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¿Cómo va a modificar la Inmuno-oncología, el panorama terapéutico
del cáncer?
José Antonio López Martín
HU 12 Octubre. Madrid
1890 !e""ie #a"$iel % el #r Cole%
?
1891 &ola
1953
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1953
Cole% v" '(ing
? ) *oc+efeller r
ué $emo" aprendido?
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1.-'l cáncer e" má" /ue un conunto decélula" tumorale"
.- 2a re"pue"ta inmune efectiva contrael cáncer e" de tipo celular
3.- 2a re"pue"ta inmune antitumoral tiene varia"
fa"e" potencialmente modula4le"
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1 - 5-cell activation - 5-cell proliferation
3 - Infiltration of tumour "ite 6 - 5umour cell de"truction
5-cell
7C
5-cell"
#e"tro%ed tumour cell"
5-cell"
T-cells
5umour
6.- Caracterí"tica" de una inmunoterapiaefectiva contra el cáncer
.- 'l tumor puede generar "upre"ión de lare"pue"ta inmune
:odulación de la re"pue"ta inmune
contra el cáncer
;<acuna"=
5ran"ferenciaCelular pa"iva
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:odulación de la re"pue"ta inmunecontra el cáncer
;<acuna"=
!C> en carcinoma urotelial 51
Cochrane Rev 2000
:ifamurtida en "teo"arcoma
• Muramiltripéptido
fosfatidil-etanolamin(M!-
!"#$ es un an%lo&o lipof'lico
del muramil dipéptido$
componente de la pared de
la C)*
• M!-!" se encapsula en
liposomas$ lo +ue favorece
la captaci,n por monocitos
macr,fa&os*
Meers.C 200
R 0*1
5 C 0*52 to 0*6
! 0*03
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2o" receptore" de reconocimiento depatógeno" "on "en"ore" de e"tré" % peligro
2o" receptore" de reconocimiento depatógeno" "on "en"ore" de e"tré" % peligro
5umour-a""ociated 7ntigen" @577"A
2o( tumour "pecificit%
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5umour-"pecific 7ntigen" @5B7"Aig$ tumour "pecificit%
:7>'-73 in re"ected DBC2C eEpre""ingt$e 7g @$A
7ansteen8iste .C 2013
:7>'-73 predictive "ignature
9lloa-Montoa .C 2013
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<acuna" antitumorale" comentario"
• Inducen reacción inmune contra la acuna.. !contra eltumor"
• La acuna puede #enerar una respuesta inmunee$ectia% pero el estroma supresor la e&tin#ue
• 'l sistema inmune reconoce sobre todo (neo)anti#enos*secundarios a mutacioneso +ic,os antí#enos deben ser personalizadoso Las acunas idealmente deben implicar tumor autólo#o
• La ma-oría de los tumores inmuno#énicos son
(autoacunas*. 'l problema es la supresión de larespuesta inmune
• Conclu"ión 2a" vacuna" "ola" no tendrán un papelrelevante "i no "e le" a"ocia otro" fármaco" /uecontrolen lo" mecani"mo" reguladore" de la re"pue"tainmune
Bipuleucel 5
<acuna de célula" dendrítica" autóloga"activada" % pre"entadora" de 7
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Bipuleucel-5 en cáncer de pró"tataBupervivencia en e"tudio I:7C5 fa"e 3
:antoff !;$ et al* < "n&l . Med* 2010=363>411-422*
0
25
50
75
100
0 6 12 18 24 30 36 42 48 54 60 66
Survival (Months)
P e r c e n t S u r v i v a l
Placebo (n= 171)Median Survival: 21.7 Mos.
Sipuleucel-T (n= 341)
Median Survival: 25.8 Mos.
P = 0.02 (Cox model)HR = 0.78 [95% Cl: 0.61-0.98)
Median Survival Benefit = 4.1 Mos.
ro"t<acF poEviru" modificado
0
40
60
80
100
0 12 24 60
Time (Months)
o v e r a l l S u r v i v a l ( )
!a"ar# $atio % 0&56 (95 ' 0&3* to 0&85)
20
'ontrol
+$,ST.'
