Intratumoral Hemorrhage of the Cervical Spinal Schwannoma ...
METHODS AND RESULTS - Idera Pharmaceuticals · 2018-06-07 · Intratumoral IMO-2125 induced potent...
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Modulation of Checkpoint Expression in Tumor Microenvironment by Intratumoral Administration of a Novel TLR9 Agonist: Rationale for Combination Therapy • New immunotherapy regimens involving mulple agents represent a highly promising area of cancer research; a challenge is to idenfy opmal combinaons. • Invesgaons of checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab have shown a correlaon between clinical acvity and checkpoint gene expression. • Preclinical data have demonstrated that intratumoral administraon of IMO-2125, a novel TLR9 agonist shown to induce interferon-α, modulates the tumor microenvironment and induces antumor immune responses. • The current study was undertaken to evaluate the tumor microenvironment following intratumoral IMO-2125 therapy. This evaluaon includes analysis of checkpoint expression in treated tumors as well as in distant tumors. Intratumoral IMO-2125 induced potent antitumor activity and tumor checkpoint expression compared to subcutaneous administration in an A20 lymphoma model CT26 colon carcinoma model (single injection, multiple dose levels) B16 melanoma model A20 lymphoma model iderapharma.com Wayne Jiang, Daqing Wang, Fugang Zhu, Lakshmi Bhagat, Jillian DiMuzio and Sudhir Agrawal Idera Pharmaceuticals, Cambridge, MA 02139 CT26 colon carcinoma model T BALB/c, female (n = 10) Parameters evaluated • Induction of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment • Tumor volume • Checkpoint gene expression in tumor nodules Placebo intratumoral subcutaneous IMO- 2125, i.t. IMO- 2125, s.c. Tumor volume, mm 3 2500 1600 800 2000 1200 400 0 0 7 14 21 Placebo IMO-2125 i.t. Days IMO-2125 s.c. CHANGES IN CHECKPOINT GENE EXPRESSION CHANGES IN TUMOR VOLUME AND TIL INFILTRATION STUDY DESIGN T umor implant 3 x 10 6 cells Day 8 12 Treatment IMO-2125, 2.5 mg/kg, i.t. or s.c. 21 0 10 14 CD3+ TILs 0.0 1.5 3.0 4.5 IDO1 TIM3 PDL1 LAG3 CTLA4 Fold increase over placebo s.c i.t. TUMOR 1500 1000 500 0 Tumor volume, mm 3 Placebo IMO-2125 900 600 300 0 Tumor volume, mm 3 Placebo IMO-2125 CHANGES IN CHECKPOINT GENE EXPRESSION CHANGES IN TUMOR VOLUME STUDY DESIGN BALB/c, female, (n = 9) Day 7 11 Treatment IMO-2125, 2.5 mg/kg, i.t. 27 0 9 13 15 T umor implant 2 x 10 6 cells Parameters evaluated • Tumor volume • Checkpoint gene expression in tumor nodules Treated tumor Distant tumor Treated tumor Distant tumor Two weeks post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor. IDO1 PDL1 LAG3 TIM3 CTLA4 0 2 4 6 8 Fold increase compared to placebo IDO1 PDL1 LAG3 TIM3 CTLA4 0 2 4 8 Fold increase compared to placebo TUMOR TUMOR Treated tumor Distant tumor BALB/c, female, (n = 5) 1.2 1.4 0.8 0.4 1 0.6 0.2 0 Fold change 0 2.5 12.5 12.5 IMO-2125, mg/kg Control DNA, mg/kg 12 10 6 8 2 4 0 Fold change 0 2.5 12.5 12.5 IMO-2125, mg/kg Control DNA, mg/kg 2.5 1.5 3 2 0.5 1 0 0 2.5 12.5 12.5 IMO-2125, mg/kg Control DNA, mg/kg Fold change 3.5 4 2.5 1.5 3 2 0.5 1 0 Fold change 0 2.5 12.5 12.5 IMO-2125, mg/kg Control DNA, mg/kg CHANGES IN CHECKPOINT GENE EXPRESSION CHANGES IN TUMOR VOLUME STUDY DESIGN PBS IMO-2125 IDO Tubulin 300 200 100 0 Tumor volume, mm 3 0 2.5 12.5 12.5 IMO-2125, mg/kg Control DNA, mg/kg 450 300 150 0 Tumor volume, mm 3 0 2.5 12.5 12.5 IMO-2125, mg/kg Control DNA, mg/kg Day 1 8 Treatment IMO-2125, 2.5 and 