le chimeric antigen receptor (car) t-cells nella leucemia ... · 1. leucemia linfoblas+ca acuta del...
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Le chimeric antigen receptor (CAR) T-cells nella leucemia e
nei linfomi
Prof. Paolo Corradini Divisione di Ematologia -Trapianto Midollo Osseo,
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Cattedra di Ematologia, Università di Milano
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CARTcells
• Chimerican+genreceptor(CARs)areproteinsthatincorporateanan+genrecogni+ondomain,cos+mulatorydomains,andT-cellac+va+ondomains.
• Tcellsgene+callymodifiedtoexpressCARsspecificallyrecognizeandeliminatemalignantcellsexpressingatargetan+gen(CD19,BCMAetc)
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CARTS1. Comefunzionanoequantofunzionano
2. Letossicitàacute
E’ una terapia che ha l’intento di guarire una malattia che non ha più terapie disponibili, questa è una differenza importante con molti altri farmaci oncologici.
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UNASTORIADISUCCESSODELL’IMMUNOTERAPIA
SadelainM,Cell2017
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STRUTTURA
BrentjensetalJCO2015
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Persistence Central memory pool SRC Mitochondrial biogenesis Oxidative metabolism
Persistence Effector memory pool SRC Mitochondrial biogenesis Glycolytic metabolism
CAR-specific
activation
CAR-specific
activation
T cell
BBz CAR
28z CAR
CAR Signaling Domains Program Cells for Metabolic Fitness
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CAR T Cells: they are bionic !
! CAR scFv or TCR can reprogram specificity of T cells for tumor target. Specificity is important to avoid toxicity
! CAR signaling domains can reprogram T cell metabolism. This can enhance survival in tumor microenvironment and effector function: • CD28 domains: enhance glycolysis via “Warburg” effect. This leads to enhanced effector function and decreased persistence
• 4-1BB domains: enhance mitochondrial biogenesis, and are associated with enhanced persistence
• ICOS domains: enhanced persistence and cellular respiration in CD4 CAR T cells
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CRISPRtechnologyforCARTS
SadelainM,Nature2018
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CRISPR technology is a simple yet powerful tool for editing genomes. It allows
researchers to easily alter DNA sequences and modify gene function. Its many
potential applications include correcting genetic defects, treating and preventing the
spread of diseases and improving crops. However, its promise also raises ethical
concerns. In popular usage, "CRISPR" (pronounced "crisper") is shorthand for
"CRISPR-Cas9." CRISPRs are specialized stretches of DNA. The protein Cas9 (or
"CRISPR-associated") is an enzyme that acts like a pair of molecular scissors,
capable of cutting strands of DNA.
CRISPR technology was adapted from the natural defense mechanisms of bacteria
and archaea (the domain of single-celled microorganisms). These organisms use
CRISPR-derived RNA and various Cas proteins, including Cas9, to foil attacks by
viruses and other foreign bodies. They do so primarily by chopping up and
destroying the DNA of a foreign invader. When these components are transferred
into other, more complex, organisms, it allows for the manipulation of genes, or
"editing."
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DavilaIntJHem2013
MECCANISMOD'AZIONE
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LATEMPISTICAPERLACOSTRUZIONEDELLECARTSELASOMMINISTRAZIONERICHIEDE
CIRCA3-4SETTIMANE
BuechnerJ,Hemasphere2018
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COMESIEFFETTUALATERAPIACONCARTS?
KochenderferJN,NatRev2013
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DOPOLAREINFUSIONEDELLECARTS:
GiraltS,BBMT2018
• FASEPRECOCE(giorno0al+30):
Lasomministrazioneèunasempliceinfusioneendovenosa,puòavvenireinregimediricovero(solitamentedipochigiorni).Ilrischioditossicitàacuteèesclusivodiquestoperiodo.
• FASEPOSTINFUSIONE(dalgiorno+30):
Ilpazientevienemonitoratoambulatorialmentepercomplicanzelungotermine(neurotossicità)erispostadimalaYa.Ilrischiodioncogenesiviralevienemonitoratofinoa15annidallareinfusione.