40
82
3*
6516&6
25&1
/ eaths Me#ian
36 48
verall Burvival
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• )7?@> 2 irradiated$ )M-CABsecretin&
allo&eneic !D?cell lines
• 24 h after treatment Eith loE-dose C@
• )7?@ induces cells a&ainst a Froad
arra of !D? anti&ens$ and mesothelin-
specific -cellresponses
• CRA-20> recomFinant live-attenuated$
douFle-deleted Listeria monocytogenes
en&ineered to secrete mesothelininto
the ctosol of infected anti&en
presentation cells*
*epertorio de neoantígeno" encáncere" $umano"
Achumacher Acience 2015* ?leGandrov<ature 2013
:uerte inmunogénica % cáncer
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ru n#ications
Cyclophosphamide
?HH$ ?MH$ Freast cancer$ CHH$ CMH$ lupusnephritis$ lmphoma$ multiple meloma$
mcosis fun&oides$ neuroFlastoma$ nephrotic
sndrome$ ovarian cancer$ retinoFlastoma*
Doxorubicin
?HH$ ?MH$ Freast cancer$ Froncho&enic
carcinoma$ cervical carcinoma$ &astric
carcinoma$ &erm cell tumors$ hepatic
carcinoma$ <C$ lmphoma$ mesothelioma$
multiple meloma$ neuroFlastoma$ ovarian
carcinoma$ pancreatic carcinoma$ prostate
cancer$ ACHC$ soft tissue and Fone sarcomas$
throidcarcinoma$ transitional cell Fladder
carcinoma$ uterine carcinoma$ ;ilmsI tumor*
Oxaliplatin Metastaticcolorectal cancer$ ovarian cancer*
Mitoxantrone?cute leu8emia$ Freast cancer$ <H$ multiple
sclerosis$ prostate cancer*
Vacchelli et al, Oncoimmunology,2012
:uerte inmunogénica % antineoplá"ico"
ABSCOPAL, from the latin“ab scopus”, away from the target.
MOLE, RH BR. J. RADIOL 1953 :26 (305):234-241
:uerte inmunogénica % radioterapia
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5alimogene 2a$erparepvecInmuno-viroterapia oncolítica
ecto local
lisis tumoral #irecta
ecto sistmico
$esuestainmune esec7ica#e tumor
Replicaci,n viral selectivaenteJidotumoral
Hisisde células tumorales
!resentaci,n anti&énica e
inducci,nde una
respuesta inmune
Muertecelular a distancia
1* 7ar&hese A$ et al* Cancer Gene Ther * 2002=>6-*2* aE8ins H:$ et al* Lancet Oncol * 2002=3>1-26* 3* Bu8uhara$ et al*CurrCancer Drug Targets*
200=>14-155* 4* AoFol!$ et al* * Mol Ther * 2011=1>335-344* 5* Hiu H$ et al* Gene Ther * 2003=10>22-303* 6* Melcher ?$ et al* Mol Ther * 2011=1>100-
1016* * Ba&oa&aR n> Mc!herson R?$ !incusMR$ eds* enrKs Clinical Dia&nosis and Mana&ement F HaForator Methods$ 22nd ed* !hiladelphia$ !?>
"lsevier= 2011>33-53** Dranoff)* Oncogene* 2003=22>31-312*
Liu T-C et al. (2007) Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progressNat ClinPractOncol 4: 101–117 doi:10.1038/ncponc0736
• Bluming AZ and Ziegler JL (1971)Regression of Burkitt's lymphoma inassociation with measles infection.Lancet 2: 105–106.
• Hansen RM and Libnoch JA (1978)Remission of chronic lymphocyticleukemia after smallpox vaccination.Arch Intern Med 138: 1137–1138.
• Kawa A and Arakawa S (1987) The effectof attenuated vaccinia virus AS strainon multiple myeloma: a case report.Jpn J Exp Med 57: 79–81.
