inmuno gral sep2015

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21/11/2015

1

¿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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3

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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4

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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5

: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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6

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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11

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


Clinical activit% of I2-1 @p$a"e 1A



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14


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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1

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




21/11/2015

1

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



21/11/2015

1

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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()





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()

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


()



D !a&e* ?nnu* Rev* Med* 2014* 65>15202




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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


'o-stimulator; T/B lian#s rovi#e crucial

sinals or eneration o antitumor T-cellresonses

" remer* AR< ncolo&$ 2013



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sinals or eneration o antitumor T-cell

resonses



sinals or eneration o antitumor T-cell

resonses



sinals or eneration o antitumor T-cellresonses




21/11/2015

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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


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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2

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



21/11/2015

2

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"



21/11/2015

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..

inmuno gral sep2015

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