Langtitel Verordnung des Bundesministers f 3 agreement on the exploration, development and production sharing for the shah deniz prospective area in the azerbaijan sector of the caspian sea. How to cite this article: Wadosky KM, Koochekpour S. Therapeutic Rationales, Progresses, Failures, and Future Directions for Advanced Prostate Cancer. Gulley, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 1. Center Drive, Room 8. B0. 9, Bethesda, MD 2. Phone: (3. 01) 4. Fax: (3. 01) 4. 80- 5. Email: vog. hin. liam@jyellug. See other articles in PMC that cite the published article. Abstract. Prostvac is a prostate cancer vaccine regimen consisting of a recombinant vaccinia vector as a primary vaccination, followed by multiple booster vaccinations employing a recombinant fowlpox vector. Both vectors contain the transgenes for prostate- specific antigen (PSA) and multiple T- cell costimulatory molecules (TRICOM). The PSA- TRICOM vaccines infect antigen- presenting cells (APCs) and generate proteins that are expressed on the surface of the APCs in an immune context. The interaction of these APCs with T cells initiates a targeted immune response and T cell- mediated tumor cell destruction. Preliminary clinical trials have indicated negligible toxicity and determined the optimal dosing schedule. In addition, these trials indicate that Prostvac may hold promise in the treatment of prostate cancer. Phase II trials have shown a survival benefit after treatment with Prostvac, especially in patients with indolent disease characteristics. Preclinical and clinical data indicate that radiation, hormonal therapy, and chemotherapy may be combined with Prostvac to enhance the vaccine’s efficacy. Additional strategies are in development to further enhance the clinical benefits of Prostvac, and a phase III trial is being planned in metastatic castration- resistant prostate cancer. Keywords: prostate cancer, therapeutic cancer vaccine, immunotherapy. Introduction. The last 2 decades have seen great advances in the treatment of cancer, beginning with monoclonal antibody (m. Der Extrakt aus dem Prostatakrebs-Forum von KISP und BPS. Diagnostik – Das prostataspezifische Antigen (PSA) . Die PSA-Verdoppelungszeit. Ab)- based treatments such as rituximab and trastuzumab . Shortly thereafter, imatinib mesylate ushered in targeted molecular therapies, and numerous similar agents are currently part of clinical practice or clinical trials . Prostate cancer treatment has also made strides in the last decade. Food and Drug Administration (FDA) approved docetaxel, the first, and as yet only, chemotherapeutic agent demonstrating improved overall survival in metastatic castration- resistant prostate cancer (CRPC) . As with other malignancies, many molecular targeted agents have been investigated in prostate cancer, although none has been approved to date. However, one targeted treatment strategy that has shown promise in prostate cancer is the use of therapeutic cancer vaccines. One if these is Prostvac (developed by the National Cancer Institute and licensed to BN Immunotherapeutics, Mountain View, CA), which has been investigated in both early- (castration- sensitive) and late- stage (castration- resistant) disease. Rationale for use of vaccines in prostate cancer. There may be several reasons why therapeutic cancer vaccines have shown more promise in prostate cancer than in other tumor types. Prostate cancer tumors grow more slowly than most other malignancies, potentially allowing more time to generate a targeted immune response and yield a clinical benefit . Furthermore, prostate- specific antigen (PSA), a unique marker of recurrent or early- stage prostate cancer, allows for the detection of minimal tumor volume before it is evident on imaging studies . Finally, and perhaps most critically, prostate cancer generates unique gene products that are potential targets for immunotherapy . In many patients with prostate cancer, cytolytic T cells mount a weak response to these tumor- associated antigens (TAAs), with levels of immune recognition that are clinically insignificant and do not affect tumor growth. The goal of therapeutic cancer vaccines is to enhance immune recognition so that T cells can target these prostate- specific TAAs, leading to tumor- specific T cell- mediated destruction . PSA is not merely a serum marker of disease in patients with prostate cancer. The 3. 4- k. D protein is distinctively expressed in virtually all prostate cancer cells and nonessential epithelial cells within the prostate, making it a potential target for many prostate cancer vaccines . As an added benefit, tumor cell lysis generated by a vaccine that targets PSA may expose the immune system to additional TAAs, such as prostate- specific membrane antigen, prostatic acid phosphatase, and MUC- 1, leading to an immune response against TAAs not targeted specifically by the vaccine. Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy. Crook, M.D., Christopher J. O'Callaghan, D.V.M., Ph.D., Graeme. Generation Peugeot Expert und Citro. Generation Toyota Proace (seit 2016) Die zwischen PSA und Toyota entwickelte neue Generation wird neben den. Prostate cancer is common and a frequent cause of cancer death. In the United States, prostate cancer is the most commonly diagnosed visceral cancer; in 2016, there. This phenomenon, called antigen spreading or antigen cascade, ultimately results in the immune targeting of tumor cells via multiple TAAs . Development of poxviral vaccines and TRICOMRecombinant poxviruses are developed by the insertion of a recombinant plasmid containing the transgenes that will code for selected proteins, in this case TAAs. Upon infection, the viruses then transfer the plasmid into a permissive eukaryotic cell line. Next, the cell line is reinfected by wild- type poxviruses, and as they reproduce within the cell, a small proportion of poxviruses will contain the recombinant plasmid. Expression of markers inserted into the plasmid identifies which viruses contain the recombinant plasmid. These particular poxviruses are then selected and amplified for use as a cancer vaccine . The presence of viral proteins at the injection site causes an inflammatory response, drawing APCs to the injection site where they can be infected . The large poxviral genome allows for the inclusion of costimulatory molecules, in addition to TAAs, which enhance the efficacy of APCs . Vaccinia has been safely administered to over a billion people in the form of smallpox vaccines. Furthermore, there is no risk of disrupting host DNA as all poxviral replication occurs in the cell cytoplasm. Advantages of using poxviral vectors in therapeutic cancer vaccines. The goal of therapeutic vaccines is to generate an immune response to weakly immunogenic TAAs such as PSA. Poxviruses, which serve as a vehicle for vaccine delivery, have high infectivity rates and can infect APCs when injected into subcutaneous tissue. Once delivered inside the APC, transgenes for TAAs are then processed and expressed by the APC within the major histocompatibility complex (MHC), leading to T- cell activation. Several important preclinical studies of poxviral vaccines targeting PSA illustrated methods for augmenting the vaccines’ clinical efficacy. Initial development of the vaccine required enhancement of the PSA peptide. In vivo, cytolytic T cells must recognize peptides bound to MHCs in order to become activated and initiate a targeted immune response. Computer imaging analysis and investigational peptide binding data have previously demonstrated this phenomenon . The alteration of even a single amino acid in a peptide has the potential to enhance T cell- MHC interaction. The more stable and thermodynamically favorable this interface is, the greater the likelihood that a T cell will bind to the MHC and initiate a tumor- specific immune response . Early preclinical studies led to slight alterations in the PSA peptide to optimize T cell- MHC interactions and the subsequent immune response . This costimulation is of greater consequence when the antigen involved is a weakly immuogenic TAA such as PSA. An interaction that lacks costimulation could lead to T- cell anergy or apoptosis . Although early poxviral vaccines targeting PSA did not contain costimulatory molecules, recombinant vaccinia (r. V) containing the transgene for costimulatory molecule B7. V- B7. 1) was often admixed with the priming dose of recombinant vaccinia- PSA (r. V- PSA). When the next generation of poxviral vaccines was developed, however, a triad of costimulatory molecules called TRICOM, which included the transgenes for the costimulatory molecules B7. LFA- 3), and intercellular adhesion molecule- 1 (ICAM- 1), were included. In vitro and in vivo studies have shown that TRICOM significantly enhances T- cell activation relative to just 1 or 2 costimulatory molecules . Further benefits of TRICOM include enhancement of T- cell avidity, which ultimately leads to enhanced T cell- mediated tumor- cell killing . Costimulation with TRICOM also increases the number of antigen- specific memory T cells, which may help sustain the immune response . Preclinical studies demonstrated that GM- CSF at the inoculation site stimulates APCs and enhances the immune response to weakly immunogenic self- antigens . Furthermore, administering GM- CSF to the vaccination site in combination with TRICOM- based vaccines resulted in enhanced immune response . For this reason, GM- CSF was used as an adjuvant for most early trials involving poxviral vaccines. However, recent trial results may lead to a re- evaluation of its role as a vaccine adjuvant . Preliminary clinical studies demonstrate safety, efficacy, and optimal dosing schedule of vector- based prostate cancer vaccines. Initial poxviral- based vaccines contained only the transgene for PSA, with no costimulatory molecules. A phase I study of r. V- PSA enrolled 4. CRPC at 5 escalating dose levels; treatments were administered monthly for 3 months. GM- CSF was given as an immune adjuvant at the vaccination site in an extension phase of the study. The vaccine was well tolerated and no dose- limiting toxicity was seen. Common side effects included self- limited fever, fatigue, and injection- site reactions. Three of 5 evaluable patients were found to have increases in PSA- specific T cells, demonstrating the effects of the vaccine on the immune system . Although vaccinia is highly immunogenic and induces a vigorous immune response with a single vaccination, multiple exposures to vaccinia may lead to neutralization by host antibodies that target viral coat proteins and reduce efficacy . Fowlpox- based vectors were thus studied as a platform for booster vaccinations to sustain the immune response after an initial prime with a vaccinia- based vaccine.
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