T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer

Mercader, Maria; Bodner, Barbara; Moser, Micheal T.; Kwon, Pamela S.; Park, Eugene S. Y.; Manecke, Ryan G.; Ellis, Thomas M.; Wojcik, Eva M.; Yang, Damu; Flanigan, Robert C.; Waters, W. Bedford; Kast, W. Martin; Kwon, Eugene D.

doi:10.1073/pnas.251140998

Cited by 353 publications

(336 citation statements)

References 48 publications

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“…This may be due to an underlying immune response to PSA produced by the cells in the tumor or normal prostate gland as has been published previously (54). In addition, it is possible that ADT, which has been shown to cause apoptosis with an influx of lymphocytes into tumor, may have had an effect on this (55). This would be expected to be greatest when ADT is started in conjunction with vaccination.…”

Section: Discussionmentioning

confidence: 84%

Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer

Gulley¹,

Arlen²,

Bastian³

et al. 2005

Clinical Cancer Research

338

249

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Purpose: Many patients with clinically localized prostate cancer develop biochemical failure despite excellent local therapy perhaps due to occult metastatic disease. One potential solution is the utilization of a well-tolerated systemic therapy (e.g., vaccine) in concert with local therapy. Experimental Design:We present a randomized phase II clinical trial designed to determine if a poxviral vaccine encoding prostate-specific antigen (PSA) can induce a PSA-specific T-cell response when combined with radiotherapy in patients with clinically localized prostate cancer. Thirty patients were randomized in a 2:1 ratio into vaccine plus radiotherapy or radiotherapyonly arms. Those patients in the combination arm received a ''priming'' vaccine with recombinant vaccinia (r V) PSA plus r V containing theT-cell costimulatory molecule B7.1 (r V-B7.1) followed by monthly booster vaccines with recombinant fowlpox PSA. The vaccines were given with local granulocyte-macrophage colony-stimulating factor andlow-dose systemicinterleukin-2. Standard external beam radiation therapy was given between the fourth and the sixth vaccinations. Results: Seventeen of 19 patients in the combination arm completed all eight vaccinations and 13 of these 17 patients had increases in PSA-specificTcells of at least 3-fold versus no detectable increases in the radiotherapy-only arm (P <0.0005).There was also evidence ofde novo generation of T cells to well-described prostate-associated antigens not found in the vaccine, providing indirect evidence of immune-mediated tumor killing. The vaccine was well tolerated. Conclusion:This vaccine regimen can be safely given in patients undergoing radiation therapy for localized prostate cancer, with the majority of patients generating a PSA-specific cellular immune response to vaccine.

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Section: Discussionmentioning

confidence: 84%

Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer

Gulley¹,

Arlen²,

Bastian³

et al. 2005

Clinical Cancer Research

338

249

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“…Target the stromal AR at an early stage It is apparent that ADT will have some beneficial effects on early prostate cancer, but will eventually fail in view of the dual functions of AR signals in prostate cancer (Mercader et al, 2001) and decreased stromal cells, including the cancer-associated fibroblasts (CAF). progression ( Figure 3).…”

Section: The Impact Of Ar Dual Functions On Current Clinical Adtmentioning

confidence: 99%

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

et al. 2010

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Prostate cancer is one of the major causes of cancerrelated death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fails leading to recurrent tumor growth in a hormonerefractory manner, even though AR remains to function in hormone-refractory prostate cancer. Interestingly, some prostate cancer survivors who received androgen replacement therapy had improved quality of life without adverse effect on their cancer progression. These contrasting clinical data suggest that differential androgen/ AR signals in individual cells of prostate tumors can exist in the same or different patients, and may be used to explain why ADT of prostate cancer fails. Such a hypothesis is supported by the results obtained from transgenic mice with selective knockout of AR in prostatic stromal vs epithelial cells and orthotopic transplants of various human prostate cancer cell lines with AR overexpression or knockout. These studies concluded that AR functions as a stimulator for prostate cancer proliferation and metastasis in stromal cells, as a survival factor of prostatic cancer epithelial luminal cells, and as a suppressor for prostate cancer basal intermediate cell growth and metastasis. These dual yet opposite functions of the stromal and epithelial AR may challenge the current ADT to battle prostate cancer and should be taken into consideration when developing new AR-targeting therapies in selective prostate cancer cells.

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“…10,12,13 The remaining 60-95% cases of clinical prostatitis (categories IIIA and IIIB) may involve (i) hormonal imbalance; 14,15 (ii) neurological dysfunction; 16,17 (iii) a-adrenergic system abnormalities; [18][19][20] (iv) urinary reflux into the prostate; [21][22][23] (v) inappropriate cytokine release [24][25][26][27][28][29][30][31][32] and/or (vi) an autoimmune response. [33][34][35][36][37] The patients typically have repeat episodes of prostatitis and therapy is 'hit or miss'.…”

Section: Introductionmentioning

confidence: 99%

Experimental rodent models of prostatitis: limitations and potential

Vykhovanets

Resnick

MacLennan

et al. 2007

Prostate Cancer Prostatic Dis

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Prostatitis is a polyetiological inflammation of the prostate gland in men characterized by pelvic pain, irritative voiding symptoms, and sexual dysfunction. Histologically prostatitis is characterized by poly-and mononuclear cell infiltrates (neutrophils, lymphocytes, macrophages and plasma cells) in the stromal connective tissue around the acini or ducts. Prostatitis is an important worldwide health problem in men. The pathogenesis and diagnostic criteria for the condition are obscure, with the result that the development of management programs for this condition has been hindered. Animal model(s) might be useful in elucidating mechanisms involved in the molecular pathogenesis of chronic nonbacterial prostatitis and chronic pelvic pain syndrome. Given that prostatitis might have a multifactorial etiology, several animal models with unique features may prove helpful. This review examines a number of experimental rodent models of prostatitis and evaluates their advantages and limitations.

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T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer

Abstract: adenocarcinoma of the prostate ͉ CD4ϩ and͞or CD8 ϩ T cell ͉ cytotoxic T cell ͉ antigen-presenting cell ͉ hormone therapy

Cited by 353 publications

References 48 publications

Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer

Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

Experimental rodent models of prostatitis: limitations and potential

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