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Immunotherapy for Prostate Cancer:
Are we on the right target?
Susan F. Slovin, MD, PhD
Sidney Kimmel Center for Prostate and Urologic Cancers
Memorial Sloan-Kettering Cancer Center
New York, New York
Rationale for Vaccines in Prostate Cancer
1. Well-characterized glycoprotein and carbohydrate
antigens: PSA, PSMA, PSCA, Globo H, GM2, MUC-1,2, Tn,
TF, Lewisy.
2. Biomarker (PSA) available to study disease progression.
3. Can be used in all disease states: biochemical relapse thru
castration resistant disease.
4. Can be potentiated via combinatorial approaches:
chemotherapy, biologic agents (GM-CSF) or checkpoint
inhibitors (anti-CTLA-4, anti-PD-1).
Is there a “best” approach?
A
Whole cell or
shed antigen
brief history of
cancer vaccines
(very)
Purified
protein
Peptide
Where does immunotherapy end and
vaccines begin?
PSMA Expression on LNCaP Cell
Vaccines: DNA,
alhydrogel, DG, VRP T cell
MoAbs
J415, J591 - ADCC
NH2...
Extracellular
Intracellular
MoAb 7E11
ProstaScint
Scan
Antibody Drug
Conjugate:
auristatin
maytansinoid
Cell membrane
Modified from P. Smith-Jones 2004
Results of Clinical Trial Endpoints
• Tumor responds
-
target is hit
• Tumor responds
-
target is missed
• Tumor  respond
-
target is hit
• Tumor  respond
-
target is missed
All say something about the biology of the tumor and how the therapy should be directed
Immunotherapy / Vaccine Approaches in
Development for Treatment of CRPC
• Tumor antigen vaccines
– Vaccinate patient with antigens that activate tumor-specific T-cell
responses
• Autologous dendritic cells (DCs)
– GM-CSF; lenalidomide
• Cytokines and DC stimulation
• CTLA-4 (cytotoxic T-lymphocyte-associated antigen)
blockade
Ipilimumab
•
A fully human anti-CTLA-4 mAb (IgG1k)
–
Effectively blocks CTLA4–B7 interactions
•
Currently in Phase III trials and in first and second line melanoma
–
Survival benefit in patients with treated melanoma – phase III
•
Clinically significant and durable tumor regression in multiple tumors
(melanoma, prostate, renal, ovarian,…)
–
Immune Related Responses can occur with initial progression followed by
regression
•
Immune-related adverse events (irAE)
–
Likely mechanism based; consistent with enhanced activity of T cells due
to the blockade of CTLA-4 function
–
Usually reversible and associated with clinical response in melanoma, renal
cell, and prostate cancer
CTLA-4 Blockade
Enhances Tumor-Specific Immune Responses
Attenuated or
Terminated
Proliferation
Unrestrained
Proliferation
IL-2
Tumor
APC
APC
Necrotic Death
Vaccines
Chemotherapy
Irradiation
Hormone therapy
Anti-angiogenesis
TCR
Peptide/MHC
CD28
CTLA-4
B7-1,2
Leach & Allison
Science 1996
M.O.A. of CTLA-4
2
1
TCR + Ag
on DC =
Engagement
Door to CTLA-4
activation is
closed
3
4
5
Abort!
“Go or No Go?”–
Awaiting T cell
activation
or shutdown
Full go !!
T cell proliferation…
or…
Skin reactions at the GVAX injection sites
GVAX IT alone
GVAX IT + MDX-010
(0.3 mg/kg)
GVAX IT + MDX-010
(3 mg/kg)
After 1 week
Injection site reactions were the most common adverse event (100%)
No DLTs nor auto-immunity observed
PSA curves – Dose Level 3 (3 mg/kg)
Pt 7
100
90
80
70
60
50
40
30
20
10
0
60
Pt 8
50
40
a
30
b
20
10
a : 13Mar06: SAE -Hypophysitis
(7 mo)
b: 03Feb06: Hypophysitis
(5 mo)
c: 09Feb06: SAE –
Hypophysitis (5 mo)
Gerritsen, ASCO 2006
3/20/06
2/20/06
1/20/06
12/20/05
11/20/05
10/20/05
9/20/05
8/20/05
7/20/05
6/20/05
4/9/06
3/9/06
2/9/06
1/9/06
12/9/05
11/9/05
10/9/05
9/9/05
c
8/9/05
7/9/05
Pt 9
3/7/06
2/7/06
1/7/06
12/7/05
11/7/05
10/7/05
9/7/05
8/7/05
7/7/05
50
45
40
35
30
25
20
15
10
5
0
6/9/05
6/7/05
0
Patient 8
Bone Scan Improvement in Patient 8 (3 mg/kg)
15Sept05
Gerritsen ASCO2006
29Mar06
Objective Tumor Response
Patient 12 (5 mg/kg)
14Feb06
16May06
Gerritsen, ASCO 2006
Immune Breakthrough Events (IBE)
• No IBE in DL 1 and 2
• 5 of 6 patients in 3 mg/kg and 5 mg/kg with IBE
– All associated with PSA response
– All delayed
– All endocrine-related & treatable with standard
hormone replacement therapy
Patient
Primary Event
Onset
Secondary Events
007
Hypophysitis
7 mo
Adrenal Insuff
008
Hypophysitis
5 mo
Adrenal Insuff
009
Hypophysitis
5 mo
Adrenal Insuff
Leukopenia
Hypothyroidism
010
Hypophysitis
4.5 mo
Adrenal Insuff
Hypothyroidism
012
Alveolitis (IBE?) 2 mo
Low TSH
Pathology of Autoimmune Breakthrough Events:
Colitis
D
C
E
CD4
F
CD3
CD8
Histopathologic analyses of selected
patients experiencing autoimmune
events.
