Sarcoma Immunotherapy: The Future Is Near!
Transcript of Sarcoma Immunotherapy: The Future Is Near!
Sarcoma Immunotherapy:
The Future Is Near!
Seth M. Pollack, MD
Assistant Member
Outline
1. Introduction
2. Immune Response to Sarcoma Subtypes
3. Targeting NY-ESO-1
4. Looking into tumors
© Fred Hutchinson Cancer Research Center 2
Outline
1. Introduction
2. Immune Response to Sarcoma Subtypes
3. Targeting NY-ESO-1
4. Looking into tumors
© Fred Hutchinson Cancer Research Center 3
Sarcoma is a heterogeneous group of diseases
© Fred Hutchinson Cancer Research Center 4
Sarcoma (1% of all cancer - percentages include children and adults)
Bone Sarcomas
(10%):
•Osteosarcoma
•Ewings Sarcoma
•Chondrosarcoma
•Giant Cell Tumor
•Other
Soft Tissue Sarcoma (STS)
GIST (18%)
RMS
Other “special” STS:
Kaposi’s
DFSP etc.
Non-GIST
Non-RMS
Not special
STS:
Or, in other
words, what I
usually call: STS
Ducimetriere et al 2011
Is STS really that rare?
Rare cancers are more than 25% of all adult cancers.
Approximately 12,000 Americans are diagnosed with STS annually (non-gist,
per American Cancer Society).
5000 people die annually.
Rare cancers lead to important scientific breakthroughs:
•Merkel Cell Carcinoma – 1500 patients/year
•ALL – 6590 patients/year
•Hodgkins Lymphoma – 8,500 patients/year
•Allogeneic transplant - 8000 patients/year
•Testicular cancer – 8720 patients/year
Greenlee et al. et al 2010
There are over 50 STS subtypes
Ducimetriere et al 2011
Total=438
Undifferentiated Pleomorphic Sarcoma (UPS)
Liposarcoma
Leiomyosarcoma
Other
Synovial
UPS – very highly mutated subtypes
LMS – less than UPS, but also highly mutated
SS – most common translocation associated sarcoma
Liposarcoma – genetically “simple”
“Liposarcoma” is actually at least 3 diseases
© Fred Hutchinson Cancer Research Center 7
Well-
differentiated
(WD)
De-differentiated
(DD)
WD/DD
MRCL
Pleomorphic
Other/NOS
Basic Sarcoma Vocabulary
• Localized Disease
• Locally recurrent disease
• Metastatic Disease
• Neoadjuvant Therapy
• Adjuvant Therapy
• Palliative Therapy
© Fred Hutchinson Cancer Research Center 8
What are the FDA approved drugs for sarcoma?
•First line therapy: Single Agent Doxorubicin (Average 4.6 month PFS)
•Recent approval: olaratumab (may improve OS combined with dox, phase III
results pending)
•Votrient (3 month PFS, no proven OS benefit – approved for STS other than
liposarcomas)
•Eribulin (2 month OS benefit, approved for liposarcoma only)
•Trabectedin (3 month PFS improvement liposarcoma and leiomyosarcoma)
© Fred Hutchinson Cancer Research Center 9
Outline
1. Introduction
2. Immune Response to Sarcoma Subtypes
3. Targeting NY-ESO-1
4. Looking into tumors
© Fred Hutchinson Cancer Research Center 10
Different Types of Immunotherapy
• Cytokine
• Checkpoint inhibitor
• T cell therapy
• Vaccine
• Other
© Fred Hutchinson Cancer Research Center 11
Checkpoint Inhibitors
© Fred Hutchinson Cancer Research Center 12
Ott P A et al. Clin Cancer Res 2013;19:5300-5309
Checkpoint Inhibition in Melanoma
© Fred Hutchinson Cancer Research Center 13
© Fred Hutchinson Cancer Research Center 14
Topalian SL et al. N Engl J Med 2012;366:2443-2454.