12.5 mg/kg, i.t. 10 T umor implant 3 x 10 6 cells Parameters evaluated • Tumor volume • Checkpoint gene expression in tumor nodules Treated tumor Distant tumor IDO1 PDL1 CEA CAM1 O X40 TUMOR TUMOR Treated tumor Distant tumor C57BL/6, female, (n = 9) 1500 2000 1000 500 0 Tumor volume, mm 3 Placebo IMO-2125 1500 1000 500 0 Tumor volume, mm 3 Placebo IMO-2125 CHANGES IN CHECKPOINT GENE EXPRESSION CHANGES IN TUMOR VOLUME STUDY DESIGN Day 7 11 Treatment IMO-2125, 2.5 mg/kg, i.t. 22 0 9 13 15 T umor implant 1 x 10 6 cells Parameters evaluated • Tumor volume • Checkpoint gene expression in tumor nodules Treated tumor Distant tumor Treated tumor Distant tumor One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor. IDO1 PDL1 LAG3 CTLA4 TIM3 0 3 6 9 12 Fold increase compared to placebo IDO1 PDL1 LAG3 CTLA4 TIM3 0 3 12 Fold increase compared to placebo TUMOR TUMOR Treated tumor Distant tumor BALB/c, female, (n = 10) 2000 1000 1500 500 0 Tumor volume, mm 3 Placebo IMO-2125 2500 2000 1500 1000 Tumor volume, mm 3 Placebo IMO-2125 CHANGES IN CHECKPOINT GENE EXPRESSION CHANGES IN TUMOR VOLUME STUDY DESIGN Day 8 12 Treatment IMO-2125, 2.5 mg/kg, i.t. 21 0 10 14 T umor implant 3 x 10 6 cells Parameters evaluated • Tumor volume • Checkpoint gene expression in tumor nodules Treated tumor Distant tumor Distant tumor Treated tumor One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor. IDO1 TIM3 PDL1 LAG3 CTLA4 0 2 4 6 8 Fold increase compared to placebo IDO1 TIM3 PDL1 LAG3 CTLA4 0 2 4 6 8 Fold increase compared to placebo TUMOR TUMOR Treated tumor Distant tumor • Intratumoral IMO-2125 stimulated potent antitumor activity in preclinical models of lymphoma, colon carcinoma and melanoma. - Treatment led to increases in CD3+ TILs. • Intratumoral IMO-2125 induced a systemic antumor effect. - Treatment led to decreases in tumor volume in treated and distant tumors. • Intratumoral IMO-2125 modulated immune checkpoint gene expression, including IDO1, PDL1, TIM3, LAG3 and CTLA4, in both treated and distant tumor nodules. • Together, these data showed that intratumoral IMO-2125 sensized the tumor microenvironment for potenal combinatorial effects with various checkpoint inhibitors. • Planning for a clinical trial of intratumoral IMO-2125 in combinaon with ipilimumab, an an- CTLA4 monoclonal anbody, in paents with metastac melanoma is currently underway with study iniaon expected in 4Q 2015. Single and multiple intratumoral IMO-2125 doses induced potent antitumor activity and checkpoint gene expression METHODS AND RESULTS CONCLUSIONS INTRODUCTION
Transcript of METHODS AND RESULTS - Idera Pharmaceuticals · 2018-06-07 · Intratumoral IMO-2125 induced potent...
Modulation of Checkpoint Expression in Tumor Microenvironment by Intratumoral Administration of a Novel TLR9 Agonist: Rationale for Combination Therapy
• Newimmunotherapyregimensinvolvingmultipleagentsrepresentahighlypromisingareaofcancerresearch;achallengeistoidentifyoptimalcombinations.
• Investigationsofcheckpointinhibitorssuchasipilimumab,nivolumab,andpembrolizumabhaveshownacorrelationbetweenclinicalactivityandcheckpointgeneexpression.
• PreclinicaldatahavedemonstratedthatintratumoraladministrationofIMO-2125,anovelTLR9agonistshowntoinduceinterferon-α,modulatesthetumormicroenvironmentandinducesantitumorimmuneresponses.
• ThecurrentstudywasundertakentoevaluatethetumormicroenvironmentfollowingintratumoralIMO-2125therapy.Thisevaluationincludesanalysisofcheckpointexpressionintreatedtumorsaswellasindistanttumors.
