PTEN Knockout Prostate Cancer as a Model for Experimental Immunotherapy

Department of Medicine, University of California-Los Angeles, California, USA.
The Journal of urology (Impact Factor: 4.47). 12/2008; 181(1):354-62. DOI: 10.1016/j.juro.2008.08.124
Source: PubMed


Testing immunotherapeutic strategies for prostate cancer has been impeded by the lack of relevant tumor models in immunocompetent animals. This opportunity is now provided by the recent development of prostate specific PTEN knockout mice, which show spontaneous development of true adenocarcinoma arising from prostate epithelium and more faithfully recapitulate the human disease than any previous model. We investigated the feasibility of using tumor cells derived from this model to test tumor vaccination and adoptive immunotherapeutic strategies for prostate cancer.
PTEN-CaP8 adenocarcinoma cells derived from the biallelic PTEN knockout prostate cancer model were used to vaccinate nontumor bearing litter mates. Tumor specific effector cells were generated from splenocytes of vaccinated mice by mixed lymphocyte-tumor reactions, and antiproliferative effects and cytokine generation were examined in vitro. The effect of vaccination or adoptive immunotherapy on luciferase marked PTEN-CaP8 subcutaneous tumors was monitored by tumor volumetric measurements and noninvasive bioluminescence imaging.
Vaccination of litter mate mice with irradiated PTEN-CaP8 cells showed a significant prophylactic effect against the subsequent tumor challenge. Effector cells harvested from vaccinated litter mates showed significant interferon-gamma secretion upon co-incubation with PTEN-CaP8 target cells and they were capable of efficient target cell growth inhibition in vitro. Intratumor adoptive transfer of effector cells resulted in significant growth inhibition of preestablished prostate tumors in vivo.
The PTEN knockout model serves as a highly useful model in which to investigate tumor cell vaccination and adoptive immunotherapeutic strategies in the context of true adenocarcinoma of the prostate. This model should accelerate efforts to develop effective immunotherapies for human prostate cancer.

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Available from: Takahiro Kimura,
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    Department of Molecular Medicine, Wake Forest University, 08/2009, Degree: Ph.D.
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    ABSTRACT: Replication-competent retrovirus (RCR) vectors can propagate specifically within actively dividing cancer cells and achieve highly efficient and tumor-selective gene delivery. To improve their tumor-specificity and safety profile, we have developed RCR vectors regulated by two different tissue-specific promoters. The first is regulated by a synthetic variant of the probasin promoter (ARR2PB), exhibits high specificity for androgen receptor (AR)-positive prostate cancer cells. The second incorporates a newly developed androgen-independent synthetic regulatory element (PSES) which is highly active in PSA-/PSMA-positive prostate cancer cells, both in the presence and absence of androgen. The wild type promoter in the retrovirus long-terminal repeat (LTR) sequence was replaced with ARR2PB and PSES promoter sequences, and the efficiency and specificity of transduction and replication by the resultant RCR vectors was examined in vitro and in vivo. We have also developed prostate-targeted RCR vectors carrying the yeast cytosine deaminase (yCD) gene, which converts the nontoxic prodrug 5-fluorocytosine (5FC) into the chemotoxin 5-fluorouracil, and the potency and selectivity of the cytotoxic effect mediated by these vectors was examined.