TCR recognition of tumor requires MHC
© Fred Hutchinson Cancer Research Center 16
T cell
TCR
tumor cell
peptide
MHC
Intracellular protein
activation
Retrospective Analysis
© Fred Hutchinson Cancer Research Center 17
• Two highly mutated, genetically complex STS
types: UPS and LMS
• Two genetically “simple” STS types liposarcoma
(WD/DD and MRCL) and SS
Pollack et al., Cancer. In press
Focused Clustering Analysis
© Fred Hutchinson Cancer Research Center 18
1" 2" 3" 4" 5" 6" 7"
Leiomyosarcoma"
Liposarcoma"
Pleomorphic/"
Undiff"Sarcoma"
Synovial"Sarcoma"
• Genes included if
p≤0.05 difference for
at least one subtype
• 367/760 genes
• Regions defined based
on dendrogram
clustering
• Most striking
separation for genes
related to antigen
presentation and T cell
infiltration
Pollack et al., Cancer. In press
Class I MHC Molecules
© Fred Hutchinson Cancer Research Center 19
UPS
SS
LMS
MRCL
WD D
D
0
500
1000
1500
2000
HLA-A
RN
A (
co
un
t)
*
**
UPS
SS
LMS
MRCL
WD D
D
0
500
1000
1500
2000
2500
HLA-B
RN
A (
co
un
t)
*
**
*
**
UPS
SS
LMS
MRCL
WD D
D
0
500
1000
1500
HLA-C
RN
A (
co
un
t)
Pollack et al., Cancer. In press
Genes Related to T cell Infiltration
© Fred Hutchinson Cancer Research Center 20
*
UPS
SS
LMS
MRCL
WD D
D
0
10
20
30
40
50
CD3D
RN
A (
co
un
t)*
**
UPS
SS
LMS
MRCL
WD D
D
0
50
100
150
200
250
IL7R
RN
A (
co
un
t)
Pollack et al., Cancer. In press
TCR Vβ Sequencing
© Fred Hutchinson Cancer Research Center 21
A
T-c
ell
fra
ctio
nM
ax. C
lon
al F
req
ue
ncy
B
*
C
Clo
na
lity
0.0
0.2
0.4
0.6
Lipo LMS UPS SS
0
10
20
30
40
Lipo LMS UPS SS
0.1
0.2
0.3
0.4
Lipo LMS UPS SS
**
**
*** *
*
A
T-c
ell
fra
ctio
nM
ax.
Clo
na
l F
req
uen
cy
B
*
CC
lon
alit
y
0.0
0.2
0.4
0.6
Lipo LMS UPS SS
0
10
20
30
40
Lipo LMS UPS SS
0.1
0.2
0.3
0.4
Lipo LMS UPS SS
**
**
*** *
*
A
T-c
ell
fra
ctio
nM
ax.
Clo
na
l F
req
ue
ncy
B
*
C
Clo
na
lity
0.0
0.2
0.4
0.6
Lipo LMS UPS SS
0
10
20
30
40
Lipo LMS UPS SS
0.1
0.2
0.3
0.4
Lipo LMS UPS SS
**
**
*** *
*
T-cell Fraction Clonality Max Frequency
Pollack et al., Cancer. In press
Maybe those STS types rely more on PD-L1/L2?
