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CGTG-102 oncolytic virus in breast cancer (IIR Conference May 5, 2010)
1. Gene therapy for
treatment of breast
cancer
cancer
Akseli Hemminki, MD, PhD
Specialist in Oncology
Specialist in Oncology
K. Albin Johansson Research Professor,
Finnish Cancer Institute
Cancer Gene Therapy Group
Molecular Cancer Biology Program &
Transplantation Laboratory &
Haartman Institute & FIMM
University of Helsinki and Disclaimer: AH is co‐founder and shareholder of
Disclaimer AH is co founder and shareholder of
Oncos Therapeutics Inc., a company founded for
Helsinki Univ. Central Hospital
facilitating clinical trials with oncolytic viruses
3. Cancer is not a beaten
disease
CANCER
> 1/2 of people alive today will get cancer*
• 1/3 of us will die of cancer
• few disseminated solid tumors can be cured with
currently available treatments
Novel treatments are needed!
* Jemal CA Cancer J Clin 2005 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3
4. Bert Vogelstein:
Cancer
Cancer
therapeutics
after the cancer
ft th
genome project
(ASCO 2009)
( )
Sequencing of tumor genomes revealed hundreds of mutations in each (Wood
S i ft l dh d d f t ti i h (W d
Science 2007, Parsons Science 2008)
Combination different in each tumor ‐> Each tumor is an individual
‐> Each tumor would require a different combination of inhibitors
‐> For long term efficacy, each pt would have to be treated with hundreds of inhibitors
‐ > Impossible because of side effects
> Impossible because of side effects
All of these mutations seem to fall in 12 pathways (Jones Science 2008).
‐ > Use pathway selective drugs (Vogelstein ASCO 2009)
For example, p16/Rb pathway selective oncolytic virus
http://cgap.nci.nih.gov/ A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 4
5. Deletion mutant oncolytic
adenoviruses: ∆24
d i ∆24
Fueyo Oncogene 2000
Heise Nature Med 2000
E2F • S-phase
E2F Rb • Virus replication
• normal cell
• wt Ad Rb E1A & cell lysis
E1A
24 bp deletion in Rb
binding site of E1A
• normal cell E2F Rb E2F Rb • No S phase entry
S-phase
• ∆24 • No virus replication
• Replication in cells ∆24-E1A ∆24-E1A
mutant in Rb-p16
Rb p16
pathway E2F E2F
• cancer cell E2FE2F E2FE2F • S-phase
• ∆24 • Virus replication
• Includes all human ∆24 E1A
∆24-E1A ∆24-E1A
∆24 E1A & cell lysis
cancers
(Sherr Science 1996) A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 5
6. How Far is Clinical Gene Therapy ?
Phase I: Safety and toxicity ?
Phase II: Any evidence of efficacy ?
Phase II: Any evidence of efficacy ?
Phase III: Proof of efficacy
(randomization)
N= 1579
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 6
7. Mutation compensation
Randomized ph. III trial: head & neck ca.
‐ Ad p53 + radiation vs radiation alone
Ad‐p53 + radiation vs. radiation alone
‐ 67% vs. 24% CR (N= 82, P<0.01)
‐ Pan J Clin Oncol 2008
‐ Gendicine® for sale in China
‐ More than 10 000 patients treated
Promoter p53 gene
p53 gene pA
Infection of cells
Infection of cells
Normal cells Cancer cells
Press release 23 Jul 2008: Ad‐p53 (Advexin®) with p53 mutation
with healthy p53
phase III SCCHN trial positive in US: not
approved by FDA Cell death, also sensitation to
chemotherapy and radiation
h h d di i
No cell death
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 7
8. Prodrug converting enzymes
Randomized Phase III trial for glioma (ASPECT):
• Ad-TK + standard care vs. standard care: 1.43
HR (p=0.02)
(p )
Ad coding for
Ad di f
• 40d increase in median survival
thymidine TK • More temozolomide use in control group due to
kinase (TK)
non blinded
non-blinded gene therapy-> dilution of results
therapy >
• EMEA did not approve because non-standard
end-point (time to re-intervention or death)
o to c p od ug
Non‐toxic prodrug
Advantage vs.
