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Challenges in Establishing the Role of
Immunotherapy in Prostate Cancer
Susan F. Slovin, MD, PhD
Associate Attending Physician and Associate Member
Memorial Sloan-Kettering Cancer Center
Associate Professor of Medicine
Weill-Cornell Hospital
New York, New York
Aims
• Review approaches to induce anti-tumor
responses by the host
• Issues faced in the development of these
strategies
• How to proceed toward successful “drug”
development
• Goals of the academic / governmental /
industrial community
2
Pathway to Metastasis
Primary Growth
Local gene therapy (proof of principle)
Anti-angiogenesis
Angiogenesis
Anti-metastatic
Invasion
MMPI
Detachment
Embolization
Vaccine and
Circulation
immunologic Rx
Arrest
Adhesion
Differentiating
Extravasation
agents
Growth
Cytostatic/Cytotoxic/Pro-apoptotic
Metastasis
Carducci MA, et al. Seminars in Oncology. 1996;23:56-62.
3
Applicability of Immunotherapy
by Clinical States
Castrate, Rising PSAs
PRO
CON
• Known
natural
history
• Time to POD
based on risk
• Possibility of
increases
CTCs
• Volume of
CTCs
• Tumor Ags,
unknown
Castrate Metastatic
PRO
CON
•
•
•
•
•
•
•
Shorter natural
history
Larger tumor
burden
Expected clinical
outcome
Increased CTCs
Increased soluble
tumor Ags
Combination with
chemotherapy
Survival preferred
FDA endpoint
•
•
•
•
Heterogeneous
population
No defined
immune
endpoint
Delayed
treatment effect
Intercurrent
symptoms may
delay
assessment or
lead to ∆ in
treatment
4
Applicability of Immunotherapy
by Clinical States
Localized: Neoadjuvant
PRO
CON
• Direct tissue
assessment:
penetration?
• Impact on
local milieu
• Signaling
pathways
• Easy to
screen novel
agents
• Likely hitting
a target
• Systemic
• No defined
endpoint
• Unclear if
any impact
on future
POD
• Unclear if
target is hit
Biochemically Relapsed
PRO
CON
• Minimal tumor
burden
history
• Measurement
of soluble Ag
• High-risk
population
exists
• Long natural
• No feasible
endpoint
• CTCs minimal
• Unclear if
target is hit
5
Issues / Solutions
• Harmonization of assays
– Established validated assays in designated labs
• What are the right assays?
– Dependent on the therapy
• Reconciliation of assays reflecting impact on
biology of tumor
– Impact not always evaluable based on assay
6
Unresolved …
• Integrate immunotherapy into clinical trial arena: most
productive clinical state?
• If proven efficacy, can one really improve on other endpoints
that are meaningful for the pt, ie QOL, pain, anti-tumor effect,
TTP – will it be worth the effort to further develop the
strategy?
• Standardize a therapy so that one size fits all, ie, dose, cell
number, feasibility to general population
• +/- chemotherapy? Reasonable without significant data to
demonstrate impact on immune cell populations; different
than that of using cytokines, ie, GM-CSF
• Are we leaning toward customized immunotherapy?
7
8
9
Is There A “Best” Approach?
Immunotherapy:
Humoral / Cellular
Compartments
Monoclonal
Antibodies
[Passive]
Vaccines
[Active]
T-cell
Immunotherapy
[Active]
10
Controversies …
• Defining the immunologic target …
Establishing the most appropriate screening assays that
will allow a “go/no go” approach – demonstrates
that the target has been recognized.
• Discordances between immunologic & clinical responses,
ie, generation of Abs / immunoreactive T-cells but NO
clinical benefit
• Establishing relevance of immune responses with clinical
outcome? Are the current “standards” below the limits
of detectability of the assays?
• Should the actual tumor be further examined for true
immunologic response?
11
Lastly …
• Does it make a difference whether the
immunologic target is B- or T-cell directed or
are both populations needed for maximal
immunologic signal and anti-tumor effects?
• Can chronic “inflammatory” conditions such
as prostatitis vs prostate cancer be mediated
by different immunologic responses?
12
Rationale for Vaccines in Prostate Cancer
1.
Well-characterized glycoprotein and carbohydrate “self”
antigens: PSA, PSMA, PSCA, ACP, Globo H, GM2,
Lewisy, MUC-1,2, Tn, TF, NY-ESO-1, CD147, and CD44
2.
Multiple ways of breaking immunologic tolerance:
[viral vectors – fowlpox, VEE, adeno +/- prime boost]
3.
