Dendreon
Encyclopedia
Dendreon is a Seattle based biotechnology
company. Its lead product, Provenge (known generically as sipuleucel-T), is an immunotherapy
for prostate cancer
. It consists of a mixture of the patient's own blood cells (autologous, with dendritic cells thought to be the most important) that have been incubated with the Dendreon PAP
-GM-CSF fusion protein.
Phase III clinical trial results demonstrating a survival benefit for prostate cancer patients receiving the drug were presented at the AUA meeting on 28 April 2009. After going through the approval process, Provenge was given full approval by the FDA on April 29, 2010. Dendreon's stock value fell 66% on August 4, 2011 after abandoning its forecast for its debut drug Provenge.
s occurs when they are exposed to the Dendreon fusion protein
which links the disease specific protein to a recognition protein. This approach is in contrast to other dendritic cell vaccines that use methods such as electroporation
to get the DC's to present antigen related epitope
s. In the case of Provenge, this disease related protein is Prostatic acid phosphatase
and the signalling component is GM-CSF.
Prior work in this area has also included that of A. Sette at Epimmune and the Altered Peptide Ligand approach typified by Neurocrine Biotech's failed MS drug.
Drs. Engleman and Strober established the company, initially named Activated Cell Therapy, in Mountain View, California after securing funding from Health Care Ventures in Edison, New Jersey. After several years the company changed its name to Dendreon and moved to Seattle, Washington.
to accommodate production for a Phase III trial and possible 2007 drug approval by the U.S. Food and Drug Administration (FDA). In January 2007, the FDA accepted Dendreon's Biologic License Application
(BLA) filing for Provenge.
On March 29, 2007, the FDA Office of Cellular, Tissue and Gene Therapies Advisory Committee voted 17-0 that Provenge is reasonably safe and 13-4 that the trial data showed substantial evidence that it is effective. However, on May 9, 2007, Dendreon received a letter from the FDA demanding more results and information before approval.
On April 14, 2009, Dendreon announced that the results for the Phase III trial of Provenge were positive, saying there had been a reduction in the odds of death compared to the use of a placebo
. On April 28, 2009, the full details of the study were released. The trial found that patients treated with Provenge lived an average of 4.1 months longer than patients treated with the control (autologous cells without the GM-CSF / PAP fusion protein).
On April 29, 2010, the FDA approved Provenge for use in the treatment of advanced prostate cancer.
Dendreonites have questioned these doctors' objectivity; as Dr. Scher was the lead clinical trial investigator for a rival prostate cancer drug from the biotech company Novacea.
Their concerns motivated organized protests at the FDA and American Society of Clinical Oncology (ASCO) meeting by various patient and investor advocacy groups which also filed a lawsuit alleging that the FDA's decision was influenced by conflicts of interest.
July 9, 2002 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu Immunostimulatory composition. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.
April 3, 2001 Laus; Reiner, Shapero; Michael H., Tsavaler; Larisa Prostate tumor polynucleotide compositions and methods of detection thereof. The present invention is directed to novel polynucleotides and the polypeptides encoded by them, each of which are specific to human prostate tumor cells. The present invention further provides chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, and antibodies which bind to the polypeptides of the present invention. Also provided herein are methods for producing the polypeptides of the present invention, as are detection assays that detect the presence of tumor cells in tissue or bodily fluid samples and methods for identifying novel compositions which modulate the activity of prostate tumor antigens and the use of such compositions in diagnosis and treatment of disease.
February 27, 2001 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu Immunostimulatory method. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.
December 7, 1999 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu
Immunostimulatory compositions. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...
company. Its lead product, Provenge (known generically as sipuleucel-T), is an immunotherapy
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
for prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
. It consists of a mixture of the patient's own blood cells (autologous, with dendritic cells thought to be the most important) that have been incubated with the Dendreon PAP
Prostatic acid phosphatase
Prostatic acid phosphatase , also prostatic specific acid phosphatase , is an enzyme produced by the prostate. It may be found in increased amounts in men who have prostate cancer or other diseases....
-GM-CSF fusion protein.
Phase III clinical trial results demonstrating a survival benefit for prostate cancer patients receiving the drug were presented at the AUA meeting on 28 April 2009. After going through the approval process, Provenge was given full approval by the FDA on April 29, 2010. Dendreon's stock value fell 66% on August 4, 2011 after abandoning its forecast for its debut drug Provenge.
Antigen delivery cassette and antigen presenting cells
Dendreon's name derives from the "Dendritic Cell" which forms a major component of the company's product candidates that use the "Dendreon Cassette Technology" to insert a disease-specific target protein into a general platform. Their lead product, Provenge, is an example of their "rationally designed therapeutic process" intended to break immune tolerance to certain disease specific proteins. It is hypothesized that receptor mediated uptake of antigen by dendritic cellDendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s occurs when they are exposed to the Dendreon fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
which links the disease specific protein to a recognition protein. This approach is in contrast to other dendritic cell vaccines that use methods such as electroporation
Electroporation
Electroporation, or electropermeabilization, is a significant increase in the electrical conductivity and permeability of the cell plasma membrane caused by an externally applied electrical field...
to get the DC's to present antigen related epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
s. In the case of Provenge, this disease related protein is Prostatic acid phosphatase
Prostatic acid phosphatase
Prostatic acid phosphatase , also prostatic specific acid phosphatase , is an enzyme produced by the prostate. It may be found in increased amounts in men who have prostate cancer or other diseases....
and the signalling component is GM-CSF.
