Immunterapi: En revolusjon for Kreftbehandling

Immunterapi:EnrevolusjonforKre5behandling

ElseMaritInderbergSec2onforCellularTherapy

OsloUniversityHospital-Radiumhospitalet

ImmunologiensDag2016

ImperialCollegeLondon

Immunresponsmotkre4 Hvaerimmunterapi? Li8historie Kre4vaksiner An<stoff Celleterapi Kombinasjoner

Agenda

Department of Cellular Therapy

Kre4erukontrollertcellevekstikroppenKre4cellerkanvandrefraderdeoppstårogspreseg<landrestederikroppen

Gene;skskadeNormalcelle

Kre4celler

Hvaerkre4?

Department of Cellular Therapy

Department of Cellular Therapy

Naturligimmunrespons

Dendrittcelle (DC) fanger og prosesserer fremmed materiale

1

Tc

Effektor T celle Hjelper B-celler til å produsere antistoff

Tc

Hukommelses Tc Husker antigen og kan svare raskt på nye angrep

TcRegulerende Tc produserer cytokiner som kontrollerer immunresponsen Tc

Dreper Tc Angriper og dreper fremmede celler eller patogener

DC presenterer fremmed antigen til T celle

2

Tc

Tc

Tc

Tc

3 Aktiverte T celler frigir cytokiner som stimulerer immunrespons, T-celle vekst og modning

Kre4-ogimmunforsvarssyklusen

Chen and Mellman, 2013

Department of Cellular Therapy

T-celleritumorervik;geforoverlevelse

Al-Shibli2008,Clin Cancer Res

T-cellinfiltra;onintumourmicroenvironment

Department of Cellular Therapy

Hvaerimmunterapi?Strategierforågjøreimmunforsvaretsterkereslikatdetkanbekjempekre4.

Hvorforimmunterapi?Fordiimmunsystemeterveldigspesifiktogkanutryddekre4medminimalskadepåandrenormaleceller.Immunsystemetharhukommelse

Department of Cellular Therapy

Coley’s Toxin injecting patients with a mixture of heat-killed bacteria

1890

1909

Paul Erlich Immune cells patrol the body for cancer cells

1959

BCG inhibits tumour growth in mice

1973

Dendritic cells Described by Steinman and Cohn

1957

Interferon discovered. Cytokine becomes non-specific immunotherapy

1983

T-cell receptor discovered.

1953

Immunity to tumour cells tumour antigens exist

1986

1st Humanized Antibody approved by FDA

1997

1st Monoclonal Antibody approved by FDA for lymphoma

2008

1st cancer vaccine approved in Russia: Oncophage

2010

1st cancer vaccine approved by FDA Provenge

2011

1st FDA approval of immuno- modulating Ab

1st FDA approval of anti PD-1 2014

Li8historie

Department of Cellular Therapy

Svingendeholdninger<limmunterapimotkre4

Parish,20013

1890-tallet: JA (Coley’s toxin) 1900-50: NEI (Coley’s toxin ikke veldig effektiv, toksisk, Erlich) 1950-tallet: NEI (men Burnet’s tolerance theory ) 1960-tallet: JA (Burnet’s immunosruveillance theory, tumorantigen) 1970-85: NEI (Mus uten immunsystem ikke mer kreft, autoimmunitet) 1985-95: JA ? (Tumor har mutasjoner, toleranse) 1995-2002: JA!!! (DC kan presentere Ag,

mus uten immunsystem mer kreft Medfødt immunsystem Tumor kan unngå immunsystemet

2002-2010: Ja, men skuffende effekt i klinikk Nå: JA!! Kombinasjonsterapi, biomarkører

målrettet mot mutasjoner, skreddersydd

Måliimmunterapimotkre5

•  Lage/styrkeimmunresponsermotkre4•  Kurerepasienter•  Forlengeoverlevelse•  Bedrelivskvalitet

Department of Cellular Therapy

Immunterapi

Terapeu;skevaksinerlagetforås<mulerepasientensTceller.Terapeu;skemonoklonalean;stoffmålre8etmotproteinerpåoverflatenavkre4celleneellerimmuncellene.Celleterapipasientenscellermålre8esmotentypekre4cellervedåintrodusereenreseptor.

Department of Cellular Therapy

www.pinterest.com

Sorren2no,NatureRevCancer,2002

Immuncelleriblod

Department of Cellular Therapy

Strausberg,GenomeBiology20056:211,modifiedfromSchreiber

TumourandImmuneSystemInterac<on:Immunoedi<ng

Department of Cellular Therapy

Kre4vaksiner

• Flestterapeu<ske

• Ak<vererihovedsakTceller

• Kanvirkenårdetikkeermyesykdom(<dligellervedrisikofor<lbakefall

• Kanværeeffek<vikombinasjonmedandrebehandlinger

Department of Cellular Therapy

Department of Cellular Therapy

v v

HvordanvirkerKre4vaksiner?

Telomerasevaksinerilungekre4

Brunsvig,Kyteetal2011ClinCancerRes

• Posi<vimmunresponskorrelerermedbedreoverlevelse

Department of Cellular Therapy

NobelpriseniFysiologiogMedisini2011<lRalphSteinman

"RalphM.Steinman-PhotoGallery".Nobelprize.org.1Dec2011

O’HaganandValiante2003,NatRevDrugDiscov

Dendri8cellevaksiner

Department of Cellular Therapy

Advantages-Survivalbenefitcomparedtostandardtherapy-Applicableinbroadpa<entpopula<on(dependingontarget)

Challenges

-Tumourcellsstopproducingtargetfortherapy-Tumourstoppresen<ngtargettoimmunesystem-Normallydonotcurepa<entswithveryadvanceddisease

Cancervaccines

Department of Cellular Therapy

Melanom-etøkendeproblem

CourtesyofSteinarAamdal

*Data collected using PubMed; search criteria: “melanoma clinical trial.”

