Immunotherapy in Genitourinary...

ImmunotherapyinGenitourinaryCancers

JongChul Park,MDGUOncologyFellow

SidneyKimmelComprehensiveCancerCenterJohnsHopkinsMedicine

Outline

• CancerImmunology• CurrentDataofImmunotherapyinGUCancers• NewImmunotherapyConceptsinGUcancers• FutureResearchDirections

ImmuneSystemandCancer

InnateImmunity AdaptiveImmunityAnti-tumorResponseRecognitionoftumor

DC

Tcellactivation

Tolerance

Defectiveantigenpresentation ImmunosuppressiveTMEInhibitionofCTL

CancerImmunotherapy

1908

Breaktoleranceandreinvigorateantitumorimmunity

2015


InnateImmunity AdaptiveImmunityAnti-tumorResponseRecognitionoftumor

DC

Tcellactivation

Tolerance

Defectiveantigenpresentation ImmunosuppressiveTMEInhibitionofCTL

Combinationalapproach

Vaccinecombination

InnateImmunity AdaptiveImmunityAnti-tumorResponseRecognitionofthreat

DC

Tcellactivation

Sipuleucel-TAutologousDCvaccine

• PBMCscollectedbyleukapheresis• CulturedinEXVIVOwithPA2024(fusionproteinofPAPandGM-CSF)

• Re-infusionofvaccineproductx3• Primeandboost

HR0.775;P.032(25.8vs.21.7)

*Nodifference inPFS1PR2.6%PSAresponse (↓>50%)

Kantoff PW.NEngl JMed2010

PROSTVAC-VF

1PSAresponse>80%.Noradiographicresponse

PA2024 PAP

0

10

20

30

40

50

60

70

80

C S C S C S C SN= 28 54 33 63 23 42 8 32

C S C S C S C S22 50 27 59 17 39 8 32

0

20

40

60

80

100

120

140

160

0.1

1

10

100

1000

C S C S C S C SN= 28 55 33 63 21 42 8 33

C S C S C S C S20 46 25 55 16 37 8 30

0.01

0.1

1

10

100

IFN EL

ISPOT

(per 3x

10 PB

MC)

γ5

Stimu

lation

Index

3.6 5.5 3.0 58.7 0.0 52.4 12.5 48.5

Wk0 WK6 WK14 WK26 WK0 WK6 WK14 WK26

*

% RespFreq = 2.2 5.0 0.0 23.6 0.0 16.2 0.0 26.7

3.6 5.6 3.0 50.8 8.7 40.5 0.0 37.5% RespFreq = 9.1 2.0 11.1 10.2 0.0 5.1 0.0 3.1

*

*

*

#

#

Sheikh,CancerImmunolImmunother2013

C S C S C S C SN= 70 150 60 134 41 89 18 62

PA2024 PAPWK0 WK6 WK14 WK26 WK0 WK6 WK14 WK26

C S C S C S C S70 150 60 133 41 89 18 62

4370N = 71 53

IgM + IgG

Antibod

y Titer

IgM Anti

body Tit

erIgG

Antibod

y Titer

B

A

100

1000

10000

100000

100

1000

10000

WK0 WK6 WK14 WK26

WK0 WK6 WK14 WK26

121717 16

121717 16

2.0 1.4 3.3 47.8 0.0 73.0 5.6 53.2% RespFreq = 0.7 0.0 1.7 21.1 0.0 27.0 0.0 17.7

* * **

**

100

1000

10000

100000

4370N = 71 53

100

1000

10000

100000

1000000

100

1000

10000

100000

100

1000

10000

100000

Sip-Tinduces long-lastingcellular andhumoral immuneresponses

PA2024/PSA PA2024 PSA

HypothesisI

Enhancedsipuleucel-T-inducedimmuneresponsemaytranslateintobetterclinicaloutcome

ImmuneModulationbyRadiation

• ReleaseofTAAs• EnhanceddisplayofTAAs• Enhancedexpressionofcellsurfacemolecules• MHCclass1,ICAM-1

• ComplexeffectsonTME

SharabietalOncology2015

RT-inducedcelldeath=immunogeniccelldeath?