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TOSSICITA'DELLECARTS1) SINDROMEDARILASCIOCITOCHINICO(CRS):rispostainfiammatoriasistemica
causatadarilasciodicitochinedopoinfusionedicelluleimmunieffeVrici.
15-50%diCRSgrave (grado3-4)negli studi,differenteasecondadi+podiCARTedimalaYa.
ManifestazionisimiliallasindromedaaYvazionemacrofagica.
2)NEUROTOSSICITA’:diffusionepassivadicitochineedicelluleimmunitarienelsistema nervoso centrale. Tipicamente si manifesta come encefalopa+aglobale, afasia, EEG rallentamento diffuso o convulsioni, liquor posi+vo perCARTs,larisonanzamostraedemaincasipiùgravi.
PREVALENZA5-30%neglistudi
Esordiobifasico:1)giorni0-5,+picamenteassociatoasintomidiCRS;2)dopogg+5,comparequandosintomidaCRSdiminuiscono
3)INFEZIONI:incidenzasimileallealtrechemiodisalvataggio
Hilletal,Blood2018
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Inqualipatologiesonosta\faYdeglistudiclinici:
1. leucemialinfoblas+caacutadelbambinoedelgiovaneadulto
2. linfomadiffusoagrandicelluleBelinfomafollicolare
3. leucemialinfa+cacronica
4. mielomamul+plo
SONO STATE APPROVATE COME USO “COMMERCIALE” E NONSPERIMENTALE DALLA FDA AMERICANA NELLA LEUCEMIALINFOBLASTICADELBAMBINOEDELGIOVANEADULTOENELLINFOMADIFFUSOAGRANDICELLULEB
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Key CAR-T Results: Pediatric/Young Adult ALL CTL019 (anti-CD19) JCAR017 (anti-CD19) JCAR018 (anti-CD22) KTE-C19 (anti-CD19)
Trial [sponsor] Phase I/IIa, NCT01626495 / CHP959 [Univ of Pennsylvania]
Phase I/II, NCT02028455 / PLAT-02 [Seattle Children’s Hospital]
Phase I, NCT02315612 [National Cancer Institute]
Phase I, NCT01593696 [National Cancer Institute]
Patient population 4-24 yrs*, ≥2nd r/r ALL (N=59), ≥2nd
relapse or refractory (majority refractory to multiple prior therapies) [*enrolled adults too; efficacy data here is for pediatric cohort only]
1-26 yrs, r/r ALL (N=37, evaluable N=32); majority (>75%) have had 1 or 2 relapses; ~2/3 have had transplant
7-22 yrs, r/r ALL, (N=9, 7 assessed) all had undergone ≥1 prior alloHSCT and had been previously treated with a CAR-T
4-27 yrs, r/r ALL or NHL (N=46 infused; ALL n=45, DLBCL n=1). Prior transplant history not stated.
Dosing Varied lymphodepleting chemotherapy regimens used. Target dosing 107-108 cells/kg. Median 4.3x106 cells/kg infused
Varied lymphodepleting strategies used 4 dose levels: 5x105-1x107
cells/kg; MTD 5x106 cells/kg better risk-benefit profile with much lower 5x105 cells/kg dose
Induction chemotherapy with fludarabine 25 mg/m2 days -4,- 3,-2 and cyclophosphamide 900 mg/m2 on day -2 Lowest dose: 3x105 cells/kg (6 pts treated). Next dose: 1x106 cells/kg (3 pts treated)
Initial 21 pts and all w low burden: low-dose chemo: fludarabine (25 mg/m2/day days -4 to -2) and cyc (900 mg/m2 day -2) High disease burden: high-dose individualized chemotherapy regimen Dose-finding: 1x106 or 3x106
cells/kg; MTD was 1x106 /kg Response rate CR 93% (55/59) at 1 month,
median f/u 12 mo CR 91% (21/22) as of Sept 2015 data cut-off; CMR 91% (85% MRD-negative)
