley Antigen formulation O, Chimeric defined Finney RA, al. by Gardner induced et 54. exhaustion EA, cell Chong T J, ameliorates Svoboda costimulation Lymphomas. SJ, 4-1BB Schuster al. 53. et receptors. JF, antigen chimeric Shern of WM, signaling Haso tonic Lymphoblastic AH, Acute Long in Therapy CAR 52. CD19 antigen of Follow-up chimeric Long-Term second-generation al. et of M, Gonen pharmacology Leukemia. I, Riviere The JH, M. Park Sadelain 51. M, Hamieh SJ, Stegen receptors. der van 50. 2018;2(12):1382-1385. 2018;65(9):e27265. Leukemia. a e rgDiscov. Drug Rev Nat nlJMed. J Engl N nlJMed. J Engl N 2019;33(12):2854-2866. lnInvest. Clin J 2018;378(5):449-459. nlJMed. J Engl N 2017;377(26):2545-2554. lnInvest. Clin J 2015;14(7):499-509. u lnInvest. Clin J Eur 2016;126(6):2123-2138. 2017;376(9):836-847. a Med. Nat a Med. Nat 2010;120(4):1265-1274. Leukemia. 11 2018;24(10):1499-1503. 043 up 2:12-24. Suppl 2004;34 Immunother. J 2015;21(6):581-590. acrDiscov. Cancer lo Adv. Blood Blood. 2019;33(4):884-892. Blood. 2017;129(25):3322-3331. Blood. 2017;130(18):2027-2031. Blood. 2019;3(22):3539-3549. 2017;40(5):187-195. 2015;5(12):1282-1295. 2016;127(20):2406-2410. 2017;129(1):100-104. eit Blood Pediatr Blood Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. oteaporaemnfcuigfclt o xvv oictos el r ciae n xaddusing expanded and activated are cells shipped T and frozen modifications. then ex-vivo is for which facility cells, manufacturing mononuclear appropriate blood the peripheral CD3 to patient’s the intracellular second of leukapheresis a an with incorporates starts to that joined construct 2 FMC63) CAR FIGURE second-generation as a (4-1BB). here endodomain is (shown co-stimulatory Tisagenlecleucel additional fragment domain. variable signaling single-chain zeta of composed are 1 FIGURE lymphoblastic-leukemia for-treatment-of-children-and-young-adults-with-relapsed-refractory-b-cell-acute- image1.emf file CRS Hosted Syndrome of Release Grading Cytokine Consensus for ASTCT Grading Cells. 1 Consensus Effector TABLE ASBMT Immune al. with Refractory et Associated in FL, Toxicity Therapy Locke Neurological T-Cell BD, and CAR Santomasso DW, Ciloleucel therapy Lee Axicabtagene cell 82. al. T et CAR NL, 19-28z Lymphoma. 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Decreased 75. Toxicity al. Cell et CAR-T CE, CD19 Release Annesley for Leukemia. KJ, Cytokine Strategies Leger Lymphoblastic for R, Biomarkers Acute Gardner Predictive for 74. of Therapy Identification of T-cell al. Society Receptor et American Antigen PA, Discov. Chimeric The Shaw SF, after at Lacey presented Syndrome DT, Abstract Teachey CA. receptor ALL. Diego, antigen 73. chimeric San relapsed CD19-targeted 2016; humanized with 2016, of children 2, Efficacy December in al. Hematology; Hematology; et cells of S, T Rheingold Society D, (CAR)-modified American Barrett receptor S, antigen leukemia. Maude chimeric CA. lymphoblastic 72. CD19-directed Diego, acute augment San B-cell inhibitors 2018; Checkpoint relapsed 2018, al. in 1-4, USA. et December therapy CA, AE, cell Diego, Seif San T G, 2016; (CAR) Hucks 2016, A, Lymphoblastic 2, Li Acute December Relapsed/Refractory Recep- 71. Hematology; with Antigen of Chimeric Adults CD19-Targeted Society Young Humanized American and of The Children Efficacy in Leukemia. al. Cells et T S, (CAR)-Modified Rheingold D, tor Barrett S, Maude 70. 2016;6(6):664-679. iga fCRTcl auatrn n ramn process treatment and manufacturing cell T CAR of Diagram ceai fCRsrcuei eaint D9epesn uo cells tumor expressing CD19 to relation in structure CAR of Schematic vial at available Blood. 2014;124(2):188-195. nlJMed. J Engl N https://authorea.com/users/361230/articles/482710-tisagenlecleucel- alCne Inst. Cancer Natl J c rnlMed. Transl Sci 2017;377(26):2531-2544. 2019. 12 Blood. 2014;6(224):224ra225. ilBodMro Transplant. Marrow Blood Biol 2016;128(22):586-586. c rnlMed. Transl Sci ilBodMro Transplant. Marrow Blood Biol etPatRsCi Haematol. Clin Res Pract Best 2015;7(303):303ra139. h ramn process treatment The . 2020;26(3):S39. CARs . 2018. Cancer Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. auatrdpout r hpe akt h raigfclt,weei sgvnitaeosybc othe to back intravenously given is it where facility, Successfully treating vector. the lentiviral to using back patient. transduced shipped is are CAR products of manufactured expression and beads coated anti-CD3/anti-CD28 CRS Parameter CRS Hypotension Hypoxia Fever Temp≥38 Grade 1 None None o C Low flow nasal cannula orblow-by cannula nasal flow Low Novasopressors Temp≥38 Grade 2 13 o C High flow nasal cannula, facemask, facemask, cannula, nasal flow High Onevasopressor or with without nonrebreatherorVenturi mask, Temp≥38 vasopressin Grade 3 mask o C Requires positive pressure Multiple vasopressors Multiple Temp≥38 Grade 4 o C Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. 14 Posted on Authorea 24 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160091425.51053489 — This a preprint and has not been peer reviewed. Data may be preliminary. 15