In-situpersonalized“vaccine”

InVivoEvidenceofRadiation+Vaccine

Drakeetal.Int JRadiat Oncol Biol Phys2015

Newcombetal.ClinCancerRes.2006

WBRT:UpregulationofMHC-ICD4/CD8Tcelltumor infiltration

InVivoEvidenceofRadiation+Vaccine

Radiation+Vaccine:Clinicaltrials

• PhaseIISipuleucel-T+EBRT(NCT01807065): closed• Feasibility

• PhaseIISipuleucel-T+SABR(NCT01818986): open• Timetoprogression

• PilotSipuleucel-T+EBRT(NCT01833208):open• AgspecificTcellactivation

• MulticenterSipuleucel-T+EBRT(NCT02232230): open• AgspecificTcellactivation

ImmuneModulationbyRadiopharmaceuticals

Chakraborty etal.ClinCancerRes.2008

153Sm-EDTMP

Radiopharmaceutical+Vaccine

Sm-153 Sm-153+PSA-TRICOM

PFSAt4mo 3/18(16.7%) 8/21(38.1%) p=0.13mPFS (mo) 1.7 3.7 HR=0.48,p=0.034

PSAdecline≥30% 0 4/21(19.0%) p=0.073≥50% 0 2/21(9.5%) p=0.283

Sm-153onD#8andthenQ12weeks+/- PSA-TRICOMonD#1,15,29,thenQ4weeksEarlyclosureofthistrialduetopooraccrualafter44pts

PhaseIIsamarium-153EDTMP(Sm-153)+/- PROSTVACvaccine

Heeryetal.GUASCO2013

Radium-223

Ra

Ca

HypothesisII

Enhancedsipuleucel-Tinducedimmuneresponsemaytranslateintobetterclinicaloutcome

Combinedradium-223mayenhancesipuleucel-Tinducedimmuneresponse

PhaseIIStudyofSipuleucel-TwithorwithoutRadium-223

mCRPC withnoorminimalSx

1’Objective:TodeterminewhetherRad-223tosipuleucel-Tenhancesimmuneresponsetosip-T

1’Endpoint:PA2024-specificT-cellproliferationat6weeksafter1st sip-Tinfusion reportedasSI

PA2024 PAP

0

10

20

30

40

50

60

70

80

C S C S C S C SN= 28 54 33 63 23 42 8 32

C S C S C S C S22 50 27 59 17 39 8 32

0

20

40

60

80

100

120

140

160

0.1

1

10

100

1000

C S C S C S C SN= 28 55 33 63 21 42 8 33

C S C S C S C S20 46 25 55 16 37 8 30

0.01

0.1

1

10

100

IFN EL

ISPOT

(per 3x

10 PB

MC)

γ5

Stimu

lation

Index

3.6 5.5 3.0 58.7 0.0 52.4 12.5 48.5

Wk0 WK6 WK14 WK26 WK0 WK6 WK14 WK26

*

% RespFreq = 2.2 5.0 0.0 23.6 0.0 16.2 0.0 26.7

3.6 5.6 3.0 50.8 8.7 40.5 0.0 37.5% RespFreq = 9.1 2.0 11.1 10.2 0.0 5.1 0.0 3.1

*

*

*

#

#

2’ClinicalEndpoints• Safety(CTCAEv4.0)• PSAprogression(PCWG2)• Radiographicprogression(RECIST/PCWG2)• Painprogression(Useofopioidanalgesics)• OccurrenceoffirstSRE• Firstchemotherapyuse


2’ImmuneEndpoints• PA2024-andPAP-specificT-cellproliferation• 3H-thymidineassay

• PA2024-andPAP-specificT-cellactivation• IFNγ ELISPOT

• PA2024-andPAP-specificAb(IgM/IgG)response• ELISA

• Sipuleucel-Tinducedantigen(epitope)spread• IgGresponsestooff-targetAgs (Proteinmicroarray)

• Productimmuneparameters


GuhaThakurta andDrakeetal.Clin CancerRes2015

Sipuleucel-TinducedAntigenSpreadCD8Tcellresponsestosecondaryantigens

• PBMCsobtainedfromSTAND(n=10)andSTRIDE(n=4)trial• CD8Tcellproliferationtosecondaryantigens

• KRAS,LGALS3,PSA• Atbaseline,week6,andmonth6

AntonarakisandDrakeetal.GUASCO2016

ImmuneCheckpoint


DC

Tcellactivation

Atezolizumab vs. Pambrolizumab vs. AvelumabPost-platinummUC

Petrylak etal.ASCO2015,Plimackal.ASCO2015,Apolo etal.GUASCO2016

Agents PD-L1IHC ORRCell types Stain(Cut-off)

