Dr. Ignacio Melero - Simposio Internacional 'Terapias oncológicas avanzadas''

Diciembre 2013
Immunostimulatory
Monoclonal antibodies
Adoptive T cell therapy

Understand the tumor microenvironment
Berraondo P et al. Cancer Res 2012;72:5159-5164
©2012 by American Association for Cancer Research

IGNORANT T CELL
Insufficient antigen/
lack of co-stimulatory signals
ANERGIC T CELL
Unsuccessful stimulation/
negative regulation
APOPTOTIC T CELL
(DELETED)
Programmed cell death
NAIVE T CELL PRIMED T CELL EFFECTOR T CELL MEMORY
T CELL:
Central memory cell
CD27 Effector memory cell
CD28
HVEM
TCR
MHC
-peptide
CD27L
CD80/86
LIGHT
CTLA-4
B7-H4R
LAG-3
TIM-3
CD80/86
B7-H4
PD-1
B7-H4R
B7-H1
BTLA
LAG3
B7-H1
B7-DC
B7-H4
BTLA-4R
CD137
OX40
ICOS
B7-H3R
GITR
CD137L
OX40L
B7h
B7-H3
IL-12
IFN-α

Schematic representation of the concept of immunostimulatory mAbs.
Melero I et al. Clin Cancer Res 2013;19:997-1008

Combination opportunities in
immunotherapy with
immunostimulatory mAb.
?

SYNERGY
syn-ergos, συνεργός, meaning 'working
together'.

Dose
Response
1. Different mechanism of
action.
2. Cooperative effect

Strategies for immunotherapy combinations.

The cancer-immunity cycle and immunotherapy:
targeting several rate-limiting steps in a dynamic equilibrium
Tumour
Lymph node
Blood vessel
Priming and activation
(APCs & T cells)
Anti-PDL1
Anti-PD1
Anti-CTLA-4
IL-2
Cancer antigen
presentation
2
(dendritic cells/APCs)
1 Release of cancer cell
antigens
(cancer cell death)
3
Trafficking of T cells
to tumours (CTLs)
4
Infiltration of T cells into
tumours
(CTLs, endothelial cells)
5
Recognition of cancer
cells by T cells
(CTLs, cancer cells)
6
Killing of cancer cells
7
(immune and cancer cells)
Vaccines
IFN-
TLR agonist
Anti-PDL1
Anti-PD1
Chen & Mellman. Immunity 2013
ANTIGEN
CROSSPRIMIMG

Steps in the development of a cellular immune response against tumour-associated
antigen
Melero, I. et al. (2014) Nat. Rev. Clin. Oncol.

Clec9A

Costimulatory and coinhibitory ligand receptor pairs that are amenable to manipulation with
immunostimulatory mAbs.
Phosphatases
Deubiquitinases
Transcription
factors
Unknowns
Unknown
unknowns
Melero I et al. Clin Cancer Res 2013;19:997-1008 ©2013 by American Association for Cancer Research

-OX40
Radiotherapy
Chemotherapy
Vaccination
T-reg depletion/
inactivation
Adoptive T-cell
immunotherapy
Antiangiogenic
therapy
–Clinical Standard
–Clinical Trials
–Preclinical Studies
-TIM-3
-LAG3
-CTLA-4
-CD137
-PD1
-PD-L1
-CD40

Coinhibitor
Blockade
CTLA-4
LAG3
KIRs
Individualization.
Biomarker use
Vaccination
or
In-situ
vaccination
Adoptive
cell therapy
Costimulation
PD-1 PD-L1 Blockade
CD137
OX40
CD40
GITR

Wolchok et al. N Engl J Med 2013;369:122–33

A
18.46mm 19.91mm
B
Adapted from Wolchok et al. N Engl J Med 2013;369:122–33
Change in target lesions from baseline (%)
First occurrence of new lesion
0 10 20 30 40 50 60 70 80 90 100 110 120
Patients
300
250
200
150
100
50
0
–50
–100
Weeks since treatment initiation
Change in target lesions from baseline (%)
200
100
80
60
40
20
0
–20
–40
–60
–80
–100

