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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