Genetically engineered oncolytic Newcastle disease virus mediates cytolysis of prostate cancer stem like cells.
Mai 2018 | Raghunath, Shobana; Pudupakam, Raghavendra Sumanth; Allen, Adria; Biswas, Moanaro; Sriranganathan, Nammalwar
Oncolytic virotherapy is a promising novel approach that overcomes the limitations posed by radiation and chemotherapy. In this study, the oncolytic efficacy of a recombinant Newcastle disease virus (rNDV) BC-KLQL-GFP, against prostate cancer stem-like/tumor initiating cells was evaluated. Xenograft derived prostaspheres (XPS) induced tumor more efficiently than monolayer cell derived prostaspheres (MCPS) in nude mice. Primary and secondary XPS show enhanced self-renewal and clonogenic potential compared to MCPS. XPS also expressed embryonic stem cell markers, such as Nanog, CD44 and Nestin. Further, prostate specific antigen (PSA) activated recombinant Newcastle Disease Virus (rNDV) was selectively cytotoxic to tumor derived DU145 prostaspheres. An effective concentration (EC) of 0.11-0.14 multiplicity of infection was sufficient to cause prostasphere cell death in serum free culture. DU145 tumor xenograft derived prostaspheres were used as tumor surrogates as they were enriched for a putative tumor initiating cell population. PSA activated rNDV was efficient in inducing cell death of cells and prostaspheres derived from primary xenografts ex-vivo, thus signifying a potential in vivo efficacy. The EC (∼0.1 MOI) for cytolysis of tumor initiating cells was slightly higher than that was required for the parental cell line, but within the therapeutic margin for safety and efficacy. PMID 28935568
Genetically engineered oncolytic Newcastle disease virus mediates cytolysis of prostate cancer stem like cells.
Expression of CD14, IL10, and Tolerogenic Signature in Dendritic Cells Inversely Correlate with Clinical and Immunologic Response to TARP Vaccination in Prostate Cancer Patients.
Mai 2018 | Castiello, Luciano; Sabatino, Marianna; Ren, Jiaqiang; Terabe, Masaki; Khuu, Hanh; Wood, Lauren V; Berzofsky, Jay A; Stroncek, David F
Despite the vast number of clinical trials conducted so far, dendritic cell (DC)-based cancer vaccines have mostly shown unsatisfactory results. Factors and manufacturing procedures essential for these therapeutics to induce effective antitumor immune responses have yet to be fully characterized. We here aimed to identify DC markers correlating with clinical and immunologic response in a prostate carcinoma vaccination regimen. We performed an extensive characterization of DCs used to vaccinate 18 patients with prostate carcinoma enrolled in a pilot trial of T-cell receptor gamma alternate reading frame protein (TARP) peptide vaccination (NCT00908258). Peptide-pulsed DC preparations (114) manufactured were analyzed by gene expression profiling, cell surface marker expression and cytokine release secretion, and correlated with clinical and immunologic responses. DCs showing lower expression of tolerogenic gene signature induced strong antigen-specific immune response and slowing in PSA velocity, a surrogate for clinical response. These DCs were also characterized by lower surface expression of CD14, secretion of IL10 and MCP-1, and greater secretion of MDC. When combined, these four factors were able to remarkably discriminate DCs that were sufficiently potent to induce strong immunologic response. DC factors essential for the activation of immune responses associated with TARP vaccination in prostate cancer patients were identified. This study highlights the importance of in-depth characterization of DC vaccines and other cellular therapies, to understand the critical factors that hinder potency and potential efficacy in patients. . PMID 28073842
Potentiating prostate cancer immunotherapy with oncolytic viruses.
Feb. 2018 | Lee, Patrick; Gujar, Shashi
The clinical effectiveness of immunotherapies for prostate cancer remains subpar compared with that for other cancers. The goal of most immunotherapies is the activation of immune effectors, such as T cells and natural killer cells, as the presence of these activated mediators positively correlates with patient outcomes. Clinical evidence shows that prostate cancer is immunogenic, accessible to the immune system, and can be targeted by antitumour immune responses. However, owing to the detrimental effects of prostate-cancer-associated immunosuppression, even the newest immunotherapeutic approaches fail to initiate the clinically desired antitumour immune reaction. Oncolytic viruses, originally used for their preferential cancer-killing activity, are now being recognized for their ability to overturn cancer-associated immune evasion and promote otherwise absent antitumour immunity. This oncolytic-virus-induced subversion of tumour-associated immunosuppression can potentiate the effectiveness of current immunotherapeutics, including immune checkpoint inhibitors (for example, antibodies against programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1), and cytotoxic T lymphocyte antigen 4 (CTLA4)) and chemotherapeutics that induce immunogenic cell death (for example, doxorubicin and oxaliplatin). Importantly, oncolytic-virus-induced antitumour immunity targets existing prostate cancer cells and also establishes long-term protection against future relapse. Hence, the strategic use of oncolytic viruses as monotherapies or in combination with current immunotherapies might result in the next breakthrough in prostate cancer immunotherapy. PMID 29434366
A comprehensive review of immunotherapies in prostate cancer.
Juni 2017 | Maia, Manuel Caitano; Hansen, Aaron R
Prostate cancer is the second most common malignant neoplasm in men worldwide and the fifth cause of cancer-related death. Although multiple new agents have been approved for metastatic castration resistant prostate cancer over the last decade, it is still an incurable disease. New strategies to improve cancer control are needed and agents targeting the immune system have shown encouraging results in many tumor types. Despite being attractive for immunotherapies due to the expression of various tumor associated antigens, the microenvironment in prostate cancer is relatively immunosuppressive and may be responsible for the failures of various agents targeting the immune system in this disease. To date, sipuleucel-T is the only immunotherapy that has shown significant clinical efficacy in this setting, although the high cost and potential trial flaws have precluded its widespread incorporation into clinical practice. Issues with patient selection and trial design may have contributed to the multiple failures of immunotherapy in prostate cancer and provides an opportunity to tailor future studies to evaluate these agents more accurately. We have reviewed all the completed immune therapy trials in prostate cancer and highlight important considerations for the next generation of clinical trials. PMID 28427519
Enhanced DNA Damages of Human Prostate Cancer Cells Induced by Radiofrequency Capacitive Hyperthermia Pre- and Post X-rays: 6 MV versus 15 MV.
Juni 2017 | Mahdavi, Seied Rabi; Janati Esfahani, Azam; Shiran, Mohammad Bagher; Khoei, Samideh; Estiri, Nader
This study aimed to determine the effect of 13.56 MHz radiofrequency (RF) capacitive hyperthermia (HT) on radiosensivity of human prostate cancer cells pre and post X-ray radiation treatment (RT). PMID 28580311
The Role of Radiofrequency Hyperthermia in The Radiosensitization of A Human Prostate Cancer Cell Line.
Juni 2017 | Janati Esfahani, Azam; Mahdavi, Seied Rabi; Shiran, Mohammad Bagher; Khoei, Samideh
This study evaluated enhanced induced DNA damages and apoptosis of a spheroid culture of DU145 prostate cancer cells treated by a combination of radiofrequency hyperthermia (RF HT) with radiation treatment (RT) from an external radiotherapy machine compared to RT alone. PMID 28580312
Current status of clinical trials assessing oncolytic virus therapy for urological cancers.
März 2017 | Taguchi, Satoru; Fukuhara, Hiroshi; Homma, Yukio; Todo, Tomoki
Oncolytic virus therapy has recently been recognized as a promising new option for cancer treatment. Oncolytic viruses replicate selectively in cancer cells, thus killing them without harming normal cells. Notably, T-VEC (talimogene laherparepvec, formerly called OncoVEX(GM)(-)(CSF) ), an oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in October 2015, and was subsequently approved in Europe and Australia in 2016. The efficacies of many types of oncolytic viruses against urological cancers have been investigated in preclinical studies during the past decade, and some have already been tested in clinical trials. For example, a phase I trial of the third-generation oncolytic Herpes simplex virus type 1, G47Δ, in patients with prostate cancer was completed in 2016. We summarize the current status of clinical trials of oncolytic virus therapy in patients with the three major urological cancers: prostate, bladder and renal cell cancers. In addition to Herpes simplex virus type 1, adenoviruses, reoviruses, vaccinia virus, Sendai virus and Newcastle disease virus have also been used as parental viruses in these trials. We believe that oncolytic virus therapy is likely to become an important and major treatment option for urological cancers in the near future. PMID 28326624
Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer: A randomized phase II study.
Feb. 2017 | Kongsted, Per; Borch, Troels Holz; Ellebaek, Eva; Iversen, Trine Zeeberg; Andersen, Rikke; Met, Özcan; Hansen, Morten; Lindberg, Henriette; Sengeløv, Lisa; Svane, Inge Marie
We investigated whether the addition of an autologous dendritic cell-based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel. PMID 28215654
Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance.
Jan. 2017 | Alberti, C
Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation. Unlike afore said immune check point inhibitors, both cell-based (by the use of prostate specific antigen carriers autologous dendritic cells or even whole cancer cells) and recombinant viral vector vaccines are able to induce immune-mediated focused killing of specific antigen-presenting prostate cancer cells. Such vaccines, either used alone or concurrently/sequentially combined with above-mentioned conventional therapies, led to generally reach, in the field of various clinical trials, reasonable results particularly as regards the patient's overall survival. Adoptive trasferred T-cells, as adoptive T-cell passive immunotherapy, and monoclonal antibodies against specific antigen-endowed prostate cancer cells can improve immune micro-environmental conditions. On the basis of a preliminary survey about various immunotherapy strategies, are here also outlined their effects when combined with androgen deprivation therapy or radiation. What's more, as regard the immune-based treatment effectiveness, it has to be pointed out that suitable personalized epigenetic/gene profile-achieved pharmacogenomic approaches to target identified gene aberrations, may lead to overcome - as well as for conventional therapies - possible prostate cancer resistance to immunotherapy. PMID 28098061
The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma.
Dez. 2016 | McNeel, Douglas G; Bander, Neil H; Beer, Tomasz M; Drake, Charles G; Fong, Lawrence; Harrelson, Stacey; Kantoff, Philip W; Madan, Ravi A; Oh, William K; Peace, David J; Petrylak, Daniel P; Porterfield, Hank; Sartor, Oliver; Shore, Neal D; Slovin, Susan F; Stein, Mark N; Vieweg, Johannes; Gulley, James L
Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly. PMID 28031820
Recent advances in immuno-oncology and its application to urological cancers.
Sep. 2016 | Mataraza, Jennifer M; Gotwals, Philip
Recent advances in immuno-oncology have the potential to transform the practice of medical oncology. Antibodies directed against negative regulators of T-cell function (checkpoint inhibitors), engineered cell therapies and innate immune stimulators, such as oncolytic viruses, are effective in a wide range of cancers. Immune'based therapies have had a clinically meaningful impact on the treatment of advanced melanoma, and the lessons regarding use of single agents and combinations in melanoma may be applicable to the treatment of urological cancers. Checkpoint inhibitors, cytokine therapy and therapeutic vaccines are already showing promise in urothelial bladder cancer, renal cell carcinoma and prostate cancer. Critical areas of future immuno-oncology research include the prospective identification of patients who will respond to current immune-based cancer therapies and the identification of new therapeutic agents that promote immune priming in tumours, and increase the rate of durable clinical responses. PMID 27123757
A Perspective of Immunotherapy for Prostate Cancer.
