Local immunotherapy with ONCOS-102 shapes harmful tumor associated CD68+ macrophages to become beneficial cells that correlate with increased overall survival
Pesonen S1, Lundin J2, Linder N2, Turkki R2, Ristimäki A3, Joensuu T4, Kairemo K4, Partanen K4, Alanko T4, Jäger E5, Karbach J5, Wahle C5, Hemminki A6, Backman C1, von Euler M1, Hakonen T1, Ranki T1, Vuolanto A1, Jaderberg M1. 1Targovax Oy, Helsinki, Finland, 2Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland, 3Division of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital, Helsinki, Finland, 4Docrates Cancer Center, Helsinki, Finland, 5Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany, 6Cancer Gene Therapy Group, Haartman Institute, University of Helsinki, Helsinki, Finland.
ONCOS-102 (Ad5/3-D24-GMCSF) is a tumor-targeted oncolyticadenovirus coding for human GM-CSF
Intratumoral ONCOS-102 induces a systemic CD8+ T cell response against patient’s unique cancer cells:
INTRODUCTION
Innate Immune System Adaptive Immune System Anti-tumor Immune Response
”Recognition of threat” ”T cell activation” ”Immune attack”
tumor lymph node tumor
metastasisStrongco-stimulation
ONCOS-102
T cellactivation
SystemicT cell attack
Multiple activatory mechanisms:• Immunogenic cell death• Pro-inflammatory cytokines• Release of tumor antigens• Local GMCSF expression
Targeted anti-tumor immune response:• ONCOS-102 teaches immune
system to recognize unique cancer cells of each patient
Systemic anti-tumor immune response• In situ vaccination• Immunological memory
provides long term protection
• High density of tumor infiltrating CD68+ macrophages at baseline was associated with short survival suggesting that these macrophages had tumor promoting phenotype
• ONCOS-102 –triggered CD68+ cell infiltration correlated with prolonged survival suggesting that these cells had different phenotype from CD68+ cells present in tumors before ONCOS-102 treatment
• Infiltration of multiple innate and adaptive immune cell populations after ONCOS-102 administration correlated with increased OS
• ONCOS-102 has potential to activate immunologically silent tumor and reduce the local immune suppression in advanced tumors
Phase I study - design 12 last-line patients with 100% chemo refractory solid tumors were treated at 3 dose levels (3+3+6 pts)
0 1 4 8 15 29 57 113 141 169Day
ONCOS-102
85
Biopsy
PET / CT
X X X X X X X X XX X X
X X X
PBMCs X X X X X X X X X
Dose cohorts: 3x1010, 1x1011, 3x1011 viral particles
01 02 04 06 08 09 13 14 15 17 18 19
CD68
(Abs
olute
expr
essio
n)
Patient number
0.000
0.020
0.040
0.060
0.080
0.1000.150
Heterogeneity in CD68+ macrophage density was seen in tumors before and after ONCOS-102 administration
Pt 06
Pt 02
Pt 19
Pt 08
Baseline After
CD68+ cells in tumors (IHC)
Figure 3. The density of CD68+macrophages in tumor biopsies wasassessed by quantitativeimmunohistochemistry. A correlationbetween absolute expression levelof CD68+ macrophages in tumorsand overall survival (OS) wasassessed by Spearman´s rankcorrelation analysis.
Infiltration of innate and adaptive immune cells into tumors was seen following ONCOS-102 administration
1,E-02
1,E-01
1,E+00
1,E+01
1,E+02
1,E+03
1,E+04
1,E-02
1,E-01
1,E+00
1,E+01
1,E+02
1,E+03
1,E+04
1,E-02
1,E-01
1,E+00
1,E+01
1,E+02
1,E+03
1,E+04 CD68+ macrophages CD8+ T cells CD4+ T cells
Immu
ne ce
lls in
tumo
rs(F
old ch
ange
from
base
line)
01 02
04
0608 09
13 14
1517
18
19
01
02 04
06
0809
13
14
1517
18
19
01
02 04 06
08
09 1314
1517
18
19** *
** *
01 02 04 06 08 09 13 14 15 17 18 19
SD at 3 months (RECIST)
PD at 3 months (RECIST)
Post-treatment induction of tumor-specific CD8+ T cells*
CD68+ cells in baseline tumors were associated with short OS while post-treatment increase in CD68+ cells correlated with increased OS
Post-treatment increase in tumor infiltrating innate and adaptive immune cells was associated with increased OS
CD68
+ ce
lls in
tumo
rs(a
bsolu
te ex
pres
sion)
Survival (months)
Tumor afterONCOS-102
Tumor beforeONCOS-102
Baseline After ONCOS-102
Survival (months)
1,E-04
1,E-03
1,E-02
1,E-01
0 10 20 301,E-03
1,E-02
1,E-01
1,E+00
0 10 20 30
(alive)
(alive)
r= - 0.59, p= 0.04 r= 0.71, p= 0.01
Figure 2. Immune cells in tumors were assessed by IHC before and after ONCOS-102 administration.
CD68
+ ce
lls in
tumo
rs(a
bsolu
te ex
pres
sion)
1,E-02
1,E-01
1,E+00
1,E+01
1,E+02
1,E+03
0 5 10 15 20 25
CD11c+(Dendritic cells)
1,E-01
1,E+00
1,E+01
1,E+02
1,E+03
1,E+04
0 5 10 15 20 25
CD8+(Cytotoxic T cells)
1,E-01
1,E+00
1,E+01
1,E+02
1,E+03
0 5 10 15 20 25
CD3+(All T cells)
1,E-01
1,E+00
1,E+01
1,E+02
1,E+03
0 5 10 15 20 25
CD163+(Macrophages)
Immu
ne ce
lls in
tumo
rs(F
old-ch
ange
from
base
line)
Survival (months) Survival (months) Survival (months)Figure 4. Frequency of immune cells in tumor biopsies were measured by immunohistochemistry before and afterONCOS-102 administration. A correlation between post-treatment increase in immune cells and overall survival (OS)was assessed by Spearman´s rank correlation analysis.
(alive)(alive) (alive)
(alive)
CONCLUSIONS
Figure 1. Sequential biopsies were collected at baseline and after ONCOS-102 treatment initiation and analyzed for the presence of immune cells by immunohistochemistry (IHC) in digitally scanned samples. Readout of the expression levels for immune cells was performed by the use of an image analysis algorithm based on color deconvolution and segmentation of the IHC stained cells.
RECIST evaluation not done
Survival (months)
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