(Preliminary data) 2/7 pts had MRD-negative CR (1 at each dose), 2 with SD, 3 with PD, 2 pts too early to assess
CR 60%
Response durability 18 pts in remission >1 yr, 13 without further therapy
Longest CR: 7 mos In the 1 MRD-negative CR pt, sustained at 2 mo (relapsed at 3 mo)
Longest CR 28 mo (in pt with primary refractory ALL) Median LFS 17.7 mo (45.5% probability of LFS at 18 mo), based on 20 pts who achieved MRD-negative CR
Persistence of CAR T cells
Detectable 3 yrs or longer 3 mos In the 1 MRD-negative CR pt, 19% CAR T cells in bone marrow at 2 mo
68 days
Safety sCRS in 27% (8/30) among early (N=30) cohort/ CRS (all grades) 88% of larger pediatrics cohort (N=59). Severe AEs: 43% (13/30) neurotoxicity; self-limiting. 3 CRS-related deaths among adult pts (none among pediatric pts)
CRS 27% (n=22) 18% (n=22) neurotoxicity. No deaths reported
Max CRS was gr 2; no dose- limiting CRS. At lowest CAR-T dose, 1 pt had gr 3 diarrhea. No deaths reported
sCRS 7/46 (15%); grade 3/4 neurotox 3/46 (7%); no permanent neurocognitive decline
No deaths reported.
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93%CRrateforr/rALLaferCTL019
>200 patients with CLL, ALL, NHL, MM have gotten CTL019
• 59r/rpediatricALLpts:
55inCRat1mo(93%)medianf/u12mo
• 6wenttosubsequenttransplant,1toDLI
• 6moRFS: 76%(95%ci65-89%)12moRFS:55%(95%ci42-73%)
• Norelapsespast1year• 18pa+entsinremission
beyond1year
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CTL019 Phase I Trial for r/r CLL: 5 yr follow up Summary of patient baseline characteristics
N= 14 patients, protocol 04409 (NCT01029366)
! ORR: 57%
! CR 4/14 (28%)
! PR 4/14 (28%)
! NR 6/14 (43%)
Characteristics Statistics, N(%) N 14 Age at infusion in years
Mean (SD) Median (range)
66.9 (8.1) 66 (51-78)
Gender Male Female
12 (85%) 2 (14%)
Number of prior therapies Mean (SD) Median (range)
5.3 (2.8) 5 (1-11)
P53 or 17p deletion
No
Yes
8 (57%) 6 (43%)
IGHV mutation No Yes
9 (64%) 4 (29%)
Porter et al, Science Trans Med 2015
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SOMMARIOSTUDICLINICICARTSinNHL(adults)Studio CAR design Istologia #Pts ORR(%) CR(%) Tossicità grado
3-4 (%)
NCI, 2015
CD19/CD3z/CD28 with Cy/Flu (hi-dose)
DLBL,NHL,CLL 15 80 53 CRS 50% Neurotox 30%
NCI , 2016
CD19/CD3z/CD28 post alloSCT
DLBCL,MCL,CLL,ALL
20 40 30 CRS 50% Neurotox 5%
U Penn, 2016
CD19/CD3z/4-1BB variable conditioning
DLBLCL,FL,MCL 28 57 51 CRS 14% Neurotox 7%
FHCRC, 2016
CD19/CD3z/4-1BB with Cy/Flu
DLBCL,FL,MCL 18 72 50 CRS 13% Neurotox 28%
NCI, 2017
CD19/Cd3z/CD28 with Cy/Flu (lo-dose)
DLBLCL,FL,MCL 22 73 55 NO SEVERE CRS Neurotox 55%
ZUMA1 Kite
Cd19/CD3z/4-1BB with Cy/Flu
DLBCL,TFL,PMBCL
101 82 54 CRS 13%
JULIET Novartis
Cd19/CD3z/4-1BB with Cy/Flu
DLBCL 51 59 43 Neurotox 28%
TRASCEND Juno
CD19/Cd3z/4-1BB;fixed CD43/CD8 with Cy/Flu
DLBCL,MCL,PMBCL,FL
69 75 56 CRS 1 Neurotox 14%
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20 Terapie con CART anti-CD19 nei linfomi CTL0191-4 KTE-C194,5 JCAR0174,6
