the renaissance of immunotherapy is a revolution for ...3cbd9efd-f400-4f9c-8... · the renaissance...
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The renaissance of immunotherapy is a revolution for cancer patients and for oncology
Ira Mellman, Ph.D. Vice President, Cancer Immunology, Genentech
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Traditional drug development Is linear development path the best approach?
Research
Generate Hypothesis
Late Development
Verify Hypothesis
Early Development
Test Hypothesis Launch
Marketing
Cancer immunotherapy requires a cyclical “learning organization”
Research
Early Development
Post-Launch
Late Development
Cancer Immunotherapy Strategy Group
(CITS)
PII 1/2L Dx+ ORR FIR
BIRCH
PII 2L+ Dx+/- vs. Doce OS POPLAR
PIII 2L+ Dx+/- vs. Doce OS OAK
PII Dx+ ORR
Cancer immunotherapy at Genentech/Roche Pipeline overview
Anti-PDL1 trials
Stimulator
Inhibitor
Phase I Anti-PDL1 Solid tumors
Anti-PDL1+Avastin Solid tumors
Anti-PDL1+cobimetinib Solid tumors
Anti-PDL1+Zelboraf Met. Melanoma
Anti-PDL1+Tarceva NSCLC
Anti-PDL1 + immune m. Solid tumors
Anti-PDL1 + Gazyva Heme tumors
CSF1R huMAb solid tumors
CEA IL-2v
Phase II Anti-PDL1
NSCLC (Dx+) Anti-PDL1
NSCLC Anti-PDL1+Avastin
Renal Anti-PDL1
Bladder
Anti-PDL1 NSCLC 2/3 L
Phase III
Anti-PDL1 Bladder
Pre-clinical
ImmTAC
Neg. Regulator NME 1
Anti-cytokine NME 2
T-cell bispecific
IMA 942
Note: Anti-PDL1 is listed as MPDL3280A in clinicaltrials.gov
Anti-OX40
IDO (GDC-0919)
Anti-CD40
CSF1R huMAb PVNS
Trial planned
Anti-PDL1 NSCLC 1L Dx+
Immuno-supression
The Cancer Immunity Cycle Immunosuppression is the rate limiting step to effective anti-tumor immunity
• PD-1/PD-L1 interaction inhibits T cell activation, attenuates target killing: prevents overstimulation of T cells during acute virus infection
• A large percentage of tumors also up-regulate PD-L1 and evade killing by T cells
• Blocking PD-1 binding restores effector T cell activity
IFNγ-mediated up-regulation of
tumor PD-L1
Shp-2
PD-‐L1/PD-‐1 inhibits tumor cell killing
“Adaptive expression” of PD-L1
MAPK"PI3K
pathways"
or tumor-infiltrating immune cells
Targeting immuno-supression PD-1/PD-L1 pathway
Targeting PD-L1 produces dramatic responses in many cancers (lung)
64-year-old male with squamous NSCLC s/p R lobectomy; cisplatin + gemcitabine, docetaxel, erlotinib; PD-L1 positive
Hospital Universitario Vall d´Hebron (Cruz/Tabernero).
Post C12 (Week 36) Baseline Post C2 (Week 6)
Herbst et al. MPDL3280A Anti-PDL1 Phase I ASCO 2013
Patients with clinical benefit rarely progress
Herbst et al., (2013) J Clin Oncol. 31, (suppl; abstr 3000)
Chan
ge in
Sum
of L
onge
st D
iam
eter
s
(SLD
) Fro
m B
asel
ine,
%
100
50
-50
0 21 42 63 84 105
Time on Study (Days)
0
126 147 168 189 210 231 252 273 294 315 336 357 378 399 420
-100
441
20 mg/kg (n = 39)
Patients dosed at 1-20 mg/kg prior to Aug 1, 2012 with at least 1 post-baseline evaluable tumor assessment; data cutoff Feb 1, 2013.
