Download Exploring Therapeutic Combinations with anti-CTLA

Exploring Therapeutic Combinations
with anti-CTLA-4 Antibody
Padmanee Sharma, MD, PhD
Associate Professor
GU Medical Oncology and Immunology
M. D. Anderson Cancer Center
iSBTc
Hot Topic Symposium
October 2010
Disclosures
• Served on advisory board, BMS, received
honorarium
• Served on advisory board, Dendreon,
received honorarium
Improving on CTLA-4 blockade
• CTLA-4 blockade has a consistent anti-tumor
response rate of ~10% and survival benefit of
~20-30%; Phase III trial with documented
survival benefit
• Durable partial and complete regression of
disease observed in a subset of patients
• How can we do better?
– Identify immunologic markers that predict which
patients will benefit and provide therapy to those
patients
– Explore combination therapies to increase the
numbers of patients who will benefit
Part I
Identification of immunologic markers:
Pre-surgical clinical trial
with anti-CTLA-4 monotherapy
anti-CTLA-4
antibody
Study
Week
0
3
PreAfter
therapy dose #1
blood* blood*
Post-operative
follow-up visits
Surgery
#1
#2
7
11-15
23-24
After
dose #2
blood*
Blood
Blood
*Blood drawn prior to antibody dose administered and prior to surgery
Tissue Analysis
RNA later
Core biopsy (~ 1 cm x 1mm x 1mm)
Core biopsy
TIL expansion
+
Fine needle aspiration and chunks
IF in frozen sections
Histology sections
IHC in paraffin sections
Clinical Trial
• Patients who are surgical candidates (N=12)
– 6 patients dosed at 3mg/kg/dose and 6
patients dosed at 10 mg/kg/dose
– Organ-confined localized disease; did not
require any therapy other than surgery as
treatment
• Primary endpoint: safety
• Secondary endpoint: immunologic correlates
Choosing biomarkers for immune monitoring
PD-l
10
0
100
70
0
10
mB7-H3
mB7h
91
?
hB7h
100
96
100
hB7x
mB7-H2
100
mB7x
hB7-H2
10
0
mB7-H1
hB7-H1
10
0
hB7-H3
mB7-2
hB7-2
hB7-1
mB7-1
CD28, CTLA-4
ICOS
Immune Monitoring
• Assessed T cell markers including: HLA-DR,
CD69, CD45RA, CD45RO, PD-1, etc. and
• Inducible costimulator (ICOS)
-belongs to CD28 family
-expression increased on activated T cells
-plays a role in function of Th1, Th2, Th17,
Tfh, Treg cells
-is not a marker of a particular T cell subset
but plays a role in the function of a given T
cell subset that has been activated
Increased frequency of ICOShi T cells in
tumors from anti-CTLA-4 treated patients
Non-malignant tissues:
untreated
Tumor tissues:
untreated
16%
ICOS
40%
CD4
CD4
CD4
13%
Tumor tissues:
anti-CTLA-4 treated
ICOS
ICOS
Liakou et al., Proc Natl Acad Sci, 2008
ICOS expression increases in tumor
tissues of treated patients
% CD4+ICOShi T cells
80
p < 0.05
70
60
50
40
30
20
10
0
Non-malignant
tissues
Tumor tissues
untreated
Tumor tissues
anti-CTLA-4 treated
Liakou et al., Proc Natl Acad Sci, 2008
FOXP3 expression is lower in tumor
tissues from anti-CTLA-4 treated patients
Non-malignant tissues:
untreated
Tumor tissues:
untreated
95%
FOXP3
8%
CD4
CD4
CD4
3%
Tumor tissues:
anti-CTLA-4 treated
FOXP3
FOXP3
Liakou et al., Proc Natl Acad Sci, 2008
% CD4+FOXP3+ T cells
FOXP3 expression decreases in tumor
tissues of treated patients
100
90
80
70
60
50
40
30
20
10
0
p < 0.05
Non-malignant
tissues
Tumor tissues
untreated
Tumor tissues
anti-CTLA-4 treated
Liakou et al., Proc Natl Acad Sci, 2008
Relative expression normalized to GAPDH
Increased IFN- and T-bet mRNA
in treated tissues with
concomitant decrease in FOXP3 mRNA levels
120
Non-malignant tissues
Cancer tissues: untreated
100
Cancer tissues: anti-CTLA-4 treated
80
60
40
20
0
CD3-
IFN-
IL-10
IL-4
IL-2
FOXP3
T-bet GATA-3
Liakou et al., Proc Natl Acad Sci, 2008
What is the function of ICOShi cells in
tumors?: Expression of NY-ESO-1 antigen
allowed for functional analyses of TILs
H&E
CD4 T cells
NY-ESO-1
Chen et al., Proc Natl Acad Sci, 2009
Number of spots / 25,000 CD4 T cells
Recognition of NY-ESO-1 by TILs
250
200
150
100
50
0
No Peptide
NY-ESO-1 Peptides
IFN- production
6%
ICOS
ICOS
2%
TNF-
MIP-1
Chen et al., Proc Natl Acad Sci, 2009
What about immunologic events in
the systemic circulation?