Juli 2016 | Silvestri, Ida; Cattarino, Susanna; Giantulli, Sabrina; Nazzari, Cristina; Collalti, Giulia; Sciarra, Alessandro
In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa. PMID 27399780
Oncolytic virotherapy for urological cancers.
Mai 2016 | Delwar, Zahid; Zhang, Kaixin; Rennie, Paul S; Jia, William
Oncolytic virotherapy is a cancer treatment in which replication-competent viruses are used that specifically infect, replicate in and lyse malignant tumour cells, while minimizing harm to normal cells. Anecdotal evidence of the effectiveness of this strategy has existed since the late nineteenth century, but advances and innovations in biotechnological methods in the 1980s and 1990s led to a renewed interest in this type of therapy. Multiple clinical trials investigating the use of agents constructed from a wide range of viruses have since been performed, and several of these enrolled patients with urological malignancies. Data from these clinical trials and from preclinical studies revealed a number of challenges to the effectiveness of oncolytic virotherapy that have prompted the development of further sophisticated strategies. Urological cancers have a range of distinctive features, such as specific genetic mutations and cell surface markers, which enable improving both effectiveness and safety of oncolytic virus treatments. The strategies employed in creating advanced oncolytic agents include alteration of the virus tropism, regulating transcription and translation of viral genes, combination with chemotherapy, radiotherapy or gene therapy, arming viruses with factors that stimulate the immune response against tumour cells and delivery technologies to ensure that the viral agent reaches its target tissue. PMID 27215429
Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer.
Juni 2015 | Xi, Hai-Bo; Wang, Gong-Xian; Fu, Bin; Liu, Wei-Peng; Li, Yu
Dendritic cell (DC)-based vaccines are a promising therapeutic modality for cancer. Results from recent trials and approval of the first DC vaccine by the U.S. Food and Drugs Administration for prostate cancer have paved the way for DC-based vaccines. A total of 21 hormone refractory prostate cancer (HRPC) patients with a life expectancy >3 months were randomised into two groups. DC loaded with recombinant Prostate Specific Membrane Antigen (rPSMA) and recombinant Survivin (rSurvivin) peptides was administered as an subcutaneous (s.c.) injection (5×10(6) cells). Docetaxel (75 mg/m(2) intravenous (i.v.)) and prednisone (5 mg, bis in die (b.i.d.)) served as control. Clinical and immunological responses were evaluated. Primary endpoints were safety and feasibility; secondary endpoint was overall survival. Responses were evaluated on day 15, day 30, day 60, and day 90. DC vaccination was well tolerated with no signs of grade 2 toxicity. DC vaccination induced delayed-type hypersensitivity reactivity and an immune response in all patients. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumours (RECIST) was 72.7% (8/11) versus 45.4 (5/11) in the docetaxel arm and immune related response criteria (irRC) was 54.5% (6/11) compared with 27.2% (3/11) in the control arm. The DC arm showed stable disease (SD) in 6 patients, progressive disease (PD) in 3 patients, and partial remission (PR) in two patients compared to SD in 5 patients, PD in 6 patients, and PR in none in the docetaxel arm. There was a cellular response, disease stabilization, no adverse events, and partial remission with the rPSMA and rSurvivin primed DC vaccine. PMID 25787895
Immunotherapy for castration-resistant prostate cancer: Progress and new paradigms.
Mai 2015 | Quinn, David I; Shore, Neal D; Egawa, Shin; Gerritsen, Winald R; Fizazi, Karim
The approval of sipuleucel-T in conjunction with data from other immunotherapeutic trials for prostate cancer and other solid tumors demonstrates the potential of harnessing the patients' immune system for long-term survival. Thus, a range of therapeutic approaches are under evaluation. This review describes the rationale for immunotherapy for prostate cancer, summarizes the approaches under evaluation, and discusses sequencing options for immunotherapy in the current treatment paradigm. PMID 25575714
A vaccine strategy with multiple prostatic acid phosphatase-fused cytokines for prostate cancer treatment.
Feb. 2015 | Fujio, Kei; Watanabe, Masami; Ueki, Hideo; Li, Shun-Ai; Kinoshita, Rie; Ochiai, Kazuhiko; Futami, Junichiro; Watanabe, Toyohiko; Nasu, Yasutomo; Kumon, Hiromi
Immunotherapy is one of the attractive treatment strategies for advanced prostate cancer. The US Food and Drug Administration (FDA) previously approved the therapeutic vaccine, sipuleucel-T, which is composed of autologous antigen-presenting cells cultured with a fusion protein [prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF)]. Although sipuleucel-T has been shown to prolong the median survival of patients for 4.1 months, more robust therapeutic effects may be expected by modifying the vaccination protocol. In the present study, we aimed to develop and validate a novel vaccination strategy using multiple PAP-fused cytokines for prostate cancer treatment. Using a super gene expression (SGE) system that we previously established to amplify the production of a recombinant protein, significant amounts of PAP-fused cytokines [human GMCSF, interleukin-2 (IL2), IL4, IL7 and mouse GMCSF and IL4] were obtained. We examined the activity of the fusion proteins in vitro to validate their cytokine functions. A significant upregulation of dendritic cell differentiation from monocytes was achieved by PAP-GMCSF when used with the other PAP-fused cytokines. The PAP-fused human IL2 significantly increased the proliferation of lymphocytes, as determined by flow cytometry. We also investigated the in vivo therapeutic effects of multiple PAP-fused cytokines in a mouse prostate cancer model bearing prostate-specific antigen (PSA)- and PAP-expressing tumors. The simultaneous intraperitoneal administration of PAP-GMCSF, -IL2, -IL4 and -IL7 significantly prevented tumor induction and inhibited the tumor growth in the PAP-expressing tumors, yet not in the PSA-expressing tumors. The in vivo therapeutic effects with the multiple PAP-fused cytokines were superior to the effects of PAP-GMCSF alone. We thus demonstrated the advantages of the combined use of multiple PAP-fused cytokines including PAP-GMCSF, and propose a promising prostatic antigen-vaccination strategy to enhance the therapeutic effects. PMID 25632844
Long-term remission of prostate cancer with extensive bone metastases upon immuno- and virotherapy: A case report.
Nov. 2014 | Schirrmacher, Volker; Bihari, Akos-Sigmund; Stücker, Wilfried; Sprenger, Tobias
The present study reports the case of a patient with hormone-refractory metastatic prostate cancer who had failed standard therapy, but then achieved complete remission following combined treatment with local hyperthermia (LHT), Newcastle disease virus and dendritic cell (DC) vaccination, which was an unusual combination. In August 2005, the patient underwent a radical prostatectomy. Despite standard treatment, the patient developed progressive bone metastases and stopped conventional therapy in June 2007. Starting in October 2007, the patient was treated with LHT, oncolytic virotherapy and DC vaccination. Prostate-specific antigen (PSA)-levels, with the highest level of 233.8 ng/ml in January 2008, decreased to 0.8 ng/ml in late February 2008. In March 2008, a reduction in bone metastases could be detected by positron emission tomography/computed tomography. Since then, the PSA levels have remained low and the patient is doing well. The treatment induced a long-lasting antitumor memory T-cell response. This possibly explains the long-term effectiveness of this novel experimental combined treatment approach. PMID 25364402
Cancer immunotherapy: a paradigm shift for prostate cancer treatment.
Mai 2013 | Karan, Dev; Holzbeierlein, Jeffrey M; Van Veldhuizen, Peter; Thrasher, J Brantley
Prostate cancer remains a significant health problem for men in the Western world. Although treatment modalities are available, these do not confer long-term benefit and are accompanied by deleterious side effects. Immunotherapy represents a valuable alternative to conventional treatments by inducing tumour-specific immune responses that control the growth of cancer cells. Sipuleucel-T is approved by the FDA as an immunotherapeutic agent for the treatment of patients with asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC). Although this approval has raised cost-versus-benefit issues, it has provided proof of concept for the therapeutic potential of active immunotherapy approaches for metastatic CRPC. Numerous clinical studies have demonstrated clinical benefit using immunotherapy compared to traditional chemotherapy and several active immunotherapy approaches (at various developmental stages)have demonstrated the potential to change the face of prostate cancer treatment. PMID 22641164
Prostate-specific antigen-retargeted recombinant newcastle disease virus for prostate cancer virotherapy.
März 2013 | Shobana, Raghunath; Samal, Siba K; Elankumaran, Subbiah
Oncolytic virus (OV) therapies of cancer are based on the use of replication-competent, tumor-selective viruses with limited toxicity. Newcastle disease virus (NDV), an avian paramyxovirus, is a promising OV and is inherently tumor selective and cytotoxic only to tumor cells. Replication is restricted in normal cells. Despite encouraging phase I/II clinical trials with NDV, further refinements for tumor-specific targeting are needed to enhance its therapeutic index. Systemically delivered NDV fails to reach solid tumors in therapeutic concentrations and also spreads poorly within the tumors due to barriers including complement, innate immunity, and the extracellular matrix. Overcoming these hurdles is paramount to realizing the exceptional oncolytic efficacy of NDV. We engineered the F protein of NDV and generated a recombinant NDV (rNDV) whose F protein is cleavable exclusively by prostate-specific antigen (PSA). The rNDV replicated efficiently and specifically in prostate cancer (CaP) cells and 3-dimensional prostaspheres but failed to replicate in the absence of PSA. Induction of intracellular PSA production by a synthetic androgen analog (R1881) enhanced fusogenicity in androgen-responsive CaP cells. Further, PSA-cleavable rNDV caused specific lysis of androgen-independent and androgen-responsive/nonresponsive CaP cells and prostaspheres, with a half-maximal effective concentration (EC50) ranging from a multiplicity of infection of 0.01 to 0.1. PSA-retargeted NDV efficiently lysed prostasphere tumor mimics, suggesting efficacy in vivo. Also, PSA-cleavable NDV failed to replicate in chicken embryos, indicating no pathogenicity for chickens. Prostate-specific antigen targeting is likely to enhance the therapeutic index of rNDV owing to tumor-restricted replication and enhanced fusogenicity. PMID 23345509
Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer.