US National Library of Medicine and National Institutes of Health.

Total number of clinical trial publications*: 3337

>3000Studiermellom1970-2010haddelitenkliniskeffekt

0

50

100

150

200

250

1970 1995 2005 2010

Clin

ical

Tri

al P

ub

licat

ion

s (n

)*

Publication Yr

2000 1975 1980 1985 1990

CourtesyofSteinarAamdal

Revolusjonen

Department of Cellular Therapy

FROMPUBLICHEALTHWATCH⋅JUNE4,2015

Kreftcellen unngår immunsystemet Kreftcellen kan drepes

ImmunmodulerendeAn<stoff:Ipilimumab

ImmunmodulerendeAn<stoff:Ipilimumab

Department of Cellular Therapy

• FørsteterapisomvistebedreoverlevelseimelanomstadiumIVienfaseIIIrandomisertstudie.• Bi-effekter:diaré,utsle8,fa<gueogmeralvorligesomhjerteproblemerogblødninger(steriodbehandling) Source:BMS,PharmaStrategyblog

ImmunmodulerendeAn<stoff:an<-PD-1

Ak<vertTcelleInak<vertTcelle

M. Guha, The Pharmaceutical Journal Nov 2014

Department of Cellular Therapy

Source:S.Branson,OncoLog,February2014,Vol.59,No.2

Effektavan<-PD

Pre-treatment 1cycle 3cycles

Department of Cellular Therapy

Department of Cellular Therapy

Kombinasjonermereffek<ve?

Fordeler-O4eeffek<veistørrepasientgrupper-Enkeltågi<lmangepasienter

Ulemper

-Bieffekter-Kliniskresponshosmangepasienter-Tapavmålan<gen-An<stoffdegraderes,mågisflereganger

An<stoff

Department of Cellular Therapy

CourtesyofHildeAlmåsbak

• BrukerT-cellersomkandrepe<låangripekre4celler

• Tcellermednaturligellergene<skmodifisertreak<vitetmotenpasientskre4blirlagetoggis<lbake<lpasienten

Adop<vcelleterapi(ACT)

Department of Cellular Therapy

Se8einnTcsomkangjenkjenneogdrepetumor

Cellerfrablod

Isolereimmunceller

ekspandere

endregene2sk

1millffLucNALM-6

5millCARTcellsday1

20millday21

A

Day1

Day22

Short-28 Full-28-OX NoTcells EmptyTcells

1,E+001,E+011,E+021,E+031,E+041,E+051,E+061,E+07

0 1 3 7 9 141722

coun

ts/sec/cm2

Days

short-28

full-28-OX(H)

noTcells

mockTcells

noleukemia

10millday15

5millday7

5millday4

C

B

D E

Full-28 Short-28F

Førbehandling

E8erbehandling

CART-celler Kontroll

Almåsbaketal,Genetherapy,2015

CARTcellervirkerimus

Department of Cellular Therapy

Sadelain,JCI,2015

CARmotleukemisomerresistentmotcellegi4

Department of Cellular Therapy

Novar<skliniskstudieCTL019

Aftenposten Des 2015

Inkluderte pasienter Lymphoma: 3 ALL children: 4

Department of Cellular Therapy

T-cell expansion and modification

Collect T-cells from patient

Reinfusion into patient

CART-celleterapi

Fordeler-Kliniskeresponseripasienterutenannetalterna<v-Avhengerikkeavpasientensgentype

Ulemper

-Begrensetmedangrepspunkterpåtumorcellene-Toksisitet-Inflammasjonpgastorkre4celledød

Department of Cellular Therapy

Kombinasjon-flereangrepsvinklerSynergiavimmunterapiogbådestandardognyebehandlinger:• Noentypercellegi4• Stråleterapi• Målre8etterapi(e.g.BRAFsignallinginhibitors)• Immunmodulerendean<stoff(Ipilimumab.PD-1)

Source:SciencePhotoLibrary

Dendrittcelle (DC) Aktivert DC

Opptakavdøendekre5celler

An;genprosesseringogak;veringavDC

Dreperkre5celler

T-celleak;vering

Department of Cellular Therapy

Iden<fisererik<gpasientpopulasjon

Jackson&Sood,2011NatRevClinOncol

Hvilketerapiervilvirke,ikkevirkeellerhahøyrisikoforbieffekterihvilkepasienter?Hvilketerapikombinasjonerkanovervinneresistens,bedreresponsellergibieffekter?

RESISTANCE RESPONSE RISK

Department of Cellular Therapy

Department of Cellular Therapy

Oppsummering• Immunterapiharha8drama<skeffektipasienterutenalterna<vbehandling

• Kre4vaksinerkanværeeffek<ve,men<dligisykdommenellere8erkirurgi/cellegi4medlitetumorigjen

• Chekpointinhibitors:veldigbraresultaterinoenpasienter,mentrengerkombinasjonforeffektiflere.

• T-celleterapi:utroligeffektileukemi,mensolidekre4svulsterervanskeligere.

• Potentterapikangiutroligeresultater,menogsåalvorligebivirkningersommåtestesut.

AcknowledgementsDept.ofCellularTherapyGunnarKvalheim

Sec;onforClinicalCancerResearchSteinarAamdalSec;onforCancerImmunology

GustavGaudernack

Department of Cellular Therapyv

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