Prostvac; prostate-specific antigen (PSA) vaccine; vPSA-TRI; vaccinia-PSA-TRICOM/Fowlpox-PSA-TRICOM; vaccinia virus vector expressing prostate-specific antigen (PSA) and TRICOM, consisting of three co-stimulatory molecule transgenes B7.1, ICAM-1, and LFA-3, with co-administration of plus granulocyte-macrophage colony-stimulating factor (GM-CSF), followed by fowlpox virus vector expressing prostate-specific antigen (PSA) and TRICOM, recombinant
Status: BLA filing expected
Organizations involved:
Bavarian Nordic – Manuf.; R&D; Tech.; World mark.
National Cancer Institute (NCI) – R&D; Tech.
National Institutes of Health – Parent
Description: Prostvac is a therapeutic (not prophylactic) prime-boost prostate cancer vaccine regimen consisting of two antigen-bearing poxvirus vectors - a live (replication-competent) recombinant vaccinia virus (smallpox vaccine-based) vector as a primary vaccination with granulocyte-macrophage colony stimulating factor (GM-CSF; Leukine from Genzyme), followed by multiple booster vaccinations employing a non-replicating recombinant fowlpox vector bearing the same antigens. The poxvirus vectors encode/express human prostate-specific antigen (PSA) with a single alteration in HLA-A2 epitope at position 155, plus T-cell co-stimulatory molecules (TRICOM) -- B7.1, intercellular cell adhesion molecule-1 (ICAM-1), and lymphocyte function-associated antigen-3 (LFA-3).
The replication-competent (live) vaccinia vector was derived from Dryvax from Wyeth (see related entry) and has a molecular weight of about 200 kDa. Unlike Dryvax and other poxvirus vectors, there is no local scarring with this vector, and subcuteneous administration is considered safe and effective.
Unlike Provenge (see related entry), PROSTVAC is an off-the-shelf vial vaccine that does not require complex individualized therapy or manufacture.
Nomenclature: Prostate Cancer Vaccine, Poxvirus Vectors (rDNA) [BIO]; Prostvac [TR]; vaccinia-PSA-TRICOM vaccine/ fowlpox virus-PSA-TRICOM vaccine [SY]; vPSA-TRI [SY]
Biological.: PSA-TRICOM vaccines infect antigen-presenting cells (APCs) and generate proteins that are expressed on the surface of the APCs in an immune context. The interaction of these APCs with T cells initiates a targeted immune response and T cell-mediated tumor cell destruction.
PROSTVAC contains a tumor-associated antigen which is more immunogenic or more likely to cause an immune response than native PSA, because Bavarian Nordic altered its amino acid structure slightly.
PROSTVAC is administered subcutaneously and induces a specific, targeted immune response that attacks the cancerous cells in the prostate. Vaccination with PSA in combination with TRICOM enhances antigen presentation, resulting in the augmentation of a cytotoxic T cell (CTL) immune response against tumor cells expressing PSA.
PROSTVAC works by stimulating an immune response against prostate tumors through multiple mechanisms. PROSTVAC targets a unique cancer cell antigen, prostate-specific antigen (PSA), rarely present on normal cells. PSA can be found circulating in the blood, as well as on prostate cancer cells, and PSA assays are used in prostate cancer diagnosis. PSA generally is present in small amounts in men who do not have cancer, but the quantity of PSA generally rises as prostate tumors develop. The higher a man's PSA level is, the more likely it is that cancer is present, but there are many other possible reasons for an elevated PSA level.
Poxviruses efficiently infect a wide range of host cells and confer high level gene expression of transgenic PSA. The inclusion of TRICOM further increases immunogenicity of PSA vaccination, including increases in number and particularly avidity of T-cell responses. Advantages of using poxviral over other viral vectors include the large size of the genomes, which allows transgenes to be expressed in vaccinia virus vectors, as well as greater immunogenicity of expressed proteins compared to native proteins, attributed to the inflammatory response triggered against highly immunogenic poxviral proteins. [Live vector vaccines are generally more potent or effective than other types of vaccines].
