Induction of tissue-specific autoimmune prostatitis with prostatic acid phosphatase immunization: implications for immunotherapy of prostate cancer

Prostatic acid phosphatase (PAP) is uniquely expressed in prostatic tissue and prostate cancer. In this study, the immunogenicity of PAP was investigated in a male rat model. We show that immunization with recombinant rat or human PAP in CFA leads to a significant Ab response, but does not generate CTL or result in autoimmune prostatitis. In contrast, immunization with recombinant vaccinia expressing human PAP, but not rat PAP, generates a CTL response and tissue-specific prostatitis in the absence of detectable PAP-specific Abs. These findings suggest that a cellular immune response to PAP, rather than Abs, mediates destructive autoimmune prostatitis. Thus, xenogeneic forms of PAP are a new tool for the induction of prostate-specific immunity and may prove useful for the immunotherapy of prostate cancer.     

Molecular approaches to cancer immunotherapy

The use of cytokines and costimulatory molecule gene-engineered tumor cells to enhance tumor immunogenicity and elicit curative responses against established tumors and tumor recurrences has become an attractive prospect. The immunotherapy data obtained in many experimental tumor systems using these engineered cells are reviewed here to provide a realistic assessment of the potential and limits of this technique.     

Dendritic cells in the treatment of cancer

Thomas Berdmore's book, Disorders of Deformities of the Teeth and Gums, presents examples of early concepts of preventive dentistry and treatment of periodontal diseases. Various aspects of dental calculus formation and composition are analyzed. Also the effects of periodontal disease as seen by Berdmore are discussed, and ways of treatment in 1770 summarized.     

Experimental vaccine strategies for cancer immunotherapy

Recently, cancer immunotherapy has emerged as a therapeutic option for the management of cancer patients. This is based on the fact that our immune system, once activated, is capable of developing specific immunity against neoplastic but not normal cells. Increasing evidence suggests that cell-mediated immunity, particularly T-cell-mediated immunity, is important for the control of tumor cells. Several experimental vaccine strategies have been developed to enhance cell-mediated immunity against tumors. Some of these tumor vaccines have generated promising results in murine tumor systems. In addition, several phase I/II clinical trials using these vaccine strategies have shown extremely encouraging results in patients. In this review, we will discuss many of these promising cancer vaccine strategies. We will pay particular attention to the strategies employing dendritic cells, the central player for tumor vaccine development.     

Gene-based strategies for the immunotherapy of cancer

T lymphocytes play a crucial role in the host's immune response to cancer. Although there is ample evidence for the presence of tumor-associated antigens on a variety of tumors, they are seemingly unable to elicit an adequate antitumor immune response. Modern cancer immunotherapies are therefore designed to induce or enhance T cell reactivity against tumor antigens. Vaccines consisting of tumor cells transduced with cytokine genes in order to enhance their immunogenicity have been intensely investigated in the past decade and are currently being tested in clinical trials. With the development of novel gene transfer technologies it has now become possible to transfer cytokine genes directly into tumors in vivo. The identification of genes encoding tumor-associated antigens and their peptide products which are recognized by cytotoxic T lymphocytes in the context of major histocompatibility complex class I molecules has allowed development of DNA-based vaccines against defined tumor antigens. Recombinant viral vectors expressing model tumor antigens have shown promising results in experimental models. This has led to clinical trials with replication-defective adenoviruses encoding melanoma-associated antigens for the treatment of patients with melanoma. An attractive alternative concept is the use of plasmid DNA, which can elicit both humoral and cellular immune responses following injection into muscle or skin. New insights into the molecular biology of antigen processing and presentation have revealed the importance of dendritic cells for the induction of primary antigen-specific T cell responses. Considerable clinical interest has arisen to employ dendritic cells as a vehicle to induce tumor antigen-specific immunity. Advances in culture techniques have allowed the generation of large numbers of immunostimulatory dendritic cells in vitro from precursor populations derived from blood or bone marrow. Experimental immunotherapies which now transfer genes encoding tumor-associated antigens or cytokines directly into professional antigen-presenting cells such as dendritic cells are under evaluation in pre-clinical studies at many centers. Gene therapy strategies, such as in vivo cytokine gene transfer directly into tumors as well as the introduction of genes encoding tumor-associated antigens into antigen-presenting cells hold considerable promise for the treatment of patients with cancer.     

Screening for prostate cancer

In an attempt to detect prostate cancer when the tumor is still confined to the prostate, a screening program was established. We studied the efficacy of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) in the early detection of prostate cancer. One thousand men aged 50-75 years underwent DRE and serum PSA determination. Transrectal ultrasound-guided biopsies were obtained in each case of a suspicious DRE. Six systematic biopsies were performed if the PSA level was > 10 ng/ml, even if DRE and transrectal ultrasonography revealed no areas suspicious of cancer. A suspicious DRE was noted in 11.5% of the subjects; 16% had elevated levels of serum PSA (> 4 ng/ml) and 3.9% had serum PSA > 10 ng/ml. Biopsies were obtained from 90 patients, of which 31 were positive for prostate cancer. The cancer detection rate was 2.2% for DRE, 2.0% for PSA > 10 ng/ml, and 3.1% for the two methods combined. Clinical staging revealed that in 29 of the 31 patients with prostate cancer, the tumor was confined to the prostate: Stage A in 9 cases and stage B in 20 cases. Only two patients had clinically advanced cancer, and 22 patients underwent radical prostatectomy. Pathological examination disclosed biologically significant tumors in 91% of the cases in terms of tumor volume and grade. Although there is little evidence that screening will result in the reduction of the disease-specific mortality rate, early detection of prostate cancer by DRE, serum PSA, and transrectal ultrasound should be encouraged.     

Clinical staging of prostate cancer

Clinical staging of prostate cancer was reviewed on the basis of TNM classification edited by UICC in 1997. In this revision, (1) T1c was newly categorized among T1 for cases of high PSA level without any abnormal sign of DRE, (2) T2 was subdivided into T2a and T2b in accordance with unilateral or bilateral nodule in the prostate, respectively, (3) T3 was also subdivided into T3a with capsular invasion and T3b with seminal vesicle invasion. It is hoped that present classification will become useful tools for the detection of the tumor burden cancer patients.     

Molecular cytogenetics of prostate cancer

Prostate cancer is the most common malignancy among men in many developed countries. One-fourth of prostate cancers are diagnosed at metastatic stage but there is no curative treatment for such disease and palliative androgen withdrawal therapy remains the most used one. Thus, understanding the molecular events that underlie the development and progression of prostate cancer could help to answer many clinical questions on its treatment. In this review article, I want to illustrate some of the most interesting findings (by fluorescence in situ hybridization and comparative genomic hybridization) in the molecular cytogenetics of prostate cancer.