poster imprimepgg (imprime) plus pembrolizumab(pem): a ...€¦ · 4. innate effector activation...
TRANSCRIPT
Abstract
Imprime PGG(Imprime)pluspembrolizumab (PEM):aphase2immunotherapeuticcombinationinpatientsselectedforanImprime-specificbiomarker.
StevenO’Day1, Nandita Bose2,MarkUhlik2,Radha Prathikanti2,BenHarrison2,StevenLeonardo2,RichardHuhn2, NadineOttoson2,Xiaohong Qiu2,RichardWalsh3,PauletteMattson2,MableMa2,KatieErtelt2,JamieLowe2,MicheleGargano2,MichaelChisamore5,BrunoOsterwalder4,JeremyRGraff21JohnWayneCancerInstitute,SantaMonica,CA90404,2BiotheraPharmaceuticals,Inc.Eagan,MN55121,3ImmunoResearch,Eagan,MN55121,4B.O.ConsultingGmbH,Riehen,SwitzerlandCH-41255Merck&Co.,Inc.,Kenilworth,NJ,USA
Poster#733LB-A31
AACR-NCI-EORTCMolecularTargetsandCancerTherapeutics,BiotheraPharmaceuticals,Inc.,Philadelphia,PA,Oct26-30,2017
Imprime PGG (Imprime) is a novel immunotherapeutic that acts as a non-self danger signal to activatethe innate immune system and coordinate an adaptive immune system response. In multiple preclinicaltumor models, Imprime significantly enhances anti-tumor efficacy of multiple immune checkpointinhibitors (CPI). Mechanistically, Imprime directly binds to innate immune effector cells via theformation of an immune complex with naturally-occurring anti-b glucan antibodies (ABA). This immunecomplex is required for Imprime to activate innate effector functions- monocyte and dendritic cellactivation, and enhanced cytokine production. In a recently completed healthy volunteer study,activation of innate immune cell functions was demonstrated after intravenous (IV) infusion of Imprimein subjects with pre-treatment [Tx] ABA levels > 20 µg/ml. In ex vivo human donor blood studies, wholeblood from subjects with low (i.e. insufficient) ABA failed to show innate immune activation unlessrescued by the addition of purified ABA (ABA from the serum of high ABA donors) or commercialimmunoglobulin (IVIg). Retrospective analyses of data from previous clinical trials showed that higherpre-Tx ABA levels correlated with enhanced overall survival in patients (pts) treated with Imprime.Collectively, these data support the hypothesis that ABA are essential to the therapeutic benefit ofImprime. A phase 2 clinical trial combining Imprime (4 mg/kg weekly IV) with Pembro (200 mg, q3w)has begun in metastatic melanoma pts who have failed a CPI and in CPI naïve, triple-negative breastcancer (TNBC) pts who have failed chemotherapy. Pts are screened for sufficient ABA (> 20 µg/ml) byELISA. Pre- and early-on Tx biopsies (6 wks) and at time of response/progression or end of Tx arerequested to assess immune cells at the tumor site by multispectral immunofluorescence. Bloodsamples are collected pre- and post- Imprime infusion on Day 1 of each treatment cycle for the first 6cycles and q4 cycle thereafter. The first TNBC pt had a pre-Tx ABA of 31 µg/ml. Following 6 wks of Tx,the pt’s total target lesion mass was reduced >40%. Partial response continued at 12, 18 and 24 wks(>50% reduction vs baseline). A biopsy of a remaining pelvic lesion after 18 wks Tx revealed primarilyfibrotic tissue. Blood samples showed evidence of innate immune activation including increasedexpression of MCP-1, IL-8, chemokines targeting CCR5 and CXCR3 that are associated with enhanced Tcell infiltration and effector function. The first melanoma pt (pre-Tx ABA 42 µg/ml) showed a modestincrease in lesion size at 12 wks (+12% versus baseline). Pre- and on-Tx (6 wk) biopsy material (from twodifferent lesion locations) was obtained for multichannel immunofluorescence. The pre-Tx biopsy tumorsample was primarily devoid of immune cells. In contrast, the on-Tx biopsy tumor sample indicatesextensive infiltration of the tumor bed by CD8 and CD4 T cells, and innate immune cells. PreviousImprime clinical and ex vivo data suggest that sufficient ABA may be important for Imprime-mediatedinnate immune activation. Early clinical observations in ABA pre-selected patients support the notionthat Imprime may provide benefit in combination with Pembro in these two populations.