Juni 2012 | Sims, Robert B
Sipuleucel-T, the first autologous cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous antigen presenting cells (APCs), with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase [PAP]) and granulocyte colony-macrophage stimulating factor (GM-CSF). A full course of treatment comprises 3 infusions of sipuleucel-T, given at approximately 2-week intervals. The pattern of APC activation is consistent with priming by the first infusion, and boosting by the second and third infusions. Preclinical and clinical studies have demonstrated evidence of a robust antigen-specific immune response that includes a progressive and persistent increase in antigen-specific cellular and humoral immune responses. Treatment with sipuleucel-T has demonstrated a survival benefit in Phase 3 studies of subjects with metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Adverse events with sipuleucel-T were generally mild to moderate and resolved within 2 days. Serious adverse events, autoimmune events, and cerebrovascular events occurred at a similar rate to control subjects. As the first autologous cellular immunotherapy to demonstrate an improvement in overall survival in asymptomatic or minimally symptomatic mCRPC patients, sipuleucel-T represents a new treatment paradigm in oncology. PMID 22122856
Current status of immunological approaches for the treatment of prostate cancer.
Apr. 2012 | Drake, Charles G; Antonarakis, Emmanuel S
The recent Food and Drug Administration approval of sipuleucel-T for metastatic castration-resistant prostate cancer and of the anticytotoxic T-lymphocyte antigen 4 antibody (Ipilimumab) for metastatic melanoma has led to a renewed interest in immunotherapy for prostate and other cancers. Ipilimumab has entered phase III testing for prostate cancer, as has a viral-based anti-prostate-specific antigen vaccine (ProstVac-VF). Complementing these phase III studies are a number of innovative phase II studies, aimed at bringing immunotherapy forward in the setting of less advanced disease, as well as a number of interesting trials combining immunotherapy with conventional therapy for prostate cancer. PMID 22328018
Prostate cancer vaccines: moving therapeutic vaccination forward in the post-Provenge era.
März 2012 | Arlen, Philip M; Wood, Lauren V
The focus of extensive research in the area of prostate cancer vaccines has led to the approval of the first therapeutic vaccine by the US FDA, sipuleucel-T. As our understanding of immunotherapy has increased, novel approaches have been investigated that have shown considerable promise. As the field has continued to evolve, questions have arisen regarding the potential role of immunotherapy: which populations of patients are most likely to benefit from immunotherapy and how and when should these therapies be administered? In addition, what are the best tools that can be used as surrogates to monitor immune responses to cancer vaccines that truly can give meaningful insight toward improving clinical outcomes? Finally, how can combination approaches be applied to prostate cancer vaccines in terms of both standard of care and experimental therapies? This review will address many of these important concepts with regard to prostate cancer vaccine therapy. PMID 22380822
[Prostate carcinoma: vaccination as a new option for treatment].
Jan. 2012 | Bedke, J; Gouttefangeas, C; Stenzl, A
Immune therapy and tumor cell vaccination is a challenging option in prostate cancer therapy, especially as side effects rarely occur. This review highlights recent developments in vaccination therapy of prostate cancer. The FDA approved antigen presenting cell vaccine Sipuleucel-T is described and new strategies of immune therapy like RNA and peptide vaccination are discussed in detail. Currently the effect of prostate cancer vaccination has still limitations, at least partially due to the immune suppressive effects of the tumor microenvironment and regulatory T cells, which suppress the immune effector function. To overcome these hurdles the concept of immune checkpoint modulation, which has the aim to break tolerance mechanisms, is discussed. Potential clinical therapies of checkpoint modulation are outlined. PMID 21989588
Current vaccination strategies for prostate cancer.
Dez. 2011 | Joniau, Steven; Abrahamsson, Per-Anders; Bellmunt, Joaquim; Figdor, Carl; Hamdy, Freddie; Verhagen, Paul; Vogelzang, Nicholas J; Wirth, Manfred; Van Poppel, Hendrik; Osanto, Susanne
The first therapeutic cancer vaccine demonstrating effectiveness in a phase 3 study was approved by the US Food and Drug Administration on 29 April 2010. The pivotal trial demonstrated overall survival (OS) benefit in patients treated with antigen-loaded leukapheresis cells compared with a control infusion. Results of other prostate cancer (PCa) vaccination strategies are awaited, as this approach may herald a new era in the care for patients with advanced PCa. PMID 22001436
Proving the principle: dendritic cell-based vaccines in urogenital cancers.
Okt. 2011 | Draube, Andreas; Klein-González, Nela; von Bergwelt-Baildon, Michael
Immunotherapy for prostate cancer: biology and therapeutic approaches.
Sep. 2011 | Cha, Edward; Fong, Lawrence
Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy. PMID 21825260
Immunotherapy for the treatment of prostate cancer.
Aug. 2011 | Di Lorenzo, Giuseppe; Buonerba, Carlo; Kantoff, Philip W
Failure of immune surveillance has a prominent role in tumorigenesis. Cancerous cells can evade T-cell responses to tumor-associated antigens by multiple mechanisms. Active immunotherapy aims to stimulate the immune response against cancer cells. Unlike normal prostate tissue, prostate cancer is not ignored by the immune system, as shown by the presence of tumor infiltrating lymphocytes. This characteristic renders prostate cancer particularly suitable for immunotherapy. The existence of well-defined antigens, largely limited to prostate tissue, allows prostate cancer cells to be targeted without the risk of systemic autoimmune reactions, as autoimmunity specifically directed at the prostate is the goal of prostate cancer immunotherapy. Active immunotherapy directed towards prostate cancer can be conducted using multiple strategies, involving dendritic cells, whole-cell vaccines, viral vectors, DNA-based and peptide-based agents, as well as immunostimulatory agents. The only FDA-approved immunotherapy for prostate cancer is the dendritic-cell-based agent Sipuleucel-T, which yielded an advantage in overall survival, but not in progression-free survival in a phase III trial. We present the clinical developments in the field of immunotherapy and critically analyze methodological issues related to the evaluation of tumor responses to immunotherapy, trial design, and surrogate end points. PMID 21606971
Oncolytic virus-initiated protective immunity against prostate cancer.
Aug. 2011 | Gujar, Shashi A; Pan, D A; Marcato, Paola; Garant, Katy A; Lee, Patrick W K
Recently reovirus-based oncotherapy has been successfully implemented for the treatment of prostate cancer. In this report, we show that apart from its primary direct cancer-killing activity, reovirus oncotherapy overrides tumor-associated immune evasion strategies and confers protective antiprostate cancer immunity. Prostate cancer represents an ideal target for immunotherapies. However, currently available immune interventions fail to induce clinically significant antiprostate cancer immune responses, owing to the immunosuppressive microenvironment associated with this disease. We show here that during the process of oncolysis, reovirus acts upon prostate cancer cells and initiates proinflammatory cytokines and major histocompatibility complex (MHC) class I molecule expression. In an immunocompetent transgenic adenocarcinoma of mouse prostate (TRAMP) model, reovirus oncotherapy induces the homing of CD8(+) T and NK cells in tumors and the display of tumor-associated antigens (TAAs) on antigen-presenting cells (APCs), and endows dendritic cells (DCs) with a capacity to successfully present TAAs to tumor-specific CD8(+) T cells. These newly generated immunological events lead to the development of strong antiprostate cancer T cell responses, which restrict the growth of subsequently, implanted syngeneic tumor in an antigen-specific, but reovirus-independent manner. Such reovirus-initiated antiprostate cancer immunity represents a clinically valuable entity that can promote long-term cancer-free health even after discontinuation of the primary oncotherapy. PMID 21245852
Prostate cancer immunotherapy.
Aug. 2011 | May, Kenneth F; Gulley, James L; Drake, Charles G; Dranoff, Glenn; Kantoff, Philip W
The interaction between the immune system and prostate cancer has been an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of 2 first-in-class proof-of-concept immunotherapies (sipuleucel-T and ipilimumab) has stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies that have garnered the most interest are the therapeutic vaccination strategies, exemplified by sipuleucel-T and PROSTVAC-VF, and immune checkpoint blockade of CTLA-4 and PD-1. Improved understanding of the immune responses generated by these strategies and development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide building blocks for future immunotherapies. PMID 21700764
Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer.
Juli 2011 | Beer, Tomasz M; Bernstein, Guy T; Corman, John M; Glode, L Michael; Hall, Simon J; Poll, Wayne L; Schellhammer, Paul F; Jones, Lori A; Xu, Yi; Kylstra, Jelle W; Frohlich, Mark W
Sipuleucel-T, an autologous cellular immunotherapy, was investigated in a randomized, double-blind, controlled trial to determine its biologic activity in androgen-dependent prostate cancer (ADPC). PMID 21558406
Sipuleucel-T: autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.
Juni 2011 | Sims, Robert B
Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population. PMID 21716715
Recent advances in immunotherapy for the treatment of prostate cancer.
Juni 2011 | Sonpavde, Guru; Agarwal, Neeraj; Choueiri, Toni K; Kantoff, Philip W
Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development. PMID 21675925
Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research.
Juni 2011 | Gulley, James L; Drake, Charles G
A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival-with substantially limited side effects compared with chemotherapy-in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well. PMID 21680544
Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis.
Mai 2011 | Draube, Andreas; Klein-González, Nela; Mattheus, Stefanie; Brillant, Corinne; Hellmich, Martin; Engert, Andreas; von Bergwelt-Baildon, Michael
More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis. PMID 21533099
KNK437, a benzylidene lactam compound, sensitises prostate cancer cells to the apoptotic effect of hyperthermia.
Jan. 2011 | Sahin, Emel; Sahin, Mehmet; Sanlioğlu, Ahter Dilsad; Gümüslü, Saadet
Hyperthermia is known to serve as a powerful tool in the treatment of prostate cancer which is commonly diagnosed in men. Quercetin and KNK437, Hsp70 inhibitors, play an important role in blocking thermotolerance in some cancer cells. In the present study we investigated the effects of KNK437 and quercetin on the acquisition of thermotolerance and heat-induced apoptosis. Also, it was examined whether the possible mechanism triggering apoptotic pathway included caspase-3 activation in prostate cancer cells. For this purpose, PC-3 and LNCaP cells were treated with hyperthermia following pretreatment with or without KNK437 or quercetin. Thermotolerance was investigated by colony formation assay in these cells, while Hsp70 mRNA levels were measured by real time RT-PCR. Sandwich ELISA was used for detection of Hsp70 protein levels. Apoptosis was detected by flow cytometric annexin V binding assay and by western blot analysis of procaspase-3 and cleaved poly (ADP-ribose) polymerase levels. In our study, KNK437 and quercetin inhibited thermotolerance in a dose-dependent manner in PC-3 cells. KNK437 and quercetin decreased heat-induced accumulation of Hsp70 mRNA and protein in PC-3 and LNCaP cells. KNK437 and quercetin pretreatment enhanced the apoptotic effect of hyperthermia in both cells. We found that KNK437 was more effective than quercetin in inducing apoptotic cell death, activation of caspase-3, and cleavage of PARP in prostate cancer cells. We suggest that KNK437 is a useful agent for enhancing the efficiency of hyperthermic therapy which has less toxic side-effects in prostate cancer. PMID 21204621
Hyperthermia combined with radiation for the treatment of locally advanced prostate cancer: long-term results from Dana-Farber Cancer Institute study 94-153.