Ad t
= ganciclovir
mutation
compensation:
bystander
effect via gap
Activated
Activated junctions
CHALLENGE: even with bystander
toxin
Cell death effect, can we get effective penetration
into established tumors ?
SOLUTIONS: locally amplifying
systems A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 8
10. H101 (Oncorine®) phase III trial in
advanced head and neck cancer
d dh d d k
H101 (≈dl1520=ONYX‐015 descibed earlier in the US)
Randomized phase III trial (N 105)
Randomized phase III trial (N=105)
H101 + cisplatin + 5‐FU vs. cisplatin + 5‐FU
CR+PR = 79% vs. 38%, P<0.0001
CR PR 79% 38% P 0 0001
Mild tox: flu‐like symptoms, injection site pain
More than 800 patients now enrolled
H101 approved in China
H101 approved in China
Yu Curr Cancer Drug Targets 2007
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 0
11. Cancer Gene Therapy is maturing
as a treatment approach
h
Safety has been good – over 15 000 pts treated with both repli‐
cation deficient and replication competent (oncolytic) viruses
Recent randomized trials (N=5) have confirmed efficacy of even
early generation approaches*
early generation approaches*
No patients w/ metastatic cancer cured: much work remains
TUMOR PENETRATION NEEDS IMPROVEMENT
Replication competent oncolytic viruses
Replication competent oncolytic viruses
Transcriptional tumor targeting (activation only in tumor)
Transductional tumor targeting (gene delivery only to tumor)
g g (g y y )
Armed oncolytic viruses
* Immonen Mol Ther 2004, Li Clin Cancer Res 2007, Yu Curr Cancer Drug
Targets 2007, Pan J Clin Oncol 2008, Ylä‐Herttuala ESGCT 2008, A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 1
12. Our own experience with oncolytic
adenovirus (update 5 Feb 2010)
adenovirus (update 5 Feb 2010)
• 171 patients since Nov 07. 8 different viruses
• All had metastatic solid tumors progressing after routine
All had metastatic solid tumors progressing after routine
treatments (chemo, radiation, etc)
• Written informed consent. Full GCP implemented.
• Side effects: gr. 1‐2 flu‐like symptoms, fever, fatigue, pain in all pt
Side effects: gr 1 2 flu like symptoms fever fatigue pain in all pt
• SAE in < 5% (eg. pain, embolus, thrombosis, cholecystitis)
• No treatment related deaths so far (compare to chemo, surgery)
• Clinical benefit (imaging CR, PR, SD): 61% overall, 76% best virus
• Some patients have benefited for > 2 years (= length of follow‐up)
• Additive/synergistic benefits from 2nd ‐ 12th treatments
Additive/synergistic benefits from 2 treatments
• Long term (>300 d) survival in 50% with best virus
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 2
13. Inclusion and exclusion criteria for
oncolytic virus treatment
oncolytic virus treatment
Inclusion criteria Exclusion criteria
Solid tumor confirmed brain met. or glioma
Refractory disease = failed
Refractory disease = failed organ transplant, HIV
g p ,
treatments for which there is severe cardiovascular, metabolic
strong scientific evidence* or pulmonary disease
Good performance status: WHO 0‐ Elevated serum bilirubin
Elevated serum bilirubin
2. (WHO 3‐4 safe but less efficacy) Serum AST or ALT > 3 x normal
Written informed consent
Written informed consent Thrombocytes < 75.
y
* In most cases this means 1st line chemotherapy for metastatic
disease, and in some cases several lines of chemotherapy (eg.
