vectors, rDNA
Panvac-VF; Panvac-V (inalimarev) plus Panvac-F (falimarev); rV-CEA(6D)-TRICOM plus rF-CEA (6D)-TRICOM; vaccinia virus expressing carcinoembryonic antigen (CEA), mucin-1 (MUC-1) tumor antigens and costimulatory B7-1, ICAM-1 and LFA-3 (TRICOM), plus fowlpox virus expressing B7-1, ICAM-1 and LFA-3 (TRICOM), recombinant
Status: abandoned in 6/2006, then in late development
Organizations involved:
Therion Biologics Corp. – Manuf.; R&D; Tech.; World mark.
National Cancer Institute (NCI) – R&D; Tech.
National Institutes of Health (NIH) – Parent
Boehringer Ingelheim Pharma KG – Tech.
Description: Panvac-VF refers to two formulations containing two live recombinant poxvirus vectors each expressing tumor and immune response-boosting antigens plus costimulatory proteins, with one vector used to prime the immune system and the other subsequently boosting immune responses. The priming vector, Panvac-V (inalimarev; rV-CEA(6D)-TRICOM), is composed of a live vaccinia virus vector, New York Board of Health strain (NYBH, the same strain used in vaccinia vaccines, e.g., Dryvax and ACAM2000; see related entries) transformed with human genes for expression of two tumor antigens, carcinoembryonic antigen (CEA), a tumor antigen, and mucin-1 (MUC-1), plus three immune stimulatory proteins (termed TRICOM) - B7.1, intercellular adhesion molecule 1 (ICAM-1) and LFA-3. The boosting vector, Panvac-F (falimarev; rF-CEA(6D)-TRICOM), is composed of a live NYVAC fowlpox virus vector transformed with genes for CEA and MUC-1, plus TRICOM (B7-1, ICAM-1 and LFA-3). Virus for both vaccines is cultured in primary chicken embryo dermal cells. The genome size of both vectors is approximately 290,000 ± 50,000 base sequences (290 ± 50 Kb).
rV-CEA(6D)-TRICOM is packaged in glass vials at a titer of 1.75 x 108 pfu/0.3 mL; and rF-CEA(6D)-TRICOM is packaged in glass vials at a titer of 4.2 x 108 pfu/0.3 mL. For administration, each vaccine is diluted with normal saline to a total of 750 L, and 500 L is withdrawn into two Bioject syringes. The vaccines are administered over several months.
The patient receives an initial “priming” dose with Panvac-V, intended to initiate immune response, followed by a series of “booster” vaccinations with Panvac-F to sustain immune responses.
Nomenclature: Cancer vaccine, poxvirus vectors, rDNA [BIO]; Panvac-VF [TR]; Panvac-V [TR for component]; Panvac-F [TR for component]; inalimarev [SY for Panvac-V]; falimarev [SY for Panvac-F]; vaccinia virus expressing carcinoembryonic antigen (CEA) and mucin-1 (MUC-1) tumor antigens, plus fowlpox virus expressing CEA and MUC-1, recombinant [SY]; rV-CEA(6D)-TRICOM [SY for Panvac-V]; rF-CEA(6D)-TRICOM [SY for Panvac-F]
Biological.: Panvac-VF acts to specifically target immune cells, particularly cellular immune responses, to tumor cells expressing carcinoembryonic antigen (CEA) and mucin-1 (MUC-1). These antigens are found on over 90% of pancreatic tumor cells. Panvac-VF and Panvac-F are administered via subcutaneous injection in a “prime-boost” fashion, first employing the vaccinia virus vector as the priming vaccine, followed by sequential booster doses with the fowlpox vector. The vaccines each also incorporate TRICOM, Therion’s proprietary triad of costimulatory molecules (B7.1, ICAM-1 and LFA-3), designed to enhance and sustain targeted immune responses.