Jan. 2011 | Hurwitz, Mark D; Hansen, Jorgen L; Prokopios-Davos, Savina; Manola, Judith; Wang, Qian; Bornstein, Bruce A; Hynynen, Kullervo; Kaplan, Irving D
The authors present long-term results from a phase 2 study that assessed the efficacy of transrectal ultrasound hyperthermia plus radiation with or without androgen suppression for the treatment of locally advanced prostate cancer. PMID 20886629
Sipuleucel-T: in metastatic castration-resistant prostate cancer.
Dez. 2010 | Plosker, Greg L
Sipuleucel-T is an autologous active cellular immunotherapy used in the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). It is the first therapeutic cancer vaccine to receive US FDA approval. Approximately 3 days prior to each infusion of sipuleucel-T, patients undergo a leukapheresis procedure for collection of autologous peripheral blood mononuclear cells. Preparation of sipuleucel-T involves enrichment for antigen-presenting cells from the leukapheresis product and activation ex vivo with a recombinant fusion protein (PA2024). In the randomized, double-blind, placebo-controlled IMPACT study in patients with metastatic CRPC, sipuleucel-T was associated with a 22% relative reduction in the risk of death (hazard ratio 0.78; p = 0.03), which was the primary endpoint of the trial. After a median follow-up period of 34.1 months, median survival was 4.1 months longer with sipuleucel-T than placebo (25.8 vs 21.7 months). There was no significant between-group difference for the median time to objective disease progression (a secondary endpoint). Almost all patients treated with sipuleucel-T in clinical trials reported an adverse event, although these were mild or moderate in severity (grade 1 or 2) in most patients. The most common adverse events (e.g. infusion-related events, such as chills and fever) generally occurred within the first day after administration of sipuleucel-T and resolved within 2 days. PMID 21175243
[Auto-dendritic cell vaccines pulsed with PSA, PSMA and PAP peptides for hormone-refractory prostate cancer].
Nov. 2010 | Zhuang, Zhi-Xiang; Shen, Li-Qin; Shi, Yang; Lu, Xiao; Shi, Hong-Zhen
To investigate the clinical safety and effects of auto-dendritic cells pulsed with HLA-A201-binding peptides prostate-specific antigen (PSA) , prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP) in the treatment of hormone-refractory metastatic prostate cancer (HRPC). PMID 21090344
RIG-I helicase-independent pathway in sendai virus-activated dendritic cells is critical for preventing lung metastasis of AT6.3 prostate cancer.
Nov. 2010 | Kato, Tomonori; Ueda, Yasuji; Kinoh, Hiroaki; Yoneyama, Yasuo; Matsunaga, Akinao; Komaru, Atsushi; Harada, Yui; Suzuki, Hiroyoshi; Komiya, Akira; Shibata, Satoko; Hasegawa, Mamoru; Hayashi, Hideki; Ichikawa, Tomohiko; Yonemitsu, Yoshikazu
We recently demonstrated highly efficient antitumor immunity against dermal tumors of B16F10 murine melanoma with the use of dendritic cells (DCs) activated by replication-competent, as well as nontransmissible-type, recombinant Sendai viruses (rSeV), and proposed a new concept, "immunostimulatory virotherapy," for cancer immunotherapy. However, there has been little information on the efficacies of this method: 1) in more clinically relevant situations including metastatic diseases, 2) on other tumor types and other animal species, and 3) on the related molecular/cellular mechanisms. In this study, therefore, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV on a rat model of lung metastasis using a highly malignant subline of Dunning R-3327 prostate cancer, AT6.3. rSeV/dF-green fluorescent protein (GFP)-activated bone marrow-derived DCs (rSeV/dF-GFP-DC), consistent with results previously observed in murine DCs. Vaccination of rSeV/dF-GFP-DC was highly effective at preventing lung metastasis after intravenous loading of R-3327 tumor cells, compared with the effects observed with immature DCs or lipopolysaccharide-activated DCs. Interestingly, neither CTL activity nor DC trafficking showed any apparent difference among groups. Notably, rSeV/dF-DCs expressing a dominant-negative mutant of retinoic acid-inducible gene I (RIG-I) (rSeV/dF-RIGIC-DC), an RNA helicase that recognizes the rSeV genome for inducing type I interferons, largely lost the expression of proinflammatory cytokines without any impairment of antitumor activity. These results indicate the essential role of RIG-I-independent signaling on antimetastatic effect induced by rSeV-activated DCs and may provide important insights to DC-based immunotherapy for advanced malignancies. PMID 21076616
Dendritic cell-based immunotherapy for prostate cancer.
Nov. 2010 | Jähnisch, Hanka; Füssel, Susanne; Kiessling, Andrea; Wehner, Rebekka; Zastrow, Stefan; Bachmann, Michael; Rieber, Ernst Peter; Wirth, Manfred P; Schmitz, Marc
Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce, sustain, and regulate T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Thus, clinical trials enrolling prostate cancer patients were conducted, which were based on the administration of DCs loaded with tumor-associated antigens. These clinical trials revealed that DC-based immunotherapeutic strategies represent safe and feasible concepts for the induction of immunological and clinical responses in prostate cancer patients. In this context, the administration of the vaccine sipuleucel-T consisting of autologous peripheral blood mononuclear cells including APCs, which were pre-exposed in vitro to the fusion protein PA2024, resulted in a prolonged overall survival among patients with metastatic castration-resistant prostate cancer. In April 2010, sipuleucel-T was approved by the United States Food and Drug Administration for prostate cancer therapy. PMID 21076523
Measurement and mathematical modeling of thermally induced injury and heat shock protein expression kinetics in normal and cancerous prostate cells.
Nov. 2010 | Rylander, Marissa Nichole; Feng, Yusheng; Zimmermann, Kristen; Diller, Kenneth R
Hyperthermia can induce heat shock protein (HSP) expression in tumours, which will cause enhanced tumour viability and increased resistance to additional thermal, chemotherapy, and radiation treatments. The study objective was to determine the relationship of hyperthermia protocols with HSP expression kinetics and cell death and develop corresponding computational predictive models of normal and cancerous prostate cell response. PMID 20858083
Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.
Sep. 2010 | Frank, Mayu O; Kaufman, Julia; Tian, Suyan; Suárez-Fariñas, Mayte; Parveen, Salina; Blachère, Nathalie E; Morris, Michael J; Slovin, Susan; Scher, Howard I; Albert, Matthew L; Darnell, Robert B
Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine. PMID 20824184
Prostate cancer as a model for tumour immunotherapy.
Juli 2010 | Drake, Charles G
Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context. PMID 20651745
Cutting edge: delay and reversal of T cell tolerance by intratumoral injection of antigen-loaded dendritic cells in an autochthonous tumor model.
Mai 2010 | Higham, Eileen M; Shen, Ching-Hung; Wittrup, K Dane; Chen, Jianzhu
The tumor environment exerts a powerful suppressive influence on infiltrating tumor-reactive T cells. It induces tolerance of adoptively transferred effector T cells as they enter tumors and maintains the tolerance of persisting tumor-infiltrating T cells. In an autochthonous prostate cancer model, in which tumor-reactive CD8 T cells are trackable, we demonstrate that both depletion of endogenous dendritic cells (DCs) and intratumoral injection of Ag-loaded mature DCs delayed the tolerization of tumor-infiltrating effector CD8 T cells. Intratumoral injection of Ag-loaded DCs also reactivated tolerized CD8 T cells in the tumor tissue. The observed effects lasted as long as the injected DCs persisted. These findings are consistent with a critical role of DCs in modulating T cell reactivity in the tumor environment. They also suggest new potential strategies to extend the functionality of transferred effector T cells and to restore function to tolerized tumor-infiltrating T cells for cancer immunotherapy. PMID 20427765
Tumor specific cytotoxicity and telomerase down-regulation in prostate cancer by autologous dendritic cells loaded with whole tumor cell antigens.
Mai 2010 | Turkeri, Levent; Onol, Fikret Fatih; Ozyurek, Mustafa
We investigated the efficacy of cytotoxic activity of whole tumor cell-antigen loaded dendritic cells in the treatment of hormone refractory prostate cancer. PMID 19362861
Current status of immunological therapies for prostate cancer.
Apr. 2010 | Antonarakis, Emmanuel S; Drake, Charles G
Considerable progress has been made in prostate cancer immunotherapy over the last year, and two agents have completed phase III testing. This review will discuss the most promising immune-directed strategies in development for prostate cancer, outlining interventions that mitigate tumor-induced tolerance and highlighting several combination immunotherapy approaches. PMID 20179598
Oncolytic virus therapy for prostate cancer.
Apr. 2010 | Fukuhara, Hiroshi; Homma, Yukio; Todo, Tomoki
The use of replication-competent viruses that can selectively replicate in and destroy neoplastic cells is an attractive strategy for treating cancer. Various oncolytic viruses have been taken to clinical trials since a recombinant virus was first applied to cancer patients a decade ago. The concept of the therapy is simple: infectious virus kills the host cancer cells in the course of viral replication. It is important, however, that the virus does not harm the surrounding normal tissue. Oncolytic viruses can be classified largely into two groups: DNA viruses genetically engineered to achieve cancer specificity (e.g. adenovirus, herpes simplex virus and vaccinia) and RNA viruses of which human is not the natural host (e.g. Newcastle disease virus and reovirus). Prostate cancer has always been one of the major targets of oncolytic virus therapy development. The result of six clinical trials for prostate cancer has been published and several trials are now going on. Forty-eight of 83 (58%) patients evaluated in the phase I studies demonstrated a >25% decrease in serum prostate-specific antigen level without evidence of severe toxicities. The result shows the oncolytic virus therapy is promising toward clinical application. Here, we review the recent advances in the field and summarize the results from clinical trials. PMID 19832925
The choice of the antigen in the dendritic cell-based vaccine therapy for prostate cancer.
März 2010 | Matera, Lina
Tumor antigens (TA) are promising candidates for targeted treatment of prostate cancer (PCa). Critical issues in the preparation of dendritic cell (DC)-based TA vaccines are the DC maturation state and the appropriateness of the TA. Prostate-specific antigen (PSA) and prostate acide pshosphatase (PAP) presented by DC have produced encouraging results and PAP-loaded DCs are at late-stage development for PCa patients. TAs indispensable for tumor survival and propagation are now emerging as first choice TAs for future vaccines. The increased expression and enzymatic activity of prostate specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) by aggressive prostate tumors is indicative of a unique, selective advantage on the part of cells expressing them. Human telomerase reverse transcriptase (hTERT) and survivin are both involved in tumor cell survival and considered universal TAs. The T cell epitope potential of peptides derived from these TAs has been defined by computer-assisted prediction programs and has been tested in vitro and in vivo in terms of their ability to recruit cytotoxic T lymphocytes (CTL) and to be recognised as CTL targets. Results, reviewed here, show that anti-tumor immunity can be induced in vivo by DC loaded with both whole TAs and TA peptides. The promising, but still limited clinical success suggests further exploration of this immune therapy in the more appropriate setting of minimal disease. In advanced stages, vaccine can still be effective when combined with systemic or local cytoreductive therapies, which may overcome antigen specific tolerance and subvert the tumor immunosuppressive environment. PMID 19954892
A changing world for DCvax: a PSMA loaded autologous dendritic cell vaccine for prostate cancer.