di di l li f h th (
breast, ovarian and colorectal cancer)
In practice, the median number of prior chemo regimens is 3 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 3
14. Findings possible only in pts: Mechanisms of anti‐
tumor efficacy
y inflammation
3. Induction of
cytotoxic T‐cells
1. Killing of differentiated tumor cells
1 Killing of differentiated tumor cells against tumors
against tumors
6 CD8+
5
vitiligo
E+8
4
10E
3
2
0 17 41 48
2. Killing of tumor initiating ”stem” cells
4. Induction
of specific
immunity
against
tumor
epitope
(survivin)
Cerullo Cancer Res in press 2010 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 4
Eriksson Mol Ther 2007, Bauerschmitz Cancer Res 2008
15. Case: Systemic efficacy of Ad5/3‐Cox2L‐D24 in
chemo refractory neuroblastoma
chemo refractory neuroblastoma
• Ad5/3‐Cox2L‐D24 replicates in cells overexpressing Cox2 and
defective in the Rb/p16 pathway
Previous
Previous
treatments: • 6 yr old boy, WHO 1
Vincristine + • Progressive disease in bone marrow, left kidney, lymph nodes.
cis/carboplatin • Single oncolytic adenovirus treatment: i v intratumoral
cis/carboplatin Single oncolytic adenovirus treatment: i.v., intratumoral.
+ etoposide + • Gr. 1 stomach pain, diarrhea, flu‐like symptoms, liver enzymes
cyclophospham • 4 wk later: complete response in bone marrow, partial
ide response in primary
i i
Doxorubicin +
etoposide +
iphosphamide;
iphosphamide;
Intensive chemo
and autologous
stem cell
stem cell
transplant;
Oral 13‐cis‐retinoic
acid
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 5
16. Ad5/3‐
Cox2L‐D24
in neuro‐
blastoma
→ CD56 staining (brown) for
tumor cells in bone
marrow
→ Imaging of primary before
and after treatment
Oncolytic replication alone is usually
Oncolytic replication alone is usually
not enough to cure advanced tumors
→ Increase in cytotoxic T‐cells
→→ Increase in virus
neutralizing antibodies
→→→ Extended presence of
virus in blood
0
→→→→ Cox2 expression in
6540
tumor (reason for
( f
500
selectivity and efficacy)
Pesonen Submitted 2008| 1 6
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0
Pesonen Acta Oncol 2010
17. Higher efficacy with a second round of
treatment: role of immune response ?
treatment: role of immune response ?
• Metastatic pancreatic ca. WHO 2
• Prior gemcitabine and gemcitabine chemoradiation
• Second round of treatment with Ad5‐24‐RGD (Bauerschmitz
Cancer Res 2002) produced response
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 7
Pesonen in preparation
18. Improving antitumor immunity: oncolytic
adenoviruses coding for GM‐CSF
adenoviruses coding for GM CSF
Cerullo Mol Ther ASGT suppl 2009
GM‐CSF
• GM‐CSF is the most potent inducer of anti‐ GM-CSF
GM CSF anti G CS
tumor immunity (Dranoff Immunol Rev 2002)
GM-CSF
• GM‐CSF in E3: expression starts at 8h
⇒ GM‐CSF expressed only in cells that allow
replication of the virus
• Hi h expression at tumor, l systemic
High i low i
GM CSF
GM-CSF
GM-CSF
Cerullo Cancer Res in press 2010 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 8
19. GMCSF approach validated in first approved
immunotherapy product 29 Apr 2010
immunotherapy product 29 Apr 2010
Provenge (Sipuleucel‐T)
Hormone
Hormone
refactory prostate
cancer
Collection of
Collection of
white blood cells
Gene therapy w/
PAP & GMCSF to
activate antigen
presenting cells
Return cells into
patient
ti t
First product
using active
immunotherapy
PAP = prostatic acid
phosphatase
GMCSF = granulocyte
macrophage colony
stimulating factor
i l i f
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 1 9
www.provenge.com
20. GM‐CSF can enhance antigen presentation
and induce NK and cytotoxic T cells
and induce NK and cytotoxic T‐cells
