美羅華在淋巴瘤治療中的應(yīng)用課件

Lymphoma:

A

DecadeofRituximab

and

the

Next

Chapter1Wenru

Song,

MD,

PhDPfizer

Global

Research

&

Development-Oncology&Baylor

Institute

for

Immunology

Research.Outline2Historical

perspective

&

reflections

inRituximab’s

developmentImpact

of

Rituximab-Lymphoma-Rheumatoid

arthristis,

lupus,

and

other

autoimmunediseases-Other

solid

tumorsNew

emerging

therapies

in

lymphoma.Monoclonal

Antibodies

from

Hybridoma

TechnologyAntigenCells

Fuse

into

aHybridomaCancerousPlasma

CellAntibody-producingPlasma

CellMonoclonal

AntibodiesGeorges

Kohler

and

CesarMilstein

(1975)

in

Nature.Monoclonal

antibodies

areartificially

produced

against

aspecific

antigen.Production

of

monoclonalantibodies

(mAbs)

withhybridoma

technique.With

this

technique

a

group

oflymphocytes

producing

all

thesame

antibody

proteinisobtained.

revolutionizing

diagnosticmedicine.

Mabs

against

cancer,infections,

and

other

diseases..3History

of

Monoclonal

Antibody

(Mab)

TherapyMurineMab*Ibritomomab*tositumomabHumanized*trastuzumab*bevacizumab*TheraCIMChimeric*Cetuximab*rituximab*131I

-Ch-TNTHuman*panitumumabCH1CH2CH3VHCLVLCDR1975:1980’s-90’s:1997:1998:First

murine

Mab

from

hybridoma

(Kohler

and

Milstein,

Nature)Humanization

of

murine

Mabs

(chimeric

Mab)1st

Mab

for

cancer

immunotherapy:

RituximabFully

human

Mab: -XenoMouse

(Abgenix),

HuMab-mouse

(Medarex)or

Phage

scFv

library

1997-

2007: 11

Mabs

approvedfor

use

in

cancer

by

US

FDA.4FDA

Approved

Monoclonal

Antibodies.YEARProductTargetIndication1986OrthocloneCD3Transplant

Rejection1994ReoProGPIIa/IIIbAngioplasty1997RituxanCD20B

CellLymphoma1998ZenapaxIL2RTransplant

Rejection1998SimulectIL2RTransplant

Rejection1998RemicadeTNFCrohn’s,

RA1998HerceptinHer2Breast

Cancer2000MylotargCD33AML2001CampathCD52CLL2002ZevalinCD20B

CellLymphoma2003BexxarCD20B

CellLymphoma2003RaptivaCD11aPsoriasis2004AvastinVEGFColon

Cancer2004ErbituxEGFRColon

Cancer2004Tysabriα4β1

integrinMultiple

sclerosis2006LucentisVEGF-AMacular

degeneration2006VectibixEGFRColon

Cancer

52007SolirisC5PNHThe

“Ups

&

Downs”

of

MonoclonalAntibody(mAb)

Development“Hey,

these

aremagic

bullets”“mAbs

should

beeven

in

soup”“I

heard

thereare

someproblems”“I’d

applythemonly

to

myenemies”“mAbs

work

insome

cases!”First

mAbproduced1975Success

inlymphoma1982OKT3approved1986LillypurchaseHybritech($350m)Wellcome

dropsCampathGeneticengineering.Panorex

&ReoPro

app.

Rituximab1994

6

1997Jesus

Gomez-Navarro5th

most

common

cancer

in

both

men

and

women

in

USHodgkin’s

lymphoma

and

Non-Hodgkin’s

Lymphoma

(NHL)Incidence

increases

3-4%

annually

(doubled

in

last

2

decades),

one

of

only

twocancers

with

continued

increaseManysub-types

of

NHL,

majority

with

B-cellorigin-Diffuse

large

B

cell

lymphoma

(DLBCL):

most

common

NHL(30%)-Follicular

lymphoma

(FL):

2nd

most

common

NHL(20%)-Mantle

cell

lymphoma

(MCL):

poorest

prognosis

(6-10%)Leading

the

oncology

field

in

disease

biology,

diagnosis,

and

therapy(radiation,chemo,

immunotherapy,

chemo-immunotherapy)Lymphoma.7Rituximab

(Rituxan,

MabThera).Targeted

therapy-CD20

on

lymphoma-direct

tumor

killing

by

RituximabImmunotherapy-host

immune

system-indirect

tumor

killing

by

host

immune

cells8Natural

Killler

CellsMonocytesFcR1)

Apoptosis,Anti-proliferation 2)Complement-mediated

Killing3)