Panvac-VF was developed based on the theory that a T-lymphocyte (T-cell)-mediated immune response can target and destroy cancer cells expressing specific tumor-associated antigens. Tumor cells express a variety of tumor-associated antigens (or proteins). Normally, these tumor antigens do not trigger an immune response in the patient. Panvac-VF is intended to teach the immune system to recognize specific antigens and generate a cellular immune response to recognize and attack cancer cells. For pancreatic cancer, Panvac-VF targets the tumor antigens CEA and MUC-1. The comparable fowlpox virus vector, Panvac-F, boosts and sustains immune responses to the priming antigens.
Companies.: Panvac-VF was commercially developed and will be manufactured by Therion Biologics Corp. (originally Applied bioTechnology, Inc.).
The National Cancer Institute (NCI), National Institutes of Health (NIH), discovered, conducted early studies and collaborated with Therion for development of Panvac-VF (and also Prostvac, a prostate cancer vaccine), including conducting many of the product’s and components’ clinical trials. The NCI’s primary investigators were Drs. Jeffrey Schlom and Steven A. Rosenberg.
In June 2006, with PANVAC-VF having failed in its pivotal Phase III trial, development was halted, and Therion announced that the company was for sale.
FDA class: Biologic BLA
Status: Therion expected to file a BLA in late 2006. FDA granted orphan status for pancreatic cancer in Feb. 2006.
Therion conducted its pivotal, randomized, controlled Phase III trial for Panvac-VF under the guidance of a Special Protocol Assessment (SPA) from FDA. The SPA indicated that, if the trial successfully mes its primary endpoint of overall survival, the data would provide the basis for an efficacy claim in a BLA for PANVAC-VF.
On June 28, 2006, Therion announced that PANVAC-VF failed to meet its primary endpoint in its pivotal Phase III trial, further development was halted, and the company placed itself on the market for sale.
Tech. transfer: Therion has obtained licenses from the National Institutes of Health (NIH) including exclusive worldwide rights under 21 patents and patent applications related to immunotherapy and cancer vaccines. These cover technologies, methods of use, and specific vaccines developed in conjunction with the company’s two Cooperative Research and Development Agreements (CRADAs) with the National Cancer Institute (NCI). CRADA CACR #0220, ‘Development of Recombinant Cancer Vaccines,” between Dr. Schlom, NCI, and Dr. Panicali, Therion, began in Sept. 1994. Earlier, in June 1992, NCI awarded Therion a Master Agreement (CRADA-like contract) for the development and manufacture of cancer vaccines for testing and trials by NCI.
Licensed NIH patents included coverage for recombinant poxvirus vectors incorporating CEA for immunization against CEA-expressing cancers and melanoma; multiple co-stimulatory molecules and specific cancer antigens used in conjunction with Therion’s virus vectors; modified costimulatory peptides/proteins used in combination with recombinant poxvirus-based vaccines. NIH-assigned patents include U.S. 6,893,869; 6,548,068; and 6,045,802, each entitled, “Enhanced immune response to an antigen by a composition of a recombinant virus expressing the antigen with a recombinant virus expressing an immunostimulatory molecule,” including claims covering poxvirus vectors expressing tumor antigen(s), e.g., CEA and MUC-1, and immunostimulatory molecules, e.g., B7-1; and 5,698,530, “Recombinant virus expressing human carcinoembryonic antigen and methods of use thereof.” Panvac-VF-related patents coassigned to Therion and NIH include U.S. 6,319,496 and 6,001,349, “Generation of human cytotoxic T-cells specific for carcinoma self-associated antigens and uses thereof;” and 6,969,609, “Recombinant vector expressing multiple costimulatory molecules and uses thereof.”
Therion nonexclusively licensed ICAM-1 from Boehringer Ingelheim Pharma KG for use in its vaccines in Sept. 2002. Therion has the rights to develop, manufacture and commercialize oncology and infectious disease product candidates incorporating the ICAM-1 co-stimulatory molecule. In return, Therion paid an upfront licensing fee, along with milestone payments and royalties based on product sales.
