Prostate Cancer Vaccines

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Prostate Cancer Vaccines
Douglas McNeel, MD PhD Associate Professor of
Medicine University of Wisconsin - Madison Paul
P. Carbone Comprehensive Cancer Center
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Anti-Tumor Immunotherapy - Rationale

• Evidence that tumors avoid immune detection
• Some cancers are more common in immuno-suppressed
  patients
• Many tumors contain infiltrating lymphocytes
• Immune responses to tumor-associated proteins can
  be detected in patients with cancer
• Cures to some malignancies associated with
  autoreactive immunity
• Spontaneous resolution of some tumors

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Anti-Tumor Vaccines ??

• Goal is to elicit a tissue-destructive
  autoimmune tumor rejection response
• Specific
• Safe and inexpensive
• Able to penetrate all sites
• Long-term memory response

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Tumor Immunology - Vaccines Rationale for
Prostate Cancer

• Significant health problem
• Long interval between diagnosis and progression
• Currently no adjuvant treatment
• Several prostate cancer-associated proteins
  already identified
• Immune responses to prostate may be therapeutic

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Prostate Cancer Natural History
Normal prostate
PIN
Localized prostate cancer
Rising PSA (D0)
Lymph node/bone metastases
Androgen-independent
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Prostate Cancer - Possible Roles for Vaccines
Normal prostate
PIN
Localized prostate cancer
Rising PSA (D0)
Lymph node/bone metastases
Androgen-independent
VACCINES
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Prostate Cancer - Types of Vaccines
Cell-Based
Antigen-Specific

• Autologous inactivated cells
• Gene-transduced tumor cells
• Dendritic cell

• Protein / Carbohydrates
• Peptide
• Vectors
• Bacterial
• Viral
• Nucleic acid

Spitler - Jenner Biotherapeutics
Dillman - Hoag Cancer Center
Slovin - Memorial Sloan Kettering
McNeel - University of WA Peace University of IL
Simons - Johns Hopkins Cell Genesys - GVAX
Sanda - University of MI Kufe - Dana Farber ECOG
/ NCI
Murphy - Northwest Biotherapeutics -
CaPVax Dendreon Corporation PAP-GM-CSF
(APC8015) - phase III Gilboa, Vieweg - Duke
University, University of Florida
Pisa Karolinska - PSA Wolchok MSKCC -
PSMA McNeel UW Madison - PAP
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Prostate Cancer - Types of Vaccines
Cell-Based
Antigen-Specific

• Autologous inactivated cells
• Gene-transduced tumor cells
• Dendritic cell

• Protein / Carbohydrates
• Peptide
• Vectors
• Bacterial
• Viral
• Nucleic acid

Spitler - Jenner Biotherapeutics
Dillman - Hoag Cancer Center
Slovin - Memorial Sloan Kettering
McNeel - University of WA Peace University of IL
Simons - Johns Hopkins Cell Genesys - GVAX
Sanda - University of MI Kufe - Dana Farber ECOG
/ NCI
Murphy - Northwest Biotherapeutics -
CaPVax Dendreon Corporation PAP-GM-CSF
(APC8015) - phase III Gilboa, Vieweg - Duke
University, University of Florida
Pisa Karolinska - PSA Wolchok MSKCC -
PSMA McNeel UW Madison - PAP
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Laboratory / Translational Research Objectives

• To identify immunologically recognized antigens
  of the prostate
• To determine whether DNA vaccines can elicit
  antigen-specific anti-tumor immune responses
• To translate these research findings to clinical
  trials

What are appropriate targets for vaccines? Can
feasible immunization strategies be used to
deliver antigens and elicit antigen-specific
CTL? Can these therapies work in patients
with minimal residual disease?
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Research Objective 1

• Objective To identify prostate vaccine target
  antigens
• Hypotheses
• 1. Autoimmune responses to prostate are
  restricted to a set of antigenic proteins
• 2. The presence of tumors, and treatment of
  these tumors, elicit tumor antigen-specific
  immune responses that might serve as tissue/tumor
  rejection antigens

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Methods SEREX
Sequence and identify gene encoding phage plaque
Grow bacterial lawn on agar Transfect phage
cDNA library
Transfer to membrane Overlay with human sera
Detect IgG
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SEREX Chronic Prostatitis
A
B
Initial Screen
Selection
Prostatitis
Normal
Prostatitis
Normal
Plaque Purification and Identification by
Sequencing
Ed Dunphy
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SEREX Chronic Prostatitis
Ed Dunphy
JCI 04 24492
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Are there other rational prostate tumor
antigens?

• Tumor-specific proteins
• Biologically important targets

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Methods Phage Immunoblot
Jason Dubovsky
J Immunotherapy 07 30675
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Identification of Prostate Tumor-Specific
Antigens
Jason Dubovsky
Prostate 07 671781
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Androgen Receptor as a Prostate Cancer Antigen

• Steroid hormone receptor that is the essential
  regulator of normal prostate development
• Also plays a important role in prostate cancer
• Active and/or overexpressed and/or mutated in up
  to 50 of androgen-independent cancers
• High AR expression correlates with poor prognosis
• AR inhibitors and cofactor regulators active
  treatments and active area of new drug development

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Many Patients with Prostate Cancer have IgG
Specific for AR LBD
Brian Olson
Prostate 07 671729
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Identification of Prostate Tissue/Tumor
AntigensConclusions
Known prostate proteins
Prostatic acid phosphatase MAD-Pro-34 SSX-2 And
rogen-receptor ligand-binding domain
Chronic prostatitis
Prostate antigens
Following treatment
Cancer-testis antigens
Biologically relevant
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Research Objective - 2