Modulation of immune response via cytokines (GM-CSF,
IL-2) and immunomodulatory molecules (CD40, PD-1,
CTLA-4)
4.
Ease of administration [skin]
5.
Can be used in all disease states
6.
Biomarker to study disease progression
13
Antibody Responses to Prostate-Associated
Antigens in Patients With Prostatitis and
Prostate Cancer
•
Using a phage immunoblot approach, we evaluated IgG responses in
patients with prostate cancer (n = 126), patients with chronic prostatitis
(n = 45), and men without prostate disease (n = 53)
•
RESULTS: We found that patients with prostate cancer or prostatitis have
IgG specific for multiple common antigens. A subset of 23 proteins was
identified to which IgG were detected in 38% of patients with prostate
cancer and 33% patients with prostatitis versus 6% of controls (P < 0.001
and P = 0.003, respectively). Responses to multiple members were not
higher in patients with advanced disease, suggesting antibody immune
responses occur early in the natural history of cancer progression
•
CONCLUSIONS: These findings suggest an association between
inflammatory conditions of the prostate and prostate cancer, and suggest
that IgG responses to a panel of commonly recognized prostate antigens
could be potentially used in the identification of patients at risk for prostate
cancer or as a tool to identify immune responses elicited to prostate tissue
Maricque BB, et al. The Prostate. 2011;71(2):134-146.
14
Work Before Implementation
• Identify the target
molecule(s)
• Natural target –
omnipresent?
• Size: large / small
• Level of inherent
immunogenicity
• Best method of
inducing immunity
• How to prove that
induction of immunity
truly HITS the target
15
A (very) Brief History of
Cancer Vaccines
Whole cell or
shed antigen
Purified
protein
Peptide
16
17
PSMA Expression on LNCaP Cell
Vaccines: DNA,
alhydrogel, DG, VRP T-cell
NH2...
MoAbs
J415, J591 - ADCC
Extracellular
Intracellular
MoAb 7E11
ProstaScintпѓ¤
Scan
Antibody Drug
Conjugates:
auristatin
maytansinoid
Cell membrane
Modified from Smith-Jones PM. The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2004;48(4):297-304.
18
Prostate Vaccine Trials Experience …
1)
Chemical mimes of known cell surface “self” molecules –
immunogenic пѓ–
2)
Carriers and adjuvants enhance immunogenicity; change in
conformation can affect immunogenicity
3)
п‚­ doses of vaccine в‰ augmentation of immunogenicity, ie, lower
doses – more immunogenic 
4)
Specific Abs induced but no way to potentiate T-cell responses пѓ–
5)
Immunologic responses - not immediate; no role for boosters
6)
s in pre- vs posttreatment PSA slopes – No major clinical
impact on pts with high-risk disease пѓ– пѓ–
*No clear cut immunologic endpoints.пѓ– пѓ– пѓ–
19
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
20
Problems
• How to ensure target is hit
• Are we targeting one antigen but impacting
on another?
• How to reconcile differences in clinical vs
immunologic response
• Establishing endpoints that FDA will accept
• Standardization / harmonization of immune
assays [“immune monitoring”]
21
Do We Need to Change Our Current
Paradigms in Designing Immune-Based
Clinical Trials?
Sufficient data now exist that we can
generate humoral / cellular responses; our
immune read-outs correlate clinically
•
Despite immune “responses”, target is
not really “hit”; NO direct correlation
between development of humoral / cellular
immunity and clinical benefit
22
Why Have We Not
Succeeded, If …?
1) Immunogenicity is confirmed, ie, induction of
specific effector populations, Treg, DC
2) Can modulate immune system with cytokines
or checkpoint inhibitors
3) Vaccine is safe
4) Impact in PSA doubling time or slope
5) “Stable disease”
6) But … clinical benefit uncertain
23
Constructing A Better
Vaccine …
• Structural conformation
• Type of adjuvant
• Optimizing systemic conditions:
immunosuppressant drugs (CTX); cytokines;
immunomodulatory drugs, XRT
• Timing may be everything in combination
therapies and in booster vaccines
• Are the issues in clinical trial design or in the
therapy itself?
24
Are Single Antigen Vaccines
Enough or Are Multiple
Antigens Better?
25
Flow Cytometric Analyses of Patients’
Sera Against MCF-7 Cell Line
Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930.
26
27
Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930.
28
Slovin S, et al. Cancer Immunology, Immunotherapy. 2007;56(12):1921-1930.
“Treat” by Example
• Provenge -
• G-VAX
-
• Tri-Com
-
• Onyvax-P • Polyvalent -
Issues of “n” and endpoints
+ survival benefit but NO
significant anti-tumor effects
or ↓ PSA
Chemo combo / trials neg
(poor design?)
