Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sipuleucel-T [APC 8015, Provenge] is an autologous, dendritic cell-based vaccine under development with Dendreon Corporation for the treatment of androgen-independent and androgen-dependent prostate cancer. It was generated using the company's active immunotherapy platform to stimulate a patient's own immune system to specifically target and destroy cancer cells, while leaving healthy cells unharmed. This approach could provide patients with a meaningful survival benefit and an improved tolerability profile over existing anticancer therapies. Sipuleucel-T selectively targets the prostate-specific antigen (PSA) known as prostatic acid phosphatase (PAP) that is expressed in approximately 95% of prostate cancers. It is produced by ex vivo exposure of dendritic cell precursors to PA 2024, a recombinant fusion protein composed of the PAP target fused to granulocyte-macrophage colony-stimulating factor (GM-CSF) and incorporated into Dendreon's proprietary Antigen Delivery Cassette. Patients are typically administered three intravenous (IV)-infusions of the vaccine over a 1-month period as a complete course of therapy. It is undergoing late-stage clinical evaluation among patients with early and advanced prostate cancer. In November 2003, Kirin Brewery returned to Dendreon the full rights to Sipuleucel-T for Asia. In exchange, Dendreon licensed patent rights relating to the use of certain HLA-DR antibodies to Kirin for $US20 million. This amended agreement enables Dendreon to complete ongoing discussions for a worldwide marketing and sales partnership for Sipuleucel-T. Similarly, Kirin is able to develop its HLA-DR monoclonal antibodies free of potential infringement claims arising from Dendreon's patent rights to HLA-DR. The licensing agreement relates to patent rights owned by Dendreon relating to monoclonal antibodies against the HLA-DR antigen. In addition, Dendreon retains rights to develop and commercialise its two existing HLA-DR monoclonal antibodies, DN 1921 and DN 1924, as well as other HLA-DR antibodies not being developed by Kirin. Previously, in May 1999, Dendreon and Kirin established a collaboration for the development of dendritic cell-based immunotherapeutics for cancer, including Sipuleucel-T. Under the agreement, Kirin would provide financial support for Dendreon's research on dendritic cells focused on developing immunotherapies for cancers most prevalent in Asia. Dendreon would retain US rights to products arising from the collaboration while Kirin would hold the rights to such immuno-therapeutics in Asia and Oceania. In August 2005, Dendreon signed an agreement to lease a commercial manufacturing facility in Hanover, New Jersey, USA. The company intends to develop the facility to meet anticipated clinical and commercial demands of Sipuleucel-T as well as other active immunotherapy product candidates. Dendreon and Diosynth Biotechnology (Akzo Nobel) have an agreement for the commercial production of the PA 2024 antigen component of Sipuleucel-T. In November 2003, Dendreon announced that Diosynth successfully manufactured PA 2024 on a commercial scale. In October 2001, Dendreon announced that Gambro Healthcare Inc. would provide a network of centres for cell collection to support commercial production and clinical development of various Dendreon vaccines, including Sipuleucel-T. Dendreon has outsourced its cell processing operations in Mountain View, California, USA to Progenitor Cell Therapy under an amended agreement signed in August 2002. This agreement is an expansion of an existing agreement, under which Progenitor provided Dendreon with cell-processing services through its facility in Hackensack, New Jersey, USA. The pivotal, two-stage, phase III trial (D9902 study) has been initiated at clinical sites in the US. The first stage of the trial (D9902A study) is a double-blind, placebo-controlled phase III trial designed to evaluate Sipuleucel-T in men with asymptomatic, metastatic, androgen-independent prostate cancer. The trial was originally designed to be the companion study to a previously completed phase III trial, called D9901. However, the D9902A study with 98 patients recruited was halted in December 2002, when analysis of the D9901 study revealed no statistically significant benefit in time to disease progression in the overall group, although a benefit was seen in a subgroup of patients with Gleason scores of < or =7. In April 2002, the US FDA requested clarification regarding cellular composition of Sipuleucel-T and the suspension of additional patient enrollment for the D9902 study; the request was related solely to manufacturing issues without patient safety being an issue. Trial enrollment resumed in October 2002 following FDA authorisation. Dendreon amended the protocol for the D9902 study and is only recruiting patients with asymptomatic, metastatic, androgen-independent prostate cancer, regardless of their Gleason Score (D9902B study). The ongoing pivotal phase III trial underwent