5umor re"pon"e" follo(ing incidental viralinfection, vaccination or treatment (it$
non-engineered viru" "train"
3 months
6 months
$esonse in the liver uninecte#
'Eample" of *e"pon"e" Been Git$
5alimogene 2a$erparepvec
1 AenLer<<$ et al* J ClinOncol. 200=2>563-51*
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'"tudio 5i: con 5-<'C en :elanoma"upervivencia
Survival,%
T- Vec G M- CSF D if fer ence ,% (95% CI)
12 mos 73.7 69.1 4.6 (-4.7 to 13.8)
24 mos 49.8 40.3 9.5 (-0.5 to 19.6)
36 mos 38.6 30.1 8.5 (-1.2 to 18.1)
48 mos 32.6 21.3 11.3 (1.0 to 21.5)
Events/N (%)Median (95% CI)
in Mos
-7ec 1 /2 5 (6 4# 23*3 (1* 5-2 *6#
) M- CA B 1 01 /1 41 (2 # 1 * (1 6* 0- 23 * #
R> 0* (5 C> 0*62-1*00=
unadJusted lo&-ran8 P *051#
Kaufman HL, et al. ASCO 2014. Abstract 9008a.
100
80
60
40
20
0
O S , %
600 10 15 205 25 30 35 40 45 50 55
Months
:odulación de la re"pue"ta inmunecontra el cáncer
Clinical activit% of I2-1 @p$a"e 1A
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:odulación de la re"pue"ta inmunecontra el cáncer
5ran"ferenciaCelular pa"iva
RoFFins !B$ et al* <at Med* 2013=1>4-52*
+ r o 6
o r t i o n S u r v i v i n 1
1*0
0*
0*
0*
0*6
0*5
0*4
0*3
0*2
0*1
0*0
Survival Time (Mos)
1020 6 12 1 24 30 36 42 4 54 60 66 2 4 0 6
+$ (n%32)
/$ (n%41)
'$ (n%20)
Initial eEperience (it$ 5I2 trial"from 1988 5I2 (it$ $ig$-do"e I2-
6t$ generation 7C5 t$erapie"
5cell engineering
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Schuster et al. ASH 2014, Abstract 3087.
scFv = anti-CD19
4-1BB +TCR ζ
signaling domains
:odificación genética de célula" 5
Retrovirusor
Lentivirus
C$imeric 7ntigen *eceptor @C7*A 5-cell"
( apte rom u e; nney; awson,
Alta afinidad para el Antígeno
Independiente de MHC
No restringidos a secuencias
peptídicas derivadas del Ag
Válido para varios haplotipos
HLA
No necesita TILs
Evita autotolerancia
<entaa" de la" célula" 5-C7*
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*e"ultado" con célula" 5-C7* C#19
I ns ti tut io n D is ea se N um be r o fpatients
Responses Ref.
COH FL 2 none Jensen et al. BBMT 2010
Baylor Indolent
lymphomas
6 2 SD Saoldo et al. JCI 2011
!CI FL" CLL # 1 C$" 2 SD" % &$ 'o(hender)er et al." Blood 2010" 2011
MS'CC CLL" 1 *LL + , SD" 1 &$ Brent-ens et al." Blood 2011
MS'CC *LL 16 ## C$ Brent-ens et al." S(/ TM 201,
Da/la et al." S(/TM 201
&enn CLL , 2 C$" 1 &$ &orter et al." !JM 2011"
'alos et al." S(/ TM 2011
&enn *LL 2 2 C$ 3M$D45 r7pp et al." !JM 201,
!CI CLL"
lymphoma
10 1 C$" 2 &$ 'o(hender)er et al." Blood 201,
Baylor *LL" CLL # 2 o) 6 &$" 2 8 C$ Cr79 et al." Blood 201,
64 + ASH 2013: Man more !omin" up soon
5oEicidad On-target de célula" 5 -C#19-C7*7pla"ia prolongada de célula" !
Kochenderer et al.! "lood #$%#
Bíndrome de li4eración de Cito/uina"
?lta car&a tumoral
nicio tard'o (hasta el d'a35#
uena respuesta a m?F anti H-6
Porter et al.! &'JM #$%%
AteroidsociliLumaF
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tra" célula" 5 C7* en de"arrollo
Taret '.$ 'ancer ,:ectiveresonse
CD20 C?R>CD13-CD2-
CD3ζ<H <3> 1!R$ 2<"D
C"? C?R-CD3ζ (1st &en# Colorectal N
Freast
<> minor
responses in tEo
patients
)D2 C?R-CD3ζ (1st &en# <euroFlastoma <1> 3CR
"R2 C?R>CD2-CD13-
CD3ζColorectal
cancer
<1$ patient died
:ershaE et* al* 2013 <ature RevieEs cancer
:odulación de la re"pue"ta inmunecontra el cáncer
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Melero … Ascierto.
