TheFutureofChimericAn1genReceptorT(CART)cellTherapyinLymphoma
CaronJacobsonMD,MMSc
AssistantProfessorofMedicine,HarvardMedicalSchoolMedicalDirectoroftheImmuneEffectorCellTherapyProgram,
Dana-FarberCancerIns1tute
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• Honoraria from Kite Pharma, Novartis, Bayer, Pfizer, Humanigen, Precision Biosciences
Disclosures
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• Clinical efficacy and toxicity overview • Remaining questions and challenges – Toxicity prediction, prevention and management – Resistance mechanisms
• Antigen loss • T cell exhaustion/tumor microenvironment • T cell product
– Cost and manufacturing time
• Future Directions – New constructs – New combinations – New targets
Overview:CART-cellsinLymphoma
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ClinicalEfficacyandToxicityOverview
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CurrentResults:AnB-CD19CART-cellsinDLBCL
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ZUMA-1 JULIET JULIETPackageInsert
TRANSCENDFULL
TRANSCENDCORE
Product KTE-C19(axi-cel) CTL019(t-cel) CTL019(t-cel) JCAR017(Liso-cel) JCAR017(Liso-cel)
#pheresed 111 165 160 134 NR#treated 101 111 106 114 NR#evaluable 101 93 68 102 73
#nevertreated 10/111(9%) 50/161(31%) 49/160(30%) 20/134(15%) NR
Bridgingtx(%) 0 92 90 NR NR
ORR(%) 82 52 50 75 80CR(%) 54 40 32 55 59
6mORR(%) 41 37* NR NR 476mCR(%) 36 30* NR NR 41ITTORR(%) 75(83/111) 30(48/161) N/A 63(77/122) N/A
AnB-CD19CARTcellsinDLBCL:DuraBonofResponse
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ORR26%CR7%MedianOS6.3m
SCHOLAR-1
KITEZUMA-1Medianf/u15.4m
JUNOTRANSCENDMedianf/u12m
NOVARTISJULIETMedianf/u12m
• Cytokine Release Syndrome (CRS) – Activation/expansion of CAR T-cells and increased levels cytokines like IL-6, IL-15,
INF-γ, and others – Onset: 1-3 days; Duration: 3-5 days
• Neurotoxicity – Mechanism less well understood
• Evidence of endothelial activation and BBB breakdown • CAR T-cells and non-CAR T-cells are found in CSF • Higher levels of pro-inflammatory cytokines in CSF compared to blood
– Cytokines appear to be coming from myeloid cells rather than lymphocytes – Onset: 5-7 days; Duration: 5-10 days
• Fully reversible except in cases of fatal cerebral edema
• B cell aplasia
CurrentResults:CART-cellToxicityinDLBCL
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CurrentResults:CART-cellToxicityinDLBCL
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ZUMA-1 JULIET JULIETPackageInsert
TRANSCENDFULL
TRANSCENDCORE
Product KTE-C19(axi-cel) CTL019(t-cel) CTL019(t-cel) JCAR017(Liso-cel) JCAR017(Liso-cel)
#pheresed 111 147 160 134 NR#treated 101 111 106 114 NR#evaluable 101 93 68 102 73
#nevertreated 10/111(9%) 50/161(31%) 49/160(30%) 20/134(15%) NR
Bridgingtx(%) 0 92 90 NR NR
CRS(%) 93 58 74 39 37Gr3+CRS(%) 13 22 23 1 3
NT(%) 64 21 58 23 25Gr3+NT(%) 28 12 18 13 15
Neurotoxicity:BiomarkersfromClinicalTrialsandAnimalModels
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GustJ,etal.CancerDiscovery2017SantomassoBD,etal.CancerDiscovery2018NorelliM,etal.NatureMedicine2018GiavridisT,etal.NatureMedicine2018TaraseviciuteA,etal.CancerDiscovery201
• Diseaseburden• PeakCARTcelllevels• EarlyandhighgradeCRS• DIC• Peakcytokines:CRP,ferriBn,IL6,IL8,
INFγ,TNFα,GM-CSF,MCP-1,IP10