Tumor cells killed with 3 mechanisms:
- Oncolytic effect of virus replication
- NK cell mediated direct cell killing
- DCs mediated tumor specific immunity
NK NK CD8+ CD8+ CD8+
NK NK CD8+ CD8+
CD8+
NK CD8+ CD8+
NK
= personalized
NK Ca Ca cancer vaccine
GM-CSF Ca
Ca Ca Ca
C DC
Ca Ca Ca
GM-CSF A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 0
22. Syrian hamsters cured of HapT1 tumors
with Ad5D24 GMCSF: protection from
with Ad5D24‐GMCSF: protection from
HapT1 challenge
N=5
**
***
***
N=5
*
N=5
Cerullo Cancer Res in press 2010 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 2
23. Syrian hamsters cured of HapT1 tumors
with Ad5D24‐GMCSF: no protection
with Ad5D24 GMCSF: no protection
from HaK challenge
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 3
Cerullo Cancer Res in press 2010
24. Efficacy Ad5‐D24‐GMCSF: Single round of treatment
Neutralizing Antibody Titer
g y Virus Load in Serum Response
p
Patient Dosea Primary Week post-treatment Days post-treatment
code (VP) Tumor RECISTa
0 1 2 4 0 1 2 3-7 8-12 21-40 Density/o Marker Survival
ther
C3 8x109 Jejunum ca 0 1024 16834 0 0 <500 <500 0 MR 120
M3 1 1010
1x10 HCC 0 16384 4096 0 0 4896 0 0 0 SD (+5.2%)
( 5 2%) 548b
O12 3.6x1010 Ovarian ca 0 16384 16384 0 0 0 0 0 SD (+7.7.%) SD 106
O14 1x1011 Ovarian ca 64 64 0 0 0 <500 0 0 CR (-100%) CR 528b
G15 1x1011 Gastric ca 1024 16384 16384 0 0 565 <500 0 0 -4.6% 308b
K18 2x1011 NSCLC 16384 16384 16384 0 <500 0 0 856 PD (+15%) 59
T19 2x1011 Thyroid ca 0 16384 0 765 <500 <500 0 0 SD (-8.9%) MR 490b
U89 2x1011 Renal ca 64 16384 0 0 0 PD (+13%) 144
S100 2x1011 Leiomyosar 0 0 16384 0 <500 <500 PD (+39%) 121
c
S108 2x1011 Synovial 0 0 256 0 <500 <500 0 PD (+59%) 74
sarc
M50 2.5x1011 Mesothelio 256 16384 0 0 <500 0 SD (-5.7%) 403b
ma
R8 3x1011 Breast ca 64 16384 0 <500 <500 0 CR (-100%) PR 447b
M32 3x1011 Mesothelio 0 256 16384 0 0 0 0 PDc 125
ma
X49 3x1011 Cervical ca 16 4096 1024 0 4290 1211 PD (+55%) -27% 92
I52 3x1011 Melanoma 0 256 256 0 576 PD (+25%) 112
I78 3x1011 Choroideal 0 64 0 44876 <500 63
mel
C58 4x1011 Colon ca 256 16384 16384 0 1978 4236 PD (+37%) 118
R73 4x1011 Breast ca 0 256 1024 0 <500 25787 SD (-3.6%) 245b
O88 4 1011
4x10 Ovarian
O i ca 0 1024 0 <500 yesd PR 126
O9e 2x1011 Ovarian ca 16384 16384 0 2133f MR (-20%) 142
Overall efficacy (radiology)
Summary of side effects
- CR 2/16
- All pts: gr 1-2 flu-like symptoms, fatigue, fever
- MR 1/16
- One gr 3 ileus (OvCa pt w similar previous episodes)
- SD 5/16 Cerullo Cancer Res in press 2010
- Lab: gr 1-2 AST/ALT, hypo-K+, m i n k i | hypo-Na+ | 2 4
A k s e l i H e m gr 1-3 5 M a y 2 0 1 0
- PD 8/16
25. Systemic efficacy of Ad5‐D24‐GMCSF in
injected and non injected tumors: virus
injected and non‐injected tumors: virus
circulation, immune response
• 60 yr mesothelioma patient, asbestos exposure
60 yr mesothelioma patient asbestos exposure
• Prior treatment with cisplatin+pemetrexed
• WHO 1
• Single intrapleural and i.v. injection
Single intrapleural and i v injection
• More prominent reduction of non‐injected tumor than injected tumor
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 5
Cerullo Cancer Res in press 2010
26. Complete response in OvCa pt
with small disease burden
ith ll di b d
Operation, adjuvant CEF x6, taxol+carbo x6, docetaxel,
O ti dj t CEF 6 t l b 6 d t l
bevacizumab, topotecan, erlotinib, aromatase inhibitor
Progressive disease, WHO 1
Single intraperitoneal treatment
Complete response (CT, markers) for 9 mo
Cerullo Cancer
Cerullo Cancer
Res in press
2010
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 6
27. Rapid response upon re‐treatment with
GM CSF coding oncolytic
GM‐CSF coding oncolytic adenovirus
• Peritoneally metastatic ovarian cancer since 2005.
