Cancer Clinical Trial
Official title:
Neoadjuvant Estradiol or Androgen Deprivation in Clinically Localized Prostate Cancer
Prostate cancer is the most commonly diagnosed cancer among males in the U.S. More than
220,000 men will be diagnosed with prostate cancer in the USA this year and more that 31,000
will die of this disease.
Androgen deprivation, the elimination of testosterone and its active metabolites, remains
the single most effective intervention available for the treatment of advanced prostate
carcinoma. Androgen deprivation induces an immune response to normal prostate and prostate
cancer, which is usually short-lived. Estradiol induces activation of many arms of the
immune system and may be a more effective and long lasting means of inducing immunity to
prostate tissue.
This study will treat clinically localized prostate cancer patients with either estrogens,
or standard androgen deprivation without estrogens, prior to prostatectomy in order more
completely to describe immune regulation by estradiol in men. Control tissue from patients
who have not been treated with androgen deprivation will be procured from the Northwest
Special Projects in Oncology Research Excellence (SPORE) tissue core and used as comparisons
against the cancers treated before prostatectomy. Tumors removed at prostatectomy, tissue
samples and blood samples will be assessed for immune system changes.
Estrogens are effective means of treating advanced prostate cancer. In randomized studies
estrogens have better cancer control rates than orchiectomy alone, suggesting that estrogen
efficacy is not limited to its ability to suppress testosterone. One hypothesis is that
estrogens modulate immunity to prostate cancer through direct activation of effector cells
and by upregulating cytokines in prostatic stroma. Administration of estrogen in murine
models induces infiltration of normal prostate with T lymphocytes even in castrate male
animals potentially through induction of autoimmunity to normally cryptic prostate antigens.
Estrogens activate multiple immune effectors and autoimmunity in a broad variety of
experimental settings, suggesting upregulation of immune recognition on many levels. Pilot
data demonstrates that estrogens upregulate expression of interferon regulated genes, major
histocompatibility antigens (MHC) on prostate cancer, and increase both number and
activation of natural killer (NK) cells. Other groups have shown that standard forms of
androgen deprivation also induce immunity against both normal and malignant prostate tissue.
We propose to test the hypothesis that administration of estrogen and/or androgen
deprivation induces immune recognition of prostate cancer in humans through upregulation of
major histocompatibility antigens on tumor and induction of tumor specific immunity. The
specificity of estrogen effect will be tested by comparing measures of immunity in patients
treated with estradiol, androgen deprivation or no neoadjuvant therapy.
Plan of therapy
The specific aims of this proposal are:
1. To treat patients with clinically localized, low to intermediate risk prostate cancer
who are candidates for radical prostatectomy with either standard androgen deprivation
prior to surgery (neoadjuvant androgen deprivation) or neoadjuvant transdermal
estradiol. Patients will undergo radical prostatectomy 21 days after initiation of
treatment.
2. To evaluate radical prostatectomy specimens obtained from these patients for expression
of MHC class I and II, and NK ligands MICA and MICB in prostate carcinoma and adjacent
prostate by immunohistochemistry (IHC) and Western analysis.
3. To evaluate tumor tissue for infiltration by clonal T lymphocytes, NK cells, and
plasmacytoid dendritic cells using IHC and spectratyping of T cell receptor gene
rearrangements.
4. To evaluate patients for the induction of tumor specific antibodies using patient
immunoglobulin collected before and after neoadjuvant therapy (SEREX)
5. To evaluate patients for induction of NK cells and upregulation of the NK receptor
NKG2D on patient lymphocytes by androgen deprivation and estradiol.
6. To evaluate the effects of androgen deprivation and estradiol on induction of plasma
and tissue levels of interferon gamma, alpha, beta, IL-4 and GM-CSF by ELISA and
ribonuclease protection assay.
;
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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