Imprime MechanismofAction
Cytokine Chemokine Production
IFNs
MonocyteMacrophageDendritic CellNeutrophil
Proposed mechanism of action ignites a fully functional immune response against cancer
1. Imprime forms an immune complex• Anti-β glucan antibodies (ABA) (IgG2a)• Complement fragment (iC3b)• Imprime-β glucan
2. Binds to and co-ligates 3 surface receptors• ABAs bind Fcγ receptor IIa (CD32a)• iC3b binds complement receptor 3 (CR3)• Imprime binds dectin-1 receptor
3. Receptor co-ligation provides activation signal• Type 1 interferon gene expression• Chemokines/cytokines
4. Innate effector activation• Promotes tumor killing– Macrophages, neutrophils
• Alleviates immunosuppression– M2èM1 repolarization– MDSC maturation/differentiation
• Activates antigen presentation– Dendritic cell maturation– M1 APCs
Imprime PGG: An Immunological “Ignition Switch”
IgG ABA Complement opsoniniC3b
iC3b
4
Imprime andCPI:PreclinicalEfficacy
Imprime
ABA (RAU/mL): 0 350 700
0500
100015002000
15000
20000
25000
IL-8MCP-1
Che
mok
ine
(pg/
mL)
0 10 20 30 40 50 60 700
20
40
60
80
100
Citrate + RajiImprime + RajiImprime + 175 RAU/mL ABAImprime + 250 RAU/mL ABAImprime + 350 RAU/mL ABA
Time (min)
Reac
tive
Oxyg
en S
pecie
s (R
OS) i
n RL
U
PD Effects ROS Generation
Left Panel- Imprime induced pharmacodynamic effects (MCP-1, IL-8) are enhanced in whole blood from a “low binder” by purified ABA supplementation. Right Panel- The generation of Reactive Oxygen Species (ROS) is enhanced in neutrophils isolated from a “low binder” when exposed to rituximab-opsonized Raji B cell lymphomas. Note: Dose dependent ROS generation with ABA supplementation. RAU = relative antibody units.
ABA Supplementation in a Non-Responsive Donor Rescues ImmunoPD Effects and Functional Tumor Cell Killing Activities
Neutrophils
Monocytes
Vehicle Imprime PGG Imprime PGG + ABA
Imprime BindingCanBeRescuedbyABASupplementationin“LowBinding”Individuals
Wholebloodwasisolatedfromalow-bindinghealthyhumandonor.Imprime wasdetectedonthesurfaceofNeutrophilsandMonocytesusingananti-βglucan imagingantibodyBfDIV followedbyflowcytometry.BindingwassubstantiallyenhancedbytheadditionofpurifiedhumanIgG ABAasindicatedbytheshiftup(rightpanels).
Imprime andABA:ExVivoStudies
Imprime andABA:RetrospectiveStudies
HumanHealthyVolunteerStudy
CONFIDENTIAL
Imprime PGG Enhances the Response to Checkpoint Inhibitor Therapy
0
10
20
30
40
50
60
70
80
90
100
Control Imprime PGG only
PDL-1 only Imprime PGG + PDL-1
% of
Inje
cted
mice
with
out t
umor
(d
ay 29
)
5.6% 11%
33%
83%*
Control Imprime PGG αPD-L1 Imprime + αPD-L1MC-38 colon cancers were subcutaneously injected into C57BL/6 mice. 3 days later, treatment was initiated. N = 18 per group except Imprime PGG + PD-L1, n =17. Tumor-free mice were re-injected in the opposite flank with MC-38 and remained tumor-free for another month, without any additional therapy. Tumors grew in all age-matched, tumor naïve control mice injected with MC-38. * ANOVA analysis, Tukey adjustment, p = 0.001 vs. aPD-L1, p < 0.0001 vs vehicle control. Differences between all other groups were not significant ( p ≤ 0.05).