Atezolizumab(Anti-PD-L1) TIL

+(≥5%) 50%

- (<5%) 17%

Pembrolizumab(Anti-PD1)

Tumor/TIL+ 29%

- 0%

Tumor+ 33%

- 9%

Avelumabb(Anti-PD-L1) Tumor

+(≥5%) 40%

- (<5%) 9%

Atezolizumab vs. Pembrolizumab vs. AvelumabPost-platinummUC

Petrylak etal.ASCO2015,Plimackal.ASCO2015,Apolo etal.GUASCO2016

Agents PD-L1IHC ORRCell types Stain(Cut-off)

Atezolizumab(Anti-PD-L1) TIL

+(≥5%) 50%

- (<5%) 17%

Pembrolizumab(Anti-PD1)

Tumor/TIL+ 29%

- 0%

Tumor+ 33%

- 9%

Avelumabb(Anti-PD-L1) Tumor

+(≥5%) 40%

- (<5%) 9%

DualImmuneCheckpointInhibition:Anti-PD-1/PD-L1+Anti-CTLA-4

CTLA-4

PD-1

Bruggemannetal.ASCO2015

Author Population Agent Target PD-L1+ORR

PD-L1-ORR

Petrylak mUC Atezolizumab PD-L1 50% 17%Herbst mSolidTumors Atezolizumab PD-L1 34% 16%McDermott mRCC Atezolizumab PD-L1 20% 10%Horn mNSCLC Atezolizumab PD-L1 45% 14%Plimack mUC Pembrolizumab PD-1 33% 9%Daud mMel Pembrolizumab PD-1 53% 6%Garon mNSCLC Pembrolizumab PD-1 45% 17%Choueiri mRCC Nivolumab PD-1 22% 8%Brahmer mNSCLC Nivolumab PD-1 15% 14%Callahan mMel Nivolumab+Ipilimumab PD-1/CTLA-4 41% 46%Hammers mRCC Nivolumab+Ipilimumab PD-1/CTLA-4 50% 55%Larkin mMel Nivolumab+Ipilimumab PD-1/CTLA-4 72% 58%Grasso mMel Nivolumab PD-1 44% 17%Topalian mSolid Tumors Nivolumab PD-1 36% 0%

DualImmuneCheckpointInhibitionPD-1/PD-L1+/- CTLA-4


PD-L1-ORR


DualImmuneCheckpointInhibition

MIBCCisplatin-ineligible(n=20)

CrCl <60mL/minuteHearingloss≥G2Neuropathy≥G2

TURBTMEDI4736 10mg/kg

Tremelimumab 1mg/kg

q21dx2cycles

Cystectomy

PrimaryEndpoint:• TumorinfiltratingCD8+T-cellatcystectomyafterMEDI4736/tremelimumabSecondaryEndpoints:• SafetyandantitumorefficacyofMEDI4736/tremelimumabExploratoryEndpoints:• Characterizationoftumortissueandperipherallymphocytes• Analysisofsolubleimmunemarkers(cytokines/chemokines)• Analysisoftumorandbloodgeneticandepigeneticprofiles• AssessmentofT-cellrepertoire


TumorInfiltratingLymphocyte(TIL):prognosticmarker?

• ThepresenceofTILsassociatedwithimprovedsurvivalinMIBC(n=154)• ↑CD8+TILs(≥8/0.0625mm2)correlatedwithbettersurvivalinMIBC(N=69)

Lipponen etal.Eur JCancer.1992,Sharmaetal.PNSA2007

8/0.0625mm2≈4/100tumorcells

Intratumor vs.margin/stroma?TILvs.subtype?densityvs%vs.ratio?


Drake,andNettoetal.Urology2015

Intratumoral CD8+Tcells(400x)

HighCD8density:≥60CD8+/HPF:11/56(19.6%):intratumoral (n=56)


Nakanoetal.CancerRes2001

ParadoxicalcorrelationofCD8+ T-cellinfiltrationwithpoorprognosis

>50CD8/0.25mm2


Remarketal.Clin CancerRes2013Giraldoetal.ClinCancerRes2015

Coloncancerlungmets RCClungmets

PrimaryRCCtumor RCCLungmets

Unresectable/metastaticUrothelialCa(n=10)RenalcellCa(n=10)

Week03679121518

REGN2810

C#1 C#2 C#3 C#4 C#5 C#6

Pre-Tx Bx Post-Tx Bx

ImmunePredictiveBiomarkerPharmacodynamics

TIL:CD8densityvs.CD8deltavs.CD8/Treg ratiovs.OtherImmunegeneexpressionsignature(velocity?)PD-L1expressionTCRclonalityMutationalburdenMMRgene(microsatelliteinstability)Prognosticvspredictive?