© Fred Hutchinson Cancer Research Center 22
UPS
SS
LMS
MRCL
WD D
D
0
20
40
60
80
100
CD274 (PD-L1)
RN
A (
co
un
t)
UPS
SS
LMS
MRCL
WD D
D
0
20
40
60
80
PDCD1LG2 (PD-L2)
RN
A (
co
un
t)
Pollack et al., Cancer. In press
PD-1 Immunohistochemistry
© Fred Hutchinson Cancer Research Center 23
4+ (above) and 5+ (below)
Staining showing infiltration with
PD-1+ cells
0 1 2 3 4 5
0
5
10
15
SS PD-1
# s
am
ple
s
0 1 2 3 4 5
0
2
4
6
8
10
UPS PD-1
# s
am
ple
s
0 1 2 3 4 5
0
2
4
6
8
LMS PD-1
# s
am
ple
s
0 1 2 3 4 5
0
5
10
15
Lipo PD-1
# s
am
ple
s
Pollack et al., Cancer. In press
PD-L1 Immunohistochemistry
© Fred Hutchinson Cancer Research Center 24
Very high PD-L1 Staining in
a UPS tumor
0 1 2 3 4 5
0
2
4
6
8
SS PD-L1
# s
am
ple
s
0 1 2 3 4 5
0
2
4
6
UPS PD-L1
# s
am
ple
s0 1 2 3 4 5
0
2
4
6
8
10
LMS PD-L1
# s
am
ple
s0 1 2 3 4 5
0
5
10
15
Lipo PD-L1
# s
am
ple
s
Pollack et al., Cancer. In press
PD-1 and PD-L1 IHC Scores
© Fred Hutchinson Cancer Research Center 25
SS
MRCL
WD/D
D L
ipo
LMS
UPS
0
1
2
3
4
5IH
C S
co
re
PD-1 Score
*
SS
MRCL
WD/D
D L
ipo
LMS
UPS
0
1
2
3
4
5
IHC
Sco
re
PD-L1 Score
*
Pollack et al., Cancer. In press
PD-1 Inhibition in STS
Burgess/Tawbii ASCO 2016: SARC28 – 40 patients (4 of 10 UPS
responses, LMS – 0/10, SS – 1/10, Lipo 1/10)
Suzanne George ASCO 2016: 12 Uterine LMS - no responses
26
TAM impact for STS But are Killed by Trabectedin
© Fred Hutchinson Cancer Research Center 27
Ganjoo et al., Am J Clin Oncol 2011 Germano et al. Cell 2013
TAM Markers in Uterine LMS
FHCRC 9717: Avelumab (anti-PD-L1) + trabectedin
© Fred Hutchinson Cancer Research Center 28
PI: Pollack
For patients with liposarcoma and leiomyosarcoma.
FHCRC 9624: Doxorubicin + Pembrolizumab
© Fred Hutchinson Cancer Research Center 29
Cycle 1: Pembrolizumab
200mgsingle agent
Cycle 2-7: Pembrolizumab
200mg+ Doxoribicin
Cycle ³8:
Pembrolizumab200mg
single agent
Phase I3+3 design:
Part 1: Doxorubicin 45 mg/m2
Part 2: Doxorubicin 75 mg/m2
Phase II2-stage design:
Part 1: 20 patients (requires ³ 2 responses)
Part 2: 15 patients PI: Pollack
Outline
1. Introduction
2. Immune Response to Sarcoma Subtypes
3. Targeting NY-ESO-1
4. Looking into tumors
© Fred Hutchinson Cancer Research Center 30
NY-ESO-1 is a CT Antigen Expressed by SS
