Transcript Rational Combinations in Cancer Immunotherapy

Rational Combination of Immunotherapies
in Preclinical Cancer Models
October 23, 2014
John C. Lin, M.D. Ph.D.
Vice President, Experimental Medicine
Combination PD-1 and CTLA-4 Abs Leads to A
Superior Anti-tumor Activity
Mouse melanoma
5 × 104 B16-BL6 cells
Vaccinated on days 3, 6, and 9 with 1 × 106 Fvax
Curran et al PNAS 2010
Human melanoma
1 mg/kg nivolumab + 3mg/kg ipilimumab
ORR=9/17
Wolchok et al. NEJM (June 2013)
Combination Therapy of -PD-1 and -Lag-3 Shows
Synergy in MC38 but not in B16 Tumor Model
The combined anti-PD-1 and anti-Lag-3 had no effect against established B16 tumors
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Combination of Immune Modulators
Melero I et al. Clin Cancer Res 2013;19:997-1008
Syngeneic tumor models in response to single
agent 4-1BB treatment
4-1BB sensitive models
(ORU, La Jolla)
4-1BB resistant models
T u m o r v o lu m e ( m m
3
 SEM)
B 16F10
2000
Is o ty p e ( r a t Ig G 2 a , 1 m g /k g )
4 -1 B B (1 m g /k g )
1500
4 -1 B B (3 m g /k g )
4 -1 B B (1 0 m g /k g )
1000
500
4 -1 B B d o s in g
0
8
10
12
14
16
18
20
22
D a y s P o s t In o c u la t i o n
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Tumor Response in Merkel Cell Carcinoma Patient
Treated with 0.6 mg/kg of PF-05082566 (4-1BB)
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34 treated, up to 5 mg/kg (as of ASCO 2014)
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24 evaluable for response
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1 patient - PR (0.6 mg/kg)
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1 patient - Mixed response (0.06 mg/kg)
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7 patients –Stable disease across multiple doses
Baseline PET Scan
Week 16 PET Scan
ASCO (2014)
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Adverse Events-Related
• No Grade 2 or higher treatment related adverse events were
observed up to the current dose level of 5.0 mg/kg
• AE possibly related to single agent PF-566 up to 1.2 mg/kg are
listed below (all Grade 1)
Adverse event
Rash
Fever
Nausea/vomiting
Weight loss
Headache
Fatigue
Thrombocytopenia
N (%)
3 (9)
2 (6)
2 (6)
1 (3)
1 (3)
1 (3)
1 (3)
Adapted from ASCO, 2014
Vaccination Is Required for Tumor Suppression by
anti-4-1BB / anti-CTLA-4 Combination
Curran et al. PLoS ONE 2011
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Induction of PD-1+ 4-1BB+ CD8 T cells by 4-1BB
antibody in B16 melanoma bearing mice
Live cells
CD3
PD-1
4-1BB
CD3+
CD8
NK1.1
FSC-A
CD4
CD4
CD8+
4-1BB
CD4+
CD8+
PD-1
(B) Anti-4-1BB-treated
Live/Dead
CD8
CD3
CD4+
PD-1
FSC-A
CD3+
PD-1
Live cells
NK1.1
Live/Dead
(A) Isotype-treated
4-1BB
4-1BB
(Chen et al, in press)
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Anti-4-1BB and anti-PD1 Combo Therapy Showed
Synergistic Anti-tumor Effect in B16 Tumor
Strategies to enhance 4-1BB agonism Combine with immune checkpoint PD-1 inhibitor
4-1BB/PD-1 combination is superior to 4-1BB/LAG-3
in suppressing B16F10 tumor growth
1200
A n ti- 4 -1 B B
A n t i-P D -1
900
A n t i- L A G -3
600
A n ti- P D - 1 /A n t i-L A G -3
300
A n t i- 4 - 1 B B /A n t i- P D -1
0
8
10
12
14
16
18
20
 SEM)
R a t Ig G 2 a
M C 3 8 C o lo n C a r c in o m a
1500
3
1500
1200
T u m o r v o lu m e ( m m
3
T u m o r V o lu m e ( m m )
B16F10 Melanoma
3
( s t a r t in g v o l ~ 1 0 0 m m )
R a t Ig G 2 a
4 -1 B B
P D -1
900
600
4 - 1 B B /P D - 1
300
0
12
14
16
18
20
22
24
26
28
22
D a y s A f t e r T u m o r In o c u la t io n
D a y s A f t e r T u m o r In o c u la t i o n
Chen et al. (in press)
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Anti-4-1BB and anti-PD1 Combo Therapy Showed
Synergistic Anti-tumor Effect in Large Tumors
Tumor size between 64-209 mm3
Chen et al. (in press)
The anti-tumor activity of 4-1BB/PD-1
combination requires CD8+ T cells and INF-g
CD8+ T cell depletion abrogates anti-tumor activity
Loss of anti-tumor activity in IFN-g-deficient mice
Chen et al. (in press)
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Anti-4-1BB and anti-PD1 Combo Therapy
Increased the Availability of Target Molecules
Chen et al. (in press)
Anti-4-1BB and anti-PD1 Treatment
Promoted Anti-Tumor Immune Response
Chen et al. (in press)
Anti-4-1BB and Anti-PD1 Combo Therapy Induced
T Cell Effector/Memory Differentiation
Chen et al. (in press)
Anti-4-1BB and Anti-PD1 Combo Therapy
Enhanced Antigen-Specific T Cell Response
KSTPFTTL MC38 CD8 dominant epitope
Chen et al. (in press)
Summary of Anti-4-1BB / anti-PD-1 combination
• Anti-tumor efficacy demonstrated in two murine models
– MC38 colon cancer and B16 melanoma
– Anti-4-1BB induces PD-1 expression
– Increase in memory-phenotype T cells
– Tcm and Tem
– Eomes up-regulation
– Antigen-specific response
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Acknowledgements
Rinat and Oncology Research Unit
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Shihao Chen
Li-Fen Lee
Guang Huan Tu
Kathryn Logronio
Tim Fisher
Mark Elliott
• Clinical Team
• Bart Jessen, other Drug Safety R&D
members
• Oncology Business Unit
• Patients and their family members
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