(C) Colon biopsy from Patient 9
illustrating severe colitis with
infiltration of the lamina propria
with neutrophils, lymphocytes,
monocytes, plasmacytes and
eosinophils. Neutrophils and
lymphocytes also infiltrate the
crypts; numerous mitotic figures
can be seen in the epithelial cells
lining the crypts (20X).
Immunohistochemistry evaluating
expression of CD3+ (D), CD4+ (E),
and CD8+ markers (F) (20X).
Source: Abstract #3424, ASCO 2003
Rationale: Radiotherapy as an Immune-Supportive
Intervention for CTLA-4 Blockade
AntiCTLA4
mAb
CTLA4
Anti-CTLA4
mAb
CTLA-4
Modified after: Demaria, et al, Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 3, pp. 655–666, 2005
Subject 3020, 10 mg/kg monotherapy
200
%Baseline PSA
150
#3020
10 mg/kg mono
< 1 cycle (2.5)
PSA0= 655
(-) Prior Chemo
PSA - CR
RECIST - uCR
S-irAEs:hepatitis, colitis,
irAE - abnormal TFTs
100
50
Hepatitis
Colitis
abnl TSH PR
PR
CR
PR
0
-4
0
4
8
12
16
20
24
28
Weeks
Beer, et al, ASCO 2008
32
36
40
44
48
52
56
60
Subject 3020:
Resolution of Prostate Mass
Screening
14 months
Best PSA Changes: Each Subject
Best PSA Change from Baseline (%)
100.00
50.00
0.00
-50.00
-100.00
Mono
Slovin, et al, ASCO 2009)
XRT in NoCHEMO
XRT in CHEMO
Time-to-Response and Durability of Confirmed
PSA Response
*XRT NoCHEMO +
*XRT NoCHEMO +
XRT NoCHEMO
XRT NoCHEMO
XRT CHEMO
Mono +
Mono
Mono
**Mono +
Mono +
0
10
20
30
40
50
60
Weeks
Time-to-Response (>50% decrease)
*: PSA CR
**: Objective CR
Response Durability
+: Durability ongoing
Slovin, et al, ASCO 2009
Conclusions
•
Safety of Ipilimumab 10 mg/kg +/- additional XRT in patients with mCRPC
– No new emergent toxicity due to XRT in 32 subjects
– Tolerated in both chemo naïve and chemo experienced population
– 15/50 patients (30%) with Grade 3 or 4 irAE
– Severity, rate and duration similar to Ipilimumab oncology program
– Resolution using established management algorithms
•
Ten subjects had confirmed 50% reductions in PSA responses (20%)
– 2 of these declines were correlated with a serious irAE
– Duration of declines: median 30.5 weeks; range: 6.0 to 60+ weeks
– Occurrence of declines seen with or without XRT
– Occurrence of declines in both chemo naïve and chemo experienced patients
– Differences not significant in these small cohorts
•
Objective response by RECIST) was observed.
– All with 50% PSA declines had SD according to RECIST criteria except one patient who
had CR for both PSA and RECIST.
•
Ipilimumab has anti-tumor activity in mCRPC, with and without XRT, and in both the chemo
experienced and chemo naïve settings and should be explored in larger studies
Sipuleucel-T Immunotherapy for Advanced Prostate
Cancer: A Randomized, Double-Blind, PlaceboControlled Phase 3 Trial
IMPACT STUDY
AUA, 2009
Vaccination With Antigen (GM-CSF/PAP) Loaded
APCs
Leukapheresis
PAP-GM-CSF
“Antigen”
Isolation of APC
Patient
Sheikh et al, 2008.