© Fred Hutchinson Cancer Research Center 31
Cancer Testis Antigens
(CTA) are well established
self-antigens - Not expressed at the protein level in most normal
tissues
- Unknown biologic function
- Epigenetically regulated
- NY-ESO-1, PRAME, MAGE family antigens included
-NY-ESO-1 frequently and
homogenously expressed by SS
-Positive 20/25; homogenous 14/20
Jungbluth et al., Int J Cancer 2001
Screening Tumors for Tissue Bank for CTA Expression
© Fred Hutchinson Cancer Research Center 32
relative
row min row max
no
rmal te
stis
RL
B F
ibro
-M
el A
37
5U
266
HC
T11
6S
YO
-1M
RC
L 4
02
MR
CL 1
76
5S
YO
-1F
UJI
10
5K
CF
SS
W1
35
3S
W8
72
SK
-UT
-1o
ste
o 1
oste
o 2
oste
o 3
oste
o 4
oste
o 5
oste
o 6
oste
o 7
oste
o 8
ch
on
dro
1ch
on
dro
2ch
on
dro
3ch
on
dro
4ch
on
dro
5ch
on
dro
6lip
o 1
lipo
2lip
o 3
lipo
4lip
o 5
lipo
6le
io 1
leio
2le
io 3
leio
4le
io 5
leio
6le
io 7
leio
8le
io 9
leio
10
Ple
o 1
Ple
o 2
Ple
o 3
Ple
o 4
Ple
o 5
SS
1S
S 2
SS
3S
S 4
SS
5M
RC
L 1
MR
CL 2
MR
CL 3
MR
CL 4
MR
CL 5
MR
CL 6
MR
CL 7
MR
CL 8
MR
CL 9
MR
CL 1
0
Number Gene
BAGECTAG1BCTAG2CTCFLDDX53GAGE1MAGEA1MAGEA2MAGEA3/6MAGEA4MAGEA9MAGEA10MAGEA12MAGEC2RAGESSX1SSX2TAGPRAME
relative
row min row max
norm
al te
stis
RL
B F
ibro
-M
el A
37
5U
26
6H
CT
116
SY
O-1
MR
CL
40
2M
RC
L 1
765
SY
O-1
FU
JI
105
KC
FS
SW
13
53
SW
87
2S
K-U
T-1
oste
o 1
oste
o 2
oste
o 3
oste
o 4
oste
o 5
oste
o 6
oste
o 7
oste
o 8
ch
ond
ro 1
ch
ond
ro 2
ch
ond
ro 3
ch
ond
ro 4
ch
ond
ro 5
ch
ond
ro 6
lipo 1
lipo 2
lipo 3
lipo 4
lipo 5
lipo 6
leio
1le
io 2
leio
3le
io 4
leio
5le
io 6
leio
7le
io 8
leio
9le
io 1
0P
leo
1P
leo
2P
leo
3P
leo
4P
leo
5S
S 1
SS
2S
S 3
SS
4S
S 5
MR
CL
1M
RC
L 2
MR
CL
3M
RC
L 4
MR
CL
5M
RC
L 6
MR
CL
7M
RC
L 8
MR
CL
9M
RC
L 1
0
Number Gene
BAGECTAG1BCTAG2CTCFLDDX53GAGE1MAGEA1MAGEA2MAGEA3/6MAGEA4MAGEA9MAGEA10MAGEA12MAGEC2RAGESSX1SSX2TAGPRAME
relative
row min row max
norm
al te
stis
RLB
Fib
ro-
Mel A
375
U26
6H
CT
11
6S
YO
-1M
RC
L 4
02
MR
CL 1
765
SY
O-1
FU
JI
105K
CF
SS
W135
3S
W872
SK
-UT
-1oste
o 1
oste
o 2
oste
o 3
oste
o 4
oste
o 5
oste
o 6
oste
o 7
oste
o 8
ch
ondro
1ch
ondro
2ch
ondro
3ch
ondro
4ch
ondro
5ch
ondro
6lip
o 1
lipo 2
lipo 3
lipo 4
lipo 5
lipo 6
leio
1le
io 2
leio
3le
io 4
leio
5le
io 6
leio
7le
io 8
leio
9le
io 1
0P
leo 1
Ple
o 2
Ple
o 3
Ple
o 4