PD-L1-ORR


Hammersetal.ASCO2014



DC

Tcellactivation

Loss/down-regulationofMHCILoss/maskingofTAAs

Failedantigenpresentation:MHC(HLA)Idownregulation

Sharmaetal.PNSA 2007,Kitamuraetal.JUrol 2007,Kitamuraetal.JUrol 2006

Bladder

RCC

InnateImmunity

CytotoxicityintheabsenceofMHC/Agcomplex

NKCells

• Rc-basedrecognitionof“abnormalcell”• Missing-self:lossofMHCI• Non-self:pathogen-encodedmolecules• Stressed-self:stress-inducedligands

• Tumorimmunesurveillance• Directtumorcellcytotoxicity

• Perforinandgranzymes-dependentnecrosis• DeathRc-mediatedapoptosis(TRAIL,FasL)

• Bridgetoadaptiveimmuneresponse• Releaseofcytokinesandchemokines• Recruitmentofotheraccessory/effectorimmunecells

RoleofNKCellsinAntitumorResponse

NKcelldepletion

T-cell depletion

NK-WTmice

NKcelldeficientbeigemice

Brandau.Int JCancer.2001,Kumanoetal.JUrol2007

BladderBCGtherapy RCCIL-21therapy

Bladder RCC

NKCellActivityBalanceofactivatingandinhibitoryRc stimulation

Vivier.Science.2011

Anti-KIR2DLmAb

Agonistic4-1BBmAb

KillercellIg-likeReceptors(KIRs):KIR2DL:InhibitoryRc

• MHCI-specificreceptors:inhibitoryvsactivating• KIR2DL (1/2/3)interactswithHLA-Callotypes• KIR3DLinteractswithHLA-AandBallotypes

• KIR/HLAinteractiondeterminestheresponsiveness• NKcellspreferentiallykillcellswithlowMHCI

Veyetal.ASCO2015AnnualMeeting

Lirirumab

CombinationofAdaptive andInnateImmunity


DC

Tcellactivation

CombinationofAdaptive andInnate ImmunityAnti-PD-1 andKIR mAB

Control

Anti-KIRmAB

Anti-PD-1mAB

Anti-PD-1mABAnti-KIRmAB

PhaseIINivolumab +Lirilumab

Pri

PrimaryEndpoint:• TumorinfiltratingCD8+T-cellatcystectomyafterSecondaryEndpoints:• Safetyandantitumorefficacy(therateof<pT2N0)• ImmunologicBiomarkersandclinicalassociation:

Peripheral/tissuelymphocytesubsets, cytokine,PD-L1,KIR2DL1/2/3expression

4-1BB(CD137):Co-stimulatoryRc:Urelumab

Vinayetal.JImmunol 2004Wilcoxetal.JImmunol 2002

PhaseIINivolumab +Urelumab

Pri

PrimaryEndpoint:• TumorinfiltratingCD8+T-cellatcystectomyafterSecondaryEndpoints:• Safetyandantitumorefficacy(therateof<pT2N0)• ImmunologicBiomarkersandclinicalassociation:

Peripheral/tissuelymphocytesubsets, cytokine,PD-L1,KIR2DL1/2/3expression

SelectiveOngoingCombinationImmunotherapyTrials

• Dualcheckpointinhibition• Anti-PD-1/PD-L1+Anti-CTLA-4• INCB24360,Indoximod (IDO1)• BMS-986016(LAG3)• MGA271(B7-H3)

• Checkpoint+costim Rc• Varlilumab (CD27)• Urelumab,PF-05082566(4-1BB)• MEDI6469(OX40)• MK-4166(GITR)

• Checkpoint+Radiation• EBRT,SBRT

• Checkpoint+chemoRx• Checkpoint+NK-cell

• ALT-803(IL-15),Lirilumab (Anti-KIR)

• Checkpoint+Epigeneticagents• Demethylating agents:5-azacitidine• HDACi:Entinostat,Vorinostat

