Dendritic Cell (DC)-Based Vaccines Loaded With Allogeneic Prostate Cell Lines in Combination With Androgen Ablation in Patients With Prostate Cancer

Dendritic cells or "DCs" are special white blood cells that stimulate the immune system. This
study is being done to test the feasibility, safety and efficacy of a specific type of
dendritic cell when injected under the skin of patients with prostate cancer. The researchers
conducting this study will evaluate the time to prostate specific antigen (PSA) progression
and will also be performing tests to see how the immune system is responding to the
injections.

This is a 2 group crossover trial in which patients are randomly assigned to one of two
treatment arms:

A. 3 months of androgen ablation (AA) to be followed at PSA progression by 3 months of the
combination of AA and alpha-type 1 dendritic cell vaccine (DC1); B. 3 months of the
combination of AA and alpha-type 1 dendritic cell vaccine followed at PSA progression by 3
months of AA.

Primary Objectives

- Feasibility objective: the ability to successfully generate and administer the alpha-DC1
vaccine.

- Safety objective: assess the tolerability and toxicity of the alpha-DC1 vaccine.

- Efficacy objective: evaluate the effect of the alpha-DC1 vaccine on time to PSA
progression compared to AA alone. PSA progression is defined as a rise in the PSA value
to e 1.0 ng/mL.

Secondary Objectives

- To determine the change in PSA velocity prior to and following the proposed treatment.

- To evaluate (in all subjects) the vaccination-induced DTH responses to LNCap, the cell
line vaccine, and to compare this with vaccination-induced responses to tumor-untreated
antigen (KLH).

- To evaluate the vaccination-induced changes of Th1/Th2 profiles of the responses to PAP
and PSMA.

- To evaluate the CTL responses in blood to the whole LNCap cells (in all subjects) and
(in all subjects who are HLA-A2 positive) the CTL responses to HLA-A2.1 restricted
peptides derived from PAP and PSMA.

- To comprehensively evaluate the CD4+ and CD8+ T cell responses (fine specificity and
Th1/Th2/Treg cytokine profile) to the previously-identified and novel immunogenic
epitopes of PAP and PSMA, using the EPIMAX system.

This is a 2 group crossover trial in which patients are randomly assigned to one of two
treatment arms:

A. 3 months of androgen ablation (AA) to be followed at PSA progression by 3 months of the
combination of AA and alpha-type 1 dendritic cell vaccine (DC1); B. 3 months of the
combination of AA and alpha-type 1 dendritic cell vaccine followed at PSA progression by 3
months of AA.

In this crossover trial each patient will serve as their own control. Following either
therapy the time to PSA progression, defined as the time between treatment and the first
instance of PSA increase to 1ng/ml. The endpoint is the difference between time to PSA
progression for the combination of AA + DC1 compared to AA alone. A total of 12 evaluable
patients (6 patients/arm) will be enrolled on the trial. Patients who do not complete both
courses (AA and AA+DCV) will be replaced. This schema will also help us better estimate the
time to PSA recovery following 3 months of limited androgen ablation in our cohort of
patients.

All patients in Cohort B, will commence DC1-based vaccination 2 weeks prior to treatment with
the LHRH analogue. Each patient will receive four i.d. doses of the vaccine at weeks 1, 4, 8,
and 12. The LHRH analogue (Lupron 22.5 mg or Zoladex 10.8 mg), will be administered 2 weeks
after the 1st dose of the DC vaccine. Additional courses of vaccination can be administered
to any patients without evidence of disease progression, every 3 months for up to 12 months.

Patients will undergo a thorough pre-study evaluation, and then undergo leukapheresis to
generate the DC-based vaccine. Each patient will receive 4 doses of intradermal (i.d.)
DC1-based vaccine at weeks 1, 4, 8, and 12.

Eligibility Criteria

- Patients with histologically proven prostate cancer and tumors limited to the prostate
(including seminal vesicle involvement, provided all visible disease was surgically
removed) who have completed local therapy and have an elevated PSA after surgery or
rising PSA after radiation therapy, as defined below.

- Age 18 years or older

- Histologically confirmed diagnosis of prostate cancer.

- Previous treatment with definitive surgery or radiation therapy or both.

- No evidence of metastatic disease on physical exam, CT/MRI/CXR (see Section 7.1 for
radiologic imaging), and bone scan within 4 weeks prior to randomization.

- Prior neoadjuvant/adjuvant hormonal, androgen deprivation therapy, or chemotherapy is
allowed if it was last used > 12 months prior to first vaccination.

- No therapy modulating testosterone levels (such as leuteinizing-hormone
releasing-hormone agonists/antagonists and antiandrogens) is permitted within 12
months prior to first vaccination. Agents such as 5α-reductase inhibitors,
ketoconazole, megestrol acetate, systemic steroids (replacement doses of steroids are
allowed), PC-SPES, and Saw Palmetto are not permitted at any time during the period
that the PSA values are being collected.

- Hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150
ng/dL or > 6 nmol/L at the time of enrollment within 4 weeks prior to randomization.

- All patients must have evidence of biochemical progression as determined by a
reference PSA value followed by 1 confirmatory rising PSA value, higher than the
previous value, obtained at least 2 weeks apart. All of these PSA values must be
obtained at the same reference lab, and all must be done within 6 months prior to
enrollment.

- The most recent of the PSA values must be ≥ 2.0 ng/mL. This measurement must be
obtained within 1 month prior to enrollment.

- The PSA doubling time (PSA-DT) must be less than 12 months.

- ECOG performance status 0 or 1.

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count > 1,500/µL

- Platelets > 100,000/µL

- Total bilirubin 1.5 x upper limit of normal (ULN)

- SGOT (AST) and SGPT (ALT) < 2.5 x institutional ULN

- Creatinine 1.5 x ULN

- The effects of dendritic cell vaccines on the developing human fetus are unknown. For
this reason men must agree to use adequate contraception (hormonal or barrier method
of birth control) prior to study entry and for the duration of study participation.

Exclusion Criteria

- Patients must not be receiving other investigational agents or concurrent anticancer
therapy.

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Patients must not have active eczema, atopic dermatitis, or other exfoliative skin
conditions (e.g., burns, impetigo, varicella zoster, severe acne, contact dermatitis,
psoriasis, herpes or other open rashes or wounds).

- Presence of an active acute or chronic infection, including urinary tract infection,
HIV or viral hepatitis. HIV patients are excluded based on immunosuppression which may
render them unable to respond to the vaccine; patients with chronic hepatitis are
excluded because of concern that hepatitis could be exacerbated by the injections. If
clinically indicate, HIV/viral hepatitis testing will be performed to confirm status.

- Patients with a history of auto-immune disease such as, but not restricted to,
inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis,
scleroderma, or multiple sclerosis. Patients receiving replacement thyroid hormone
would be eligible.

- No concurrent use of systemic steroids, except for local (topical, nasal, or inhaled)
steroid use. Adrenal replacement doses of corticosteroids are allowed.

- Subjects with concurrent additional malignancy (with exception of non-melanoma skin
cancers and superficial bladder cancer or malignancy within last 3 years).