Antigen selection
Dendreon believes its process can be optimized and generalized to other diseases by exchanging the PAP component of Provenge with better targets specific to different diseased cells. Antigen selection is a significant issue with cancer vaccines in general. Presumably, therapeutic effect can be obtained by provoking a selective response against the diseased cells only. Dendreon has explored approaches to obtaining tumour-specific antigen targets under the theory that the immune system may be able to mount a more effective response than is otherwise possible against tumor associated antigens. Unaltered human PAP is expressed by normal prostate cells but recent discoveries suggest that cancer cells produce many more unique targets as well as proteins that are more highly expressed than in normal tissue. It has also been recently discovered that other enzymes expressed in nerves are identical to PAP and there is ongoing work to examine post-translational modifications to PAP and its correlation to disease state by Dendreon collaborators. PAP also appears to be expressed in breast cysts.Prior work in this area has also included that of A. Sette at Epimmune and the Altered Peptide Ligand approach typified by Neurocrine Biotech's failed MS drug.
Acquired from Corvas
A nematode anticoagulant licensed to Nuvelo was acquired. Selected Corvas patents include technologies and for peptide analog synthesis and drugs that target coagulation and immune processes.Early history
Dendreon was founded in 1992 by Edgar Engleman and Samuel Strober based on the research performed in their laboratories at the Stanford University School of Medicine.Drs. Engleman and Strober established the company, initially named Activated Cell Therapy, in Mountain View, California after securing funding from Health Care Ventures in Edison, New Jersey. After several years the company changed its name to Dendreon and moved to Seattle, Washington.
Provenge
Initial clinical results for Provenge in 2000 showed immune responses supporting the expected mode-of-action, as well as a PSA reduction which was thought to relate to clinical improvement. In 2006, Dendreon built a manufacturing facility in Morris Plains, New JerseyMorris Plains, New Jersey
Morris Plains, billing itself "the Community of Caring," is a Borough in Morris County, New Jersey, United States. As of the United States 2000 Census, the borough population was 5,236....
to accommodate production for a Phase III trial and possible 2007 drug approval by the U.S. Food and Drug Administration (FDA). In January 2007, the FDA accepted Dendreon's Biologic License Application
Biologic License Application
As defined by the US FDA, a Biologic License Application is: Biological products are approved for marketing under the provisions of the Public Health Service Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product...
(BLA) filing for Provenge.
On March 29, 2007, the FDA Office of Cellular, Tissue and Gene Therapies Advisory Committee voted 17-0 that Provenge is reasonably safe and 13-4 that the trial data showed substantial evidence that it is effective. However, on May 9, 2007, Dendreon received a letter from the FDA demanding more results and information before approval.
On April 14, 2009, Dendreon announced that the results for the Phase III trial of Provenge were positive, saying there had been a reduction in the odds of death compared to the use of a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. On April 28, 2009, the full details of the study were released. The trial found that patients treated with Provenge lived an average of 4.1 months longer than patients treated with the control (autologous cells without the GM-CSF / PAP fusion protein).
On April 29, 2010, the FDA approved Provenge for use in the treatment of advanced prostate cancer.
Dendreonites
Some journalists have referred to Provenge supporters as "Dendreonites" and the name is in routine usage in colloquial forums. Concerns for personal safety were raised among some doctors who were thought responsible for the delay of Provenge approval.Dendreonites have questioned these doctors' objectivity; as Dr. Scher was the lead clinical trial investigator for a rival prostate cancer drug from the biotech company Novacea.
Their concerns motivated organized protests at the FDA and American Society of Clinical Oncology (ASCO) meeting by various patient and investor advocacy groups which also filed a lawsuit alleging that the FDA's decision was influenced by conflicts of interest.
List of US patents and patent applications
August 19, 2008 Laus; Reiner, Ruegg; Curtis L., Shapero; Michael H., Yang; Demao Composition and method for producing an immune response against tumor-related antigens. Disclosed are a novel prostatic acid phosphatase and corresponding coding region derived from mouse. Also disclosed is a method of producing an immune response against an autologous polypeptide tumor antigen by immunizing a subject with a xenogeneic polypeptide antigen, either alone, as part of a viral antigen construct, or as part of a pulsed dendritic cell preparation.July 9, 2002 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu Immunostimulatory composition. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.
April 3, 2001 Laus; Reiner, Shapero; Michael H., Tsavaler; Larisa Prostate tumor polynucleotide compositions and methods of detection thereof. The present invention is directed to novel polynucleotides and the polypeptides encoded by them, each of which are specific to human prostate tumor cells. The present invention further provides chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, and antibodies which bind to the polypeptides of the present invention. Also provided herein are methods for producing the polypeptides of the present invention, as are detection assays that detect the presence of tumor cells in tissue or bodily fluid samples and methods for identifying novel compositions which modulate the activity of prostate tumor antigens and the use of such compositions in diagnosis and treatment of disease.
February 27, 2001 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu Immunostimulatory method. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.
December 7, 1999 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu
Immunostimulatory compositions. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.