• Objective To determine whether DNA vaccines can
  elicit antigen-specific anti-tumor immune
  responses
• Hypothesis
• DNA vaccines encoding a specific protein target
  will elicit antigen-specific CD8 T cells and
  anti-tumor responses

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Antigen-Specific DNA Vaccines
From Liu, JIM [phone]
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Model antigen Prostatic Acid Phosphatase (PAP)
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DNA vaccines encoding PAP elicit antigen-specific
immune responses
Vaccine 06 24293
Laura Johnson
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Research Objective 3

• Objective To translate preclinical findings to
  human clinical vaccine trials
• Hypotheses
• 1. DNA vaccines encoding a specific protein
  target will elicit antigen-specific CD8 T cells
  in humans
• 2. The generation of prostate tumor
  antigen-specific CD8 T cells should have
  anti-tumor efficacy

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Phase I Trial DNA Vaccine Encoding
PAP Objectives

• Primary Objectives
• Safety - Toxicity
• Immune Response - PAP-specific IFNg-secreting
  CD8 T-cell response
• Secondary Objectives
• Dose response to plasmid vaccine
• PSA response

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Phase I Trial DNA Vaccine Encoding PAP Study
Population

• Study Subjects / Enrollment
• Patients with stage D0 (non-castrate,
  non-metastatic) prostate cancer
• Rising serum PSA
• No immunosuppressive or hormonal therapy

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Phase I Trial DNA Vaccine Encoding PAP Study
Design

• Dose escalation typical phase I design
• Level 1 100 µg 200 µg GM-CSF
• Level 2 500 µg 200 µg GM-CSF
• Level 3 1500 µg 200 µg GM-CSF
• Vaccine administered in 2-3 divided doses
  intradermally, at 14-day intervals x 6
• 16 patients treated at maximum tolerated dose
  (MTD)

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Phase I Trial DNA Vaccine Encoding PAP Safety /
Adverse Events
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Immunological Analysis Antigen-Specific
IFNg-Secreting CD8 T cells
p lt 0.001

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Immunological Analysis Antigen-Specific
IFNg-Secreting CD8 T cells



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Immunological Analysis Antigen-Specific T-Cell
Proliferation
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Immunological Analysis Antigen-Specific T-Cell
Proliferation
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Phase I Trial DNA Vaccine Encoding PAP PSA
Responses

• No complete responses
• No decreases by gt50

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Phase I Trial DNA Vaccine Encoding PAP PSA
Responses
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Phase I Trial DNA Vaccine Encoding PAP Changes
in PSA Doubling Time
ID Pre-tx
On-tx   1
8.6288 7.7412 2
13.4797 -31.1694 3
18.0251 43.9007 4
5.1660 7.1581 5
15.6540 -96.7860
6 6.5500 9.3052
7 6.8339 26.6429
8 3.6411 8.2044
9 4.5831 4.6463
10 2.7344 4.0744
11 27.9629 37.1649
12 7.2305 20.7324
13 15.9634 8.4724
14 6.2244 3.8500
15 3.4895 3.6371
16 4.4780 7.5374
17 5.1178 5.0191
18 2.3951 14.2733
19 8.6923 8.2517
20 5.4177 5.9936
21 2.5934 2.4713
22 12.4250 15.0104
Median Range
p-value (months) Pre-treatment 6.39 2.40
- 27.97 On-treatment 8.23 2.47
45.0 0.0034
Svatek, R. S., Shulman, M., Choudhary, P. K. and
Benaim, E. (2006) "Critical analysis of
prostate-specific antigen doubling time
calculation methodology" Cancer 1061047-53.
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Phase I Trial DNA Vaccine Encoding
PAP Development of Delayed Immune Response
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If immune responses can be elicited, and if PSA
doubling time may be prolonged, should we
consider continuing booster immunizations?
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Phase I Trial DNA Vaccine Encoding PAP Booster
Immunizations
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Phase I Trial DNA Vaccine Encoding PAP Booster
Immunizations
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Conclusions from Phase I trial

• Immunization of patients with a DNA vaccine
  encoding PAP did not elicit severe adverse events
• Evidence of T-cell immune responses elicited at
  each dose tested
• DNA vaccine able to elicit antigen-specific T
  cells, and this response was boostable
• Several patients experienced prolonged PSA
  doubling time
• Long-term analysis underway to identify whether
  changes in PSA doubling time are durable, and
  whether immune response elicited is associated
  with change in PSA doubling time

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Conclusions from Phase I trial (cont.)

• These results suggest that a phase II trial is
  warranted
• Randomized, blinded, multi-institutional design
• These results suggest further that continued
  immunization may be important/necessary to elicit
  long-term effector/memory tumor antigen-specific
  T cells
• Randomized, pilot trial evaluation of
  continuous immunization with schedule determined
  by ongoing immune monitoring

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Future Directions

• Phase II clinical trial
• Current trial establishes safety and
  immunological efficacy of DNA immunization
• Evaluation of other antigens
• Combination approaches with other
  immunoregulatory strategies
• Rational design of DNA vaccines encoding
  modified tumor antigens

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Acknowledgements

• Lab
• Sheeba Alam, PhD
• Jordan Becker
• Robert Cronk
• James Davies
• Jason Dubovsky
• Ed Dunphy
• Tom Frye
• Laura Johnson, PhD
• Brett Maricque
• Matt Morse
• Brian Olson
• Heath Smith

• Clinical Research
• George Wilding, MD
• Glenn Liu, MD
• Mary Jane Staab, RN
• Jane Straus, RN
• Dottie Horvath, RN
• Janna Bergum
• Mary Beth Wims
• Jessica Simmons
• Jens Eickhoff, PhD

• Funding
• DOD Prostate Cancer Research Program
• NIH
• UWCCC
• UW Graduate School

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