New Lesions Discontinued Study
PD-L1 positive kidney cancer patient with rapid response to MDL3280A
Baseline
Carolina BioOncology Institute (Powderly)
After 4 weeks
51-year-old male with RCC s/p L nephrectomy, sunitinib, XRT T9, temsirolimus
Cho et al., (2013) J Clin Oncol. 31, (suppl; abstr 4505)
Baseline
CD8 PD-L1 PD-L1
Biomarkers*at*baseline:*
On-Tx
CD8$PD&L1$
Biomarkers*at*week*4*post*C1D1:*
Biomarkers at baseline
Baseline
CD8 PD-L1 PD-L1
Biomarkers*at*baseline:*
On-Tx
CD8$PD&L1$
Biomarkers*at*week*4*post*C1D1:*Biomarkers at week 4 post C1D1
MPDL3280A Phase Ia response correlates with expression of PD-L1 on tumor infiltrating cells (bladder cancer)
PD-L1 IHC (IC) ORR, Best Response % (95% CI)
ORR, Best Response % (95% CI)
IHC 3 (n = 10) 60% (27, 85) 52% (34, 69)
IHC 2 (n = 23) 48% (27, 68)
IHC 1 (n = 24) 17% (6, 37) 14% (6, 28)
IHC 0 (n = 12) 8% (0, 35)
!100$!90$!80$!70$!60$!50$!40$!30$!20$!10$0$10$20$30$40$50$60$70$80$90$
100$
Maxim
um'SLD
'Red
uc/o
n'From
'Baseline,'%'
IHC$(IC)$0$IHC$(IC)$1$IHC$(IC)$2$IHC$(IC)$3$IHC$(IC)$unknown$
a$a$a$
Summary of ORR in UBC
12 Powles et al (2014) Nature Nov 26;515(7528):558-‐62
Using patient data to understand cancer immunity and find new treatments
MPDL3280A Phase 1 Data: Urothelial Bladder Cancer Patients Progressive Disease (PD) Why do many patients not respond? • No pre-existing immunity?
Stable disease (SD) What combinations will promote PRs & CRs? • Insufficient T cell immunity? • Multiple negative regulators?
Monotherapy durable responses (PR/CR) What are the drivers of single agent response? How can PRs be enhanced to CRs? • Insufficient T cell immunity? • Multiple negative regulators?
Powles et al (2014) Nature Nov 26;515(7528):558-‐62
Comprehensive approach to biomarker discovery
Multi-parametric immunofluorescence
T-Cell Receptor Repertoire
Genentech ImmunoChip
Mutliplex cytokine assay
Multi-channel fluorescence activated
cell sorting
Molecular Imaging
On-treatment biomarker profile defines response and lack of response
Responder
Non-responder
0"
2"
4"
6"
8"
10"
12"
14"
16"
PD*L1"
Granzym
e*A"
Granzym
e*B"
Perforin"
EOMES"
IFNg"
CXCL9"
CD8A"
rela%v
e'expression
'(to'BS
L)'
Baseline'
On5Tx'
0"
2"
4"
6"
8"
10"
12"
14"
16"
PD*L1"
Granzym
e*A"
Granzym
e*B"
Perforin"
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IFNg"
CXCL9"
CD8A"
rela%v
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'(to'BS
L)''
Baseline'
On5Tx'
PD-L1 PD-L1
Baseline On-treatment 4 weeks
PD-L1 PD-L1
Baseline On-treatment 6 weeks
Herbst et al (2014) Nature Nov 27;515(7528):563-7
PD-L1 patient immune biomarker analysis guides research and clinical development
Compounds moving into clinic • Negative regulator NME1 • Positive regulator: OX40
Targets elevated in non-responders
Activating receptors Inhibitory receptors
OX40*
CD27*
TIGIT
B7H4
TIM-3
PD-1*
BTLA
VISTA
LAG-3*
CD96
CD226 2B4
NKG2D
HVEM
ICOS
GITR
2B4
CTLA-4*
CD137*
CD28
T cell
T"cell"stimulation"
Example: NME1 is a negative regulator discovered from biomarker analysis
0 10 20 30 40 6010
100
1000
10000
Day
Median Tumor Volume (mm3)�
Control �anti-PD-L1 �NME1 �
anti-PD-L1 �+ NME1�
Complete Remission (CR)�
010
2030
4060
10100
1000
10000
Day
Med
ian
Tum
or V
olum
e (m
m3 )�
Con
trol�
anti-
PD-L
1�NM
E1�
anti-
PD-L
1 �
+ NM
E1�
Com
plet
e Re
miss
ion
(CR)�
Negative regulator combines in PD-L1 non-responsive model
Immuno- suppression
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Accelerate T cell response to antigen
Positive regulator targeting two steps in the cycle Anti-OX40
Anti-PDL1
anti-OX40
Inhibit T regs
anti-OX40
OX40 function and potential in oncology Promote antigen dependent effector T cell activation and T regulatory cell inhibition
Adapted from Nature Rev Immunol. 4:420 (2004).