• Impairedvascular/BBBintegrity• HighCSFcytokines• CAR++CAR-TcellsinCSF• HighexcitatoryNTs(glutamate)• Autopsy:microthrombi/hemorrhage,
endothelialacBvaBon,diffusegliosis
MouseleukemiaPDXpost-CD19CARs• IL1*andIL6importantinCRS/NT• Monocytes=sourceofIL1&IL6Non-humanprimatepost-CD20CARs• CAR+andCAR-TcellsinCSF• CytokinesCSF>PB:IL6,IL2,GM-CSF,
VEGF• Necroscopy:widespread
intraparenchymalCAR+andCAR-Tcellinfiltrate
• VLA-4increasedinCAR+Tcells
ClinicalAssocia1ons PathologicAssocia1ons Animalmodels
UnansweredQuesBons:ToxicityPredicBon,PrevenBon,andManagement
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PrevenBngandTreaBngNeurotoxicity
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BaselineHostFactors• DiseaseBurden• Pre-treatment
inflammaBon• Pre-treatment
endothelialacBvaBon
CARTresponse• PeakCARTnumber• Cytokinelevels• Biomarkersof
endothelialacBvaBon
NeurotoxicityPathology• BBBdisrupBon• Passivecytokineand
cellulartrafficking• AcBvecytokine
producBon• Neurologicsymptoms
RiskAssessmentProphylaxis
• AllPaBentsvsHigh-Risk• IL-1,IL6,GM-CSF,endothelium,VEGF
Treatment
Toolate?
CanCARsbebuilttobesafer(andmoreeffecBve)?
• A variety of engineering technologies may lead to more natural and controlled T cell activation and thus a safer and more potent CAR T-cell – Switch mediated CAR T-cells – Boolean-gated CAR T-cell receptors – CRISPR engineered CAR T-cells – T cell antigen coupler (TAC) T-cells
• Requirement for multiple cell-cell interactions
strengthens the immunologic synapse, improves specificity, and decreases tonic signaling
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RodgersetalPNAS2016:E459RoybaletalCell2016;164:770EyquemetalNature2017;543:113HelsenetalNatCommun2018;9:3049
UnansweredQuesBons:MechanismsofResistance
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TcellExhausBon• CAR T-cells upregulate PD-1 and other
immunomodulatory molecules upon activation • PD-L1 upregulation within the tumor
microenvironment inhibits CAR T cell function in animal models – This can be reversed with PD-1 blockade
• PD-1 inhibitors have activity in patients who progressed following CAR T-cell therapy – This is associated with an increase in CAR T-cell
numbers and pro-inflammatory cytokines
• Two ongoing trials combining PD1 blockade with CAR T-cells – One following relapse – One upfront in conjunction with CAR T-cells
14ChongEAetal.Blood2017;23:1039-1041
• N=9 – Nearly all patients had PDL1 either on
the tumor or in the microenvironment
• Efficacy: – ORR 89%, CR rate 56% – Two CRs converted from PRs between
6-9 months
• Safety: – CRS any grade 100%; grade 3 33% – Neurotoxicity any grade 78%; grade
3+ 56% – Similar levels of IFNγ, IL-15, CRP, and
granzyme B between patients on ZUMA-1 and ZUMA-6
CombinaBonStrategies:Axi-cel+Atezolizumab(ZUMA-6)
15LockeASH2017
• Genetic analysis of B-ALL post-CAR T-cell relapses revealed: • Loss of one copy of CD19 • Alternative splicing of the other copy,
resulting in loss of exon 2
• Loss of exon 2 results in truncated CD19 that: • is not detected by CD19 immunostains
and antibodies • fails to trigger CAR T-cell killing • partially rescues cells from the effects
of CD19 loss
16SoBllaetal.CancerDiscov2015;5:128201295
AnBgenLoss:AlternateCD19Splicing
DualAnBgenCART-cells
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CD19,CD22
CD19,CD20