CA209-004 Phase I Study: Dose Cohorts
Presented By Mario Sznol at 2014 ASCO Annual Meeting

Activity Summary: Concurrent and Sequenced Cohorts from 004

Safety Overview

Evaluating PD-L1 status as a candidate biomarker
22
60
40
20
0
Objective Response Rate (%)
60
40
20
0
Objective Response Rate (%)
Nivolumab
monotherapy
(Grosso et al. ASCO 2013)
Combination
nivolumab plus
ipilimumab
Sequenced
nivolumab after
ipilimumab
3/21
7/17 9/22
6/13
1/13
4/8
_ + _ + _ +
Positivity rate = 45% (17/38, monotherapy), 37% (13/35, combination therapy),
and 38% (8/21, sequenced therapy)

Overview of efficacy and safety for anti-PDL1/PD1
therapies in NSCLC
Therapy Number of patients Key efficacy data Key safety data
MPDL3280A1 175 (85 with NSCLC: 53
evaluable, 85% PDL1+
ORR 23%
• 66% related AEs, 11% Grade 3–4 AEs (fatigue)
• No grade 3–5 pneumonitis
MEDI47362 367 (155 with NSCLC,
58 evaluable)
ORR 16%
• 29% related AEs, 3% Grade 3–4 AEs
• Pneumonitis: 1%, no Grade 3–4 pneumonitis
• No colitis
Nivolumab3 129 with NSCLC
ORR 17.1% (21.7%*)4
• 50% responded in 8 weeks
• median OS 9.9 months
• 53% related AEs, 5% Grade 3–4AEs
• Pneumonitis – 6%, Grade 3–4: 3 patients (2%) – 2 deaths
Pembrolizumab
38 with NSCLC4 ORR 21% (24%*)4
221 with NSCLC (80%
• 48% related AEs (fatigue), 6% Grade 3–4 AEs5
ORR 15% (21%‡)5 PDL1+)5 • Pneumonitis – Grade 3–4: 3 patients (1%)5
*including immune responders, irRECIST,
‡unconfirmed response
1. Soria. European Cancer Congress 2013 (abstract 3408); 2. Brahmer et al. ASCO 2014
(Abstract 8021); 3. Brahmer et al. IASLC WCLC, 2013; 4. Garon et al. IASLC WCLC, 2013;
5. Garon et al. ASCO 2014 (abstract 8020)

4-1BBL
CD137 (4-1BB, TNFRSF9)
4-1BB
APC T Cell
CD137,also known as 4-1BB, is a surface glycoprotein involved
in T-cell costimulation.
Its cognate ligand is CD137L, which is expressed on APCs.
Functions:T cell proliferation, inhibition of apoptosis, enhances citotoxic
activity, cytokine production.
Therapeutic target, treatment with agonist anti-CD137 mAb can
overcome tumor antigen tolerance.
Anti-human CD137 agonist mAb are undergoing phase I/phase II clinical
trials

Activated
CTL
-Resistance to apoptosis
-Proliferation
-Gain effector functions
-Differentiation to memory cells
Activated
NK cell
Early Cytokine production
Early Tumor cell killing
Enhancement of ADCC
Provision of tumor cell
debris for cross-priming
Dendritic
cell
Activated
CD4+ T cell
Tumor
endothelium
Tumor antigen
Cross-presentation
Cytokine
Secretion
IL-13 and
IFN-g
Proinflammatory molecules
Lymphocyte infiltration?
Memory
CD8+ T cell
Inhibition/activation
In vivo paradox
T regs ?
IKDC?
Antigen-independent
activation
NKT
cell
Controversial
effects
on regulatory
function
Anti-CD137
mAb