Trial phase 2 (NCT02030834) 2 (NCT02348216) 1 (NCT02631044)
Vector Lentiviral Gammaretroviral Lentiviral
Costim domain 4-1BB CD28 4-1BB
Disease state r/r DLBCL, non-GC DLBCL, DHL, TFL, FL r/r DLBCL, TFL/PMBCL r/r DLBCL, NOS,
tDLBCL, FL3B
Key inclusion criteria
• Age ≥18 years • ECOG 0-1 • R/R disease after ASCT or
ineligible for ASCT
• Age ≥18 years • ECOG 0-1 • Stable or progressive disease as best
response to last line of therapy, or disease progression ≤12 months after ASCT
• Age ≥18 years • ECOG 0-2 • R/R disease after at
least 2 lines of therapy or after ASCT
Key exclusion criteria
• Uncontrolled active infection • Active hepatitis B/C • Concurrent use of steroids • Active CNS involvement • Patients in CR
• Infections that are uncontrolled or require IV antimicrobials for management
• HBaAG-positive or anti-HCV positive • detectable CSF malignant cells, brain
metastases, history of CNS lymphoma, CSF malignant cells or brain metastases
• Uncontrolled systemic infection
• Active hepatitis B/C • Therapeutic doses of
steroids within 7 days of leukapheresis or 72 hours prior to infusion
• Active CNS involvement
ASCT, autologous stem cell transplant; CNS, central nervous system; CR, complete response; CSF, cerebrospinal fluid; DHL, double-hit lymphoma; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; FL3B, FL grade 3B; GC, germinal center; HCV, hepatitis C virus; NHL, non-Hodgkin lymphoma; NOS, not otherwise specified; PMBCL, primary mediastinal B-cell lymphoma; R/R, relapsed or refractory; tDLBCL, transformed DLBCL; tFL, transformed FL. 1. Schuster, SJ, et al. Blood. 2015;126(23) [abstract 183]; 2. Schuster, SJ, et al. Blood. 2016;128(22) [abstract 3026]; 3. Chong EA, et al. Blood. 2016;128(22) [abstract 1100]; 4. www.clinicaltrials.gov. Accessed April 25, 2017; 5. Locke FL, et al. AACR 2017 [abstract CT019]. 6. Abramson JS, et al. Blood. 2016;128(22) [abstract 4192].
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Per riassumere i bisogni clinici insoddisfatti
1. Pazien+ refraVari primari o ricadu+ entro un anno dalla
chemioterapiadiprimalinea
2. Pazien+ che falliscono il trapianto autologo o non idonei al
trapianto. Va ricordato che il trapianto allogenico è una strategia
pra+cabilesolonel10-20%deipazien+,principalmenteacausadella
malaYachemiorefraVaria,dellaetàodellecomorbidità
3. Pazien+ricadu+dopotrapiantoallogenico
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Salvage regimens: R-ICE vs R-DHAP
Event grade 3-4, n (%) R-ICE R-DHAP Infection with neutropenia 33 (17) 31 (16) Infection without neutropenia 11 (6) 15 (8) Renal 2 (1) 11 (6) Platelet transfusions, % 35 57 Toxic deaths, n 1 3
Gisselbrecht C et al, J Clin Oncol 2010
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NOT ELIGIBLE TO TRANSPLANT: R-GEMOX
REGIMEN N^ Medianage
RR% CR% FFS F.U.
(R)GEMOX 32 65 78 50 9mos 42mos
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NOT ELIGIBLE TO TRANSPLANT: R-bendamustine
REGIMEN N^ Medianage
RR% CR% PFS F.U.