Tumor-free mice were re-challenged with MC-38 cells on the opposite flank and remained tumor-free. This suggests the
establishment of immunological memory.
1.0
0.8
0.2
0.0
0.6
0.4
0 10 20 30 40 50
ABA ≥ 35
ABA < 35
HR=0.40 (0.22-0.73)p=0.0018
Surv
ival P
roba
bilit
y
85 36 8 1 0 027 17 6 2 1 1
Significant (p<0.05) tests: 36 out of 86 (41.9%)
Imprime + Cetuximab
2
1
0.5
10 20 30 40 50
Imprime + Cetuximab
1.0
0.8
0.2
0.0
0.6
0.4
Surv
ival P
roba
bilit
y
HR=0.24 (0.1-0.55)p=0.00031
ABA > 45
ABA < 45
0 10 20 30 40 50
0 10 20 30 40 50
ABA < 20
ABA ≥ 20
1.0
0.8
0.2
0.0
0.6
0.4
HR=0.77 (0.49-1.22)p=0.27
Surv
ival P
roba
bilit
y
% Subjects- ABA levels:49% ≥2024% ≥35 16% ≥45
57 25 5 1 0 55 28 9 2 1 1
94 40 10 1 0 18 13 4 2 1 1
ABA IgG (μg/ml)
CRC Primus Trial: Higher Pre-Treatment ABA Levels Correspond with Improved Overall Survival
0.25
0.13HR w
ith 9
5% C
I
Retrospective analyses: Primus trial, 3rd line CRC cetuximab ± Imprime. Pre-treatment ABA levels were measured by ELISA. Sample “cutpoints” for ABA are noted at 20, 35 and 45 !g/ml.
0 20 40 60 80 100 120 140 160 180 200 220
ABA IgG (ug/ml)
Don
ors
Distribution of ABA IgG in Lung Cancer Samples
53.5%
0 20 40 60 80 100 120 140 160 180 200 220
ABA IgG (ug/ml)
Dono
rs
Distribution of ABA IgG in Breast Cancer Samples
45.8%
0 20 40 60 80 100 120
ABA IgG (ug/ml)
Dono
rs
Distribution of ABA IgG in Ovarian Cancer Samples
58.6%
IgG ABA Distribution in Patients with Different Cancers
Biothera Trials
Indication n median IgG ABAColon (Primus) 169 18.7 μg/mlNSCLC (0821) 58 20.4 μg/mlNSCLC (0822) 59 23.0 μg/ml
Tumor(EphA2+Ki67+)
CD8 T-cells(CD3+CD8+)
Activated CD8 T-cells(CD3+CD8+Ki67+GrzBHigh)
Vehic
leIm
prim
e
Increased Activation of T-Cells in the MC-38 Tumor Bed after Imprime Treatment
MC-38- Imprime dosed IV 1.2mg/mouse twice weekly. 10 days treatment. Tumor Tissues imaged using the Perkin Elmer Vectra Multi-spectral Imaging System.
Phase2Imprime +Pembro Studies Imprime andPembro:CPIExperiencedMetastaticMelanoma
Pre Treatment Sample Post Treatment Sample
2mm 800 µm
Pre Treatment Sample Post Treatment Sample
Patient 103103
Hematoxylin and Eosin Stains for Pre- and On-Tx Melanoma Biopsies
Pharmacodynamic Effects of Imprime are Restricted to Biomarker Positive Human Subjects
Blue=ABAIgG+Red =ABAIgG-/IgM-Black=ABA IgG-/IgM+
0.10
1.00
10.00
100.00
1000.00IL-6
IL-8
IP-10
MCP-1
MIG
MIP-1 ALPHA
MIP-1 BETA
TNF-ALPHA
Cytokine/chemokine expression. At the end of infusion, serum was taken to assesscytokine and chemokine expression changes versus pre-dose values in each subject (foldincrease shown) using the Luminex XMAP technology.