*Presented by Levy, Ronald Stanford
Home Annual Meeting Primer Workshop Hot Topic Symposium Early Career Scientists Abstracts
SITC 28th Annual Meeting
November 8-10,
2013
Gaylord National Hotel & Convention Center
National Harbor, MD
Program Schedule
(As of 10/14/13 -subject
to change)
Thursday, November 7, 2013
7:00 am -6:
00 pm Registration
5:30 pm -6:
15 pm State of SITC: Membership Business Meeting
6:15 pm -7:
30 pm Welcome Reception Featuring Speed Networking
Friday, November 8, 2013
7:00 am -6:
00 pm Registration
7:00 am -8:
00 am Breakfast
7:15 am -8:
00 am Meet-the-
Expert
Breakfast
8:15 am -8:
20 am Presidential Welcome
Francesco M. Marincola, MD -Sidra
Medical and Research Center
8:20 am -8:
40 am Update Session: Cancer Immunotherapy Trials Network
Martin A. Cheever, MD -Fred
Hutchinson Cancer Research Center
SITC Quick Links
Register
Hotel Information
Faculty Log In & Resources
Connect with us!

Combinations with virotherapy?

Semliki Forest Virus
Lipid bilayer
(SFV)
• (+)ssRNA virus
• induces apoptosis of infected cells
• broad host range and efficient replication
• it has been developed in gene therapy as a vector for genes encoding vaccines and
antitumoral agents.

SFV EXPRESSION VECTOR
+ nsp1 nsp2 nsp3 nsp4 Heterologous Gene An
Rep
-
pr Sg
+
• Cytoplasmic Replication
• High protein expression
• Host proteins shut-off
• Apoptosis
Rep
Heterologous Gene An

SFV VECTOR EXPRESSING IL-12
SFV Rep sg Pr
p35
sg Pr
p40 SFV-IL-12
+RNAs helper
BHK cells
Viral particles

SUBCUTANEOUS TUMOR MODEL: COLON
day 11
MC38 SFV-IL-12
tumor measurement
C57BL/6
ADENOCARCINOMA MC38

Tumor cell
Rep IL-12
SFV-IL-12
-
Rep
+
IL-12
+
Tumor
Ag
APCs
Antitumoral Immunity
Apoptosis
Immunocytes
IFN-I

ANTITUMORAL EFFECT OF SFV VECTORS IN scMC38
Rodriguez-Madoz et al., Mol Ther. 2005
100
90
80
70
60
50
40
30
20
10
0
2x106 1x107 5x107 1x108
SFV-IL-12
Ad-IL-12
SFV-LacZ
Ad-LacZ
saline
complete tumoral regressions (%)
Viral dose (vp)

SFV-IL12 + mAb CD137 in B16OVA model
B16OVA (5x105) SFV-IL12 (108 vp) Tumor
evaluation
α-CD137 ip (100 μg)
Day 0 7 10 14 >25

SFV-IL-12 + CD137 agonist antibody
SFV-IL12 (108) + -CD137
0 10 20 30 40 50
25
20
15
10
5
25
20
15
10
5
0
6/8 (75%)
Time (Days)
Saline + -CD137
20
15
10
5
0 10 20 30 40 50
25
20
15
10
5
0
1/6 (17%)
Time (Days)
Tumor diameter (mm)
Saline + Rat IgG
0 10 20 30 40 50
0
0/5 (0%)
Tumor diameter (mm)
SFV-IL12 (108) + Rat IgG
0 10 20 30 40 50
0
2/8 (25%)
Quetglas, Dubrot et al., Mol. Ther. 2012

SFV-IL-12 + CD137: Survival
0 25 50 75 100
100
75
50
25
0
SFV-IL12 + -CD137
SFV-IL12
-CD137
Saline
Time (Days)
% Survival
** *
***
Quetglas, Dubrot et al., Mol. Ther. 2012

SFV-IL-12 + -CD137: melanoma B16
Salino
0 20 40 60
20
15
10
5
0
0/6(0%)
Tiempo (días)
Diámetro tumor (mm)
Salino + -CD137
0 20 40 60
20
15
10
5
0
0/6(0%)
Tiempo (días)
Tumor diameter (mm)
SFV-IL-12 (107 vp)
0 20 40 60
20
15
10
5
0
0/6(0%)
Tiempo (Días)
SFV-IL-12 (107 vp) + -CD137
0 20 40 60
20
15
10
5
0
2/6(33.3%)
Tiempo (Días)
0 20 40 60 80
100
75
50
25
0
Salino
Salino +  -CD137
SFV-IL-12
SFV-IL-12 +  -CD137
n.s.
**
Tiempo (días)
% Supervivencia