Antibody-dependentCellularCytotoxicity

(ADCC)Tumor

CellFcRDendritic

CellsRituximab

Anti-tumor

Effect:

Proposed

MechanismsCD20

orother

tumor

AgsT

Cells.4)

Antigen

PresentationandCross-priming

9Vaccine-like

effectafter

Rituximab

TreatmentFcRDendritic

Cells*

In

vivo:

longer

duration

of

remission

after

re-treatmentwith

Rituxan

than

the

initial

Rituxan

treatment*In

vitro:

enhanced

cross-priming

of

cytoxic

T

cells

byRituxan-induced

apopotic

tumorcellsT

CellsTumor.101st

FDA-approved

therapeutic

antibody

to

treat

cancer

(11/1997)1st

fully

integrated

into

chemo-immunotherapy

(R-chemo)1st

and

only

biologic

therapy

in

combination

with

chemo

(R-CVP,etc)that

improvedprogress-free

survival

(PFS)

in

pts

with

1st

linefollicularlymphoma,

with

emerging

trend

to

improve

overall

survival

for

the

1st

time1st

treatment

of

any

kind

(with

CHOP

oranthracycline-based

chemo)

tohave

improved

overall

survival

(OS)

in

1st

line

DLBCL

in

more

than

25

yrs11Rituximab

(Rituxan,

MabThera):

Ahistory

of

firsts.Chimeric

mab

to

CD20,IgG1Weekly

x

4

(375mg/m2):

Rapid

CD20+B

cell

depletion

in

blood

(100%-few

days),

BM

(90%-1wk),

and

LN

(80%-

a

few

wks),

returnnormallevel

in9-12monthsOnset

and

maximal

clinical

response:

1mt

and

3-4

mtsInitial

Rx

in

relapsed

FL:

50%

ORR

(6%CR;

44%PR);

mDR

11mt;Re-Rx:

ORR

40%

(10%CR/30%PR);

mDR

15mtMaintenance

Rx:

Qwk

X4

every

6

mt

or

Q3mt

for

2

yrsNo

change

of

serum

Ig

and

incidence

of

infection,

and

the

T

cellresponse

from

vaccination

is

stillOK12Rituximab

(Rituxan,

MabThera):

Facts.LymphomaB

cellTwo

lines

of

Monoclonal

Antibody

TherapyDevelopment

For

LymphomaRituximabCD20Anti-idiotype

(Id)

antibodyTumor

Idiotype

(Id).13New

England

Journal

of

Medicine,

306:517.

1982Treatment

of

B

Cell

Lymphomawith

Monoclonal

Anti-Idiotype

AntibodyRichard

A

Miller,

David

G.

Maloney,

Roger

Warnke,

and

Ronald

Levy14Cancer

Res.

1980;40:3147Serotherapy

of

a

patient

with

a

monoclonal

antibody(murineanti-human

CD20Mab)directed

against

ahuman

lymphoma-associatedantigenLee

Nadler,

et

al.Antibodies:

a

slow

breakthrough

of

a

new

technology2006

Panitumumab

(Vectibix)19751984198619901994Technologies

toreduceimmunogenicity

ofmonoclonalantibodies:technologicalevolution

towardshumanization,human

antibodiesinnovation biography

of

drugsChristian

Zeller.151976 1978,

1985,198612/1992

03/19931995

03/9611/97,

06/982006INDfromIDEC1st

ptInP1Levylast

ptInP3FDAEMEA1st

line;R-chemo;maintenanceTimeline

of

Rituximab

DevelopmentIDEC

&Genentech/RocheCo-developHybritechIDECBiotherapySystemLevy/MillerGenentechBoyer/CohenCD20geneIn

1980NadlerIDEC.16Development

of

IDEC’s

Stock

PricesPhase

I

trial

doneIDEC

&

Genentech Co-developFDAapproval.17Christian

ZellerPhase

I:

1993-94-single

dose:

10,

50,

100,

250,

500

mg/m2,

No

MTD-15

pts:

2

PR

(100,

500

mg/m2)-Maloney

DG,

Blood

84:2457,1994Phase

I:

1994-95-multiple

dose

(weekly

x

4):

125,

250,

375

mg/m2,

No

MTD-20

pts:

6

PRs

(1/3

in

125,

2/6

in

250,

3/9

in

375),ORR=33%-Maloney

DG,

J

Clin

Onc

15:3266,

1997Phase

II:

1995-96-Fixed

dose

(375

mg/m2),

weekly

x4

(determined

by

the

availableMab)-37

pts:

3

CR/14PR

(ORR=46%),

mTTP

10.2

months-Maloney

DG,

Blood

90:2188,1997Phase

II/III

Pivotal

trial:

1995-96Early

clinical

development

of

Rituximab.18Rituximab

Pivotal

Phase

II/IIITrial:Clinical

Response

in

Relapsed

Indolent

orFollicular

LymphomaMcLaughlin

et

al.J

Clin

Oncol.