R-BENDA 59 67 63 37 6.7mos 5mos
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Allo-SCT in refractory/relapsed DLBCL
Analysis of the EBMT Registry
Van Kampen RJW et al, J Clin Oncol 2011
Inclusion Criteria: " first allo-SCT in relapsed DLBCL after a previous ASCT between 1997
and 2006. " age at allo-SCT >= 18 years " availability of an HLA-identical sibling or a matched unrelated donor
101pa\ents;medianage,46years(18-66)
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Allo-SCT in refractory/relapsed DLBCL: EBMT Registry
Van Kampen RJW et al, J Clin Oncol 2011
101pa\ents;medianfollow-upforsurvivors36months
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Allogeneictransplanta\oninB-celllymphomas:OSandPFScurves
-R-condi+oningversuscontrolgroup-
p=0.708
OS PFS
p=0.509
65%(R)
48%(R)65%
56%
DoderoAetal.,BBMT2017
RituximabgroupControls
RituximabgroupControls
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Grakversushostdiseaseandrelapsefreesurvival(GRFS)inB-celllymphomas:anovelendpoint
p=0.644
AllPa\ents
43%4years56%1year
DoderoAetal.,BBMT2017
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29 LockeFL,etal.MolTher.2017;25(1):285-295.
Endpoint primario: l'incidenza di tossicità dose-limitante (DLT) La risposta globale è stata del 71% (n = 5/7) e la risposta completa(CR) del 57% (n = 4/7). Tre pazienti hanno CR in corso (tutti a 12 mesi)
Nello studiomul+centricoZUMA-1di fase1,hannovalutatoKTE-C19,unaterapia autologa basata su cellule T ingegnerizzate (CART specifiche perl’an+gene CD3z/CD28), in pazien+ con DLBCL refraVario. I pazien+ hannoricevuto chemioterapia condizionata a basse dosi con concomitanteciclofosfamide (500mg/m2)efludarabina (30mg/m2)per3giorni, seguitadaKTE-C19aunadosetargetdi2x10e6celluleCART/kg.
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Efficacia clinica dopo infusione di KTE-C19
30
Duratadellarispostaesopravvivenzadopol'infusioneconKTE-C19
LockeFL,etal.MolTher.2017;25(1):285-295.
CRa30ggdopol'infusionediKTE-C19nelpz5Scansioni PET-CT alla malaYa basale e 30giorni dopo l'infusione di KTE-C19 in unpaziente con recidiva di DLBCL dopoprecedenteterapiaconR-CHOP,R-ICEeASCTc o n R i t u x i m a b - g e m c i t a b i n a -busulfanmelphalan+azaci+dina-vorinostat
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James N. Kochenderfer et al.
22pazien+: il tasso totaledi remissione (ORR)è statodel 73%con il 55%diremissionicomplete(CR)eil18%diremissioniparziali(PR).Sonoincorso11di 12 CR; Il 55% dei pazien+ aveva tossicità neurologiche di grado 3 o 4completamenterisolte.Ilregimedicondizionamentoachemioterapiaabassodosaggioha ridoVo i linfoci+del sangueeha aumentato la IL-15nel siero. Ipazien+ che hanno raggiunto una remissione avevano un picco mediano dicellule CAR+ di 98/mcl e quelli che non avevano oVenuto una remissioneavevanounpiccomediodicelluleCAR+di15/mcl(P=0,027).
RISULTATI
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A B
James N. Kochenderfer et al. JCO 2017
LecelluleCARThannomandatoinremissionedeilinfomichemio-refranari
B)PFSapar+redalgiornodell'infusionecellulareetermineilgiornodellaprogressionedellamalaYaè mostrato per tuY i pazien+. I segni rossiindicano pazien+ con CR in corso al momentodell'ul+moFUconun'eccezione:ilsegnorossoa4mesi dopo l'infusione delle CART indica il puntotemporale incui ilpaziente40èstatosoVopostoadAlloSCTmentreerainremissioneparziale.Duepazien+ sono sta+ censorizza+ ai 13 mesi, 3pazien+a14mesi,mac'èunsolosegnorossosulgraficoperciascunodiques+pun+temporali.
A)Rappresentazionegraficadei+pidirispostaan+-linfomaeladuratadellerisposte.