Intratumoral IMO-2125 induced potent antitumor activity and tumor checkpoint expression compared to subcutaneous administration in an A20 lymphoma model
CT26 colon carcinoma model (single injection, multiple dose levels)
B16 melanoma model
A20 lymphoma model
iderapharma.com
Wayne Jiang, Daqing Wang, Fugang Zhu, Lakshmi Bhagat, Jillian DiMuzio and Sudhir AgrawalIdera Pharmaceuticals, Cambridge, MA 02139
CT26 colon carcinoma model
T
BALB/c, female (n = 10)
Parameters evaluated
• Induction of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment
• Tumor volume
• Checkpoint gene expression in tumor nodules
Placebo
C57BL/6, female, (n = 9)
BALB/c, female, (n = 10)
BALB/c, female, (n = 5)
intratumoralsubcutaneous
IMO-2125, i.t.
IMO-2125, s.c.
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
900
600
300
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2000
1000
1500
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2500
2000
1500
1000
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
2000
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1.2
1.4
0.8
0.4
1
0.6
0.2
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
12
10
6
8
2
4
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
2.5
1.5
3
2
0.5
1
00 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Fold
cha
nge
3.5
4
2.5
1.5
3
2
0.5
1
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Tum
or v
olum
e, m
m3
2500
1600
800
2000
1200
400
0
0 7 14 21
Placebo IMO-2125 i.t.
Days
IMO-2125 s.c.
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSIONCHANGES IN TUMOR VOLUME AND TIL INFILTRATION
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
PBS IMO-2125
IDO
Tubulin
300
200
100
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
450
300
150
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
Day 1 8
Treatment IMO-2125, 2.5 and 12.5 mg/kg, i.t.
10
Tumor implant 3 x 106 cells
Tumor implant 3 x 106 cells
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t. or s.c.
210 10 14
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t.
210 10 14
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
220 9 13 15
BALB/c, female, (n = 9)
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
270 9 13 15
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Tumor implant 1 x 106 cells
Tumor implant 3 x 106 cells
Tumor implant 2 x 106 cells
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Distant tumor
Treated tumor Distant tumorIDO1 PDL1 CEACAM1 OX40
CD3+ TILs
Treated tumor
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
Two weeks post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
IDO1
PDL1 LAG3
CTLA4
TIM3
0
3
6
9
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3 PDL1 LAG3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3
PDL1
LAG3
CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
0.0
1.5
3.0
4.5
IDO
1 TIM
3
PDL1
LAG3
CTLA4
Fold
incr
ease
ove
r pla
cebo
s.c i.t.
IDO1
PDL1
LAG3 CTLA4 TIM3
0
3
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3
CTLA4
0
2
4
8
Fold
incr
ease
com
pare
d to
pla
cebo
TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
T
BALB/c, female (n = 10)
Parameters evaluated
• Induction of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment
• Tumor volume
• Checkpoint gene expression in tumor nodules
Placebo
C57BL/6, female, (n = 9)
BALB/c, female, (n = 10)
BALB/c, female, (n = 5)
intratumoralsubcutaneous
IMO-2125, i.t.
IMO-2125, s.c.
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
900
600
300
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2000
1000
1500
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2500
2000
1500
1000
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
2000
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1.2
1.4
0.8
0.4
1
0.6
0.2
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
12
10
6
8
2
4
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
2.5
1.5
3
2
0.5
1
00 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Fold
cha
nge
3.5
4
2.5
1.5
3
2
0.5
1
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Tum
or v
olum
e, m
m3
2500
1600
800
2000
1200
400
0
0 7 14 21
Placebo IMO-2125 i.t.
Days
IMO-2125 s.c.
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSIONCHANGES IN TUMOR VOLUME AND TIL INFILTRATION
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
PBS IMO-2125
IDO
Tubulin
300
200
100
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
450
300
150
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
Day 1 8
Treatment IMO-2125, 2.5 and 12.5 mg/kg, i.t.
10
Tumor implant 3 x 106 cells
Tumor implant 3 x 106 cells
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t. or s.c.
210 10 14
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t.
210 10 14
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
220 9 13 15
BALB/c, female, (n = 9)
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
270 9 13 15
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Tumor implant 1 x 106 cells
Tumor implant 3 x 106 cells
Tumor implant 2 x 106 cells
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Distant tumor
Treated tumor Distant tumorIDO1 PDL1 CEACAM1 OX40
CD3+ TILs
Treated tumor
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
Two weeks post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
IDO1
PDL1 LAG3
CTLA4
TIM3
0
3
6
9
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3 PDL1 LAG3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3
PDL1
LAG3
CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
0.0
1.5
3.0
4.5
IDO
1 TIM
3
PDL1
LAG3
CTLA4
Fold
incr
ease
ove
r pla
cebo
s.c i.t.