NSCLCMetastatic Melanoma
Triple-Negative Breast Cancer
Head and Neck Cancer
Phase Phase 1b/2 Phase 2 Phase 2 Phase 2
Combination Therapy Pembrolizumab Pembrolizumab Pembrolizumab Pembrolizumab
Patients 2nd line patients 2nd line patients- Pembro failure
2nd- 3rd line patients
- Pembro Naive
• Stable disease >3 mosPembro
• Pembro Failure
Number of Subjects 36 29 42 87
Randomization Single arm Single arm Single arm Single arm
Primary Endpoint PFS ORR ORR ORR
Secondary Endpoints Safety, PFS, OS Safety, PFS, OS Safety, PFS, OS Safety, PFS, OS
Initiation 3Q 2016 4Q 2016 4Q 2016 1Q 2017
Phase 2 Clinical Studies: Imprime + Pembrolizumab
24
Patients selected for Imprime-specific biomarker (Anti-Beta glucan Antibodies, ABA > than 20 μg/ml)
Pre Treatment Sample Post Treatment Sample
DAPITumorCD4CD8GrzB
Fold Increase vs Pre-TxCytotoxic T cells (CD8)
Total number = 28XProliferating = 33XActivated = 50X
Helper T Cells (CD4)
Total Number= 58XProliferating = 73XActivated = 24X
Lymphocyte Infiltration: Pre and On Tx Biopsy
Pre Treatment Sample Post Treatment Sample
NucleiTumor
Mac/MonoCD80PD-L1
Myeloid Character Post vs Pre TxMyeloid Infiltration 56X increaseCD80+ 100X increasePD-L1+ Myeloid 13X increase
Increased Myeloid Infiltration and Activation Post Treatment
Pre-Treatment Post-Treatment
% of Myeloid Cells CD80+: 6.34%% of Myeloid Cells PD-L1+: 0.90%% of Myeloid Cells CD206+: 18.45%% CD80+/CD206+ (M1:M2 ratio): 0.34
TumorCD163CD206CD80
% of Myeloid Cells CD80+: 13.79%% of Myeloid Cells PD-L1+: 14.88%% of Myeloid Cells CD206+: 3.11%% CD80+/CD206+ (M1:M2 ratio): 4.44
Evidence for increased M1:M2 Character Post TreatmentTranslational Research: Schedule of Assessments
Cycle Screening 1 2 3 4 5 6 10,Q4C EndofTrtmnt
Week Tubetype Upto-4 1 4 7 10 13 16 28
CBC/Diff:Preand4hrPostSOI ETDA X X X X X
PBMC:PreandPost Heparin X X X X
PAXGene (RNA):Pre-ImprimeandPostPembro PAXGene X X X X X
ABA:PreandPostImprime Serum X X X X X X X X X
Cytokines:PreandPostImprime Serum X X X X X X X X
ImprimePK:Pre,1.5hr postEOIImprime Serum X X
Pembo PK:PrePembro and3hrpostEOIPembro Serum X X
Biopsies(archival,pre-C1,pre-C3andupontimeofresponse/progression Tissue X X X
SOI:StartofInfusion
Imprime- Induced PD Effects Are Restricted to ABA + Subjects
0
20
40
60
80
100
Circu
lating
Immu
ne Co
mplex
es (E
q ug/m
l)
Longitudinal CIC
253967
10345570
Imprime Dose Week #1
Subjects
0
250
500
750
1000
1250
1500
Mono
cytes
(cell
/ul)
Monocyte Mobilization
25
67
10345570
Imprime Dose Week #1
Subjects
39
0
2500
5000
7500
10000
12500
15000
17500
20000
Neutr
ophil
s (ce
ll/ul)
Neutrophil Mobilization
25
67
10345570
Imprime Dose Week #1
Subjects
39
0
2500
5000
7500
10000
12500
15000
SC5b
-9 (ng
/ml)
Complement
25
67
103455
Imprime Dose Week #1
Subjects
39
70
0
5000
10000
15000
20000
25000
30000
MCP-1
(pg/m
l)
Cytokines
25
67
103455
Imprime Dose Week #1
Subjects
39
70
Biomarker + (ABA ≥ 20μg/ml)Biomarker – (ABA < 20μg/ml)
Immune Complex Monocyte Mobilization Neutrophil Mobilization
Complement Cytokines
Whole blood or serum was drawn from healthy volunteers at various time points before and after a single dose of Imprimeinfusion. ABA were measured in serum by ELISA. Circulating Immune complex formation was measured using theMicroVue Complement CIC-Raji Cell Replacement Kit. Cell mobilization was measured by complete blood cell counts, plusdifferentials. Monocyte and Neutrophil numbers are shown. Complement activity was measured by ELISA using the SC5b-9 Plus kits (Quidel). Cytokines and chemokines were measured in serum using Luminex XMAP technology. Fold over pre-dose values are plotted. Data from subjects who were treated with Imprime (4 mg/kg) and no pre-medications.