Rationale for targeting OX40 • Dual mode of action:
Co-stimulation of effector T cells Inhibition of regulatory T cells
• Reduced risk of toxicity • Complementary MoA to blocking inhibitory receptors • Potential to overcome suppressive signals from multiple
inhibitory receptors
Effector T cell
TCR
Antigen Presenting Cell
OX40
OX40L Suppressive
T cell
IFN-γ
OX40 engagement on Treg cells
Treg
OX40L OX40L
OX40
OX40L
OX40
Potential for activity in multiple tumor types Pre-clinical efficacy and durability of response OX40 is expressed in a variety of tumors
Anti-OX40 increases intratumor Teff cells while depleting T regs
Colorectal cancer
Breast cancer
control
a-OX40
control
a-OX40
-4-202468101214161820
IFN
-γ F
old
Cha
nge
(Rel
to A
vg C
ontro
l)
day 2 day 9
0 5 10 15 200
20
40
60
Foxp3/CD4(%)
day
controla-OX40
Increase in intratumoral Teff cells (CD4+CD8)
Decrease in intratumoral Treg cells (FoxP3+)
Anti-OX40 can induce durable responses and immunity as a single agent Pre-clinical efficacy and generation of tumor-specific immunity
0 10 20 30 40 500
1000
2000
3000
day
Tum
or V
olum
e (m
m3 ) Control
Anti-mouse OX40
Treatment
Primary Tumor Challenge (EMT6)
0 10 20 30
0
500
1000
1500
2000
dayTu
mor
Vol
ume
(mm
3 ) EMT6 SecondaryCT26 Secondary
EMT6 Primary
Re-challenge (EMT6 or CT26)
No Treatment day day
Chen & Mellman (2013) Immunity Jul 25;39(1):1-10
anti-OX40
anti-PDL1 CD8 T cell
receptor
HLA
PD-1
PD-L1
Tumor cell
T cell
IFNγ
PD-L1 increase
Increase in Teff cells by anti-OX40 may create need to combine with anti-PDL1
IFN-γ"
OX40L
OX40
IFNγ-‐mediated up-‐regulation of tumor PD-‐L1
Shp-2
Adaptive expression of PD-L1
MAPK"PI3K
pathways"
IFNγ-‐mediated up-‐regulation of
tumor IDO
Inhibition of effector T cell
function
Shp-2
MAPK"PI3K
pathways"
Adaptive expression of IDO
IDO
Georgia Hatzivassiliou, Yichin Liu
IDO (indoleamine di-oxygenase) Another suppressor of effector T cells
Free tryptophan
mTOR
Promote translation
high
Enhance T reg
arylhydrocarbon receptor
FoxP3
Kynurenine
IDO*
Tumor cells
IFNγ activates IDO expression
Suppress T effectors
Uncharged Tryptophanol-tRNA
GCN2 kinase
Stress response
low
suppressive cytokines
Dendritic cells Macrophages
*TDO (tryptophan dioxygenase) is a second related target to IDO
IDO mediates T cell suppression by reducing extracellular tryptophan and increasing kynurenine
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Recognition of cancer cells by T cells (CTLs, cancer cells)
ImmTACs Bispecifics
Not all patients may have pre-existing immunity: ImmTACs and bispecific antibodies as alternatives to CAR-T cells
Immune-mobilizing mTCR Against Cancer*
*In colalboaration with Immunocore
T-cell Dependent Bispecific
TCR
Tumor antigen
Cancer cell
T cell Knob into holes full-length IgG
Targeting intracellular tumor markers Targeting extracellular tumor markers
Recruiting T cells to cancer cells ImmTACs and bispecific antibodies
Chen & Mellman (2013) Immunity Jul 25;39(1):1-10
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Recognition of cancer cells by T cells (CTLs, cancer cells)
ImmTACs Bispecifics
Cancer antigen presentation
(dendritic cells/APCs) Vaccines: • Endogenous • Exogenous
Not all patients may have pre-existing immunity: Patient data defines a path to rational vaccines
Structural analysis suggests that only some mutations will be accessible to T cell receptors
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A
S
N
E
N
M
E
T
M S
S
V
I
G
V
W
Y
L
REPS1! AQLPNDVVL!
ADPGK! ASMTNRELM!
FLU-NP! ASNENMETM!
Copine-1! SSPDSLHYL!