Virogenetics, Inc., now merged into Sanofi Pasteur Inc., has pioneered development of a number of vaccinia and other poxvirus vectors, and may have licensed relevant technology to Therion, or may allege infringement as commercialization approaches.
Trials: Therion’s poxvirus vector technology platform has been evaluated over a 13-year period in more than 30 clinical trials comprising close to 1,000 patients. This has mostly been through Therion’s partnership with the NCI, NIH, in trials conducted by NIH.
The randomized, controlled pivotal Phase III trial for Panvac-VF to treat metastatic pancreatic cancer patients completed enrollment in Feb. 2006. The trial compared Panvac-VF in combination with granulocyte/macrophage colony stimulating factor (GM-CSF; Prokine; see related entry) vs. best supportive care or palliative chemotherapy (investigator’s choice) in 255 patients with metastatic (Stage IV) adenocarcinoma of the pancreas and having failed a gemcitibine-containing chemotherapy regimen. Panvac-V (priming) was administered on Day 0; and Panvac-F (boosting) was administered at week 2, 4, 6, 8, 12, 16, and every 4 weeks thereafter. The primary endpoint was overall survival. A logrank test would compare this in the vaccine arm in combination with GM-CSF vs. both best supportive care and palliative chemotherapy. Secondary endpoints were quality of life parameters; changes in serum CEA and CA19-9 levels (decrease in circulating tumor antigens); response rate; and safety.
On June 28, 2006, Therion reported that PANVAC-VF failed to meet its primary endpoint in its pivotal trial. Therion had previously announced that a Phase II randomized, double-blind, placebo-controlled trial for advanced prostate cancer had not met its primary efficacy endpoint of improving progression-free survival with PROSTVAC-VF treatment. However, preliminary data suggested that PROSTVAC-VF was associated with a potential reduction in mortality compared to placebo.
PANVAC-VF continues in studies sponsored by the National Cancer Institute (NCI) for the treatment of advanced ovarian, colorectal, and non-small cell lung cancers.
Disease: About 32,000 patients annually in the U.S. are diagnosed with pancreatic cancer, and over 31,000 patients annually die from the disease. Pancreatic cancer is one of the most difficult cancers to treat. Historical control data suggest a median overall survival in advanced-stage patients of approximately three month. Current treatments include surgery, chemotherapy, and radiation. However, pancreatic cancer is very difficult to treat with available therapies. More than 95% of pancreatic cancer patients die from the disease.
Index Terms:
Companies involvement:
Full monograph
111 Cancer vaccine, poxvirus
Nomenclature:
Cancer vaccine, poxvirus vectors, rDNA [BIO]
Panvac-VF [TR]
Panvac-F [TR for component]
Panvac-V [TR for component]
falimarev [SY for Panvac-F]
inalimarev [SY for Panvac-V]
rF-CEA(6D)-TRICOM [SY for Panvac-F]
rV-CEA(6D)-TRICOM [SY for Panvac-V]
vaccinia virus expressing carcinoembryonic antigen (CEA) and mucin-1 (MUC-1) tumor antigens, plus fowlpox virus expressing CEA and MUC-1, recombinant [SY]
FDA Class: Biologic BLA
BHK-21 (C-13)
cancer treatment adverse effects
potato medium, glycerinized
recombinant DNA
vaccines, intranasal
carcinoembryonic antigen (CEA)
chicken embryo (egg) culture
Costar cubes
Fourth Intl. Standard (WHO 88/804) for Factor VIII
MRC5 cellular proteins
neutropenia
potato medium, glycerinized
tri-n-butyl phosphate (TNBP)
vaccinia virus vaccine
virus culture
virus culture
North American coral snake
North American coral snake
octoxynol (Triton X-100)
Sp2/0 murine hybridoma/myeloma cells
EU000 Not yet/Never filed with EU
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
EM999 Not Available/Not Marketed in EU
Copyright© 2020, Biotechnology Information Institute