Advances in Immunotherapy – How to Integrate into the Prostate Care Continuum

Advances in Immunotherapy –
How to Integrate into the Prostate Care
Continuum
Susan F. Slovin MD, PhD
Genitourinary Oncology Service
Sidney Kimmel Center for Prostate and Urologic Cancers
Memorial Sloan-Kettering Cancer Center
Overview…
Rationale
Status
Integration
Pitfalls
Role of immunologic biomarkers
Prostate Cancer 2013:
A Rapidly Changing Landscape
Diagnoses
239, 341
Clinically
Localized
Disease
Non-Castrate
Androgen depletion/blockade
(bicalutamide)
Castration resistant
Deaths From Disease
30,692
Clinical
Metastases:
Rising PSA Non-Castrate
1
Rising PSA:
Castrate
2
3
Clinical
Clinical
Metastases:
Metastases:
Castrate
Castrate
Sipuleucel-T
1st Line
Abiraterone
Docetaxel
4
Clinical
Metastases:
Castrate
2nd Line
Cabazitaxel
Abiraterone
Enzalutamide
ARN 509
Radium 223
Cabozantinib
Ipilimumab
Scher and Heller, Urology, 2000
With detectable metastases: deaths from cancer exceed that from other causes
Rationale for immunologic Approaches in Prostate
Cancer
1.
Well-characterized cell surface molecules: PSA, PSMA, PAP,
STEAP, PSCA, Globo H, GM2, MUC-1,2, Tn, TF, Lewisy.
2.
Biomarkers [PSA, CTCs] to study disease progression/response.
3.
Widely applicable to all disease states:
- biochemical relapse thru castration resistant disease.
4.
Likely potentiated via combinatorial approaches: radiotherapy,
chemotherapy, biologic agents (GM-CSF, IL-2) or checkpoint
inhibitors (anti-CTLA-4, anti-PD-1), monoclonal antibody-chemo
conjugates.
Immunotherapies to date…
•
•
•
•
Successes (limited)
Sipuleucel-T
Ipilimumab
PROST-Vac
Anti-PD-1
•
•
•
•
Failures (many)
G-Vax
Protein
Peptide
DNA
Is overall survival sufficient in the absence of clinical
benefit?
Sipuleucel-T: IMPACT Phase III Trial OS
Percent Survival (%)
100
p = .032 (Cox model)
HR = 0.775 [95% CI: 0.614–0.979]
Median survival benefit = 4.1 mos
75
Sipuleucel-T (n = 341)
Median survival: 25.8 mos
50
25
Placebo (n = 171)
Median survival: 21.7 mos
0
0
Kantoff et al, 2010.
6
12
18
24
30
36
42
48
Survival (Months)
54
60
66
Primary end point is progression-free survival.
Kantoff P W et al. JCO 2010;28:1099-1105
©2010 by American Society of Clinical Oncology
Serum tumor marker response.
Kantoff P W et al. JCO 2010;28:1099-1105
©2010 by American Society of Clinical Oncology
Effect modifier analysis.
Kantoff P W et al. JCO 2010;28:1099-1105
©2010 by American Society of Clinical Oncology
I. Immune Checkpoints - CTLA-4 Blockade
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.
Kaplan–Meier Curves for Overall Survival and Progression-free Survival in the Intention-toTreat Population
Hodi FS et al. N Engl J Med 2010;363:711-723
Subgroup Analyses of Overall Survival
Hodi FS et al. N Engl J Med 2010;363:711-723
“Ipilimumab alone or in combination with radiotherapy in
metastatic castration-resistant prostate cancer: results from
an open-label, multicenter phase I/II study”
Treatment Scheme
Slovin, et al, in press
Waterfall plots of percent change in PSA from baseline.
Slovin, et al, in press
PSA Decline and Tumor Response
Slovin, et al, in press
Disposition of Treated Patients as of May 2012
Slovin, et al, in press
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
Ipilimumab in Prostate Cancer
Phase III trials results accrued – results pending:
 “Randomized, Double-Blind, Phase 3 Trial to Compare the
Efficacy of Ipilimumab vs Placebo in Asymptomatic or
Minimally Symptomatic Patients With Metastatic
Chemotherapy-Naïve Castration Resistant Prostate Cancer”
 “A Randomized, Double-Blind, Phase 3 Trial Comparing
Ipilimumab vs. Placebo Following Radiotherapy in Subjects
With Castration Resistant Prostate Cancer That Have Received
Prior Treatment With Docetaxel”
II. Immune Checkpoints – PD-1 Blockade
Drake CG. Nat Rev Immunol. 2010;10(8):580-593.