CONFIDENTIAL
Cycle 1 Wk 1-pre
Cycle 1 Wk 1-EOI
Cycle 2 Wk 4-pre
Cycle 2 Wk 4-EOI
Cycle 3 Wk 7-pre
Cycle 3 Wk 7-EOI
Cycle 4 Wk 10-pre
Cycle 4 Wk 10-EOI
Cycle 5 Wk 13-pre
Cycle 5 Wk 13-EOI
012345
10
20
30
40
fold
ove
r pre
-C1
SC5b9 Fold changes 103102
fold over Pre-C1
Cycle
1 Pre-
Infusion
Cycle
1 EOI
Cycle
2 Pre-
Infusion
Cycle
2 EOI
Cycle
3 Pre-
Infusion
Cycle
3 EOI
Cycle
4 Pre-
Infusion
Cycle
4 EOI
Cycle
5 Pre-
Infusion
Cycle
5 EOI
0
20
40
60
80
0
100
200
300
Patient 103102CIC vs ABA
CIC
CIC
ABAABA IgG (µg/m
l)
Cycle 1 Pre-Infusion
Cycle 1 EOI
Cycle 2 Pre-Infusion
Cycle 2 EOI
Cycle 3 Pre-Infusion
Cycle 3 EOI
Cycle 4 Pre-Infusion
Cycle 4 EOI
Cycle 5 Pre-Infusion
Cycle 5 EOI0
20
40
60
80
0
100
200
300
Patient 103102CIC vs ABA
CIC
CIC
ABAABA IgG (µg/ml)
Cycle
1 Wk 1
-pre
Cycle
1 Wk 1
-EOI
Cycle
2 Wk 4
-pre
Cycle
2 Wk 4
-EOI
Cycle
3 Wk 7
-pre
Cycle
3 Wk 7
-EOI
Cycle
4 Wk 1
0-pre
Cycle
4 Wk 1
0-EOI
Cycle
5 Wk 1
3-pre
Cycle
5 Wk 1
3-EOI
012345
10
20
30
40
fold
ove
r pre
-C1
SC5b9 Fold changes 103102
fold over Pre-C1
Circulating Immune complex formation was measured using a commercial immuno assay system (MicroVue Complement CIC-Raji Cell Replacement Kit). Complement activity wasmeasured by ELISA using the SC5b-9 Plus kits (Quidel).
TNBC 103102: ABA, Immune Complex Formation and Complement Activation TNBC Pt 103102: Induction of Imprime-Responsive Cytokines
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
5
10
15500600700800900
1000
pg/m
l
IL-8
IL-8
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
020406080
100
1000200030004000
pg/m
l
MIP-1 beta
MIP-1 beta
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
010203040
100200300
100015002000
pg/m
l
RANTES
RANTES
LOD1: 0.78LOD2: 0.99
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
50
100
150
pg/m
l
Eotaxin
Eotaxin
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
020406080
2000
4000
6000
pg/m
l
MCP-1
MCP-1
LOD1: 1.23LOD2: 2.43
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
20
40
50
100
150
pg/m
l
MIP-1 alpha
MIP-1 alpha
LOD1: 0.49LOD2: 1.32
Cytokines and chemokines were measured in serum using Luminex XMAP technology.
