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
Kreftforeningen