Nov. 2009 | Fishman, Mayer
Northwest Therapeutics' DCvax-prostate consists of autologous dendritic cells (DCs) loaded with prostate-specific membrane antigen (PSMA) peptides, administered intravenously. Phase I-II testing, a decade ago, showed clinical benefit and immunological response in some patients. More recently DCvax brain, a product using a similar DC platform showed encouraging Phase I-II results and sipleucel-T, a prostatic acid phosphatase (PAP)-directed DC immunotherapy had positive Phase III results. PMID 19916735
Vaccination with recombinant adenoviruses and dendritic cells expressing prostate-specific antigens is effective in eliciting CTL and suppresses tumor growth in the experimental prostate cancer.
Mai 2009 | Kim, Sol; Lee, Jee-Boong; Lee, Geon Kook; Chang, Jun
Prostate cancer is currently the most commonly diagnosed cancer in men and the second leading cause of cancer-related death in men in the US. Immunological approaches may provide an alternative option for prevention and treatment of prostate cancer. PMID 19267351
FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer.
Apr. 2009 | Rozková, Daniela; Tiserová, Hana; Fucíková, Jitka; Last'ovicka, Jan; Podrazil, Michal; Ulcová, Hana; Budínský, Vít; Prausová, Jana; Linke, Zdenek; Minárik, Ivo; Sedivá, Anna; Spísek, Radek; Bartůnková, Jirina
Immunotherapy has emerged as another treatment modality in cancer. The goal of immunotherapy in advanced cancer patients does not have to be the complete eradication of tumor cells but rather the restoration of a dynamic balance between tumor cells and the immune response. Appropriate combination of tumor mass reduction (by surgery and/or chemotherapy) and neutralization of tumor-induced immunosuppression might set the right conditions for the induction of anti-tumor immune response by active immunotherapy. We review experimental basis and key concepts of combined chemo-immunotherapy and document its principles in the case report of patient with hormone refractory metastatic prostate cancer with sinister prognosis. More than four hundred prostate cancer patients have been treated with DC-based immunotherapy and tumor-specific immune responses have been reported in two-thirds of them. In half of these patients, DC immunotherapy resulted in transient clinical responses. Tregs, among other factors, potently inhibit tumor-specific T cells. Prostate cancer patients have elevated numbers of circulating and tumor infiltrating Tregs and there is evidence that Tregs increase tumor growth in vivo. Because of the high frequency of circulating Tregs in our patients, we first administered metronomic cyclophosphamide. After obtaining IRB approval, we started regular vaccinations with dendritic cells (DCs) loaded with killed prostate cancer cells. In accordance with the principles of combined immunotherapy, we continued palliative chemotherapy with docetaxel to reduce the tumor cell burden. DC-based vaccination induced prostate cancer cell-specific immune response. Combined chemo-immunotherapy consisting of alternate courses of chemotherapy and vaccination with mature DCs pulsed with LNCap prostate cancer cell line led to the marked improvement in the clinical and laboratory presentation and to the decrease of PSA levels by more than 90%. PMID 19201656
Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization.
März 2009 | Koh, Yi T; Gray, Andrew; Higgins, Sean A; Hubby, Bolyn; Kast, W Martin
Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy. PMID 19143030
Promising novel immunotherapies and combinations for prostate cancer.
März 2009 | Arlen, Philip M; Mohebtash, Mahsa; Madan, Ravi A; Gulley, James L
The field of therapeutic cancer vaccines is currently in a state of active preclinical and clinical investigation, and certain novel therapies involving tumor immunotherapy have recently come to the forefront of prostate cancer research. While no therapeutic cancer vaccine has yet been approved by the US FDA, recent findings have demonstrated that new paradigms of combination therapies involving vaccines, employed in clinical trials with appropriate design and end points, may ultimately lead to cancer vaccines being used to treat various malignancies. Several characteristics of prostate cancer make it an ideal target for immunotherapy. Its relative indolence allows sufficient time to generate immune responses, which usually take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal tissue. This review focuses on the future of promising new vaccines and novel perspectives in the treatment of prostate cancer. PMID 19284377
Dendritic cells transduced with a PSMA-encoding adenovirus and cocultured with autologous cytokine-induced lymphocytes induce a specific and strong immune response against prostate cancer cells.
Dez. 2008 | Wang, Kebing; Gao, Xin; Pang, Jun; Liu, Xiaopeng; Cai, Yubin; Zhang, Yan; Zhou, Jianhua; Zhan, Hailun
The lack of curative therapies for advanced prostate cancer (PCa) has prompted a search for novel treatments such as immunotherapy. In this study, we analyzed whether dendritic cells (DCs) from healthy donors transduced with a PSMA-encoding adenovirus (Ad-PSMA) and cocultured with autologous cytokine-induced killer cells (CIKs) can induce a strong specific immune response against PCa cells in vitro. PMID 18367124
Dendritic cell vaccines for the treatment of prostate cancer.
Nov. 2008 | Lehrfeld, Todd J; Lee, David I
Advanced prostate cancer remains a disease with few options beyond palliation. Over the past few decades, our understanding of immunology has led to the development of novel therapies for the treatment of many malignancies, including prostate cancer. These generally aim to induce T-cell responses against tumor specific antigens to both reduce tumor mass and potentially avoid relapse. One promising technique is to use autologous dendritic cells, the most potent antigen presenting cell. These can be loaded ex vivo with a given antigen and subsequently injected back into the patient to stimulate the desired effect. Recent trials using these techniques have shown promise in extending survival in patients with prostate cancer. This review will discuss relevant biology behind dendritic cell therapy and highlight the key trials found in the literature. PMID 18996314
A two-state cell damage model under hyperthermic conditions: theory and in vitro experiments.
Juli 2008 | Feng, Yusheng; Tinsley Oden, J; Rylander, Marissa Nichole
The ultimate goal of cancer treatment utilizing thermotherapy is to eradicate tumors and minimize damage to surrounding host tissues. To achieve this goal, it is important to develop an accurate cell damage model to characterize the population of cell death under various thermal conditions. The traditional Arrhenius model is often used to characterize the damaged cell population under the assumption that the rate of cell damage is proportional to exp(-EaRT), where Ea is the activation energy, R is the universal gas constant, and T is the absolute temperature. However, this model is unable to capture transition phenomena over the entire hyperthermia and ablation temperature range, particularly during the initial stage of heating. Inspired by classical statistical thermodynamic principles, we propose a general two-state model to characterize the entire cell population with two distinct and measurable subpopulations of cells, in which each cell is in one of the two microstates, viable (live) and damaged (dead), respectively. The resulting cell viability can be expressed as C(tau,T)=exp(-Phi(tau,T)kT)(1+exp(-Phi(tau,T)kT)), where k is a constant. The in vitro cell viability experiments revealed that the function Phi(tau,T) can be defined as a function that is linear in exposure time tau when the temperature T is fixed, and linear as well in terms of the reciprocal of temperature T when the variable tau is held as constant. To determine parameters in the function Phi(tau,T), we use in vitro cell viability data from the experiments conducted with human prostate cancerous (PC3) and normal (RWPE-1) cells exposed to thermotherapeutic protocols to correlate with the proposed cell damage model. Very good agreement between experimental data and the derived damage model is obtained. In addition, the new two-state model has the advantage that is less sensitive and more robust due to its well behaved model parameters. PMID 18601458
Immunotherapy for metastatic prostate cancer.
Juli 2008 | Drake, Charles G
Chemotherapy with docetaxel is the standard treatment for men with metastatic prostate cancer, and results in statistically significant improvements in survival, as well as in quality of life. However, the response rate to single-agent docetaxel is approximately 40% to 45%, emphasizing a need for alternative approaches. More significantly, with the onset of early, PSA-based detection of prostate cancer and closer follow-up, many men present with metastatic disease that remains asymptomatic. For such patients, the side effects of chemotherapy would compromise their current performance status and, thus, a nontoxic, early treatment option that could improve overall survival would be highly desirable. Immunotherapy represents one such approach; a number of clinical trials have suggested a survival benefit for immunotherapy in metastatic prostate cancer and confirmed that these agents are generally well-tolerated. As is the case for chemotherapy, it is doubtful that maximal survival benefit will be achieved with single-agent immunotherapy; experimental treatments in which mechanistically distinct immunotherapy approaches are combined, as well as approaches in which immunotherapy is combined with chemotherapy or hormonal therapy are currently under investigation. This review will discuss the mechanisms of action of several immunotherapy approaches for metastatic prostate cancer, focusing on active immunotherapy as opposed to administration of anti-tumor antibodies. The relative advantages and disadvantages of current approaches will be noted, and ongoing clinical trials will be highlighted. PMID 18593624
Prostate cancer vaccines: current status and future potential.
März 2008 | Doehn, Christian; Böhmer, Torsten; Kausch, Ingo; Sommerauer, Martin; Jocham, Dieter
Standard systemic treatment of prostate cancer today is comprised of antihormonal and cytostatic agents. Vaccine therapy of prostate cancer is principally attractive because of the presence of tumor-associated antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), and others. Most prostate cancer vaccine trials have demonstrated some activation of the immune system, limited clinical success, and few adverse effects.One strategy to overcome the problem of limited clinical success of vaccine therapies in prostate cancer could be strict patient selection. The clinical course of patients with prostate cancer (even in those with PSA relapse following surgery or radiotherapy with curative intention, or those with metastatic disease) can vary significantly. In patients with organ-confined prostate cancer, the most promising immunotherapeutic approach would be an adjuvant therapy following surgery or radiotherapy. Patients with PSA relapse following surgery or radiotherapy could also benefit from immunotherapy because tumor burden is usually low. However, most patients in prostate cancer vaccine trials had metastatic hormone-refractory prostate cancer (HRPC). High tumor burden correlates with immune escape phenomena. Nevertheless, 2 years ago, it was demonstrated, for the first time, that a tumor vaccine can prolong survival compared with placebo in patients with HRPC. This was demonstrated with the vaccine sipuleucel-T (APC-8015; Provenge), a mixture of cells obtained from the patient's peripheral blood by leukapheresis followed by density centrifugation and exposition. The Biologics License Application for this vaccine was denied by the US FDA in mid 2007, however, because the trial had failed to reach the primary endpoint (prolongation of time to tumor progression). Nevertheless, clinical trials with sipuleucel-T are ongoing, and the approach still looks promising. Another interesting approach is a vaccine made from whole tumor cells: GVAX. This vaccine is presently being studied in phase III trials against, and in combination with, docetaxel. The results from these trials will become available in the near future. Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation. PMID 18345705
Therapeutic dendritic cell vaccine preparation using tumor RNA transfection: a promising approach for the treatment of prostate cancer.