SFV-IL12 + -CD137
0 20 40 60 80
20
15
10
5
0
16/19(84%)
Time (Days)
Tumor diameter (mm)
SFV-IL12 + -CD137
0 20 40 60 80
20
15
10
5
0
0/9(0%)
-CD8
Time (Days)
Tumor diameter (mm)
SFV-IL12 + -CD137
-CD4
0 20 40 60 80
20
15
10
5
20
15
10
5
0
8/10(80%)
Time (Days)
Tumor diameter (mm)
SFV-IL12 + -CD137
-NK1.1
0 20 40 60 80
20
15
10
5
0
9/10(90%)
Time (Days)
Tumor diameter (mm)
SFV-IL12 + -CD137
20 -CD8 + -NK1.1
0 20 40 60 80
15
10
5
0
0/8 (0%)
Time (Days)
Tumor diameter (mm)
Saline + Rat IgG
0 20 40 60 80
0
0/16(0%)
Time (Days)
Tumor diameter (mm)
CD8+ CELLS ARE THE MAIN MEDIATORS OF RESPONSE

CD8 expansion in B16OVA model
Rat IgG α-CD137
SFV-IL12
CD8+
100 101 102 103 104
FL3-H: FL3-Height
104
103
102
101
100
FL1-H: CD8-FITC
8.5
100 101 102 103 104
FL3-H: FL3-Height
104
103
102
101
100
FL1-H: CD8-FITC
24.4
100 101 102 103 104
FL3-H: FL3-Height
104
103
102
101
100
FL1-H: CD8-FITC
8.59
100 101 102 103 104
FL3-H: FL3-Height
104
103
102
101
100
FL1-H: CD8-FITC
40.3
Saline
Rat IgG α-CD137
8.5% 24.4% 8.6% 40.3%
Naïve
5 10 15 20 25 30 35 40
3000
2500
2000
1500
1000
500
0
**
*
Time (Days)
CD8 + TRP-2-Tet + / 106 PBMCs
TRP-2
5 10 15 20 25 30 35 40
3000
2500
2000
1500
1000
500
0
**
Time (days)
CD8 + OVA-Tet + / 106 PBMCs
OVA
Saline + IgG rata
Saline + CD137
SFV-IL12 + IgG rata
SFV-IL12 + CD137

TRP-2
600
400
200
0
*
Rat IgG -CD137 Rat IgG
-CD137
Saline SFV-IL12
OVA
1000
750
500
250
0
-CD137
Saline SFV-IL12
IFNg producing cells /106 cells
***
E ** n.s.
L
I
S
P
O
T
OVA
100
75
50
25
0
-CD137
Saline SFV-IL12
% Specific lysis
*
TRP-2
100
75
50
25
0
n.s.
-CD137
Saline SFV-IL12
I
V
K

80
60
40
20
0
*
% cells T CD8 +CD137 +
*
Saline -CD137
SFV-LacZ
SFV-IL12
2000 **
rat IgG CD137
Quetglas, Dubrot et al., Mol Ther. 2012
WHY IS THERE SYNERGY?
1500
1000
500
0
SFV-IL12
SFV antibodies
A BENEFICIAL ADDITIONAL
EFFECT

Combinations
Ready for triplets?