• 5 lines of chemo (paclitaxel‐carbo, liposomal doxorubicine,
gemcitabine+carbo, gemcitabine, topotecan)
• Progressive disease, WHO 1
• 52.5% tumor size reduction in 17 days after 2nd treatment
y
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 7
Cerullo Cancer Res in press 2010
28. Long term survival in 1/3 of patients
treated with Ad5 D24 GMCSF
treated with Ad5‐D24‐GMCSF
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 8
Cerullo Cancer Res in press 2010
29. Immunological response to GM‐CSF coding
oncolytic adenovirus: against virus or tumor?
oncolytic adenovirus: against virus or tumor?
3 h before CT guided injection (3ml 10 min after
6 CD8+
5
10E+8
8
4
3
2
0 17 41 48
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 2 9
30. king of MHC I
Block
Ad5 (hexon) Specific
Immunity
Cerullo Cancer Res in press 2010 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 0
31. king of MHC I
Block
Tumor‐specific
Immunity y
(Survivin)
Cerullo Cancer Res in press 2010 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 1
32. Inflammation due to virus and/or GM‐
CSF can falsely increase tumor markers
CSF can falsely increase tumor markers
and enlarge tumors
Virus replication • 59 old man with esophageal cancer
59 old man with esophageal cancer
activates tumor
cell metabolism • Prior chemo: oxaliplatin+capesitabine,
oxaliplatin, docetaxel, irinotecan‐
paclitaxel, cyklo‐doxo‐cisplatin, oxali‐
irino‐cetuximab, capecitabine
• Progressive disease WHO 1
• Intratumoral and i.v. virus injection
Necrosis
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 2
33. Baseline 3 months 6 months
Senzer J Clin Oncol 2009
Effects of
Effects of
oncolytic
inflammation
inflammation
on tumor size
Reid Cancer Res 2002 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 3
35. Improving transduction to
improve oncolysis
i l i
Coxsackie‐ LOW CAR ‐
LOW CAR ‐
adenovirus
receptor (CAR):
key to Ad entry
key to Ad entry
LOW GENE
DELIVERY !
CAR IS AN
CAR IS AN
ADHESION
MOLECULE ‐
LOW
LOW
EXPRESSION
IN TUMORS
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 5
36. Increasing infectivity of target cells:
transductional targeting
Non-targeted Targeted
T t d
adenovirus adenovirus
Adenovirus
receptor CAR
High Low
transduction Benign cell transduction
Tumor associated
receptor
p
Low High
transduction Cancer cell transduction
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 6
37. Serotype chimerism for tumor targeting
120
Ad5 CAR 100 3x 1x108 VP i.p.