H60! SSVIGVWYL!
PA RM DY
Immunogenic solvent-exposed mutation
Non-immunogenic mutation in MHC groove
Yadav et al (2014) Nature Nov 27;515(7528):572-6
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Mutated peptides predicted to be immunogenic induce CD8 T cell responses upon immunization
+ - + - + - + - + - + -0.0
0.2
0.4
0.6
0.8
1.02.04.06.0
Reps1 Aatf Adgpk Irgq Cpne1
peptide + adjuvantadjuvant
Dpagt1
% p
eptid
e-sp
ecifi
c C
D8
T c
ells
+ - + - + - + - + - + -0.0
0.2
0.4
0.6
0.8
1.02.04.06.0
Reps1 Aatf Adgpk Irgq Cpne1
peptide + adjuvantadjuvant
Dpagt1
% p
eptid
e-sp
ecifi
c C
D8
T c
ells
+ - + - + - + - + - + -0.0
0.2
0.4
0.6
0.8
1.02.04.06.0
Reps1 Aatf Adgpk Irgq Cpne1
peptide + adjuvantadjuvant
Dpagt1
% p
eptid
e-sp
ecifi
c C
D8
T c
ells
Prime/boost immunization elongated peptides + anti-CD40 + pIC
T cell response measured 7d after boost (MHCI dextramer staining)
+ -‐ + -‐ +/-‐ +/-‐ Prediction of
immunogenicity
Anchor residue gain of function
Yadav et al (2014) Nature Nov 27;515(7528):572-6
Promise for a PHC vaccine? Immunization with antigenic peptides regresses growth of established MC38 tumors
Dose Groups● 01 − untreated control
02 − d1: anti−CD40 50µg + pIC 100µg, IP injection. d10: anti−CD40 50µg + pIC 100µg, IP injection. (n=10)03 − d1: anti−CD40 50µg + pIC 100µg + 3Xpeptide mix 100µg, IP injection. d10: 3Xpeptide mix anti−CD40 50µg + pIC 100µg, IP injection. (n=10)
Control
Adj
Adj+ Peptides
Immunization
14−0584: mutated MHCI MC38 peptide vaccine; MC−38 Raw and LME Fit Tumor Volume
Day
Tum
or V
olum
e ( m
m3 )
0
100
200
300
400
500
600
700
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Control Adj
Adj+peptides
Yadav et al (2014) Nature Nov 27;515(7528):572-6
Anti-PDL1/PD1 Anti-OX40
IDOi (GDC-0919) LM & SM NMEs
Anti-CTLA4 Anti-OX40 SM NMEs
Vaccines • Endogenous • Exogenous
Building a portfolio based on the emerging appreciation of the cancer immunity cycle
Anti-VEGF
Chen & Mellman (2013) Immunity Jul 25;39(1):1-10
Substantial investment in developing PD-L1 combinations with in house and partnered molecules
Last updated: 3 Dec 2014 Sources: TrialTrove, company presentations, clinicaltrials.gov P ✔
Partnered external combo Internal combo
Roche/GNE (PD-L1 inhibitor)
BMS (PD-1 inhibitor)
Merck (PD-1 inhibitor)
AZ (PD-L1 inhibitor)
Imm
unot
hera
pies
aCD40 ✔ Vaccines P P P P aCTLA-4 P ✔ P ✔ aOX40 ✔ ✔ aCD27 P P a4-1BB/CD137 ✔ P GITRi ✔ aCEA-IL2v ✔ T Cell Bispecifics ✔ ImmTACs P aPDL1/PD1 ✔ aLAG-3 ✔ IDOi ✔, P P P P aKIR ✔ aCSF1R ✔ P Cytokines, anti-cytokines ✔ ✔ ✔ P
Oth
er
aVEGF ✔ P P aAng-2-VEGF ✔ VEGF TKI P P EGFRi ✔ P P ✔ ALKi ✔ P P BRAFi ✔ P P P MEKi ✔ P P P BTKi ✔ P P aCD20 ✔ aHER2 ✔ P Chemo ✔ ✔ ✔ XRT ✔ ✔
Genentech’s competitive advantage: Lead the field by focusing on the science
• Identification and validation of new targets & combinations based on our
understanding of cancer immunity cycle
• An ever-expanding patient biomarker database
• Diverse, innovative portfolio
• Leverage small molecule expertise
• Leverage oncology expertise
• A uniquely integrated team, from Research to Late Stage…and back
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