Ple
o 5
SS
1S
S 2
SS
3S
S 4
SS
5M
RC
L 1
MR
CL 2
MR
CL 3
MR
CL 4
MR
CL 5
MR
CL 6
MR
CL 7
MR
CL 8
MR
CL 9
MR
CL 1
0
Number Gene
BAGECTAG1BCTAG2CTCFLDDX53GAGE1MAGEA1MAGEA2MAGEA3/6MAGEA4MAGEA9MAGEA10MAGEA12MAGEC2RAGESSX1SSX2TAGPRAME
(NY-ESO-1)
relative
row min row max
no
rma
l te
stis
RL
B F
ibro
-M
el A
37
5U
26
6H
CT
11
6S
YO
-1M
RC
L 4
02
MR
CL
17
65
SY
O-1
FU
JI
10
5K
CF
SS
W1
35
3S
W8
72
SK
-UT
-1o
ste
o 1
oste
o 2
oste
o 3
oste
o 4
oste
o 5
oste
o 6
oste
o 7
oste
o 8
ch
on
dro
1ch
on
dro
2ch
on
dro
3ch
on
dro
4ch
on
dro
5ch
on
dro
6lip
o 1
lipo
2lip
o 3
lipo
4lip
o 5
lipo
6le
io 1
leio
2le
io 3
leio
4le
io 5
leio
6le
io 7
leio
8le
io 9
leio
10
Ple
o 1
Ple
o 2
Ple
o 3
Ple
o 4
Ple
o 5
SS
1S
S 2
SS
3S
S 4
SS
5M
RC
L 1
MR
CL
2M
RC
L 3
MR
CL
4M
RC
L 5
MR
CL
6M
RC
L 7
MR
CL
8M
RC
L 9
MR
CL
10
Number Gene
BAGECTAG1BCTAG2CTCFLDDX53GAGE1MAGEA1MAGEA2MAGEA3/6MAGEA4MAGEA9MAGEA10MAGEA12MAGEC2RAGESSX1SSX2TAGPRAME
Pollack ASCO 2016
MRCL Expresses NY-ESO-1 Homogenously
© Fred Hutchinson Cancer Research Center 33
• 25 cases tested, all positive
• >70% of cases, homogenous.
•MRCL cell lines can lysed by NY-ESO-1 specific effectors
• No other disease expresses NY-ESO-1 with this frequency
Pollack et al., Cancer 2012
Culturing NY-ESO-1 Specific Cells
© Fred Hutchinson Cancer Research Center 34
tetramer
CD
8
<0.001% 8.51% 94.4%0.719% 1.6%
Stimulate Sort Expand
StimulateSort and Expand
SS and MRCL Leukapharesis
products lack clear tet+ populations.
After 2 stimulations, three wells were identified with clear tet+ populations.
Final product contained 57 x 109 cells and was over 94% CD8+,
tet+.
Pollack et al. JITC 2014
These Cells Kill Tumor Lines
© Fred Hutchinson Cancer Research Center 35
Pollack et al. JITC 2014
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
80
100
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
80
100
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
80
100
E:T
% L
ysis
Mel A375
Mel 526
Patient 5
Patient 6
Patient 4
Patient 2
Patient 3
Patient 1
aLY TCR
High Affinity gp100 clone
High Affinity NY-ESO-1 Clone
(NY-ESO-1 +; gp100 -)
(NY-ESO-1 -; gp100 +)
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
80
100
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
80
100
E:T
% L
ysis
40 20 10 52.