1998..19OutlineHistorical

perspective

in

Rituximab’s

developmentImpact

of

Rituximab-Lymphoma-Rheumatoid

arthritis,

lupus,

and

other

autoimmunediseases-Other

solid

tumorsNew

emerging

therapies

in

lymphoma.20Randomized

Trials

of

Chemotherapy

plus

Rituximab

versus

ChemotherapyAlone

in

B-Cell

Lymphoma.21Cheson

B,

Leonard

J.

N

Engl

J

Med

2008;

359:613Randomized

Trials

of

Maintenance

Treatment

withRituximab

versus

Observation22Cheson

B,

Leonard

J.

N

Engl

J

Med

2008;359:613-626.Extended

Uses

of

Rituximab:

Integrationinto

Lymphoma

Standard

ofCare23Salvage

therapy

for

chemo-refractoryorrelapsed:

lowgradeUp-front

therapyDelay

or

avoid

chemotherapy—low

gradeCombination

therapyWith

chemotherapyWith

other

biologicals-

enhance

ADCCWith

other

monoclonalsMaintenance

therapy.Mortality

Rates

of

Non-Hodgkin’s

Lymphoma24.25Rituximab

PublicationsNumber

of

publicationsPublications1st

clinical

trial200180160140120100806040200Jan/91

92Year93

9495

96

97

98FDA99

00Pivotalapproval

trial

results-1

million

ptsworldwidebeing

treated4378in2008.Rituxan

/

MabThera:

ablockbusterChristian

Zeller.26Top

5

Best

Selling

Oncology

Drugs

in

2007RankOncologyProductCompany2007WWRevenue($M)OncologyIndications1RituxanGenentech/Biogen-IDEC$3,820NHL2HerceptinGenentech$3,356BC3AvastinGenentech$2,880NSCLC,

CRC,BC4GleevecNovartis$2,737CML,

GIST,ALL5EloxatinSanofi

Aventis$2,456CRCPfizer-Oncology.27Approved

MAbs

for

Cancer

Therapy.TargetNameTumorYearFormatHer-2Trastuzumab

(Herceptin)Breast1998Humanized

IgG1VEGFBevacizumab

(Avastin)Colon,

NSCLC,Breast2004Humanized

IgG1EGFRCetuximab

(Erbitux)Colon,

H/N2004chimeric

IgG1Panitumumab

(Vectibix)Colon2006Fully

humanIgG2Nimotuzumab*

(TheraCMI)Nasopharyngel2005Humanized

IgG1DAN-associated131I

-Ch-TNT*Lung2003Chemiric,

131ICD20RituximabNHL1997Chimeric

IgG1CD52Alemtuzumab

(Campath-1H)CLL2001Humanized

IgG1CD33Gemtuzumab

(Myelotarg)AML2000Humanized

IgM-calichamy28cinCD20Ibritumomab

(Zevalin)NHL*F20ir0st2appMrouvreindein90CYh-IignGa

1OutlineHistorical

perspective

in

Rituximab’s

developmentImpact

ofRituximab-Lymphoma-Rheumatoid

arthristis,

lupus,

and

other

autoimmune

diseases-Other

solid

tumorsNew

emerging

therapies

in

lymphoma

(phase

I-III

trials)-human

or

humanized

anti-CD20:enhanced

ADCC,

CDC-Other

new

targets:

CD22,

CD40,

CD80,

mTOR,

HDAC,Revlimid,

Avastin,

Velcade,PKC-b,

TRAIL,Bcl-2,CTLA-4-Rituxan-based

combinational

Bio-Rx-In

situ

vaccines

(dendritic

cells,

CpG).29Unconjugated

Monoclonal

Antibodies

for

B-Cell

Cancers.30Cheson

B,

Leonard

J.