• Checkpoint+Vaccine• GVAX,Sipuleucel-T,ProstVac,pTVG-HP

• Checkpoint+Cytokines• IL-2,IFN

• Vaccine+Cytokine• modifiedgp100peptide+IL-2• ProstVac +GM-CSF

• Checkpoint+TKIs• VEGF• BTK(Ibrutunib,ACT-196)

SelectiveOngoingCombinationImmunotherapyTrialsinGUCancers

Agent Clinical Trial Design Phase IdentifierPROSTATE

Sipuleucel-T Sipuleucel-T with concurrent vs. sequential AA Randomized PII NCT01487863Sipuleucel-T with concurrent vs. sequential Enz Randomized PII NCT01981122Sipuleucel-T ± Radium-223 Randomized PII NCT02463799Sipuleucel-T ± RT Randomized PII NCT01807065Sipuleucel-T with immediate vs. delayed ipilimumab Randomized PII NCT01804465

Prostvac-VF Rrostvac-VF ± GM-CSF vs. placebo Randomized PIII NCT01322490Enz ± Rrostvac-VF Radomized PII NCT01867333Docetaxel ± Prostvac-VF Radomized PII NCT01145508

Ipilimumab Ipilimumab + AA Single-arm PII NCT01688492Ipilimumab + ADT Single-arm PII NCT01498978

Pembrolizumab Pembrolizumab + pTVG-HP PI/II NCT02499835ADXS-PSA +/- Pembrolizumab PI/II NCT02325557

RENAL CELLCARCINOMANivolumab/Ipilimumab

Nivolumab + Ipilimumab vs. sunitinib Randomized PIII NCT02231749Nivolumab + Bevacizumab vs. Ipilimumab Randomized PII NCT02210117

MPDL3280A MPDL3280A + Bevacizumab vs. sunitinib Randomized PIII NCT02420821Pembrolizumab Pembrolizumab ± Pazopanib PI/II NCT02014636

Pembrolizumab ± Pazopanib PI NCT02133742Pembrolizumab + PegIFN-2b vs. Pembrolizumab + Ipilimumab PI/II NCT02089685Pembrolizumab + Bevacizumab PI/II NCT02348008Pembrolizumab + INCB024360 PI/II NCT02178722

DC-vaccine DC-vaccine + Cytokine-Induced Killer Cell vs. IL-2 Randomized PII NCT00862303HD IL-2 HD IL-2 + entinostat PI/II NCT01038778

HD IL-2 + Radiation Single-arm PII NCT01884961HD IL-2 + SBRT Single-arm PII NCT02306954

UROTHELIAL CARCINOMANivolumab Cabozantinib + Nivolumab ± Ipilimumab PI NCT02496208Pembrolizumab Pembrolizumab + Docetaxel or Gemcitabine PI NCT02437370

Pembrolizumab + INCB024360 PI/II NCT02178722Pembrolizumab + Gemcitabine (Neoadjuvant) PI/II NCT02365766Pembrolizumab + ACT-196 Randomized PII NCT02351739

Mix&Match?Shotgun?

• Biologicrationale• Clinicallyunmetneed• Biomarker• Noveltrialdesign

BCG-relapsing NMIBC

IDO + BCG RP2D n = 35-45

GITR + BCG RP2D n = 35-45

4-1BB + BCG RP2D n = 35-45

OX40 + BCG RP2D n = 35-45

CD27 + BCG RP2D n = 35-45

CSF1R + BCG RP2D n = 35-45

PD-1/PD-L1 + BCG RP2D n = 35-45

CTLA-4 + BCG RP2D n = 35-45

LAG3 + BCG RP2D n = 35-45

KIR2DL + BCG RP2D n = 35-45

CD40L + BCG RP2D n = 35-45

PD-1/PD-L1 + EBRT RP2D n = 35-45

PD-1/PD-L1 RP2D n = 35-45

BCG n = 35-45NMIBC -> PD-1/PD-L1

Randomize to activated arms (some arms may activate earlier than others)

REGN2810

REGN2810

REGN2810

REGN2810

Indoximod

PLX3397

Varilumab

SEA-CD40

Conclusions/FutureDirections

• ThepromisingdataofcancervaccineandcheckpointinhibitorshaveopenednewfrontiersinITforcancer• LimitationsexistwithcurrentITsuchaslowresponserateandlackofreliablebiomarkers• CombinationalapproachisexpectedtoovercomecurrentlimitationsandmaximizethebenefitofIT• NewITtrialswithsoldbiologicrationaleandnoveltrialdesignsinclinicallyunmetneedpopulationarewarranted

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