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KochenderferJCO2015
EradicazionedeiPMBCL/DLBCLcloni
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PrimaryAnalysisofJULIET:AGlobal,Pivotal,Phase2TrialofTisagenlecleucel(CTL019)inAdultPa\entsWithRelapsedorRefractoryDiffuseLargeB-CellLymphomaStephenJ.Schusteretal.-LymphomaProgram,AbramsonCancerCenter,UniversityofPennsylvania
JULIETèuntrialdi fase IIabracciounico, inaperto,mul+centrico, di +sagenlecleucel in pazien+ adul+conDLBCLR/R(NCT02445248)I pazien+ hanno ricevuto una singola infusione conuna dose target che variava da 1×108 a 5×108 di+sagenlecleucelCARTcells
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StudioProof-of-ConceptTisagenlecleucelèstatoesaminatoinunostudiomonocentricodifaseIIsuadul+conLinfomiCD19+R/R.- Iltassodirispostaglobale(ORR)eradel64%(18/28);rispostacompleta(CR),57%(16/28)-LacoorteDLBCLhaavutounORRdel50%(7/14);CR,43%(6/14)-TuYipazien\inCRsonorimas\inCRalfollow-upmedianodi29mesi
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Arruolamento dei dei pazienti
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Efficacia•IlsetdianalisidiefficaciaincludevatuYipazien+chehannoricevutoun'infusionedi+sagenlecleucelcon≥3mesidifollow-up
•Degli81pazien+valuta+,il40%avevaunCR•L'endpointprimarioèstatoraggiunto:ORR,53%(95%CI,42%-64%;P<.0001)•Laduratadellerisposteèstatadimostratadallastabilitàtra3-e6mesideitassidirisposta•Larispostaa3mesieraindica\vadelbeneficioalungoterminediquestotranamento•GliORReranocoeren+traisoVogruppi•Duratadellarisposta(DOR)eOSmedianinonsonosta+raggiun+•Il74%deipazien+nonhaavutorecidivea6mesi•QuasituYipazien\inCRalterzomesesonorimas\inriposta•Nessunpazientehaprocedutoaltrapiantomentreerainrisposta
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Durata della Risposta
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Sicurezza
•Nessundecessoèstatoosservatoacausadi+sagenlecleucel,sindromedarilasciodicitochine(CRS)oedemacerebrale•IltempomedianodiinsorgenzadelCRSèstatodi3giorni(intervallo,1-9giorni)•Deipazien+traVa+perCRS,il15%haricevutotocilizumabel'11%haricevutocor+costeroidi
Tabella3.Even\avversidipar\colareinteresse
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40
Conclusioni 1) LaterapiaconcelluleCARTan+-CD19èpromeVente,faYbilee
può indurre remissioni complete durature in pazien+chemorefraVari.
2) Conunaformazioneappropriata,latossicitàpuòessereges+ta,maèancoraunproblemadaconsiderareseriamente.
3) È necessario migliorare il tempo di produzione per essereefficacementeeampiamenteu+lizzatonellapra+caclinica.
4) La selezione dei pazien+ in base al rischio di malaYa (COO,DHL,THL,ecc.)saràessenzialeperoYmizzareirisulta+alungotermine.
5) Vannostudia+interven+aggiun+viperipazien+inremissioneparziale.
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LE2TERAPIECONCARTSAPPROVATEDAFDA:KYMRIAHeYESCARTA
GiraltSA,BBMT2018
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TOSSICITA'“ON-target”e“OFF-tumor”
ONtarget#CARTsriconosconocorrenamentelaproteinadisuperficiecellulareCD19
OFFtumor#altrecelluleCD19+nontumoralisonodistrunedalleCARTs(Bcellaplasia)
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TOSSICITA'DELLECARTS1)SDRDARILASCIOCITOCHINICO(CRS):rispostainfiammatoriasistemicacausatada
rilasciodicitochinedopoinfusionedicelluleimmunieffenrici.
15-50%diCRSgrave(grado3-4)neglistudi,differenteasecondadi\podiCARTedimalaYa
ManifestazionisimiliaHLH
2)NEUROTOSSICITA'(CRES):diffusionepassivadicitochineedicelluleimmunitarieinSNC.Tipicamentesimanifestacomeencefalopa\aglobale,afasia,EEGrallentamentodiffusooconvulsioni,CSFposi\voperCARTs,MRImostraedemaincasipiùgravi.