•
•
•
•
•
•
N = 296 patients with advanced solid tumors
melanoma (N=104)
Non–small-cell lung cancer (N=122)
renal-cell cancer (N=34)
castration-resistant prostate cancer (N=17)
colorectal cancer (N=19)
Topalian, et al, NEJM, 2012
• Objective responses were observed in a
substantial proportion of patients with non–
small cell lung cancer, melanoma, or renal-cell
cancer;
• Includes various sites of metastasis: liver, lung,
lymph nodes, bone.
Pharmacodynamic and Molecular-Marker Assessments.
Topalian SL et al. N Engl J Med 2012;366:2443-2454
Activity of Anti–Programmed Death 1 (PD-1) Antibody in Patients with Treatment-Refractory
Melanoma, Non–Small-Cell Lung Cancer, or Renal-Cell Cancer.
Topalian SL et al. N Engl J Med 2012;366:2443-2454
EXPRESSION OF PROSTATE SPECIFIC MEMBRANE ANTIGEN
A)
C)
A)
B)
C,D)
B)
D)
Ghosh A et al, Journal of Cellular Biochemistry 91: 528-539 (2004)
Gala JL et al, Clinical Cancer Research, Vol 6, 4049-4054, October 2000
Chang SS et al., Clinical Cancer Research, Vol 5,2674-2681
PSMA Expression on LNCaP Cell
Vaccines: DNA,
alhydrogel, DG, VRP,
T cell
NH2...
MoAbs
J415, J591 - ADCC
Extracellular
Intracellular
MoAb 7E11
ProstaScint
Scan
Antibody Drug
Conjugate:
auristatin
Maytansinoid
Toxins?
Cell membrane
Modified from P. Smith-Jones 2004.
Background
Preclinical Proof of Principle
• in vivo function of Pz1, a CAR-targeting human PSMA
• Pz1 receptor encompasses the  chain of the CD3 complex
as its activation domain
• Specifically redirects in vitro cytolysis against PSMApositive tumor cell lines
 Hypothesis: Are expanded Pz1+ T cells active in vivo?
• Do they require costimulation after adoptive transfer?
• 3 tumor models established in SCID-bg/bg mice orthotopic, s.c., and pulmonary.
 Conclusion: Direct administration of Pz1+ T cells in
orthotopic and s.c. human prostate tumors eliminated a
majority of the tumors.
CHIMERIC ANTIGEN RECEPTORS (CARs)
• Genetic transfer of antigen receptors – rapidly generate tumorspecific T lymphocytes.
•Chimeric antigen receptors (CARs) encompass immunoglobulin
variable regions or receptor ligands as antigen-recognition elements
• Permits T cells to recognize cell surface tumor antigens in the
absence of HLA expression
• Requirements for genetically targeted T cells to function in vivo not
clearly defined, hence need to establish in vivo conditions
• T-cell activation - mediated by the cytoplasmic domain of the CAR,
which is typically derived from the CD3 chain or the FcRI chain
• P28z best vector
• herpes simplex virus-1 thymidine kinase (hsvtk) gene will be co-transferred with the cDNA encoding the P28z receptor, utilizing the
TP28z gamma-retroviral vector.
• Expression of hsvtk enables PET imaging using radiolabeled FIAU to image the localization of adoptively transferred T cells
Chemiluminescence
MRI/CT
IHC
Gade, et al, 2005
Rationale for Translation into Humans
PSMA as a Target for
Therapeutic Approaches
Genetically Redirected Adoptively
Transferred T Cells
•PSMA - dimeric type II integral
transmembrane protein with glutamate
carboxypeptidase activity
• Augments
• Overexpressed as prostate cancer cells
make transition to castration resistant state
• CARs that comprise both CD28 and CD3 
cytoplasmic domains were shown by our group to
better support T cell stimulation by target cells that
present antigen in the absence of activating
costimulatory ligands
• Abundantly expressed on neovasculature:
bladder, pancreas, melanoma, lung, and
kidney cancers, but not on normal
neovasculature
• Membrane-bound nature of PSMA and its
expression signature are attractive features
for targeted immunotherapy of prostate
cancer
T cell expansion
• Generates memory lymphocytes
CAR T cell Manufacturing Flow
Incubation
Dynabeads CD3/28
Przybylowski et al, Gene Ther, 2006
Day 3-4
Transduction
SFG-CAR
Vector
CD3+ enriched
activated
T cells
