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.
A pivotal phase III study using Sipuleucel-T, an autologous prostatic acid phosphatase (PAP)-loaded dendritic cell immunotherapy, in men with metastatic castration-resistant prostate cancer (CRPC) demonstrated a survival advantage over placebo. By contrast, two phase III studies of GVAX, an allogeneic tumor cell vaccine, in a similar patient population failed to show a survival benefit of GVAX or GVAX/docetaxel over standard docetaxel/prednisone. Other strategies currently in clinical development include the ProstVac poxviral vaccine, a PAP-encoding DNA vaccine, and immune checkpoint inhibitory approaches.
Although Sipuleucel-T may receive FDA approval for patients with metastatic CRPC, challenges remain in identifying immunotherapy strategies that overcome immune tolerance, especially when disease burden is substantial. An emerging paradigm focuses on using immunotherapy together with checkpoint antagonists or in combination with conventional therapies in patients with early-stage disease. Such approaches are likely to yield optimal results, but must carefully be explored in well designed phase II studies before moving forward.
"TM-PAP was localized in the plasma membrane-endosomal-lysosomal pathway and found to colocalize with the lipid raft marker flotillin-1 (Quintero et al., 2007). These findings emphasize the fact that the expression of PAP may not be exclusive to prostatic tissue, and that this issue together with non-canonical functions of PAP has to be taken into account for the success of PAP-based immunotherapy without unwanted side effects (Antonarakis and Drake, 2010; Garcia, 2011; Gerritsen, 2012). "
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is one of the most prevalent non-skin related cancers. It is the second leading cause of cancer deaths among males in most Western countries. If prostate cancer is diagnosed in its early stages, there is a higher probability that it will be completely cured. Prostatic acid phosphatase (PAP) is a non-specific phosphomonoesterase synthesized in prostate epithelial cells and its level proportionally increases with prostate cancer progression. PAP was the biochemical diagnostic mainstay for prostate cancer until the introduction of prostate-specific antigen (PSA) which improved the detection of early-stage prostate cancer and largely displaced PAP. Recently, however, there is a renewed interest in PAP because of its usefulness in prognosticating intermediate to high-risk prostate cancers and its success in the immunotherapy of prostate cancer. Although PAP is believed to be a key regulator of prostate cell growth, its exact role in normal prostate as well as detailed molecular mechanism of PAP regulation is still unclear. Here, many different aspects of PAP in prostate cancer are revisited and its emerging roles in other environment are discussed.
Biomolecules and Therapeutics 01/2013; 21(1):10-20. DOI:10.4062/biomolther.2012.095 · 1.73 Impact Factor
"This vaccine was evaluated in two randomized Phase III clinical trials, the first (VITAL 1) evaluating GVAX versus docetaxel alone and the second (VITAL 2) studying the combination of GVAX and docetaxel versus docetaxel alone. However, before these trials could be completed, the Independent Data Monitoring Committee conducted a routine safety review of the VITAL 2 trial, which found that patients receiving GVAX and docetaxel had a higher rate of death than those receiving docetaxel alone.47,48 Based on these results, the VITAL 2 trial was closed, and a subsequent futility analysis of the VITAL 1 trial led to its closure as well. "
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer continues to be one of the most serious afflictions of men of advanced age, remaining the most commonly diagnosed and second leading cause of cancer-related deaths in American men. The treatment options for patients with incurable metastatic, castrate-resistant disease have long focused on various chemotherapeutic approaches, which provide a slight survival benefit while being associated with potentially significant side effects. However, the recent approval of sipuleucel-T has given patients with advanced disease an additional treatment option that has demonstrated benefit without the side effects associated with chemotherapy. Sipuleucel-T is an antigen-presenting cell-based active immunotherapy that utilizes a patient's own immune cells, presumably to activate an antigen-specific immune response against tumor cells. This review focuses on the development and implementation of sipuleucel-T as a therapy for prostate cancer. Specifically, we present some of the issues associated with the management of advanced prostate cancer, the research and development that led to the approval of sipuleucel-T, how the approval of sipuleucel-T could change the clinical management of prostate cancer, and current and future areas of investigation that are being pursued with regard to sipuleucel-T and other treatments for advanced prostate cancer.
Open Access Journal of Urology 05/2011; 3(1):49-60. DOI:10.2147/OAJU.S13069
"Recently, immunotherapy has been recognized as a potential therapeutic strategy in prostate cancer. Several features of this epithelial malignancy including its long natural history [Coffey and Isaacs, 1981], its ability to induce autoantibodies [Wang et al. 2005], and the availability of several tumor-specific antigens, such as prostatic acid phosphatase (PAP) [Taylor et al. 2006; Rhodes et al. 2002], have allowed the development of several immune-based strategies in the treatment of this disease [Antonarakis and Drake, 2010]. In this review, we discuss the clinical data of Sipuleucel-T, a novel immunotherapeutic agent recently approved by the US Food and Drug Administration for the management of patients with asymptomatic or minimally symptomatic metastatic CRPC. "
[Show abstract][Hide abstract] ABSTRACT: Sipuleucel-T represents a novel immunotherapeutic compound designed to stimulate an immune response against castration-resistant prostate cancer (CRPC). Sipuleucel-T is an autologous active cellular immunotherapy product, which includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor. Despite the lack of prostate-specific antigen and objective response, a recent phase III randomized trial demonstrated a significant improvement in overall survival in asymptomatic and minimally symptomatic CRPC patients. This review summarizes the clinical development of Sipuleucel-T in CRPC that led to the regulatory approval of this compound in the USA.
rapeutic Advances in Medical Oncology, The 03/2011; 3(2):101-8. DOI:10.1177/1758834010397692 · 2.83 Impact Factor
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