PREVALENZA5-30%neglistudi
ONSETbifasico:1)giorni0-5,\picamenteassociatoasintomidiCRS;2)dopogg+5,comparequandosintomidaCRSdiminuiscono
3)INFEZIONI:incidenzasimileallealtrechemiodisalvataggio1
Hilletal,Blood2018
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44
Conclusioni -1
1) Con una formazione appropriata, la tossicità può essere gestita, ma è ancora un problema da considerare seriamente.
2) È necessario migliorare il tempo di produzione per essere efficacemente e ampiamente utilizzato nella pratica clinica.
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45
Conclusioni -2 1) La selezione dei pazienti in base al rischio di
malattia sarà essenziale per ottimizzare i risultati a lungo termine e contenere i costi.
2) Vanno studiati interventi aggiuntivi per i pazienti in remissione parziale dopo la terapia.
3) E’ la prima terapia cellulare commerciale per una malattia neoplastica, i medici ed i sistemi sanitari dovranno imparare a gestire questa nuova opportunità.
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46 Compara\vedescrip\onofCARTcellstrategiesusedas
immunotherapiesagainstMul\pleMyeloma
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Thiswas the first in humans clinical trial of chimeric an+gen receptor (CAR) Tcellstarge+ngBCMA(B-cellmatura+onan+gen).TcellsexpressingtheCARusedinthiswork(CAR-BCMA)specificallyrecognizedBCMAexpressingcells.Ourfindingsdemonstratean+-myelomaac+vityofCAR-BCMATcells
12pa+entsreceivedCAR-BCMATcellsinthisdose-escala+ontrial.Amongthe6pa+entstreatedonthelowest2doselevels,limitedan+-myelomaac+vityandmildtoxicityoccurred.Onthe3ddoselevel,1pa+entobtainedaVGPR.
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4th dose level of 9 x 106 CAR+ T cells/kg body weight:Before treatment, thefirst pa+enton the4thdose levelhad chemotherapy resistantMM,making up 90%of BMcells. Afer treatment, BM plasma cells becameundetectablebyflowcytometry,andthepa+ententeredastringentCRthatlastedfor17weeks.Thesecondptonthe 4th dose level had chemotherapy-resistant MMmaking up 80%of BMbefore treatment. 28weeks aferthis pa+ent received CAR-BCMAT cells, BMplasma cellswereundetectablebyflowcytometry,andtheserumMChad decreased by >95%. This pa+ent is in an ongoingVGPR.Bothpa+entshadtoxicityconsistentwithCRS.
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49 CAR-BCMATcellsspecificallyrecognizedBCMAinvitroand
exhibitedan\-myelomaac\vityinhumans
(A) Diagramof theMSGV-11D5-3-CD828Z g-retroviral vector encoding the an+-BCMACAR (CAR-BCMA) isshown.(B)CAR-BCMAexpressiononthesurfaceoftheinfusionTcellsofpa+ent10wasdetectedbystainingwith a PE-BCMA-Fc protein reagent. The plot is gated on live CD31 lymphocytes. (C) Demonstra+ngspecificity,thePE-BCMA-FcreagentdidnotstainPBMCsthatwerenottransducedwiththeCAR-BCMAgene.(E)Pa+ent8whohadMMthatwasprogressingdespite8priorlinesoftherapyobtainedaverygoodpar+alremission (VGPR) afer infusion of CAR-BCMA T cells. PET–computed tomography scans from before andafertreatmentshowelimina+onofalargenumberofMMbonelesions.
Figure1
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• Serum BCMA served as a tumor marker because substan+al decreases inserum BCMA occurred in the 3 pa+ents with the most impressive an+-myelomaresponses(Figure4D).
• These results demonstrate for the first +me that CAR T-cells targe+ng anan+gen other than CD19 can induce complete remissions of a hematologicmalignancy.
• IthasbeenshownthatCAR-BCMATcellshavepowerfulac+vityagainstMMthatwasresistanttostandardtherapies.