TNBC Pt 103102: Induction of Imprime-Responsive Cytokines
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
5
10
15
pg/m
l
GM-CSF
GM-CSF
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
5
10
50100150200250
pg/m
l
GRO-alpha
GRO-alpha
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
05
101520
2000
4000
6000
pg/m
l
IL-6
IL-6
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
1
2
3
4
5
pg/m
l
IL-7
IL-7
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
050
100150200
50000
100000
150000
pg/m
l
IL-1RA
IL-1RA
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
050
100150200
500
1000
1500
pg/m
l
IP-10 (CXCL10)
IP-10 (CXCL10)
LOD1: 0.51LOD2: 1.78
Cytokines and chemokines were measured in serum using Luminex XMAP technology.
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
10
20
30
pg/m
l
IL-18
IL-18
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
1
2
3
4
pg/m
l
IL-15
IL-15
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
50
100
150
200
pg/m
l
ITAC (CXCL11)
ITAC (CXCL11)
LOD1: 4.13LOD2: 6.4
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
500
1000
1500
2000
pg/m
l
SDF-1 alpha
SDF-1 alpha
LOD1: 2.6LOD2: 18.11
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
5
10
15
20
pg/m
l
IL-2
IL-2
Cycle 1 Week 1 PRE
Cycle 1 Week 1 EOI
Cycle 2 Week 4 PRE
Cycle 2 Week 4 EOI
Cycle 3 Week 7 PRE
Cycle 3 Week 7 EOI
Cycle 4 Week 10 PRE
Cycle 4 Week 10 E
OI
Cycle 5 Week 13 PRE
Cycle 5 Week 13 EOI
0
50
100200250300350400
pg/m
l
IL-22
IL-22
TNBC Pt 103102: Cytokine Induction
Cytokines and chemokines were measured in serum using Luminex XMAP technology.
TNBC Patient Melanoma Patient
0.1
1
10
100
1000GM-CSF
IL-7Eotaxin
GRO-alpha
IL-8
IP-10(CXCL10)
ITAC (CXCL11)
MCP-1
MIP-1alpha
MIP-1beta
RANTES
SDF-1alpha
IFN-alpha
IFN-gamma
IL-1alpha
IL-1betaIL-2IL-6TNF-alphaIL-12p70
IL-1RA
IL-10
IL-27
TNF-beta
IL-15
IL-18
IL-21
IL-17A
IL-22
IL-23
IL-4
IL-5
IL-9IL-13
IL-31
Chemokines
0.1
1
10
100
1000GM-CSF
IL-7Eotaxin
GRO-alpha
IL-8
IP-10(CXCL10)
ITAC (CXCL11)
MCP-1
MIP-1alpha
MIP-1beta
RANTES
SDF-1alpha
IFN-alpha
IFN-gamma
IL-1alphaIL-1beta
IL-2IL-6TNF-alphaIL-12p70IL-1RA
IL-10
IL-27
TNF-beta
IL-15
IL-18
IL-21
IL-17A
IL-22
IL-23
IL-4
IL-5
IL-9IL-13
IL-31
C1 C2 C3InflammatoryCytokines
Th2
Th17
Cytokine Profiles: TNBC Patient and Melanoma Patient
Cytokines and chemokines were measured in serum using Luminex XMAP technology. Eachring radiating from the center represents an order of magnitude increase in expression.
Imprime andPembro:CPINaïveTNBC Imprime +Pembro:EarlyExperience
CONFIDENTIAL
Phase 2 Imprime + Pembrolizumab: Early Clinical Experience
Triple Negative Breast Cancer Patient 103102Objective ResponderTumor Shrinkage- 44% evident at week 6Tumor Shrinkage > 50% for > 28 weeksTumor Biopsy at ~ week 18- no tumor, fibrotic tissueIncreased ABA after Imprime dosingEvidence for Imprime-induced cytokines/ chemokines
Metastatic Melanoma Patient 103103Tumor Biopsy at week 6 suggests activated T cell InfiltrationTumor Biopsy at week 6 shows myeloid infiltration and activationEvidence for Imprime- induced cytokines/ chemokinesPatient off therapy at week 18
Early clinical experience provides evidence of clinical response (TNBC) and 1st proof of mechanism- i.e. that Imprime may drive immune activation at the tumor bed