IDO1
PDL1
LAG3 CTLA4 TIM3
0
3
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3
CTLA4
0
2
4
8
Fold
incr
ease
com
pare
d to
pla
cebo
TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
T
BALB/c, female (n = 10)
Parameters evaluated
• Induction of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment
• Tumor volume
• Checkpoint gene expression in tumor nodules
Placebo
C57BL/6, female, (n = 9)
BALB/c, female, (n = 10)
BALB/c, female, (n = 5)
intratumoralsubcutaneous
IMO-2125, i.t.
IMO-2125, s.c.
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
900
600
300
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2000
1000
1500
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2500
2000
1500
1000
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
2000
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1.2
1.4
0.8
0.4
1
0.6
0.2
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
12
10
6
8
2
4
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
2.5
1.5
3
2
0.5
1
00 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Fold
cha
nge
3.5
4
2.5
1.5
3
2
0.5
1
0Fo
ld c
hang
e0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Tum
or v
olum
e, m
m3
2500
1600
800
2000
1200
400
0
0 7 14 21
Placebo IMO-2125 i.t.
Days
IMO-2125 s.c.
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSIONCHANGES IN TUMOR VOLUME AND TIL INFILTRATION
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
PBS IMO-2125
IDO
Tubulin
300
200
100
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
450
300
150
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
Day 1 8
Treatment IMO-2125, 2.5 and 12.5 mg/kg, i.t.
10
Tumor implant 3 x 106 cells
Tumor implant 3 x 106 cells
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t. or s.c.
210 10 14
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t.
210 10 14
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
220 9 13 15
BALB/c, female, (n = 9)
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
270 9 13 15
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Tumor implant 1 x 106 cells
Tumor implant 3 x 106 cells
Tumor implant 2 x 106 cells
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Distant tumor
Treated tumor Distant tumorIDO1 PDL1 CEACAM1 OX40
CD3+ TILs
Treated tumor
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
Two weeks post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
IDO1
PDL1 LAG3
CTLA4
TIM3
0
3
6
9
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3 PDL1 LAG3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3
PDL1
LAG3
CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
0.0
1.5
3.0
4.5
IDO
1 TIM
3
PDL1
LAG3
CTLA4
Fold
incr
ease
ove
r pla
cebo
s.c i.t.
IDO1
PDL1
LAG3 CTLA4 TIM3
0
3
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3
CTLA4
0
2
4
8
Fold
incr
ease
com
pare
d to
pla
cebo
TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
T
BALB/c, female (n = 10)
Parameters evaluated
• Induction of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment
• Tumor volume
• Checkpoint gene expression in tumor nodules
Placebo
C57BL/6, female, (n = 9)
BALB/c, female, (n = 10)
BALB/c, female, (n = 5)
intratumoralsubcutaneous
IMO-2125, i.t.
IMO-2125, s.c.
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
900
600
300
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2000
1000
1500
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2500
2000
1500
1000
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
2000
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1.2
1.4
0.8
0.4
1
0.6
0.2
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
12
10
6
8
2
4
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
2.5
1.5
3
2
0.5
1
00 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Fold
cha
nge
3.5
4
2.5
1.5
3
2
0.5
1
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Tum
or v
olum
e, m
m3
2500
1600
800
2000
1200
400
0
0 7 14 21
Placebo IMO-2125 i.t.
Days
IMO-2125 s.c.
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSIONCHANGES IN TUMOR VOLUME AND TIL INFILTRATION
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
PBS IMO-2125
IDO
Tubulin
300
200
100
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
450
300
150
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
Day 1 8
Treatment IMO-2125, 2.5 and 12.5 mg/kg, i.t.
10
Tumor implant 3 x 106 cells
Tumor implant 3 x 106 cells
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t. or s.c.
210 10 14
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t.
210 10 14
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
220 9 13 15
BALB/c, female, (n = 9)
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
270 9 13 15
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Tumor implant 1 x 106 cells
Tumor implant 3 x 106 cells
Tumor implant 2 x 106 cells
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Distant tumor
Treated tumor Distant tumorIDO1 PDL1 CEACAM1 OX40
CD3+ TILs
Treated tumor
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
Two weeks post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
IDO1
PDL1 LAG3
CTLA4
TIM3
0
3
6
9
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3 PDL1 LAG3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3
PDL1
LAG3
CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
0.0
1.5
3.0
4.5
IDO
1 TIM
3
PDL1
LAG3
CTLA4
Fold
incr
ease
ove
r pla
cebo
s.c i.t.