• Theseresultsshouldencouragefurthereffortstoenhancean+-BCMACARTcell therapies. The striking ac+vity of an+-BCMA CAR T cells against MMindicates that CAR T cells targe+ng BCMA have great poten+al to be aneffec+venewtreatmentofMM.
Conclusions
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12enrolled,10treatedand3hadbenerPFScomparedtofirstMel
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CARTS
1. Comefunzionanoequantofunzionano?
2. Letossicitàacute
3. IprogrammidigesConeisCtuzionalie
cosC
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PROGRAMMAGESTIONECARTSMDACC:CARTOXCOMMITTEE
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PROGRAMMAGESTIONECARTSMDACC:CARTOXCOMMITTEE
1) IncontriseYmanalididiscussionepazien\interapiaconCARTs
2) Gruppomul\disciplinarediges\oneCARTs
3) Creazionediprotocollidiges\onepazien\interapia
4) Adeguataformazionedelpersonalecheu\lizzeràCART(medici,infermieri,farmacis\)
5) Discussionedeitrialincorsoedeirisulta\pubblica\
LASOMMINISTRAZIONEDICARTsAVVIENESOLOINAMBIENTISPECIFICIDELL’OSPEDALE
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PROGRAMMAGESTIONECARTSMDACC:CARTOXCOMMITTEE
• TeamNEUROLOGI:valutazionestatusneurologicodelpazientegiornaliera
• TeamINTENSIVISTI:valutazionecondizioniclinichegiornaliera,sepeggioramentorapidoassisteiltrasferimentodelpazienteinICU
• TeamFARMACISTI:siassicuranodelladisponibilitàdifarmacisalvavitaperges\oneCRS(tocilizumab,almeno2dosiperpazientesecondoFDA)
• SupportoELETTRONICO:strumen\informa\cichefacilitanolaraccoltaomogeneadeida\circalavalutazionedelletossicitàdelleCARTs(CRS,CRES)
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PROGRAMMAGESTIONECARTSMSKCC
GiraltSA,BBMT2018
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RACCOMANDAZIONIEUROPEESUGESTIONECARTS
BuechnerJ,Hemasphere2018
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OGNIPAESEHAUNENTEREGOLATORIODIRIFERIMENTOPERLETERAPIE
CELLULARI
BuechnerJ,Hemasphere2018
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LASITUAZIONEREGOLATORIAEUROPEA
BuechnerJ,Hemasphere2018
REQUISITIEUROPEI
1)CARTScompresenellacategoria“AdvancedTherapyMedicinalProducts”(Regula\onECn°1394/2007edireYva2001/18/EC)
2)CARTSconsideratecomeOGMpertantovannoseguitenormediprotezioneambientaleedelpersonalespecifiche(DireYva2001/18/ECeDecisionedellaCommissione2002/623/EC)
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LASITUAZIONEREGOLATORIAEUROPEA
BuechnerJ,Hemasphere2018
REQUISITINAZIONALISPECIFICI
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RIMBORSIFDA
1. KYMRIAH,Novar\s(pediatricALL)#475.000USD
2. YESCARTA,Gilead(adultNHL) # 373.000USD
Nelprezzononècompresalaspesaperges\rericoveroepossibilicomplicanzedelpaziente.Intalecasopossibilianchespeseaggiun\vecompresetra100.000USDe300.000USD.
(Rimborsabilitàtrapiantoallogenicocellulestaminaliparia80.000-100.000euro+speseaggiun\vepercomplicanze)
www.medscape.comaccessed08/03/2018
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PROPOSTE1. Implementazionestandarddiqualitàperterapiecellulari(e
iden\ficazionecentridiriferimento):
• regolareEFFICIENTEMENTElages\onedeitrial(creazionedireteinterospedalieradiriferimento)
• maneggiareINSICUREZZAleCARTS(creazionedistandarddiqualitàterapiecellulari,vediFACT-IEC)
• amministrareilprodonoINSICUREZZA(personaleformatoecreazionedireteintraospedaliera)
2. Creazionediunregistronazionale/europeoperraccoltada\suterapiacellulari(vediesempioCIBMTRedEBMT)