Ph II trial survival benefit +
Immune response weak but +
Data premature
More в‰ better
29
“Treat” by Example
• DNA vaccines (PSMA, PSA) –
theoretically better, no need for adjuvant
due to CpG repeats but HLA A2+ likely
beneficial
• Peptide / CHO vaccines – modest Ab
responses, no impact on tumor biology
• Checkpoint inhibitors – may be diseasespecific with robust immune and clinical
responses (PD-1, renal, melanoma; CTLA4, melanoma, ovarian, prostate)
30
How Can We Maximize An Otherwise
Weak or Poorly Measurable Immune
Response?
• Cytokines
• Release of check-point inhibitors
• Inhibitors of immunologic “brakes” within the
system or “give it the gas” types of
strategies
• Consider pretreatment
immunosuppressives, ie, cyclophosphamide
31
Changing Paradigms
• Adoptive immunotherapy +/- cytokines …
maybe
• Single agent vaccines: enough or just sufficient?...
no
• Combinatorial approaches:
Irradiated tumor cells (antigen integrity]) +/cytokine(s)/immunomodulatory molecules (B7.1)
maybe
-
Synthetic proteins / peptide / DNA +/- adjuvants
-
Check-point inhibitors +/- vaccines …
likely
-
Prime boost
likely
-
Vaccine + chemotx / xrt
Finding the “right” endpoint that the FDA will accept – will it always be
survival?
32
Are Autoimmune Events A Must?
• Characteristic of treatment with anti-CTLA-4
• Spectrum of effects
• Associated with anti-tumor and biomarker
effects
• May be variable based on the malignancy
• Do the benefits of treatment outweigh the
potential ferocity of some autoimmune
events?
33
PSA Curves – Dose Level 3 (3 mg/kg)
100
90
80
70
60
50
40
30
20
10
0
60
Pt 7
Pt 8
50
40
a
30
b
20
10
4/9/06
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
3/7/06
3/9/06
1/9/06
12/9/05
11/9/05
10/9/05
9/9/05
8/9/05
7/9/05
6/9/05
2/7/06
1/7/06
12/7/05
11/7/05
10/7/05
9/7/05
8/7/05
c
Pt 9
2/9/06
50
45
40
35
30
25
20
15
10
5
0
7/7/05
6/7/05
0
a : 13Mar06: SAE – Hypophysitis
(7 mo)
b: 03Feb06: Hypophysitis
(5 mo)
c: 09Feb06: SAE –
Hypophysitis (5 mo)
Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500.
34
Bone Scan Improvement in Patient 8 (3 mg/kg)
September 15, 2005
March 29, 2006
Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500.
35
Objective Tumor Response
Patient 12 (5 mg/kg)
February 14, 2006
May 16, 2006
Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500.
36
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 months
Adrenal insufficiency
008
Hypophysitis
5 months
Adrenal insufficiency
009
Hypophysitis
5 months
Adrenal insufficiency
Leukopenia
Hypothyroidism
010
Hypophysitis
4.5 months
Adrenal insufficiency
Hypothyroidism
012
Alveolitis (IBE?)
2 months
Low TSH
Gerritsen W, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2006;24(18S). Abstract 2500.
37
Pathology of Autoimmune
Breakthrough Events: Colitis
D
C
Histopathologic analyses of
selected patients experiencing
autoimmune events.
CD3
E
F
CD4
Phan GQ, et al. Proc Am Soc Clin Oncol. 2003: Abstract 3424.
CD8
(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).
38
Rationale: Radiotherapy As An ImmuneSupportive Intervention for CTLA-4 Blockade
AntiCTLA4
mAb
CTLA-4
Anti-CTLA4
mAb
CTLA-4
Modified from Demaria S, et al. International Journal of Radiation Oncology Biology Physics. 2005;63(3):655-666.
39
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
32
36
40
44
48
52
56
60
Weeks
Beer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S). Abstract 5004.
40
Subject 3020:
Resolution of Prostate Mass
Screening
14 Months
Beer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S). Abstract 5004.
41
Response Details
#3021(CP) @ 10 mg/kg Mono
200
%Baseline PSA
150
#3021
10 mg/kg mono
2 cycles (4,2)
PSA0 = 181
(-) Prior Chemo
SirAE -colitis
irAE - hypopit
100
50
Colitis
Hypopit
0
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
Weeks
42
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
• Standardization of trial endpoints by
nature of the therapy
• Combinatorial strategies more appealing
but immune assays must be target-specific
43
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