März 2008 | Sousa-Canavez, Juliana M; Canavez, Flavio C; Leite, Kátia R M; Camara-Lopes, Luiz H
Early prostate adenocarcinoma can be diagnosed through seric prostate-specific antigen (PSA) screenings. However, a fraction of patients progress to an incurable metastatic disease. Therefore, novel therapies for treating these patients are extremely desirable. Therapeutic vaccines based on Dendritic Cells (DCs) carrying tumor antigens have emerged as a promising strategy to initiate an immune response against tumor cells. These vaccines can be prepared using different methodologies, such as the application of tumor mRNA described in this work. PMID 18205933
Advances in specific immunotherapy for prostate cancer.
Feb. 2008 | Kiessling, Andrea; Füssel, Susanne; Wehner, Rebekka; Bachmann, Michael; Wirth, Manfred P; Rieber, E Peter; Schmitz, Marc
The absence of effective therapies for advanced prostate cancer has entailed an intensive search for novel treatments. This review presents an overview of specific immunotherapeutic strategies for prostate cancer. PMID 18061335
[Active immunotherapy of prostate cancer with a focus on dendritic cells].
Sep. 2007 | Thomas-Kaskel, A K; Veelken, H
Recurrent or metastatic prostate cancer is generally considered an incurable disease. Given the transient benefit from hormone deprivation therapy and limited successes of systemic chemotherapy, alternative treatment modalities are needed both in the situation of PSA recurrence and in hormone-refractory disease. Prostate cancer cells express several tumor associated antigens which are currently being evaluated as targets for active and specific immunotherapy approaches. Dendritic cells (DC) are the most powerful antigen-presenting cells (APC), able to prime naive T cells and to break peripheral tolerance and thus induce tumor immune responses. Close to 1000 prostate cancer patients have been treated with DC-based or other forms of active immunotherapy to date. Vaccination-induced immune responses have been reported in two thirds of DC trials, and favorable changes in the clinical course of the disease in almost half of the patients treated. Most responses, however, were modest and transient. Therefore, mechanisms of treatment failure and possibilities to improve vaccination efficacy are being discussed. PMID 17896564
[State of the art about new therapeutic vaccines in prostate cancer: dendritic cells, engineered tumor cells and recombinant virus].
Sep. 2007 | Eymard, Jean-Christophe; Gervais, Alban; Jarcau, Rosana; Bernard, Jacky
Therapeutic vaccines for prostate cancer were initially reported as limited with low immunological responses and uncertain clinical benefit. Recently, new methods become available, such preparations of well-characterized autologous dendritic cells, and use of gene therapy tools to increase whole-tumor cells or host tissue immunogenicity. These are able to enhance and diversify therapeutic options. Indeed, several vaccinal approaches are being investigated, including optimized mature dendritic cells, allogeneic genetically modified tumor cells, or viral vectors. Due to the description of immunological and clinical responses, large phase III randomized trials are now conducted. After summarizing the mechanistic basis for these approaches, this review describes the experience with the most recent and promising clinical studies and introduces short-term perspectives that could lead to improvement in healthcare offer for prostate cancer patients. PMID 17845996
Immunology and immunotherapy approaches for prostate cancer.
Aug. 2007 | Elkord, E
Several mechanisms that impair the immune response to promote tumour progression are reported. These mechanisms aim to reduce the ability of antigen-presenting cells to present antigen and activate naïve T cells to support an active immune response or to create a suppressive environment that induce non-functional tumour-associated antigen-specific T cells. Prostate cancer (PC) alone accounts for 33% of incident cancer cases and about 9% of all cancer-related deaths among men in the USA during 2006. Whereas androgen deprivation has remained the first line of therapy for advanced PC, other therapies are still required due to progression to an androgen-resistant state and eventually loss of control in patients receiving hormonal therapy. Immunotherapy seems to be a promising approach to enhance tumour-specific T-cell responses in different cancers including prostate. More importantly, clinical trials in advanced PC patients have shown that immunotherapy may generate significant clinical responses. Immunology and immunotherapy aspects of PC with focus on prostate-specific antigen will be presented. PMID 17420764
TGF-beta insensitive dendritic cells: an efficient vaccine for murine prostate cancer.
Aug. 2007 | Wang, Fu-Li; Qin, Wei-Jun; Wen, Wei-Hong; Tian, Feng; Song, Bin; Zhang, Qiang; Lee, Chung; Zhong, Wei-de; Guo, Ying-Lu; Wang, He
Dendritic cells (DCs) are highly potent initiators of the immune response, but DC effector functions are often inhibited by immunosuppressants such as transforming growth factor beta (TGF-beta). The present study was conducted to develop a treatment strategy for prostate cancer using a TGF-beta-insensitive DC vaccine. Tumor lysate-pulsed DCs were rendered TGF-beta insensitive by dominant-negative TGF-beta type II receptor (TbetaRIIDN), leading to the blockade of TGF-beta signals to members of the Smad family, which are the principal cytoplasmic intermediates involved in the transduction of signals from TGF-beta receptors to the nucleus. Expression of TbetaRIIDN did not affect the phenotype of transduced DCs. Phosphorylated Smad-2 was undetectable and expression of surface co-stimulatory molecules (CD80/CD86) were upregulated in TbetaRIIDN DCs after antigen and TGF-beta1 stimulation. Vaccination of C57BL/6 tumor-bearing mice with the TbetaRIIDN DC vaccine induced potent tumor-specific cytotoxic T lymphocyte responses against TRAMP-C2 tumors, increased serum IFN-gamma and IL-12 level, inhibited tumor growth and increased mouse survival. Furthermore, complete tumor regression occurred in two vaccinated mice. These results demonstrate that blocking TGF-beta signals in DC enhances the efficacy of DC-based vaccines. PMID 17473921
Immunotherapy for prostate cancer using antigen-loaded antigen-presenting cells: APC8015 (Provenge).
Aug. 2007 | Harzstark, Andrea L; Small, Eric J
Dendritic cells are deficient both in number and function in patients with cancer. Loaded dendritic cell therapies aim to overcome this deficiency by delivering antigens to antigen-presenting cells under ex vivo conditions, improving dendritic cell function. APC8015 (Provenge; Dendreon Corp., Seattle, WA) is a novel immunotherapeutic, which consists of autologous dendritic cells pulsed ex vivo with PA2024, a recombinant fusion protein consisting of granulocyte macrophage colony-stimulating factor and prostatic acid phosphatase, as an immunogenic agent. A Phase III randomized clinical trial has demonstrated a survival benefit in patients with metastatic hormone-refractory prostate cancer. This review summarizes the clinical trials using APC8015 in prostate cancer and discusses its future role in the treatment of prostate cancer. PMID 17696825
Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity.
Aug. 2007 | Mukhopadhaya, Arunika; Mendecki, Joseph; Dong, Xinyuan; Liu, Laibin; Kalnicki, Shalom; Garg, Madhur; Alfieri, Alan; Guha, Chandan
Prostate adenocarcinoma, treated with localized tumor hyperthermia (LTH), can potentially serve as a source of tumor antigen, where dying apoptotic/necrotic cells release tumor peptides slowly over time. In addition, LTH-treated cells can release heat shock proteins that can chaperone antigenic peptides to antigen-presenting cells, such as dendritic cells. We attempted to discern whether sequential LTH and intratumoral dendritic cell and/or systemic granulocyte macrophage colony-stimulating factor (GM-CSF) would activate antitumor immune response in a syngeneic murine model of prostate cancer (RM-1). Palpable RM-1 tumors, grown in the distal appendage of C57BL/6 male mice, were subjected to LTH (43.7 degrees C for 1 h) x 2, separated by 5 days. Following the second LTH treatment, animals received either PBS or dendritic cells (2 x 10(6)) intratumorally (every 3 days for three injections). Separate cohorts also received i.v. injection of recombinant adenovirus-expressing murine GM-CSF (AdGMCSF), 1 day after LTH. Control animals received AdenoLacZ or AdenoGFP. Intratumoral dendritic cell injection induced tumor-specific T-helper cell activity (IFNgamma ELISPOTS) and CTL activity, which was further augmented by AdGMCSF, indicating amplification of tumor-specific TH1 immunity. The combination of LTH, AdGMCSF, and intratumoral dendritic cell injection resulted in significant tumor growth delays when compared with animal cohorts that received LTH alone. These results support an in situ autovaccination strategy where systemic administration of GM-CSF and/or intratumoral injection of autologous dendritic cells, when combined with LTH, could be an effective treatment for local and systemic recurrence of prostate cancer. PMID 17699785
Conformal radiotherapy plus local hyperthermia in patients affected by locally advanced high risk prostate cancer: preliminary results of a prospective phase II study.
Aug. 2007 | Maluta, S; Dall'Oglio, S; Romano, M; Marciai, N; Pioli, F; Giri, M G; Benecchi, P L; Comunale, L; Porcaro, A B
Hyperthermia has been used in several trials to treat pelvic cancers without excessive toxicity and with positive results. The aim of this study was to evaluate feasibility and results in terms of biochemical recurrence-free, disease-free survival, overall survival, and treatment toxicity profile of hyperthermia combined with radiotherapy in locally advanced high risk prostate cancer. PMID 17701536
Dendritic cell vaccination.
Aug. 2007 | Proudfoot, Owen; Pouniotis, Dodie; Sheng, Kuo-Ching; Loveland, Bruce E; Pietersz, Geoffrey A
There has been a surge of interest in the use of dendritic cell (DC) vaccination as cellular immunotherapy for numerous cancers. Despite some encouraging results, this therapeutic modality is far from being considered as a therapy for cancer. This review will first discuss preclinical DC vaccination in murine models of cancer, with an emphasis on comparative studies investigating different methods of antigen priming. We will then comment on the various murine DC subsets and how these relate to human DC preparations used for clinical studies. Finally, the methodology used to generate human DCs and some recent clinical trials in several cancers are reviewed. PMID 17669014
[Changes of dendritic cells in prostate cancer and dendritic cell-based immunotherapy].
Juni 2007 | Qi, Shi-yong; Wang, Meng; Xu, Yong
As the potent professional antigen present cell, dendritic cells (DC) play an important role in the initiation for anti-tumor immunity. Prostate cancer (PCa) can reduce the number and function of tumor infiltrated dendritic cells (TIDC) by a series of complicated mechanisms, escaping from immunosurveillance. With the development of immunology, more and more studies focus on TIDC and DC-based vaccines for PCa. However, all these studies are still at the exploratory stage. Here is a review of the related literature. PMID 17569266
Immunotherapy with dendritic cells for prostate cancer.