Ad3 receptor
80
% Survival
Negative
M1
60
40 Kanerva Mol Ther 2003
20
0
15 25 35 45 55 65 75 85 95 105 115 125 135
Day
Kanerva Clin Cancer Res 2002
1,E+06 Biodistribution
Ad3 receptor CAR 1,E+05
RLU / mg protein
1,E+04
1,E+03
Ad5/3 1,E+02
,
with knob domain
1,E+01 *
from Ad3
1,E+00
Kanerva Mol Ther 2002k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 7
A
38. Ad5/3‐D24‐GMCSF = CGTG‐102
Fiber chimerism for enhanced
transduction of cancer cells
CGTG‐102 (Ad5/3‐D24‐GMCSF): 76% NK
Replication in cells mutant in Rb‐p16
clinical benefit in advanced ca. pts
clinical benefit in advanced ca pts
pathy
NK
NK
CD8+
CD8+
CD8+
CD8+
NK CD8+
(Koski et al submitted 2010)
Includes most human cancers
NK
CD8+
CD8+
CD8+
NK
GM‐CSF can enhance antigen
NK Ca Ca
presentation and induce NK and
GM-CSF Ca
cytotoxic CD8+ T‐cells Ca Ca DC
Ca
Expressed under the control of E3
Ca Ca
Starts at 8h Ca
= personalized
Expression coupled to virus GM-CSF cancer vaccine
replication
p
Koski Submitted 2010 A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 8
39. Cancer stem cell (CSC) hypothesis
CSC Committed progenitors cells:
Rapid replication
PCa Limited lifespan
Self-renewal: fibro
CSC Slow replication other
Unlimited lifespan inflam vasc
Ca Ca
Most ca. treatments select target Ca
cells based on higher replication Ca Ca Ca Ca
Ca stem cells may not actively
y y
replicate: not killed Ca
C Ca Ca
Differentiated Ca
Ion transporters remove drugs ca. cells
from cells: not killed CSC Ca
Tumors
T mors are mixed
mi ed
Clinical research may have missed populations of cells
CSC specific agents A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 3 9
41. Survival of Overall survival
Serial treatment
patients treated
patients treated 50% survival 320 days
50% survival = 320 days
Survival at 300 days = 50%
with CGTG‐102 N= 23
(Ad5/3 D24
(Ad5/3‐D24‐
GMCSF)
Overall survival
All treatments
50% survival = 157 days
Survival at 300 days = 34% All patients were chemo refractory and
N= 144 progressing at treatment
progressing at treatment
Overall clinical benefit in imaging = 76%
Criteria: death due to any cause
Censoring: alive at last follow up
Censoring: alive at last follow‐up
Median overall survival of chemotherapy
resistant patients 30‐115 days (eg.
Vigano Palliat Med 2000, Llobera Eur J of
Cancer 2000)
C 2000)
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 4 1
43. Summary of breast cancer treatment with
oncolytic adenoviruses (26 Apr 2010)
oncolytic adenoviruses (26 Apr 2010)
Patient No. treatments Safety Radiology Markers
• Overall any benefit
Overall any benefit
1 R8 6 Gr. 1-2 AE only CR PR 11/16 (69%)
MR
2
3
R10
R34
2
2
Gr. 1-2 AE only
Gr. 1-2 AE only PD
• Imaging
4
5
R39
R42
1
1
Gr. 1-2 AE only
Gr. 1-2 AE only
MR
MR
– CR 1/9
6 R55 2 Gr. 1-2 AE only PD. Density PD – SD 2/9
response
7 R73 6 Gr. 1-2 AE only SD
– other response:
other response:
8 R77 1 Gr. 1-2 AE only 2/9
PD
9
10
R85
R161
1
2
Gr. 1-2 AE only
Gr. 1-2 AE only
– PD 6/9
11
12
R170
1 0
R172
3
1
Gr. 1-2 AE l
G 1 2 A only
Gr. 1-2 AE only
PD
• T
Tumor markers
k
13 R184 5 Gr. 1-2 AE only PD.
response
Effusion – PR 1/13
14 R191 3 Gr.
Gr 1-2 AE only PD SD – MR 5/13
/
15
16
R195
R196
3
3
Gr. 1-2 AE only
Gr. 1-2 AE only
PD
PD PD
– SD 3/13
17 R201 4 Gr. 1-2 AE only SD SD – PD 4/13
18 R203 3 Gr. 1-2 AE only SD MR
19 R223 1 Gr. 1-2 AE only MR
20 R247 2 Gr. 1-2 AE only
21 R248 3 Gr. 1-2 AE only A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 4 3
44. Complete response in breast cancer
patient with low tumor load
patient with low tumor load
• 60 yr woman. WHO 2
• Progressing after 7 lines of chemotherapy
• 3x10e11 VP of Ad5‐D24‐GMCSF intraperitoneally and intrapleurally
• Complete response for 26 mo (ongoing). Disappearance of pleural effusion.
