HOW THERATOPE WORKS
Cancer Immunotherapy Using Carbohydrate (THERATOPEƒ) and Peptide-Based (MUC1 Derived) Synthetic Vaccines
The human MUC1 mucin is a member of the mucin family of large, highly glycosylated proteins that are 50-80% carbohydrate. It is expressed on the surface of a number of both normal and malignant epithelial cells and contains a polypeptide core consisting of 30-100 tandem repeats of a 20 amino acid sequence. MUC1 is expressed on cancers of the breast, stomach, pancreas, colon, prostate, ovary, non small cell lung, renal and bladder. Cancer-associated MUC1 is overexpressed and underglycosylated (truncated carbohydrates) making it an excellent target for immunotherapy. The incomplete glycosylation in cancer cells exposes the peptide core and thus provides tumor-specific epitopes.
Biomira has developed synthetic cancer vaccines that are directed at either the truncated carbohydrates or the peptide core of MUC1 mucin. The THERATOPEƒ vaccine consists of synthetic STn conjugated to a protein carrier, KLH which itself is a potent immunogen. STn is a naturally occurring truncated carbohydrate found on MUC1 that is expressed on many cancer cells, and is associated with aggressive disease and poor prognosis. The vaccine is administered initially in conjunction with Detox„-BSE as an adjuvant. In addition, patients are treated with a single low dose of cyclophosphamide prior to the first vaccination with THERATOPEƒ vaccine.
The THERATOPEƒ vaccine has been tested in over 400 patients with adenocarcinomas of the breast, ovary, colon and pancreas. These previous studies have demonstrated the safety of the vaccine and its ability to generate in patients a T-cell dependent antibody response against natural (OSM) and synthetic cyclophosphamide and THERATOPEƒ as compared to frequency matched retrospective control group. There was also an association between improved survival and IgG antibody responses to OSM, a natural mucin expressing clustered STn. In addition, data was collected from patients receiving high dose chemotherapy followed by THERATOPEƒ vaccination. Immune analyses were conducted which demonstrated that the THERATOPEƒ vaccine was able to induce a cellular immune response as well as induce an antibody response in these patients.
Currently Biomira is preparing for a 950 patient double-blinded, randomized, controlled Phase III clinical trial of the THERATOPEƒ vaccine in metastatic breast cancer patients. Patients entering the trials will have completed first-line chemotherapy for metastatic breast cancer, and have either no evidence of disease or have non-progressive disease. Patients will be stratified upon entry following first-line chemotherapy (no evidence of disease [i.e. complete response] or non-progressive disease [i.e. partial response, minor response or stable disease]). The primary endpoints are time to disease progression and survival. Safety, antibody production and health-related quality of life will also be analyzed as secondary endpoints. This study will be conducted at sites in North
America, the United Kingdom and central Europe and will commence in 4Q98.
BLP25 is Biomira?s therapeutic vaccine directed against the peptide core of the MUC1 mucin. The vaccine consists of a 25 amino acid lipopeptide whose sequence is from the polypeptide core of MUC1 and lipid A in a liposomal delivery system. This vaccine was designed to elicit an antigen specific cellular immune response against MUC1. The liposomal delivery system was designed to enhance intracellular uptake of the vaccine by antigen presenting cells leading to generation of cytotoxic T cells. In pre-clinical studies in mice, BLP25 has elicited Th1 responses against MUC1 and has been shown to have penetrative and therapeutic activity against murine lung metastases expressing human MUC1.
A Phase I open label, controlled study to test the safety and immunogenicity for active specific immunotherapy with BLP25 Liposome vaccine for the treatment of patients with stage IIIb or stage IV non small cell lung cancer has recently started at the Cross Cancer Institute in Edmonton, Canada. This study will test the safety and immunogenicity of the vaccine at two different doses (20 and 200 ug). Both antibody and cellular responses against MUC1 will be examined. |