N

Engl

J

Med

2008;359:613-626Drug/SponsorDesignPhaseLine

of

TherapyGaliximab

(CD80)(Biogen)Galiximab

+Rituxan

(R)vs

Rituxan

(R)IIIRelapsed

or

refractory

FLVelcade(Millennium/JJ)Velcade

+

RituxanvsRituxanIIIRelpased

or

refractory

FLSGN-40

(CD40)(SG/Genentech)SGN-40

(CD40)+RituxanIRelapsed

FL

and

maginal

zone

NHLSGN-40(SG/Genentech)SGN-40+

R-chemovs

R-chemoIIRelapsed

DLBCLRevlimid(Celgene)Revlimid

+

RituxanIIRelapsed

or

refractory

FLOfatumumab(2nd

generation

RituxanGSK/GeneMab)Ofatumumabvs

RituxanIIIRelapsed

or

refractory

FLEpratuzumab(CD22)(Immunomedics/CALGB)Epratuzumab

+RituxanII1st

line

FLInvestigational

Combination

BioRx

for

B-Cell

Cancers.31Most

potent“antigen-presenting

cells”Reside

in

tissues

to

collect

antigen

->

travel

to

lymph

nodesCo-culture

with

antigens

->

cellular

vaccineDendritic

Cells.32In

situ

Vaccination

withDCChemo+DC15/15Chemo+

DCChemo0/8No

Rx

0/9DC

0/7Mean

Tumor

SizeDays

post

tumor

implantationSong

&

LevyCan

Res

2005.33Dendritic

CellsIntratumoral

DC

Vaccination+

Conventional

TherapyIntratumorInjectionChemotherapyOrRadiotherapy

21Leukapheresis3.US

FDA

approvd

three

InvestigationalNew

Drug

(INDs)

Applications:-Colon

cancer

with

hepatic

metasteses

(phaseI;Stanford)-Locally

advanced

pancreatic

cancer

(phaseI/II;

Stanford)-Lymphoma

and

other

solid

tumors

(phase

I/II;Baylor)Intratumoral

DC

Vaccination

+Conventional

Therapy:From

Lab

to

Clinic.35CpG

bridges

innate

and

adaptive

immunityBacterial

DNAACGTTGAGTTCGTACGCATACGAVertebrate

DNAAGCTTGAGTCmCGGATGGGTAAGAImmune

system

recognizes

CpG

through

TLR-9

andinduces

activation

of

DC,

B

&

T

cellsTumor-specific

T

CellsCpGTLR-9Dendritic

CellTLR-9B

CellTumor.CpG

Only

WorksIntra-Tumorally.37Li

J,

Song

W,

et

al.,

J

Immunol.2007,179:2493In

situ

Vaccination

with

CpGRadiationCpG.Pre-treatmentWeek

1263

yo

male

with

recurrentfollicularlymphoma:

partial

response.ASCO

2309

08US

Oncology

Growth

Market

Projections.40.41Acknowledgement42Stanford

University

Medical

Center-Ronald

Levy-Edgar

Engleman

Baylor

Institute

for

Immunology

Research

&Baylor

Sammons

Cancer

Center-Jacques

Banchereau,

Steve

Paulson-Marylene

Leogier,

Jingtao

Chen,

Licun

Wu,

ZhiqingWang$

Baylor

University

Healthcare

System

Foundation$

US

National

Cancer

Institute/NIHPfizer

Oncology:

JesusGomez-Navarro.Questions??43.44.Function:B

cellTwo

Arms

of

the

Immune

SystemB

cells

(Humoral)

T

cells

(Cellular)antibodyMakeantibodiesKill

abnormal

cellsforeignsubstance(antigen)T

cellAbnormalcell.45Antibody

Structure46.The

Immune

System

is

amixtureof

ClonesEach

B

cell

can

make

only

oneantibodyEach

T

cell

can

make

only

one

T

cellreceptor.V/VV/FF/FF

Carriers8/1012/289/2321/51(80%)(43%)(39%)(41%)p=0.037Weng

and

Levy

J

Clin

Onc

2003RituximabClinical

Response

Determined

by

Host

GeneticsFcgRIIIA 158

V/F

polymorphism.487-Year

Results

of GELA

Study

(LNH-98.5)Primary

end

point:

EFSSecondary

end

points:

PFS,

OS,

DFS,

and

RRASSESSUntreatedelderlypatients

withDLBCLstratified

byrisk

factors(0-1

vs2-3)(N=399)RANDOMIZER-CHOPq3w

×

8

(n=202)CHOPq3w

×

8

(n=197).49Coiffier

et

al.

ASCO

2007.

Abstract

8009.0.00.20.40.60.81.0P<0.00010

1

2

3

4

5

6

7

8YearsSurvival

ProbabilityR-CHOP

52CHOP

29PFS

(%)7-Year

Results

of GELA

Study

(LNH-98.5)0.00.20.40.60.81.0Survival

ProbabilityP=0.00040

1

2

3

4

5

6

7

8YearsR-CHOP

53CHOP

3650Coiffier

et

al.

ASCO

2007.

Abstract

8009.

OS

(%).Tumor

Idiotype(Id)

ProteinImmunizationKLHcarrier

proteinIdAdjuvant

(SAF)123A

Therapeutic

Vaccine

for

Lymphoma“Rescue

hybridization”Myeloma

cell+