Do they correlate with observed
changes in tumor tissues?
ICOS expression significantly increases
on T cells in peripheral blood after
treatment with anti-CTLA-4 antibody
Week 3
3%
Week 7
14%
ICOS
13%
CD4
CD4
CD4
CD4
Baseline
ICOS
ICOS
ICOS
Liakou et al., Proc Natl Acad Sci, 2008
ICOShi T cells in peripheral blood from antiCTLA-4 treated patients produce IFN-
4
Healthy donors
Pre-therapy patients
Post-therapy patients
pg/mL x 103
3.5
3
2.5
2
1.5
1
0.5
0
IFN-γ
IL-10
CD4+ICOShi T cells
IFN-γ
IL-10
CD4+ICOSlow T cells
Liakou et al., Proc Natl Acad Sci, 2008
Number of spots / 50,000 T cells
ICOShi T cells from peripheral blood recognize
NY-ESO-1 tumor antigen
APCs pulsed
w ithout peptide
(no peptide)
APCs pulsed w ith
NY-ESO-1 peptides
(all peptides)
300
250
200
150
100
50
0
Pt #2
Pretherapy
Pt #2
Posttherapy
Pt #4
Pretherapy
Pt #4
Posttherapy
Pt #6
Pretherapy
CD4+ICOShi T cells
Pt #6
Posttherapy
Are changes in ICOS
expression associated with
clinical benefit?
Pre-Operative CTLA-4 Blockade: Pathology and Cytology Data
Patient
Number
Pre-Therapy Cytology
Fluorescence in situ
hybridization (FISH)
Post-Therapy Cytology
Fluorescence in situ
hybridization (FISH)
Pre-Therapy Pathology
(UC, HighGrade)
Post-Therapy Pathology
1
T1N0M0
T0N0M0
Positive Cytology, Positive FISH
Negative Cytology, Negative FISH
2
T1N0M0
T4N0M0
Positive Cytology, Positive FISH
Positive Cytology, Positive FISH
3
T1N0M0
TisN0M0
Negative Cytology, Positive FISH
Negative Cytology, Negative FISH
4
T2N0M0
T3N1M0
Negative Cytology,
Non-contributory FISH
Negative Cytology
5
T1N0M0
TaN0M0
Positive Cytology
Positive Cytology
6
T1N0M0
T0N0M0
Positive Cytology
Negative Cytology, Negative FISH
7
T1N0M0
TaN0M0
Positive Cytology
Positive Cytology
8
T2N0M0
T0N0M0
Negative Cytology, Negative FISH
Negative Cytology, Negative FISH
9
T1N0M0
TisN0M0
Positive Cytology
Positive Cytology
10
T2N0M0
T0N0M0
Positive Cytology
Negative Cytology, Negative FISH
11
T1N0M0
pTXN0M1
Positive Cytology
Positive Cytology
12
T2N0M0, UC &
Micropapillary Disease
T2N1M0, UC,
Sarcomatoid &
Micropapillary Disease
Positive Cytology
Positive Cytology, Positive FISH
Carthon et al., Clinical Cancer Research, 2010
Metastatic Melanoma:
Sustained elevation of CD4+ICOShi T cells
correlates with survival
ICOShi
ICOSlow
Carthon et al., Clinical Cancer Research, 2010
Part II
Combination Therapies
Why Combination Therapy?