Clin Cancer Res 2013
Tarets o anti:o#; immune mo#ulators&
D !a&e* ?nnu* Rev* Med* 2014* 65>15202
The c;toto<ic T l;mhoc;teassociate# antien
4 ('T=.-4) immunoloic chec>oint&
M? !ostoE* !uFlished online ahead of print at EEE*Jco*or& on .anuar 20$ 2015
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55
'T=.-4 .ntaonistic m.:s in 'linical eveloment
:elanoma "upervivencia
()
O !ooled analsis on 446 patientes treated Eith pilimumaF in clinical trials
or in the eGpanded acces pro&ram
2o" re"pondedore" a Ipilimuma4 mue"tran un perfil de
eEpre"ión génica del tipo ;inflamación citotóEica=
Ji et al, 2011.
CXCL9, 10, 11
CCL4, CCL5
Granzima B
Perforina
CD8a
No Beneficio Beneficio
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n-der A et al. / 'n#l J Med 20134152167)2177.
Mutational =an#scae o Tumors .ccor#in to
'linical @eneit rom ilimuma: Treatment&
The roramme# cell #eath rotein 1 (+-1)
immunoloic chec>oint&
M? !ostoE* !uFlished online ahead of print at EEE*Jco*or& on .anuar 20$ 2015
+-1 an# +-=1 .nti:o#ies in 'linical
eveloment
Taret an# .ent 'lass
+-1
• <ivolumaF(MD@1106$ MA-3655# &)4 full human ?F
• !emFroliLumaF ( M:-345# &)4 en&ineered h umaniLed ? F
• !idiliLumaF (C-011# &)1 humaniLed ?F
+-=1
• MA3555 (MD@-1105# &)4 full human ?F
• M!DH320? &)1 en&ineered full human ?F
• M"D436 &)1 en&ineered full human ?F
• MA00101C &)1 full human ?F
+-1ositive T cells
• ?M!-224 Bc of human &)!D-H2 fusion
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:elanoma "upervivencia
()
O !ooled analsis on 446 patientes treated Eith pilimumaF in clinical trials
or in the eGpanded acces pro&ram
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:elanoma "upervivencia
()
04 de Marzo 2015
FDA approved nivolumab for the treatment ofpatients with metastatic squamous non-smallcell lung cancer with progression on or after
platinum-based chemotherapy.
'volution of C#8H 5-cell", 7ccording to 5reatment utcome
IHC Analysis of CD8+ T-cells in samples obtained before and
during anti-PD1 treatment
!aul C* umeh$ Christina H* arvieE$ * !eter Ahinta8u$ "mma .* M* alor
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#o4le 4lo/ueo C527-6 % #-121
Ribas A. N EnglJ Med. 2012;366:2517-2519.
