immunterapi: en revolusjon for kreftbehandling
TRANSCRIPT
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Immunterapi:EnrevolusjonforKre5behandling
ElseMaritInderbergSec2onforCellularTherapy
OsloUniversityHospital-Radiumhospitalet
ImmunologiensDag2016
ImperialCollegeLondon
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Immunresponsmotkre4 Hvaerimmunterapi? Li8historie Kre4vaksiner An<stoff Celleterapi Kombinasjoner
Agenda
Department of Cellular Therapy
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Kre4erukontrollertcellevekstikroppenKre4cellerkanvandrefraderdeoppstårogspreseg<landrestederikroppen
Gene;skskadeNormalcelle
Kre4celler
Hvaerkre4?
Department of Cellular Therapy
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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
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Kre4-ogimmunforsvarssyklusen
Chen and Mellman, 2013
Department of Cellular Therapy
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T-celleritumorervik;geforoverlevelse
Al-Shibli2008,Clin Cancer Res
T-cellinfiltra;onintumourmicroenvironment
Department of Cellular Therapy
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Hvaerimmunterapi?Strategierforågjøreimmunforsvaretsterkereslikatdetkanbekjempekre4.
Hvorforimmunterapi?Fordiimmunsystemeterveldigspesifiktogkanutryddekre4medminimalskadepåandrenormaleceller.Immunsystemetharhukommelse
Department of Cellular Therapy
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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
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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
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Måliimmunterapimotkre5
• Lage/styrkeimmunresponsermotkre4• Kurerepasienter• Forlengeoverlevelse• Bedrelivskvalitet
Department of Cellular Therapy
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Immunterapi
Terapeu;skevaksinerlagetforås<mulerepasientensTceller.Terapeu;skemonoklonalean;stoffmålre8etmotproteinerpåoverflatenavkre4celleneellerimmuncellene.Celleterapipasientenscellermålre8esmotentypekre4cellervedåintrodusereenreseptor.
Department of Cellular Therapy
www.pinterest.com
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Sorren2no,NatureRevCancer,2002
Immuncelleriblod
Department of Cellular Therapy
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Strausberg,GenomeBiology20056:211,modifiedfromSchreiber
TumourandImmuneSystemInterac<on:Immunoedi<ng
Department of Cellular Therapy
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Kre4vaksiner
• Flestterapeu<ske
• Ak<vererihovedsakTceller
• Kanvirkenårdetikkeermyesykdom(<dligellervedrisikofor<lbakefall
• Kanværeeffek<vikombinasjonmedandrebehandlinger
Department of Cellular Therapy
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Department of Cellular Therapy
v v
HvordanvirkerKre4vaksiner?
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Telomerasevaksinerilungekre4
Brunsvig,Kyteetal2011ClinCancerRes
• Posi<vimmunresponskorrelerermedbedreoverlevelse
Department of Cellular Therapy
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NobelpriseniFysiologiogMedisini2011<lRalphSteinman
"RalphM.Steinman-PhotoGallery".Nobelprize.org.1Dec2011
O’HaganandValiante2003,NatRevDrugDiscov
Dendri8cellevaksiner
Department of Cellular Therapy
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Advantages-Survivalbenefitcomparedtostandardtherapy-Applicableinbroadpa<entpopula<on(dependingontarget)
Challenges
-Tumourcellsstopproducingtargetfortherapy-Tumourstoppresen<ngtargettoimmunesystem-Normallydonotcurepa<entswithveryadvanceddisease
Cancervaccines
Department of Cellular Therapy
Melanom-etøkendeproblem
CourtesyofSteinarAamdal
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*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
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Revolusjonen
Department of Cellular Therapy
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FROMPUBLICHEALTHWATCH⋅JUNE4,2015
Kreftcellen unngår immunsystemet Kreftcellen kan drepes
ImmunmodulerendeAn<stoff:Ipilimumab
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ImmunmodulerendeAn<stoff:Ipilimumab
Department of Cellular Therapy
• FørsteterapisomvistebedreoverlevelseimelanomstadiumIVienfaseIIIrandomisertstudie.• Bi-effekter:diaré,utsle8,fa<gueogmeralvorligesomhjerteproblemerogblødninger(steriodbehandling) Source:BMS,PharmaStrategyblog
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ImmunmodulerendeAn<stoff:an<-PD-1
Ak<vertTcelleInak<vertTcelle
M. Guha, The Pharmaceutical Journal Nov 2014
Department of Cellular Therapy
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Source:S.Branson,OncoLog,February2014,Vol.59,No.2
Effektavan<-PD
Pre-treatment 1cycle 3cycles
Department of Cellular Therapy
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Department of Cellular Therapy
Kombinasjonermereffek<ve?
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Fordeler-O4eeffek<veistørrepasientgrupper-Enkeltågi<lmangepasienter
Ulemper
-Bieffekter-Kliniskresponshosmangepasienter-Tapavmålan<gen-An<stoffdegraderes,mågisflereganger
An<stoff
Department of Cellular Therapy
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CourtesyofHildeAlmåsbak
• BrukerT-cellersomkandrepe<låangripekre4celler
• Tcellermednaturligellergene<skmodifisertreak<vitetmotenpasientskre4blirlagetoggis<lbake<lpasienten
Adop<vcelleterapi(ACT)
Department of Cellular Therapy
Se8einnTcsomkangjenkjenneogdrepetumor
Cellerfrablod
Isolereimmunceller
ekspandere
endregene2sk
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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
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Sadelain,JCI,2015
CARmotleukemisomerresistentmotcellegi4
Department of Cellular Therapy
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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
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CART-celleterapi
Fordeler-Kliniskeresponseripasienterutenannetalterna<v-Avhengerikkeavpasientensgentype
Ulemper
-Begrensetmedangrepspunkterpåtumorcellene-Toksisitet-Inflammasjonpgastorkre4celledød
Department of Cellular Therapy
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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
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Iden<fisererik<gpasientpopulasjon
Jackson&Sood,2011NatRevClinOncol
Hvilketerapiervilvirke,ikkevirkeellerhahøyrisikoforbieffekterihvilkepasienter?Hvilketerapikombinasjonerkanovervinneresistens,bedreresponsellergibieffekter?
RESISTANCE RESPONSE RISK
Department of Cellular Therapy
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Department of Cellular Therapy
Oppsummering• Immunterapiharha8drama<skeffektipasienterutenalterna<vbehandling
• Kre4vaksinerkanværeeffek<ve,men<dligisykdommenellere8erkirurgi/cellegi4medlitetumorigjen
• Chekpointinhibitors:veldigbraresultaterinoenpasienter,mentrengerkombinasjonforeffektiflere.
• T-celleterapi:utroligeffektileukemi,mensolidekre4svulsterervanskeligere.
• Potentterapikangiutroligeresultater,menogsåalvorligebivirkningersommåtestesut.
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AcknowledgementsDept.ofCellularTherapyGunnarKvalheim
Sec;onforClinicalCancerResearchSteinarAamdalSec;onforCancerImmunology
GustavGaudernack
Department of Cellular Therapyv
Kreftforeningen