Day 0
Apheresis
Thaw/Wash
Cytomate
Apheresis
Patient T cell
activation
CAR
transduced
T cells
Selection
ClinExVivo Magnet
Day ≥5
Inoculation
WAVE
Bioreactor
Biosafety/
QC release tests
Infusion
Wash/Formulation
Cytomate
Effector/Memory phenotype
In vitro CTL assay
DAY ≥ 10
Debeading
ClinExVivo Magnet
Cell dose reached
CAR+
expanded T cells
Hollyman et al, J. Immunother, 2009
0.9
0.7
0.5
0.3
0.1
8/6
8/7
8/8
8/9
8/10
8/11
8/12
8/13
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
8/6
8/14
8/7
8/8
8/9
Time
Abs Lymph
Time
Temperature
ANC
39.8
39.6
39.4
39.2
39.0
38.8
38.6
38.4
38.2
38.0
37.8
37.6
37.4
37.2
37.0
36.8
36.6
36.4
36.2
ANC (k/mcl)
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
8/21
8/22
8/23
8/24
8/25
8/26
8/27
8/28
ANC (k/mcl)
39.50
8/20
39.50
11.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
8/20
8/21
8/22
8/23
Time
ABS Lymph
Temperature
R-T
Temperature (C)
R-T
0.9
39.6
39.4
39.2
39.0
38.8
38.6
38.4
38.2
38.0
37.8
37.6
37.4
37.2
37.0
36.8
36.6
36.4
36.2
8/10 8/11 8/12 8/13 8/14
39.8
39.6
39.4
39.2
39.0
38.8
38.6
38.4
38.2
38.0
37.8
37.6
37.4
37.2
37.0
36.8
36.6
36.4
36.2
8/24
8/25
8/26
Time
Temperature
ANC
Temperature
8/27
8/28
Temperature (C)
ANC (k/mcl)
1.1
39.30
9.0
ANC (k/mcl)
39.6
39.4
39.2
39.0
38.8
38.6
38.4
38.2
38.0
37.8
37.6
37.4
37.2
37.0
36.8
36.6
36.4
36.2
39.30
Temperature (C)
1.3
E-Z
Temperature (C)
E-Z
Pre/Post Infusion PSA and CTCs
25
3000
25
2500
20
2500
20
15
1500
10
1000
500
0
2000
5
500
0
0
Time on treatment (Weeks)
Time on treatment (Weeks)
Patient 4
5
4
3
2
1000
500
1
0
0
-36
-32
-28
-24
-20
-16
-12-8-4 0 4 81216202428323640444852
Time on treatment (Weeks)
PSA (ng/ml) *SCALED*
1500
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
CTC Counts
PSA (ng/ml)
2000
5
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Treatment Start
2500
10
1000
Patient 3
3000
15
1500
100
90
80
70
60
50
40
30
20
10
0
5
4
3
2
1
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time on treatment (Weeks)
CTC Counts
2000
PSA (ng/ml)
3000
CTC Counts
Patient 2
CTC Counts
PSA (ng/ml)
Patient 1
Biomarker Discovery: biomarkers to predict
disease outcome
• How to properly assess responses to biologic therapies
not standardized
• Endpoint of OS mandated by FDA
• ↑ Ab titers suggest hitting the target; need correlation
of biologic effect on tumor to be meaningful
• Ideal immunologic biomarker should show transition
from analyte to assay quantitation/qualification to
outcome measurement
Disis, Cancer Immunol Immunother 60:4333-442, 2011
Immunologic readouts
• Assessment of Type I adaptive immunity via IFN-γ ELISPOT
• Type I CD4+ T cells secrete interferon gamma (IFN-γ)
• CD4+ T cells support development of antigen-specific CD8+ T
cells (directly linked to tumor cell death)
• Several tumor types have reported an association with
immune responses measured by ELISPOT with improved
clinical outcome.
Potential Biomarkers
• Generation of T cell memory response after
immune-based cancer therapy has also been
shown to be predictive of clinical outcome.
• Delayed type hypersensitivity response (DTH) used as a measure of antigen recall or
memory
• Directly correlates with peripheral blood
antigen-specific T cell responses
Conclusions
• Screening of immunotherapeutic approaches
in neoadjuvant setting:
• Advantage: impact on local tumor
microenvironment and immune recruitment is
immediate;
• Disadvantage: systemic impact not discernible
but may still leverage potential for future
development of micrometastatic disease.
Conclusions
• Not every immunotherapy fits a specific disease and
vice versa
• Appropriateness of immune therapy for all clinical
states of disease but clinical judgment prevails, ie,
potential delay in impact of immune therapy
• Combinatorial approaches: checkpoint inhibitors
alone/together/chemo/RT/vaccines/cytokines
• MoAb-chemo conjugates