Fasede estimulación(ganglio) Fasede ejecución(tejido periféricoo tumor)
T-cell migration
Dendriticcell
T cell
MHC TCR
B7
CD28
CTLA-4
T cellCancer
cell
MHCTCR
PD-1
PD-L1
T cellCancer
cellDendritic
cellT cell
:elanoma "upervivencia
()
O !ooled analsis on 446 patientes treated Eith pilimumaF in clinical trials
or in the eGpanded acces pro&ram
D !a&e* ?nnu* Rev* Med* 2014* 65>15202
Tarets o anti:o#; immune mo#ulators&
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=.A-3
(l;mhoc;te activation ene 3 '223)
AierroA$ Romero !$ Apeiser D"* he CD4-li8e molecule H?)-3$ Fiolo& and
therapeutic applications* "Gpert pin her ar&ets* 2011=15>1-101*
• A#ents in clinical deelopment5
o !:B-98J01J @:#K-1608A is an anti8LA9)3 monoclonal antibod-in :,ase I deelopment $or adanced solidtumors
o I:31 is a recombinant soluble La#)3)l# $usion protein ;:,ase 1)2)3 in seeralsolid tumours 8 melanoma% breastcancer andpancreas% in combination<
D !a&e* ?nnu* Rev* Med* 2014* 65>15202
Tarets o anti:o#; immune mo#ulators&
'o-stimulator; T/B lian#s rovi#e crucial
sinals or eneration o antitumor T-cellresonses
" remer* AR< ncolo&$ 2013
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'o-stimulator; T/B lian#s rovi#e crucial
sinals or eneration o antitumor T-cell
resonses
" remer* AR< ncolo&$ 2013
'o-stimulator; T/B lian#s rovi#e crucial
sinals or eneration o antitumor T-cell
resonses
" remer* AR< ncolo&$ 2013
'o-stimulator; T/B lian#s rovi#e crucial
sinals or eneration o antitumor T-cellresonses
" remer* AR< ncolo&$ 2013
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T/B-$ amil; chec>oint-mo#ulatin anti:o#ies
currentl; in clinical #eveloment
Taret @ioloical role .nti:o#; C usion rotein Stae c lin # evelo
'40 Co-stimulator R '+-8*0893 f ul lhuman &)2 !h1 F (melP treme#
!h 1F (pancP&em#
=ucatumuma:full human &)1 !h2 (lmphoma#
acetu"uma:(A)<040#$
humaniLed&)1
!h 1F (meloma#
'13* Co-stimulator R Dreluma: (MA-663513#$ full
human &)4
!h 2 (mel#
!h 1F (<ACHC$ <H#
+B-05082566$ fullhuman &)2 !h1F (<H P rituG#
'2* Co-stimulator R 'E-112*$ full human &)1 !h 1
,E40 Co-stimulator R M6469 murine m?F !h 2
M6383 !h1
,E40= Co-stimulator H $,4989991$ ful lhuman &)1 !h2 (al ler&ic
asthma#
AT$ Co-stimulation T$E518$ en&ineeredhuman &)1 !h1F (mel#
D !a&e* ?nnu* Rev* Med* 2014* 65>15202
Tarets o anti:o#; immune mo#ulators&
F$ (Filler cell -li>e $ecetor)
Cali&iuri M* uman natural 8iller cells* lood* 200=112>461-46*
!urd :$ CampFell :A* <atural 8iller cellsand cancer> re&ulationF the 8illercell &-
li8e receptors (:R#* Cancer iol her* 200=>13-22*
• =I>% ?+7@/=92A% andleuoc-te I#)lie receptor)1% ne#atiel- re#ulate /=)cell actiit-
• 2iriluma4 @!:B-98J01A B a$ull- ,uman monoclonalantibod- tar#etin# =I> on/= cells% in AML andadanced solid tumors
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mmune-$elate# .#verse vents (ir.s)
Screenin
$esuestaala semana16
Semana 96
$esuesta #ura#era& /o ir.s
Cortes'ade f :* arman8aa$ 7iena
arman8aa :$ et al* !resented at "?D 200$ 7ienna$ ?ustria
Special tumor response kinetics inducedby ipilimumab
Semana 12
ncremento inicial
#e la cara total
#e tumor (mG!, +)
Inmuno-:onitoriLación
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Btrategie" for immunot$erap% com4ination".
Melero I et al. Clin Cancer Res 2009;15:1507-1509 ©2009 by American Association for Cancer Research
Hu estrateia #e riori"aciIn?
Mar&olin :$ ematol ncol Clin < ?m 2 (2014# 53-55
2o" tumore" inducen diferente" e"troma"
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tra" com4inacione" en preclínica
Melero CCR 200
+IDOi
¿Cómo va a modificar la Inmuno-oncología, el panorama terapéutico
del cáncer?• Incremento de arsenal terapéutico• Incremento de estrate#ias de
combinación@secuenciación• /ecesidad de inesti#ación traslacional
o :ersonalizacióno Monitorización
o :riorización de ''??• /ueos eentos adersos ) entrenamiento• /ueo en$oCue de la en$ermedad tumoral• Dransersalidad de conceptos• MEs multidisdiplinariedad
7$ora /ue o" "a4éi" lo 4á"ico, /uiLá"
/uerái" entrar en materiaM..