Mai 2007 | Thomas-Kaskel, Anna-Katharina; Waller, Cornelius F; Schultze-Seemann, Wolfgang; Veelken, Hendrik
Radical prostatectomy for prostate cancer is followed by PSA recurrence in up to 40% of patients. One third of patients with biochemical relapse progress to uncurable metastatic disease. Therefore, alternative treatment modalities are needed both in the situation of PSA recurrence and in hormone-refractory disease. Dendritic cells (DC) are the most powerful antigen-presenting cells, able to prime naïve T-cells and to break peripheral tolerance and thus induce tumor immune responses. More than 400 prostate cancer patients have been treated with DC-based immunotherapy to date, and immune responses have been reported in two-thirds of these, resulting in clinical responses in almost half of the patients treated. Most responses, however, were modest and transient. Therefore, mechanisms of treatment failure and possibilities to improve vaccination efficacy are being discussed. PMID 17514654
Re: Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase 1 clinical trial.
Apr. 2007 | Schmid, Hans-Peter
Immunotherapy of patients with hormone-refractory prostate carcinoma pre-treated with interferon-gamma and vaccinated with autologous PSA-peptide loaded dendritic cells--a pilot study.
März 2007 | Hildenbrand, B; Sauer, B; Kalis, O; Stoll, C; Freudenberg, M A; Niedermann, G; Giesler, J M; Jüttner, E; Peters, J H; Häring, B; Leo, R; Unger, C; Azemar, M
We conducted a pilot trial to assess the feasibility and tolerability of a prime/boost vaccine strategy using interferon-gamma (IFN-gamma) and autologous dendritic cells (DCs) pulsed with HLA-A2-specific prostate-specific antigen (PSA) peptides (PSA-1 [141-150]; PSA-2 [146-156]; PSA-3 [154-163]) for the treatment of 12 patients with hormone refractory prostate carcinoma. PMID 17262804
Advances in prostate cancer immunotherapies.
März 2007 | Basler, Michael; Groettrup, Marcus
Prostate cancer is a major cause of mortality in men in the Western world. Although treatment of early stage prostate cancer with radiation therapy or prostatectomy is efficient in most cases, some patients develop a fatal hormone-refractory disease. Treatments in this case are limited to aggressive chemotherapies, which can reduce serum prostate-specific antigen (PSA) levels in some patients. Taxane- and platinum-compound-based chemotherapies produce a survival benefit of only a few months. Therefore, it is crucial to develop novel, well tolerated treatment strategies. Over the past years, immunotherapy of hormone-refractory prostate cancer has been studied in numerous clinical trials. The fact that the prostate is a non-essential organ makes prostate cancer an excellent target for immunotherapy. Administration of antibodies targeting the human epidermal growth factor receptor-2 or the prostate-specific membrane antigen led to stabilisation of PSA levels in several patients. Vaccination of prostate cancer patients with irradiated allogeneic prostate cell lines has demonstrated that whole cell-based vaccines can significantly attenuate increases in PSA. Two different recombinant viral expression vectors have been applied in prostate cancer treatment: poxvirus and adenovirus vectors. Both vaccines have the advantages of using a natural method to induce immune responses and achieving high levels of transgene expression. Vaccinia viruses in combination with recombinant fowlpox or canarypox virus have been used to express recombinant PSA. Several studies demonstrated that this approach is safe and can lead to stabilisation of PSA values. A very promising approach in prostate cancer immunotherapy is vaccination of patients with dendritic cells. Thereby, peptides, recombinant proteins, tumour lysates or messenger RNA have been used to deliver antigens to autologous dendritic cells. Loading of dendritic cells with up to five different peptides derived from multiple proteins expressed in prostate cancer demonstrated that cytotoxic T-cell responses could be elicited in prostate cancer patients. Sipuleucel-T (APC8015), an immunotherapy product consisting of antigen-presenting cells, loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor, demonstrated in a phase III, placebo-controlled trial an improvement in median time to disease progression. The improvement in overall survival was 4.5 months for sipuleucel-T-treated patients compared with the placebo group. Although there is a minor increase in overall survival of metastatic prostate cancer patients with some approaches, more effective therapeutic strategies need to be developed. PMID 17362049
Vaccination therapy in prostate cancer.
Feb. 2007 | Marrari, Andrea; Iero, Manuela; Pilla, Lorenzo; Villa, Sergio; Salvioni, Roberto; Valdagni, Riccardo; Parmiani, Giorgio; Rivoltini, Licia
Radical prostatectomy and radiation therapy provide excellent localized prostate cancer (PC) control. Although the majority of prostate carcinoma is nowadays diagnosed at early stages with favourable risk features, in patients up to 30-40% it recurs within 10 years. Furthermore, the lack of effective therapies, once prostate carcinoma becomes refractory to androgen deprivation, mandates the development of alternative therapeutic options. There is a growing interest in harnessing the potency and specificity of anti-tumour immunity through the generation of fully competent dendritic cells and tumour reactive effector lymphocytes. Several strategies to treat or prevent the development of metastatic PC have been explored in clinical trials and are summarized in this review, considering also the feasibility and safety of these approaches. In some cases clinical responses were achieved showing that vaccine-primed T cells induced anti-tumour activity in vivo. The present findings and perspectives of the immunologic interventions in PC patients will be discussed. PMID 17031640
Vaccination of advanced prostate cancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTH responses that correlate with superior overall survival.
Okt. 2006 | Thomas-Kaskel, Anna-K; Zeiser, Robert; Jochim, Rosa; Robbel, Christian; Schultze-Seemann, Wolfgang; Waller, Cornelius F; Veelken, Hendrik
Prostate stem cell antigen (PSCA) and prostate-specific antigen (PSA) are overexpressed in most prostate cancers. PSCA- and PSA-derived, HLA-A2 binding peptides are specific targets for T-cell responses in vitro. A phase I/II trial was performed to demonstrate feasibility, safety and induction of antigen-specific immunity by vaccination with dendritic cells (DC) presenting PSCA and PSA peptides in patients with hormone- and chemotherapy-refractory prostate cancer. Patients received 4 vaccinations with a median of 2.7 x 10(7) peptide-loaded mature DC s.c. in biweekly intervals. Clinical responses were assessed 2 weeks after the 4th vaccination. Immune monitoring was performed by DTH and HLA multimer analysis. Twelve patients completed vaccination without relevant toxicities. Six patients had stable disease after 4 vaccinations. One patient had a complete disappearance of lymphadenopathy despite rising PSA. Four patients with SD and 1 progressor developed a positive DTH after the 4th vaccination. With a median survival of all patients of 13.4 months, DTH-positivity was associated with significantly superior survival (p = 0.003). HLA tetramer analysis detected high frequencies of peptide-specific T cells after 2 vaccinations in 1 patient who was also the sole responder to concomitant hepatitis B vaccination as an indicator of immune competence and survived 27 months after start of vaccination. Vaccination with PSA/PSCA peptide-loaded, autologous DCs may induce cellular responses primarily in immunocompetent patients, which appear to be associated with clinical benefit. Testing of DC-based vaccination is warranted for patients at earlier stages of prostate cancer. PMID 16977630
Immunotherapy for prostate cancer using prostatic acid phosphatase loaded antigen presenting cells.
Sep. 2006 | Lin, Amy M; Hershberg, Robert M; Small, Eric J
Dendritic cells from patients with cancer are deficient in number and functional activity, leading to inadequate tumor immunosurveillance as a result of poor induction of T-cell antitumor responses. Loaded dendritic cell therapy is a vaccination strategy aimed at eliciting tumor antigen-specific, T-cell immune responses. Loaded dendritic cell therapy using prostatic acid phosphatase (APC8015; Provenge, Dendreon Corp., Seattle, WA) as an immunogen has shown a survival benefit in patients with metastatic hormone-refractory prostate cancer in a randomized phase III trial. This review will summarize the prostate cancer clinical trials using APC8015 and discuss the potential future role of APC8015 in prostate cancer treatment. PMID 16962496
Basic overview of current immunotherapy approaches in urologic malignancy.
Sep. 2006 | Drake, Charles G
The immune response to evolving prostate cancer is a complex and carefully orchestrated process. Such a response is initiated when immature dendritic cells take up and process tumor-associated antigens. These dendritic cells must then be activated in order to present peptides to helper (CD4) T cells. Cytolytic (CD8) T cells are next "licensed" to achieve full effector function by interacting with both antigen presenting cells and tumor-specific CD4 T cells. Finally, activated CD8 T cells traffic to sites of neoplasia and mediate killing by multiple mechanisms. This article provides a basic overview of these processes, and discusses the manner by which current clinical interventions seek to augment or initiate an antitumor immune response. Various compensatory mechanisms which serve to down-regulate an antitumor response are also examined. PMID 16962493
Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma.
Sep. 2006 | Waeckerle-Men, Ying; Uetz-von Allmen, Edith; Fopp, Markus; von Moos, Roger; Böhme, Christel; Schmid, Hans-Peter; Ackermann, Daniel; Cerny, Thomas; Ludewig, Burkhard; Groettrup, Marcus; Gillessen, Silke
Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer. PMID 16612599
Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells.
Aug. 2006 | Kyte, Jon A; Gaudernack, Gustav
We have developed immuno-gene therapy for malignant melanoma and prostate cancer. The therapy is based on monocyte-derived dendritic cells (DCs) that are transfected with autologous melanoma-mRNA or mRNA from three prostate cancer cell lines (DU-145, LN-CaP and PC-3). A broad spectrum of tumour-associated antigens will be included in both DC-vaccines. The use of autologous melanoma-mRNA moreover allows targeting of individual tumour antigens that are specific to each patient. Effective protocols have been established for mRNA-transfection by square wave electroporation and for the generation of clinical grade DCs. A full scale preclinical evaluation demonstrated in vitro T cell responses in 6/6 advanced melanoma patients. The responses were specific to antigens encoded by the transfected tumour-mRNA. Recently, we have conducted two phase I/II trials, in advanced malignant melanoma and androgen-resistant prostate cancer. Successful vaccine preparations were obtained for all 41 patients elected. No serious adverse effects were observed. Specific T cell responses (T cell proliferation and/or IFNgamma ELISPOT) were demonstrated in 9/19 evaluable melanoma patients and in 12/19 prostate cancer patients. The response rates were higher for patients receiving intradermal vaccination, compared to intranodal injection. Thirteen prostate cancer patients developed a decrease in log-slope PSA. The PSA-response was significantly related to the T cell response (P=0.002). We conclude that the DC-vaccine is feasible and safe, and that T cell responses are elicited in about 50% of patients. PMID 16612595
Immunotherapy for prostate cancer: what's the future?
Juli 2006 | Arlen, Philip M; Dahut, William L; Gulley, James L
Prostate cancer is the most common noncutaneous cancer and second leading cause of cancer death among US men. A greater understanding of basic immunologic principles has led to a variety of new techniques,which has led to advancements in prostate cancer vaccines. This article discusses the rationale for the development of antibody-based therapy and vaccines therapy, including whole tumor cells, dendritic cells, and pox viral vectors. A summary of selected clinical studies incorporating these strategies and new approaches incorporating a combination of immunotherapy with traditional treatments for prostate cancer is presented. PMID 16861126
Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial.
