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October 23, 2014 John C. Lin, M.D. Ph.D. Vice President, Experimental Medicine Rational Combination...
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Transcript of October 23, 2014 John C. Lin, M.D. Ph.D. Vice President, Experimental Medicine Rational Combination...
October 23, 2014
John C. Lin, M.D. Ph.D.
Vice President, Experimental Medicine
Rational Combination of Immunotherapies in Preclinical Cancer Models
Combination PD-1 and CTLA-4 Abs Leads to A Superior Anti-tumor Activity
1 mg/kg nivolumab + 3mg/kg ipilimumab 5 × 104 B16-BL6 cells Vaccinated on days 3, 6, and 9 with 1 × 106 Fvax
Mouse melanoma Human melanoma
Wolchok et al. NEJM (June 2013)ORR=9/17Curran et al PNAS 2010
Pfizer Confidential │ 3
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
Pfizer Confidential │ 5
Syngeneic tumor models in response to single agent 4-1BB treatment
8 10 12 14 16 18 20 220
500
1000
1500
2000
B16F10
Days Post Inoculation
Tu
mo
r v
olu
me
(m
m3
SE
M)
Isotype (rat IgG2a, 1 mg/kg)
4-1BB (1 mg/kg)
4-1BB (3 mg/kg)
4-1BB (10 mg/kg)
4-1BB dosing
4-1BB resistant models
4-1BB sensitive models
(ORU, La Jolla)
Tumor Response in Merkel Cell Carcinoma Patient Treated with 0.6 mg/kg of PF-05082566 (4-1BB)
Baseline PET Scan Week 16 PET Scan
ASCO (2014)Pfizer Confidential │ 6
• 34 treated, up to 5 mg/kg (as of ASCO 2014)
• 24 evaluable for response
• 1 patient - PR (0.6 mg/kg)
• 1 patient - Mixed response (0.06 mg/kg)
• 7 patients –Stable disease across multiple doses
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 N (%)
Rash 3 (9)Fever 2 (6) Nausea/vomiting 2 (6)Weight loss 1 (3)Headache 1 (3)Fatigue 1 (3)Thrombocytopenia 1 (3)
Adapted from ASCO, 2014
Pfizer Confidential │ 8
Vaccination Is Required for Tumor Suppression by anti-4-1BB / anti-CTLA-4
Combination
Curran et al. PLoS ONE 2011
Pfizer Confidential │ 9
Induction of PD-1+ 4-1BB+ CD8 T cells by 4-1BB antibody in B16 melanoma bearing mice
FSC-A
Liv
e/D
ea
d
CD3
NK
1.1
CD4
CD
8
4-1BB
PD
-1
4-1BB
PD
-1
CD4+ CD8+CD3+Live cells(A) Isotype-treated
FSC-A
Liv
e/D
ea
d
CD3
NK
1.1
CD4
CD
8
4-1BB
PD
-1
4-1BBP
D-1
CD4+ CD8+CD3+Live cells(B) Anti-4-1BB-treated
(Chen et al, in press)
Pfizer Confidential │ 11
Strategies to enhance 4-1BB agonism - Combine with immune checkpoint PD-1 inhibitor
B16F10 Melanoma
4-1BB/PD-1 combination is superior to 4-1BB/LAG-3 in suppressing B16F10 tumor growth
8 10 12 14 16 18 20 220
300
600
900
1200
1500
Anti-4-1BB
Anti-PD-1
Days After Tumor Inoculation
Tu
mo
r V
olu
me
(m
m3)
Rat IgG2a
Anti-LAG-3
Anti-4-1BB/Anti-PD-1
Anti-PD-1/Anti-LAG-3
12 14 16 18 20 22 24 26 280
300
600
900
1200
1500
Days After Tumor Inoculation
Tu
mo
r v
olu
me
(m
m3
SE
M)
Rat IgG2a4-1BBPD-1
4-1BB/PD-1
MC38 Colon Carcinoma(starting vol ~ 100 mm3)
Chen et al. (in press)
Anti-4-1BB and anti-PD1 Combo Therapy Showed Synergistic Anti-tumor Effect in
Large TumorsTumor size between 64-209 mm3
Chen et al. (in press)
Pfizer Confidential │ 13
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)
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 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
Chen et al. (in press)
KSTPFTTL MC38 CD8 dominant epitope
Pfizer Confidential │ 18
• 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
Summary of Anti-4-1BB / anti-PD-1 combination