5
0
20
40
60
80
100
E:T
% L
ysis
Mel A375
Mel 526
Patient 5
Patient 6
Patient 4
Patient 2
Patient 3
Patient 1
aLY TCR
High Affinity gp100 clone
High Affinity NY-ESO-1 Clone
(NY-ESO-1 +; gp100 -)
(NY-ESO-1 -; gp100 +)
© Fred Hutchinson Cancer Research Center 36
Before
(from lung)
After
(from forehead) Before 10 Weeks After
T2 un
pulsed
T2 pu
lsed
Mel
A37
5
0
20
40
60
80
100
Pe
rce
nta
ge
Lysis
CD8+, Tet+ Cells Sorted and Expanded in vitro from Tumor Can Kill Targets
NY
-ES
O-1
C
lass I M
HC
0 102
103
104
105
0
5
10
15
20
LSR2-1_2537-S02 Post-Tx Blood D+71.fcs…CD8
<APC-A>: NY-ESO Dex
1.4298.6
0 102
103
104
105
0
1000
2000
3000
LSR2-1_2537-S02 Post-Tx TIL REP1.fcs…CD8
<APC-A>: NY-ESO Dex
0.1699.8
NY-ESO-1 tetramer (Gated on
CD8+ cells)
Peripheral
Blood Expanded TIL
0.16% >1.4%
Pt IFN1
However, because of safety issues with this trial, this
regimen was abandoned
LV305: A Novel NY-ESO-1 Vaccine
© Fred Hutchinson Cancer Research Center 37
LV305 is a novel hybrid viral vector gene delivery system (ZVexTM) that expresses NY-ESO-1 RNA
designed to target DCs in vivo and stimulate CD8 T cell responses against this cancer testis antigen
ZVex
DC-SIGN
ZVex
DC
Envelope:
DC Targeting: •Sindbis virus envelope targets the Dendritic Cell receptor, CD209
(DC-SIGN)
Genome:
Safety: •3rd generation lentiviral vector backbone
•Modified to be replication incompetent and integration deficient
Specificity:
•Vpx prevents degradation within DCs
Slide courtesy of Immune Design
Increased NY-ESO-1 Tet+ Cells in A0201+ Patients
© Fred Hutchinson Cancer Research Center 38
Hea
lthy SS
MRCL
Pt 1
-1 p
re
Pt 1
-1 p
ost
Pt 4
-3 p
re
Pt 4
-3 p
ost
Pt 1
-5 p
re
Pt 1
-5 p
ost
0.00
0.05
0.10
0.15
0.20
% tet+
Tetramer Staining in A2+ Patients(Percent of CD8+ Cells)
MAGE-A
3
MAG
E-A
4
MAGE-A
9
PRAM
E
NY-E
SO-1
Neg
Contr
ol
PHA
0
20
40
60
80
SF
U
1-1 PBMC Elispot
pre post
Pollack et al. Submitted
Pre and Post Tx TCR sequencing
© Fred Hutchinson Cancer Research Center 39
1.68% of
Pre-tx T cells
2.51% of
Post-tx T cells
Clonality 0.11 Clonality 0.18
0.000001
0.00001
0.0001
0.001
0.01
0.000001 0.00001 0.0001 0.001 0.01
Abundance in P
BM
C-p
ost
Abundance in PBMC-pre
T cells absent in FFPE tumor (pre)
T cells present in FFPE tumor (pre)
Pollack et al. Submitted
Durable Tumor Regression Following LV305
© Fred Hutchinson Cancer Research Center 40
Pollack et al. Submitted
Durable Tumor Regression Following LV305
© Fred Hutchinson Cancer Research Center 41
5/5/2014 6/1/2016
Pollack et al. Submitted
Survival on the LV305 Vaccine Trial
© Fred Hutchinson Cancer Research Center 42
0 5 10 15 20
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
port
ion
Pro
gre
ssio
n F
ree
0 5 10 15 20
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
po
rtio
n S
urv
ivin
g
All Sarcomas
N= 24 (progressed= 18)
95% CL: 2.6, 14.4
All Sarcomas
N= 24 (deaths= 4)
Pollack ASCO 2016
Outcomes on LV305 and Approved Drugs For Sarcoma
© Fred Hutchinson Cancer Research Center 43
Treatment Indication PFS OS