• Persistent ascites. Tumor markers not zero
Cerullo Cancer
Res in press
Res in press
2010
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 4 4
45. Overall survival of breast cancer patients
treated with oncolytic adenoviruses
treated with oncolytic adenoviruses
(26.4.2010)
All breast cancer
All b t
patients treated
with oncolytic
with oncolytic
Overall survival
adenoviruses 50% survival = 142 days
All patients were
p Survival at 200 days = 43%
Survival at 600 days = 30%
chemo refractory N= 20
and progressing
at treatment
tt t t
Criteria: death
due to any cause
due to any cause
Censoring: alive
at last follow up
at last follow‐up
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 4 5
46. Summary Overall survival of
breast ca patients
treated with
treated with
oncolytic Ad
Clinical proof‐of‐principle available
for many ca. gene therapy approaches
y g py pp
Safety has generally been excellent
Effective gene delivery continues to be key to efficacy
Oncolytic viruses amplify and help in tumor penetration
Anti‐viral and anti‐tumoral immunity key in efficacy
Clinical benefit 76% with our best virus CGTG‐102 (N=110)
Clinical benefit 76% with our best virus CGTG 102 (N=110)
50% overall survival at 300d with CGTG‐102
Earlier treatment and smaller tumor load increase benefits
CGTG‐102 now being tested in clinical trial
Clinical trials very expensive (3.5 mil€ for phase 1‐2 with 21 pts)
A k s e l i H e m m i n k i | 5 M a y 2 0 1 0 | 4 6
47. Acknowledgements
Akseli Hemminki Marko Ahonen Suvi Parviainen Institut Catala Univ. Helsinki & HUCH:
d’Oncologica: Petteri Arstila
Sari Pesonen Karoliina Autio Maria Rajecki Petri Bono
Laura Ahtiainen
La ra Ahtiainen Iulia Diaconu
I lia Diacon Tuuli Ranki
T li Ranki Ramon Alemany
a o e a y
Pekka Häyry
P kk Hä
Sophie Escutenaire João Dias Noora Rouvinen U. Washington Krister Höckerstedt
Vincenzo Cerullo Kilian Guse Andre Lieber Helena Isoniemi
Kalevi Kairemo
Anna Kanerva Theresia Gutmann Päivi Hannuksela Tuula Kiviluoto
Minna Oksanen
Minna Oksanen Otto Hemminki
Otto Hemminki Kikka Holm
Kikka Holm Transgene
Monika Lusky Jorma Paavonen
Jorma Paavonen
Anniina Koski Eerika Karli Risto Renkonen
Ilkka Liikanen U. Ottawa Ari Ristimäki
Petri Nokisalmi John Bell Mirja Ruutu
Jarmo Salo
Kalle Saksela
Kalle Saksela
Ulf‐Håkan Stenman
The Patients Mikko Tenhunen
Pekka Virkkunen
Timo Joensuu
Tuomo Alanko
Tuomo Alanko Pekka Simula Grant support:
Grant support:
Saila Eksymä‐Sillman Timo Ahopelto ERC
Anu Koskela Charlotta Backman Academy of Finland
Mauri Kouri Elina Haavisto ASCO
Jenni Kylä‐Kause Lotta Kangasniemi Biocentrum Helsinki
Leena Laasonen
Leena Laasonen Biocenter Fi l d
Bi t Finland
Aila Karioja‐Kallio
Satu Kauppinen Sigrid Juselius Foundation
Kaarina Partanen Maija Salo
University of Helsinki
Marina Rosliakova Mikko Salo
HUCH Research Funds (EVO)
Antti Vuolanto