Antigen-loaded
APCs
Small, et al, JCO, 2006
Randomized Phase 3 IMPACT Trial
(IMmunotherapy Prostate AdenoCarcinoma Treatment)
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=512)
Primary endpoint:
Secondary endpoint:
Sipuleucel-T
Q 2 weeks x 3
2:1
Placebo
Q 2 weeks x 3
P R
OG
R E
S S
I
O
N
Treated at
Physician
discretion
Treated at
Physician
discretion and/or
Salvage Protocol
Overall Survival
Time to Objective Disease Progression
S
U
R
V
I
V
A
L
Patient Demographics and Baseline Characteristics
Age, median yrs (range)
Race, white (%)
ECOG status, 0 (%)
Gleason Score ≤ 7 (%)
Sipuleucel-T
(N = 341)
72 (49 – 91)
89.4
82.1
75.4
Placebo
(N = 171)
70 (40 – 89)
91.2
81.3
75.4
Disease localization
Bone only (%)
Soft tissue only (%)
Bone & soft tissue (%)
>10 bone mets (%)
50.7
7.0
41.9
42.8
43.3
8.2
48.5
42.7
Bisphosphonate use
Prior docetaxel (%)
48.1
15.5
48.0
12.3
IMPACT Overall Survival: Primary Endpoint
Intent-to-Treat Population
100
Percent Survival
P = 0.032 (Cox model)
HR = 0.775 [95% CI: 0.614, 0.979]
75
Median Survival Benefit = 4.1 Mos.
50
Sipuleucel-T (n = 341)
Median Survival: 25.8 Mos.
25
Placebo (n = 171)
Median Survival: 21.7 Mos.
0
0
6
12
18
24
30
36
42
48
Survival (Months)
54
60
66
Overall Survival Summary
Survival Percentiles (months)
N
75%
50%
25%
Sipuleucel-T
341
15.1
25.8
41.3
Placebo
171
11.0
21.7
35.6
Sipuleucel-T
Placebo
% Survival (K-M estimates)
24 Mos.
36 Mos.
48 Mos.
52.1
31.7
20.5
41.2
23.0
16.0
Survival Consistency Between Population Subsets
Favors sipuleucel-T
Bisphosphonate Use: Yes
No
Primary Gleason Grade:  4
3
No. Bone Metastases: > 10
 10
Disease Localization: Single
Bone + Soft Tissue
ECOG Performance Status: 1
0
Age: Above Median
Below Median
PSA: Above Median
Below Median
LDH: Above Median
Below Median
Alkaline Phos: Above Median
Below Median
Hemoglobin: Above Median
Below Median
0.0
0.5
1.0
1.5
Hazard Ratio (95% Confidence Interval)
Serious Adverse Events*
Safety Population
SAE Preferred Term
Any SAE
Pyrexia
Cerebrovascular accident
Pulmonary embolism
Spinal cord compression
Nausea
Atrial fibrillation
Dehydration
Cardiac failure congestive
Pneumonia
Hematuria
Deep vein thrombosis
Renal failure acute
*Occurring in ≥ 4 patients.
Sipuleucel-T
N=338
%
24.0
1.8
1.8
1.2
1.2
0.9
0.9
0.9
0.6
0.6
0.6
0.3
0.3
Placebo
N=168
%
23.8
0.6
1.8
0.0
1.2
1.2
0.6
0.6
1.2
1.2
1.2
1.8
2.4
Consistency Across Phase 3 Studies
D9901*
D9902A*
IMPACT **
Integrated**
(N = 127)
(N = 98)
(N = 512)
0.586
0.786
0.775
(N=737)
0.735
p = 0.010
p = 0.331
p = 0.032
p < 0.001
4.5
3.3
4.1
3.9
sipuleucel-T
34%
32%
32%
33%
placebo
11%
21%
23%
20%
Hazard Ratio
p-value
Median Survival Benefit
(months)
36-Month survival (%)
*Unadjusted Cox model & log rank
**Cox model adjusted for PSA and LDH
Phase III Study of Sipuleucel-T (D9902B,
IMPACT)
Adverse Events
Sipuleucel-T
Placebo
(n = 341)
(n = 171)
Chills
54.1%
12.5%
Pyrexia
29.3%
13.7%
Headache
16.0%
4.8%
Myalgia
9.8%
4.8%
Post-Study
Interventions
Sipuleucel-T
Placebo
(n = 341)
(n = 171)
Any Intervention
81.8%
73.1%
Any Chemotherapy
65.4%
53.8%
Docetaxel
57.2%
50.3%
Hormone Therapy
12.3%
8.8%
Radiation Therapy
21.1%
26.3%
Surgical Intervention
1.5%
2.3%
Kantoff P, et al. 2010 Genitourinary Cancers Symposium. Abstract 8.
36
Conclusions
• Greater awareness of need to standardize
immune monitoring for all trials
• Improving trial design to address both clinical
and research questions – meet expectations of
FDA
• How to reconcile trials where there is an overall
survival benefit in the absence of anti-tumor
effect?
• Provenge, Prostvac – no impact on PSA or
disease? Thoughts?.......
Conclusions
• Immunologic tolerance can be broken via multiple vaccine
strategies.
• Anti-tumor effects documented with possible survival
benefits
• Concerns: do vaccines need immune modulators to exert
more relevant responses?
• Is autoimmunity good
in the short
but bad
in the long run?