• Response correlated with expansion and persistence of CAR T-cells – Products from responding patients were more effective in
mouse models too – Intrinsic T cell factors = important in response
• Gene expression profiles differed between Rs and NRs – Rs: early memory differentiation – NRs: late memory/effector T cell differentiation,
apoptosis, and aerobic glycosis • Upon ex-vivo stimulation, CAR T cells from Rs had
higher levels of STAT3 signaling • High levels of CD8+CD45RO-CD27+ memory-like T cells
correlated with response • High PD1, LAG3, and TIM3 expression correlated with
lack of response
18Fraieraetal.NatureMed2018;24:563
TcellProduct:CLL
• CLL patients s/p >6 months of ibrutinib had a healthier and more potent CAR T-cell product – Improved T cell expansion and
engraftment – Decreased expression of inhibitory
molecules like PD1 – Improved antitumor activity in mouse
models
• Pilot trial of CTL-019 in CLL patients with less than a CR after at least 6m of ibrutinib – MRD negative CR: 89% – Suggestion of an improved safety
profile 19
Fraieraetal.Blood2016:127:1117GillASCO2017
ImprovingTcellHealth:IbruBnibPre-treatment
UnansweredQuesBons:CostandManufacturingInefficiencies
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CosteffecBvenessstudies:• Pediatric/youngadultALLtreatedwithCTL-019(LinetalJCO;2018:Epubaheadofprint):
• Assuming40%5yearrelapse-freesurvivalrate,lifeexpectancyincreasesby12.1yearsatacostof$61,000/QALYgained
• AdultDLBCLtreatedwithaxi-cel(RothetalJMedEcon2018Sep1-15)• ImprovementinlifeBmeyears,qualityadjustedlifeyears,andlifeBmecostscomparedtosalvagechemotherapy• Likelihoodaxi-celiscosteffecBveatawillingnesstopay$100,000perQALY=95%
• Volunteer donor T cells engineered so that the TCR locus is edited out – Elimination of TCR serves to
prevent GVHD
• Can make larger quantities of CAR T-cells from one donor product
• Cells are available on demand for patients who lymphomas would otherwise not be able to wait for treatment 22
AllogeneicOffTheShelfCART-cells
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UsingNanoparBclestoEngineerCART-cellsinvivo
SmithetalNatNanotechnology2017;12:813
Summary:FutureofCART-cellinLymphoma• Toxicity management
– Safer CARs – Prophylactic strategies: tumor debulking, cytokine inhibitors, endothelial stabilizing agents – New treatments: cytokine inhibitors
• Overcoming resistance – Antigen loss
• Bivalent or dual antigen CAR T-cells: CD19 + CD20 or CD22 – T cell exhaustion
• Combination therapy trials: CAR T-cells + immune checkpoint blockade or other immunomodulatory agents – Gene edited CARs: edit out immunomodulatory receptors
• Uniquely engineered CARs that avoid tonic signaling – T cell product:
• Earlier lines of therapy, pre-treatment with immunomodulatory drugs like ibrutinib – Hostile tumor microenvironment
• Armored CARs: IL12, CD40L, 4-1BBL
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Summary:FutureofCART-cellinLymphomaConBnued• Overcoming issues of cost and manufacturing inefficiencies
– Universal (off the shelf) CARs – Nanoparticle CAR T-cells = in vivo CAR T cell manufacturing
• Expanding indications – CD19 CAR T-cells
• Mantle cell lymphoma • Follicular and other indolent lymphomas • CLL
– CD30 CAR T-cells • Hodgkin lymphoma • T cell lymphoma
– CD37 CAR T-cells • B cell lymphomas • T cell lymphomas
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