•Each tumor has multiple (90?) mutations resulting in
coding changes (Vogelstein et al. Science 2006)
•Many of these, depending on MHC type of host, will
represent neoantigens
Neoepitopes generated by genomic
instability inherent in cancer
•Algorithms predict 9/tumor for HLA-0201
•6 MHC alleles/tumor, so assuming even distribution
predicts 54 total neoepitopes/tumor
•Assuming algorithm is wrong 90% of time, would
predict 5-6 neoepitopes/tumor
Effective checkpoint blockade with anti-CTLA-4 therapy may turn 1
drug/therapy into 6-7, raising the possibility of combinatorial
therapies to improve anti-tumor responses
Segal N and Allison JP
Rationale for Combination Therapy
Agents that kill tumor cells (e.g. chemotherapy,
radiation, hormone therapy, antibodies, “targeted”
therapies) can be used to prime an immune response
against multiple antigens
In combination with checkpoint blockade, can
unleash the immune system to maximize T cell
responses to multiple targets
Combination Studies
with Ipilimumab
•
•
•
•
•
•
•
•
•
•
Phase III study with Ipilimumab plus XRT in patients with metastatic
prostate cancer
Phase III study with Ipilimumab plus DTIC in patients with melanoma
Phase II study with Ipilimumab plus Temozolamide in patients with
metastatic melanoma
Phase II study with Ipilimumab plus Taxol plus Paraplatin in patients
with lung cancer
Phase II study with Ipilimumab plus androgen blockade in patients
with metastatic prostate cancer
Pre-surgical Phase IIa study with Ipilimumab plus Lupron in patients
with localized prostate cancer
Phase I study with Ipilimumab plus MDX-1106 (anti-PD-1) in patients
with melanoma
Phase I/II study with Ipilimumab plus cryoablation in patients with
breast cancer
Planned study with Ipilimumab plus Sipuleucel-T in patients with
prostate cancer
Planned study with Ipilimumab plus BRAF inhibitor in patients with
melanoma
Phase III clinical trial with Ipilimumab + XRT
vs. Placebo + XRT in CRPC
800 patients
Bone Mets
Estimate participation of 145 sites
R
A
N
D
O
M
I
Z
E
XRT +
Placebo
Overall
Survival
Immune
Monitoring
XRT + antiCTLA-4
antibody
(administered
within 2 days
of XRT)
No crossovers allowed
Pre-surgical trial:
Lupron + Ipilimumab
Lupron
Therapy
Week
- 4 to -1
Blood &
Tumor
0
Blood
Ipilimumab
Dose (10 mg/kg)
Surgery
1
4
8
Blood
Blood
Blood &
Tumor
Clinical Trial for Patients with Localized Prostate Cancer
Conclusions
•
CTLA-4 blockade increases ICOS expression on T cells in tumor
tissues and peripheral blood
•
ICOShi T cells from treated patients contain a population that are
IFN-producing effector T cells and can recognize tumor antigen
•
ICOS may serve as a biologic marker of disease response but,
this has to be tested in a larger cohort of patients
•
ICOS/ICOSL may serve as another immunotherapy target
•
Pre-surgical clinical trials provide a feasible platform to study
biologic effects on tumor tissues thus providing data that can be
applied to the metastatic disease setting and improve our
understanding of mechanisms
•
Pre-clinical data supports the development of combination
therapies with anti-CTLA-4 and any agent that is capable of
killing tumor cells to prime a T cell response
Sharma Lab Team
– Derek Ng Tang
– Hong Chen
– Chrysoula Liakou
– Jingjing Sun
– Tihui Fu
– Qiuming He
– Abdol Hossein
• GU Medical Oncology, Urology, Pathology
– Chris Logothetis, Ashish Kamat, John Ward, Patricia
Troncoso
• MDACC Collaborators
– Dimitra Tsavachidou, Sijin Wen
• MSKCC and LICR Collaborators
– Lloyd Old, Achim Jungbluth, Sacha Gnjatic (LICR)
– Jim Allison, Jedd Wolchok, Jianda Yuan (LCCI, MSKCC)
• BMS Team
– Rachel Humphrey, Axel Hoos, Ramy Ibrahim
•