IDO1
PDL1
LAG3 CTLA4 TIM3
0
3
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3
CTLA4
0
2
4
8
Fold
incr
ease
com
pare
d to
pla
cebo
TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
T
BALB/c, female (n = 10)
Parameters evaluated
• Induction of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment
• Tumor volume
• Checkpoint gene expression in tumor nodules
Placebo
C57BL/6, female, (n = 9)
BALB/c, female, (n = 10)
BALB/c, female, (n = 5)
intratumoralsubcutaneous
IMO-2125, i.t.
IMO-2125, s.c.
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
900
600
300
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2000
1000
1500
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
2500
2000
1500
1000
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
2000
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1500
1000
500
0
Tum
or v
olum
e, m
m3
Placebo IM
O-2
125
1.2
1.4
0.8
0.4
1
0.6
0.2
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
12
10
6
8
2
4
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
2.5
1.5
3
2
0.5
1
00 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Fold
cha
nge
3.5
4
2.5
1.5
3
2
0.5
1
0
Fold
cha
nge
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA,mg/kg
Tum
or v
olum
e, m
m3
2500
1600
800
2000
1200
400
0
0 7 14 21
Placebo IMO-2125 i.t.
Days
IMO-2125 s.c.
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSION
CHANGES IN CHECKPOINT GENE EXPRESSIONCHANGES IN TUMOR VOLUME AND TIL INFILTRATION
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
CHANGES IN TUMOR VOLUME
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
STUDY DESIGN
PBS IMO-2125
IDO
Tubulin
300
200
100
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
450
300
150
0
Tum
or v
olum
e, m
m3
0 2.5 12.5 12.5
IMO-2125, mg/kg
Control DNA, mg/kg
Day 1 8
Treatment IMO-2125, 2.5 and 12.5 mg/kg, i.t.
10
Tumor implant 3 x 106 cells
Tumor implant 3 x 106 cells
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t. or s.c.
210 10 14
Day 8 12
Treatment IMO-2125, 2.5 mg/kg, i.t.
210 10 14
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
220 9 13 15
BALB/c, female, (n = 9)
Day 7 11
Treatment IMO-2125, 2.5 mg/kg, i.t.
270 9 13 15
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Tumor implant 1 x 106 cells
Tumor implant 3 x 106 cells
Tumor implant 2 x 106 cells
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Parameters evaluated
• Tumor volume
• Checkpoint gene expression in tumor nodules
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Treated tumor Distant tumor
Treated tumor Distant tumor Distant tumor
Treated tumor Distant tumorIDO1 PDL1 CEACAM1 OX40
CD3+ TILs
Treated tumor
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
One week post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
Two weeks post last dosing, tumor samples were collected and analyzed for checkpoint expression by qPCR. Data represented average fold change in gene expression of selected checkpoints compared to placebo treated tumor.
IDO1
PDL1 LAG3
CTLA4
TIM3
0
3
6
9
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3 PDL1 LAG3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
TIM3
PDL1
LAG3
CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3 CTLA4
0
2
4
6
8
Fold
incr
ease
com
pare
d to
pla
cebo
0.0
1.5
3.0
4.5
IDO
1 TIM
3
PDL1
LAG3
CTLA4
Fold
incr
ease
ove
r pla
cebo
s.c i.t.
IDO1
PDL1
LAG3 CTLA4 TIM3
0
3
12
Fold
incr
ease
com
pare
d to
pla
cebo
IDO1
PDL1 LAG3 TIM3
CTLA4
0
2
4
8
Fold
incr
ease
com
pare
d to
pla
cebo
TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
TUMOR TUMOR
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
Treated tumor
Distant tumor
• IntratumoralIMO-2125stimulatedpotentantitumoractivityinpreclinicalmodelsoflymphoma,coloncarcinomaandmelanoma.
- TreatmentledtoincreasesinCD3+TILs.
• IntratumoralIMO-2125inducedasystemicantitumoreffect.
- Treatmentledtodecreasesintumorvolumeintreatedanddistanttumors.
• IntratumoralIMO-2125modulatedimmunecheckpointgeneexpression,includingIDO1,PDL1,TIM3,LAG3andCTLA4,inbothtreatedanddistanttumornodules.
• Together,thesedatashowedthatintratumoralIMO-2125sensitizedthetumormicroenvironmentforpotentialcombinatorialeffectswithvariouscheckpointinhibitors.
• PlanningforaclinicaltrialofintratumoralIMO-2125incombinationwithipilimumab,ananti-CTLA4monoclonalantibody,inpatientswithmetastaticmelanomaiscurrentlyunderwaywithstudyinitiationexpectedin4Q2015.
Single and multiple intratumoral IMO-2125 doses induced potent antitumor activity and checkpoint gene expression
METHODS AND RESULTS
CONCLUSIONS
INTRODUCTION