a Special Protocol Assessment (SPA) with the FDA in August 2003 and is enrolling approximately 500 patients. The primary endpoint is overall survival with time to objective disease progression being a secondary endpoint. Final 3-year survival analysis of the D9902A study has been completed and presented. Previously, Dendreon completed an earlier phase III trial (D9901 study) that assessed Sipuleucel-T among 127 patients with late-stage, metastatic, hormone-independent prostate cancer in the US. All subjects had undergone surgical resection of the prostate, but had rising levels of PSA. Final 3-year survival data have been reported. Dendreon also conducted a phase II trial, known as D9905, that investigated Sipuleucel-T monotherapy among patients with early-stage prostate cancer. Study findings have been reported. In September 2003, the FDA designated Sipuleucel-T as a fast-track development programme for the treatment of asymptomatic, metastatic, androgen-independent prostate cancer. Subsequently, the FDA granted fast-track status to the vaccine in November 2005. Dendreon announced in September 1999 that a phase I trial of Sipuleucel-T in patients with prostate cancer had commenced in Japan. This study was being conducted at a dendritic cell processing centre that was formed as part of Dendreon's collaboration with Kirin. In addition, the US NCI is conducting a phase II trial (P-16) of Sipuleucel-T in combination with bevacizumab among patients with hormone-dependent prostate cancer. Trial results have been announced. In April 2001, Dendreon was awarded a US patent (No. 6,210,662) covering the composition of Sipuleucel-T. Dendreon acquired an exclusive worldwide licence to dendritic cell therapy for cancers and other diseases from the Immune Response Corporation; Immune Response originally received the exclusive patent rights to the technology from the University of Brussels in Belgium.
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PMID:Sipuleucel-T: APC 8015, APC-8015, prostate cancer vaccine--Dendreon. 1675 45

Classically, advanced prostate cancer has been treated with hormonal therapy and, most recently, chemotherapy. This treatment clearly demonstrated a survival benefit, but never a cure. With the ever-expanding understanding of the pathophysiology of prostate cancer, there has been a recent explosion in the potential molecular targets and novel therapeutic approaches to both advanced and potentially localized prostate cancer. This review will focus on what the author perceives to be the most promising of these new strategies. The endothelin pathway has been identified as pivotal in the viscous cycle of tumorigenesis in bone, leading to the development of endothelial receptor antagonists. Vaccine therapy using autologous granulocyte-macrophage colony-stimulating factor-producing prostate cancer cells has been effective in producing both immune and clinical responses. Randomized clinical trials of the immunotherapy cell product APC8015 (Provenge) have demonstrated improved survival in the hormone-refractory setting. The development of antisense oligonucleotides to segments of mRNA critical to the progression to androgen-independent disease has emerged as one further tool in the expanding armamentarium of potential therapies being tested. Clearly, headway is being made in improving outcomes in this most prevalent health problem.
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PMID:New molecular targets in advanced prostate cancer. 1683 Oct 72

The availability of several novel antibodies, coupled with viral, DNA, and dendritic-cell vaccines, has renewed interest in immunotherapeutic approaches to the treatment of advanced prostate cancer. Although promising, none of these approaches have led to major clinical activity, and in the case of cell-based immunotherapy with GVAX, new concerns about safety arose when this therapy was used in the castration-resistant setting. A more attractive yet toxic approach has also utilized a check-point blockade with CTLA-4 antibodies. Although initial clinical efficacy has been observed, toxicity appears to be the major limitation of its use in prostate cancer. Sipuleucel-T (Provenge) is an autologous active cellular immunotherapy product that includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphataase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite the lack of objective anti-tumor activity seen with sipuleucel-T, a recently reported phase III trial demonstrated a significant improvement in the overall survival of men with asymptomatic, minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). This agent is the first FDA-approved novel immunotherapeutic compound for the treatment of a solid malignancy. A better understanding of how clinicians should incorporate this novel agent into the current management of CRPC is needed.
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PMID:Immunotherapy in castration-resistant prostate cancer: integrating sipuleucel-T into our current treatment paradigm. 2154 69