Anti-CD137 + anti-PD-L1 + anti-OX40

Spontaneous HCC (c-mycOVA75/tTALAP)
PminCMV Pminc-myc TRE CMV ova
+ Dox
X
tTA c-myc/OVA LAP tTA
Adapted from Ney et al. Hepatol 2009;49:471–81
VP16
tetR
tetR VP16
– Dox
VP16
tetR
LAP
PminCMV Pminc-myc TRE CMV ova
c-myc/OVA x LAP tTA

Reproduced from Ney et al. Hepatol 2009;49:471–81

Efficacy of combination therapies: Preclinical data
Treatment
mAbs mAbs
Morales-Kastresana et al. Clin Cancer Res 2013;19:6151–62
100
Survival (%)
100
80
60
40
20
0
0 200
Days
Rat IgG
Anti-4-1BB
Anti-OX40
Anti-PD-L1
Combo3
Combo3
12/39
Dox
Day: -21 d 0 d 21 d 25
breeding birth weaning Survival
300

Efficacy of combination therapies: Survival
Days
Survival (%)
100
80
60
40
20
0
4/11
2/10
0 100 200 300 400 500
Rat IgG
Combo3
ACT
ACT + Combo3
Rat IgG Combo3 ACT + Combo3
Week 6 42,42 mm2 11,18 mm2 No tumour
Morales-Kastresana et al. Clin Cancer Res 2013;19:6151–62

H&E anti-CD3
Tumor
Non tumor

So what is it going
to look like?

Arch Immunol Ther Exp (Warsz). 2002;50(1):13-8.
Effective tumor immunotherapy: start the engine, release
the brakes, step on the gas pedal,...and get ready to face
autoimmunity.
Tirapu I, Mazzolini G, Rodriguez-Calvillo M, Arina A, Palencia B, Gabari I, Melero I.
Abstract
Cellular immune responses can destroy cancer cells, achieving the cure of experimental
malignancies. An expanding wealth of knowledge on the molecular basis of how to prime
and amplify a T cell response has fueled a number of strategies successful at treating
established tumors (rather than merely preventing tumor grafting). The most efficacious
approaches operate at different stages, including: 1) priming the immune response using
tumor antigen-expressing dendritic cells or tumor cells transfected with genes that render
them immunogenic, 2) sustaining and amplifying immunity using agonistic monoclonal
antibodies against costimulatory molecules or immune-potentiating cytokines, and 3)
eliminating mechanisms that self-regulate the strength of the immune response, such as
inhibitory receptors or regulatory T cells. A rational combination of such approaches holds
great hope for cumulative and synergistic effects, but there is also evidence that they can
open the flood-gates for unwanted inflammatory reactions. The next decade can be
envisioned as the time when the first reproducibly efficacious combination regimes for
cancer immunotherapy will become available and widely used in the clinic, as clinicians
learn the best strategies and try to harness their potentially damaging effects.

1. Sequenced therapy schemes in time
(induction, maintenance, reinduction)
2. Debulking (before treatment or in a neoadjuvant setting)
3. Surgical removal of residual tumors in sustained PR
or long-lasting SD.
4. Stop treatment if CR or PR and watchful
Expectation (closely observing the tumor and
The Anti-tumor immunity)
And…. BIOMARKERS, BIOMARKERS, BIOMARKERS!!!!!

Carlos Alfaro
Carmen Oñate
Inmaculada Rodriguez
José L Pérez Gracia
Miguel F Sanmamed
Salvador Martin -Algarra
Bruno Sangro
JM Lopez Picazo
Alfonso Gúrpide
Javier Rodriguez
Jesús Prieto
Alberto Benito
Ivan Peñuelas
Alvaro Gonzalez
Aizea Morales
Miguel F Sanmamed
Sandra Hervas
Jose Quetglas
Arantza Azpilikueta
Elixabet Bolaños
Sara Labiano
Cristian Smerdou
Bristol Myers Squibb Merck
Pfizer Boehringer
Oncovir Medimmune
Roche-Genentech Miltenyi

Dr. Ignacio Melero - Simposio Internacional 'Terapias oncológicas avanzadas''

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Dr. Ignacio Melero - Simposio Internacional 'Terapias oncológicas avanzadas''

Similar to Dr. Ignacio Melero - Simposio Internacional 'Terapias oncológicas avanzadas'' (20)

More from Fundación Ramón Areces

More from Fundación Ramón Areces (20)

Recently uploaded

Recently uploaded (20)

Dr. Ignacio Melero - Simposio Internacional 'Terapias oncológicas avanzadas''