LV305 STS 4.6
mo
Not
reached
Pazopanib
(Votrient)
STS (not
MRCL)
4.7
mo 12.5 mo
Trabectedin
(Yondelis)
MRCL after
Anthracycline
(all STS in EU)
4.2
mo 12.4 mo
Eribulin
(Halaven)
MRCL after
Anthracycline
2.6
mo 13.5 mo
Pollack ASCO 2016
CMB +/- Atezolizumab
© Fred Hutchinson Cancer Research Center 44
≤ 80 pts with locally advanced,
relapsed, or metastatic
synovial sarcoma or MRCL
Combination Arm Sequential regimen of LV305 and G305 for 3
months
with atezolizumab q3w up to 2 yrs
Control Arm Atezolizumab q3w up to 2 yrs
Endpoints of PFS, safety, PFR
(at 6 mo), ORR, duration of
response, and OS Randomize
Screen,
biopsy, safety run-in Biopsy, then follow up to 2 years
Outline
1. Introduction
2. Immune Response to Sarcoma Subtypes
3. Targeting NY-ESO-1
4. Looking into tumors
© Fred Hutchinson Cancer Research Center 45
© Fred Hutchinson Cancer Research Center 46
16
cm
Sarcomas Can
Be Quite Large
and Are
Relatively
Accessible
Presage’s Civo Device
© Fred Hutchinson Cancer Research Center 47
2. Ultrasound
Measurements
M1
M2
3. Microinjection 1. Device Loading
1
2
3 4
7
6
8
5
4. Confirmation
and Skin Marking
Slide courtesy of Presage
2
3 4
6 1
8
7
5 PI: Pollack
FHCRC 9145: Intratumor TLR4 Agonist + Radiation
© Fred Hutchinson Cancer Research Center 48
PI: Pollack
FHCRC 9145: Schema
© Fred Hutchinson Cancer Research Center 49
Weekly GLA-SE injections through week 8.
1 2 43 765 8
rads
week
Pre-treatmentImaging
1st Post-treatmentImaging
Biopsy Biopsy
• Two, 6-patient cohorts treated: 5 mcg and 10 mcg.
• All patients were required to have unresectable of metastatic disease.
• GLA was injected directly into a tumor.
• Radiation was started to the injected tumor during the first week of treatment.
• Patients received high dose (generally 50 Gy) in few fractions (generally 5 or less).
• Current cohort using 20 mcg.
TLR4 Agonism Can Convert M2 to M1
© Fred Hutchinson Cancer Research Center 50
0 102
103
104
105
0
20
40
60
80
100
CD163 high
0 102
103
104
105
0
20
40
60
80
100
0 102
103
104
105
0
20
40
60
80
100
CD206
CD115
% o
f m
ax
% o
f m
ax
% o
f m
ax
CD163
Before Treatment During Treatment
x
iNO
S
CD
16
3 x
CD
20
6
CD16
3
CD20
6
CD11
5
HLA
-DR
0
20
40
60
80
100
% p
os
. ga
ted
(C
D4
5+
, CD
11
B+
)Pre-treatment
Post-Treatment
© Fred Hutchinson Cancer Research Center 51
Acknowledgments
Pollack Lab
Bailey Donahue
Sara Cooper (former)
Graeme Black
Taylor Hain
Olga Vitruk
FHCRC
Stan Riddell
Silvia Christien
Deb Banker
Chad He
Yuzheng Zhang
Mary Redman
Kelsey Baker
CPF
SCCA Sarcoma Program
Lee Cranmer
Venu Pillarisetty
Ed Kim
Chappie Conrad
Ben Hoch
Bob Ricciotti
Matt Spraker
Dave Seo
Other
Achim Jungbluth
Cassian Yee
Robin Jones
Immune Design
Jan H. ter Muelen
Frank Hsu
Hailing Liu
Adaptive Biotechnologies
Sharon Benzeno
Ryan Emerson
Marissa Vignali
Merck Research Labs
Terrill K. McClanahan
Jennifer Yearley
Erin Murphy
Wendy M. Blumenschein
Steven M. Townson
Special Thanks:
Gilman Family Sarcoma Fund
NCI 1K23CA175167-01
SARC
Sarcoma Foundation of America