Companies.: Prostvac was exclusively licensed by Bavarian Nordic from the National Cancer Institute (NCI), National Institutes of Health (NIH), with much development done under a Cooperative Research and Development Agreement (CRADA) between the organizations. Preclinical and clinical research were performed in collaboration with the NCI. Prostvac is manufactured by Bavarian Nordic.
FDA class: Biologic BLA
Status: In Oct. 2009, Bavarian Nordic requested advice from EMA (EMEA), European Union. The Final Adopted Advice provided in Dec. 2009 was in general agreement with the proposed clinical program that was presented. Bavarian Nordic has also held a post-Phase II meeting with FDA.
From these meetings, the preferred Phase III program (at least for the U.S.) would involve a single, large, randomized, double-blind, placebo controlled 3-arm trial (PROSTVAC + GM-CSF; PROSTVAC + Placebo; Placebo + Placebo). Each PROSTVAC arm would be compared against placebo arm. Approval could be based on significance of one arm. The company woud also request a Special Protocol Assessment (SPAO and Fast Track status. The Phase III protocol would exclude patients eligible for chemotherapy (e.g., patients with rapidly rising PSA). The target patient population would be asymptomatic/minimally symptomatic patients with metastatic castration-resistant prostate cancer.
Tech. transfer: The National Cancer Institute (NCI), NIH, has received a number of patents concerning vaccinia and other poxvirus vectors, particularly for cancer vaccines. [Full discussion of patents will be included upon approvals (or rejections)].
Medical: PROSTVAC is given as monthly injections starting with a Vaccinia-PSA-TRICOM priming dose and followed by 6 monthly Fowlpox-PSA-TRICOM boosts. PROSTVAC is intended for use in patients whose disease has recurred after surgery or radiotherapy – fulfilling an unmet medical need. The can extend the lives of men with advanced prostate cancer where limited treatment options are available - without affecting their quality of life.
Market Prostvac will compete with Provenge (and other products) for prostate cancer treatment.
Trials: In clinical trials to date PROSTVAC(TM) and related PSA containing poxviral vaccines have been investigated in more than 500 patients for 10 years. Phase II results from a study of 125 patients with metastatic prostate cancer showed that patients receiving PROSTVAC had a statistically significantly longer median overall survival by 8.5 months. In contrast, non-specific chemotherapy extends survival by an average of only 2-3 months. PROSTVAC has a very good safety and tolerability profile.
Companies involvement:
Full monograph
242.1 Prostate Cancer Vaccine, Poxvirus Vectors (rDNA)
Nomenclature:
Prostate Cancer Vaccine, Poxvirus Vectors (rDNA) [BIO]
Prostvac [TR]
fowlpox virus-PSA-TRICOM vaccine [SY]
prostate-specific antigen (PSA) vaccine [SY]
vaccinia virus vector expressing prostate-specific antigen (PSA) and TRICOM, consisting of three co-stimulatory molecule transgenes B7.1, ICAM-1, and LFA-3, with co-administration of plus granulocyte-macrophage colony-stimulating factor (GM-CSF), followed by fowlpox virus vector expressing prostate-specific antigen (PSA) and TRICOM, recombinant [SY]
vaccinia-PSA-TRICOM vaccine [SY]
vPSA-TRI [SY]
FDA Class: Biologic BLA
Year of approval (FDA) = Biol
Date of 1st FDA approval = Biologic BLA
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
receptors, tumor necrosis factor-2 (TNFR2)
U.S. Standard Rabies Vaccine
vaccines, viral
DNA, mammalian
Fourth Intl. Standard (WHO 88/804) for Factor VIII
potato medium, glycerinized
Prostate Specific Membrane Antigen (PSMA) monoclonal antibody
vaccines, viral
autologous cells, human
Good Manufacturing Practices (GMP) violations
insulin, recombinant human
leukemia, hairy cell
lymphoblastoid cells, human
suspension cell culture
conjugates
EU001 EU application expected
UM999 Not Available/Not Marketed in US
US001 FDA application expected
EM999 Not Available/Not Marketed in EU
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