Apr. 2006 | Fuessel, Susanne; Meye, Axel; Schmitz, Marc; Zastrow, Stefan; Linné, Clemens; Richter, Katja; Löbel, Barbel; Hakenberg, Oliver W; Hoelig, Kristina; Rieber, E Peter; Wirth, Manfred P
Immunotherapies might represent promising alternatives for the treatment of patients with hormone-refractory prostate cancer (HRPC). In a Phase I clinical trial, we evaluated a vaccination with dendritic cells (DCs) loaded with a cocktail consisting of HLA-A*0201-restricted peptides derived from five different prostate cancer-associated antigens [prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), survivin, prostein, transient receptor potential p8 (trp-p8)]. PMID 16482569
Therapeutic cancer vaccines.
März 2006 | Srivastava, Pramod K
The immunological bases of current approaches to therapeutic cancer vaccination (or 'vacci-treatment') have been established for a decade or longer. The new developments lie mostly in the lessons learnt from clinical testing of these approaches. Three lessons are particularly worthy of note. First, recently completed randomized Phase 3 trials suggest that vacci-treatment with autologous dendritic cells expressing prostatic acid phosphatase (for prostate cancer) or with autologous tumor-derived heat shock protein (gp96)-peptide complexes show promise in enhancing survival of cancer patients. These two approaches are undergoing further randomized clinical testing. Second, immunological monitoring of many clinical trials has failed to identify a surrogate marker for clinical outcomes. Finally, an increasing volume of literature suggests that protective immunity to human cancers is elicited by the mutated antigenic repertoire unique to each cancer. PMID 16464565
Immunotherapy for prostate cancer.
März 2006 | Karnes, R Jeffrey; Whelan, Christopher M; Kwon, Eugene D
The absence of curative therapies for advanced or recurrent forms of prostate cancer has prompted a vigorous search for novel treatment strategies. Immunotherapy encompasses one particularly promising systemic approach to treat prostate cancer. Immune-based strategies to treat prostate cancer have recently been facilitated by the identification of a number of prostate tissue/tumor antigens that can be targeted, either by antibody or T cells, to promote prostate tumor cell injury or death. These same prostate antigens can also be used for the construction of vaccines to induce prostate-specific T cell-mediated immunity. Greater insight into specific mechanisms that govern antigen-specific T cell activation has brought with it a number of innovative methods to induce and enhance T cell-mediated responses against prostate tumors. For instance, autologous dendritic cells loaded with prostate antigens have proved useful to induce prostate-specific T cell activation. Similarly, in vivo manipulations of the T cell costimulatory pathway receptors can greatly facilitate tumor-specific T cell activation and potentiate T cell-mediated responses against a number of malignancies, including prostate cancer. Therefore, in this review we summarize recent advances pertaining to immunotherapeutic approaches to treat prostate cancer. PMID 16515497
Technology Insight: vaccine therapy for prostate cancer.
Feb. 2006 | Vieweg, Johannes; Dannull, Jens
The lack of effective therapies for advanced prostate cancer mandates continued development of alternative treatment strategies. Insights into the regulation of immune responses and the malignant process have facilitated the emergence of new immune-based strategies, currently under investigation in clinical trials. Like other forms of targeted therapy, cancer vaccines hold the promise of achieving cancer control without inducing overt toxicity. Many prostate cancer vaccines at different phases of development have been tested in clinical trials. Vaccination strategies under consideration include: immunization with defined antigenic preparations such as synthetic peptides, proteins or plasmid DNA; antigen-loaded dendritic cells; manipulated tumor cells; or with viral vectors engineered to express immunogenic genes. Although the underlying mechanisms of immunization may vary, all strategies share the common goal of eliciting immune responses against prostate tumor-associated antigens or of enhancing an otherwise weak antitumor response in the cancer patient. Unlocking the therapeutic potential of cancer vaccines will require a thorough understanding of cellular and molecular mechanisms that modulate the immune response. In this review, we provide an overview of vaccine-based strategies for prostate cancer therapy, discuss their mechanisms of action, and provide relevant clinical trial data. PMID 16474576
Prostate cancer immunology: biology, therapeutics, and challenges.
Nov. 2005 | Webster, W Scott; Small, Eric J; Rini, Brian I; Kwon, Eugene D
A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment. PMID 16278482
Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile.
Nov. 2005 | Hurwitz, Mark D; Kaplan, Irving D; Hansen, Jorgen L; Prokopios-Davos, Savina; Topulos, George P; Wishnow, Kenneth; Manola, Judith; Bornstein, Bruce A; Hynynen, Kullervo
Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented. PMID 16278168
Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients.
Sep. 2005 | Mu, L J; Kyte, J A; Kvalheim, G; Aamdal, S; Dueland, S; Hauser, M; Hammerstad, H; Waehre, H; Raabe, N; Gaudernack, G
Here, we present results from a clinical trial employing a new vaccination method using dendritic cells (DCs) transfected with mRNA from allogeneic prostate cancer cell lines (DU145, LNCaP and PC-3). In all, 20 patients were enrolled and 19 have completed vaccination. Each patient received at least four weekly injections with 2 x 10(7) transfected DCs either intranodally or intradermally. Safety and feasibility of vaccination were determined. Immune responses were measured as delayed-type hypersensitivity and by in vitro immunoassays including ELISPOT and T-cell proliferation in pre- and postvaccination peripheral blood samples. Serum prostate-specific antigen (PSA) levels and bone scans were monitored. No toxicity or serious adverse events related to vaccinations were observed. A total of 12 patients developed a specific immune response to tumour mRNA-transfected DCs. In total, 13 patients showed a decrease in log slope PSA. This effect was strengthened by booster vaccinations. Clinical outcome was significantly related to immune responses (n = 19, P = 0.002, r = 0.68). Vaccination with mRNA-transfected DCs is safe and results in cellular immune responses specific for antigens encoded by mRNA derived from the prostate cancer cell lines. The observation that in some patients vaccination affected the PSA level suggests that this approach may become useful as a treatment modality for prostate cancer patients. PMID 16136047
[Vaccine therapy of prostate cancer].
Sep. 2005 | Doehn, C; Böhmer, T; Sommerauer, M; Kausch, I; Jocham, D
Vaccine therapy of prostate cancer has been increasingly studied in trials over the past few years. The different vaccine techniques are quite variable and are predominantly used in patients with advanced hormone-refractory prostate cancer. In this review, vaccine techniques using tumor cells, dendritic cells or poxvirus are analyzed. For theses approaches phase-III trials are being planned, have been initiated or are already completed. Many trials demonstrate the efficacy with regard to endpoints such as stimulation of the immune system and/or biochemical response and/or clinical response. Recently, one vaccine approach using autologous dendritic cells demonstrated a statistically significant prolongation of overall survival compared to placebo in patients with hormone-refractory prostate cancer. Side effects of vaccination are generally mild. At present, there are trials are being planned or are already ongoing that combine vaccine with other treatment strategies or enroll patients with earlier disease stages. PMID 16163603
Regional hyperthermia in conjunction with definitive radiotherapy against recurrent or locally advanced prostate cancer T3 pN0 M0.
Jan. 2005 | Tilly, Wolfgang; Gellermann, Johanna; Graf, Reinhold; Hildebrandt, Bert; Weissbach, Lothar; Budach, Volker; Felix, Roland; Wust, Peter
Since long-term results of the standard treatment of locally advanced or recurrent prostatic carcinoma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study. PMID 15660191
Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer.
Nov. 2004 | Ragde, Haakon; Cavanagh, William A; Tjoa, Benjamin A
No effective treatment is currently available for metastatic prostate cancer. Dendritic cell (DC) based cancer vaccine research has emerged from the laboratories to human clinical trials. We describe progress in the development of DC based prostate cancer vaccine. PMID 15538202
Radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate cancer: preliminary results.
Dez. 2003 | Van Vulpen, M; De Leeuw, A A C; Raaymakers, B W; Van Moorselaar, R J A; Hofman, P; Lagendijk, J J W; Battermann, J J
To report an interim clinical evaluation of combined external beam irradiation (EBRT) and interstitial or regional hyperthermia in the treatment of locally advanced prostate cancer. PMID 14678364
External beam radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma.
Aug. 2000 | Algan, O; Fosmire, H; Hynynen, K; Dalkin, B; Cui, H; Drach, G; Stea, B; Cassady, J R
The current study was conducted to evaluate the combination of external beam radiation therapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma. PMID 10918172
[Current methods of radiation therapy in patients with prostatic cancer: subtotal body radiation, local hyperthermia].
März 1999 | Granov, A M; Vinogradov, V M; Metelev, V V; Kozlov, A A; Shkol'nik, M I; Lisitsyn, I Iu; Karelin, M I
The paper deals with the preliminary data of treatment of patients with prostatic cancer by using unconventional methods of radiation therapy (RT), such as subtotal radiation of the body (STRB) and thermoradiation treatment (TRT). Out of 72 patients receiving RT, 16 and 8 had STRB and TRT, respectively. Systemic and local drug therapies were made to prevent radiation reactions and injuries. In all cases, STRB and TRT showed a significant objective and subjective effect. To evaluate the long-term results of treatment needs further studies. PMID 9987941
Follow-up evaluation of prostate cancer patients infused with autologous dendritic cells pulsed with PSMA peptides.
Sep. 1997 | Tjoa, B A; Erickson, S J; Bowes, V A; Ragde, H; Kenny, G M; Cobb, O E; Ireton, R C; Troychak, M J; Boynton, A L; Murphy, G P
We recently conducted a phase I clinical trial administering autologous dendritic cells pulsed with prostate-specific membrane antigen (PSMA) peptides to advanced prostate cancer patients. Participants were divided into 5 groups receiving 4 or 5 infusions of peptides alone (PSM-P1 or -P2; groups 1 and 2, respectively), autologous DC (group 3), or DC pulsed with PSM-P1 or -P2 (groups 4 and 5, respectively). Seven partial responders were observed. Follow-up evaluation of these responders is presented in this report. PMID 9288186
Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-specific peptides from prostate-specific membrane antigen.
Jan. 1997 | Murphy, G; Tjoa, B; Ragde, H; Kenny, G; Boynton, A
Conventional treatment for metastatic prostate cancer have failed to demonstrate curative potential in all patients. Investigations involving the role of T-cell immunity in the clearance of neoplastic cells are now available. Development of T-cell immunotherapy may give a new approach to the treatment of advanced metastatic prostate cancer. PMID 8977634
Feasibility and toxicity of transrectal ultrasound hyperthermia in the treatment of locally advanced adenocarcinoma of the prostate.
Juni 1993 | Fosmire, H; Hynynen, K; Drach, G W; Stea, B; Swift, P; Cassady, J R
This Phase I trial tests the ability of a new hyperthermia device, the transrectal ultrasound probe, to heat the prostate gland, and evaluates the toxicity of transrectal ultrasound hyperthermia (TRUSH) given with concurrent standard external beam irradiation in the treatment of locally-advanced adenocarcinoma of the prostate. PMID 8491683