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DR. BUTTS: MUC-1 is a glycoprotein present on the luminal surfaces of many normal epithelial cells (although also present on myeloma and plasma cells) that has been identified as an important target for vaccine development, especially in patients with lung cancer. It is a long branched-chain carbohydrate that has a long extracellular component with an amino acid backbone and branched-chain carbohydrate side chains. Also present are an anchoring cell membrane component and an intracellular component that may have tyrosine kinase activity or may interact with other intracellular proteins. It is often one of the first substances that an immune effector cell might encounter.
MUC-1 possesses many key features of an ideal tumor antigen.
In cancer cells, MUC-1 is expressed over the entire cell surface. In malignant cells, the branched-chain carbohydrate becomes truncated and exposes the protein backbone. It becomes like a neoantigen.
MUC-1 possesses many key features of an ideal tumor antigen. It is expressed on tumor cells—not confined to the tumor cells, but significantly different in tumor cells as opposed to normal cells. It is broadly expressed—more than 80% of tumor cells, in general, express MUC-1; probably 60% or more of NSCLCs express MUC-1.23
It is expressed in sufficient levels or, in fact, overexpressed on many cells. It is expressed in metastatic cells as well as in primary tumors. It seems to play a role in tumorigenesis, such that if the pathway can be interrupted, the overall tumorigenic process may be affected. Most importantly, multiple studies show that MUC-1 is an immunogenic antigen in humans
For the L-BLP25 vaccine, the antigen is the entire 20 amino acid tandem repeat segment of the MUC-1 protein backbone. It uses an adjuvant for the source of cytokines, monophosphoryl lipid A, which is a nonspecific immune stimulant that may affect toll-like receptors as well. The delivery system is a liposomal formulation, which is thought to enhance delivery to immune effector cells.
The clinical development of L-BLP25 has occurred primarily in the lung cancer arena. Its safety, as well as schedule and dose, were established in phase I and II trials. The main trial of interest is the phase IIB trial, which was an open-label, randomized, multicenter trial of the vaccine in patients with stage IIIB/IV NSCLC who responded or had stable disease to first-line lung cancer therapy, whether chemotherapy alone or chemoradiation.24 Eligible patients were randomized to best supportive care or the vaccine plus best supportive care. If disease progressed, patients were eligible for second-line treatment. The primary endpoints were efficacy (survival) and safety, and secondary endpoints included health-related quality of life and the immune response elicited by the vaccine as assessed by the MUC-1 proliferative T-cell response. Tumor responses were not expected and therefore were not measured.
The vaccine strategy incorporated a single dose of cyclophosphamide, 300 mg/m2, given 3 days before the initiation of the L-BLP25 vaccine. Previous trials have shown that cyclophosphamide enhances the immune response as measured by DTH and antibody production.25,26 The vaccine was given subcutaneously at a standard dose of 1,000 µg once weekly for 8 weeks as an induction phase. Patients who were considered to have stable disease were eligible for a maintenance phase of vaccine therapy, which employed the same dose as the induction phase, but was given once every 6 weeks. Patients continued on the vaccine until disease progression.
A total of 171 patients was enrolled in the study at 17 centers in Canada and the United Kingdom over a 2-year period. Demographics were comparable in the 2 patient groups. About 95% of patients had performance status of 0 or 1; more than 95% had received standard first-line platinum-based chemotherapy. Of the patients, 35% had stage IIIB or local regional disease, and 65% had either pleural effusions or stage IV disease.
Overall, the 2-year survival rate was 43.2% for the L-BLP25 arm vs 28.9% for the best-supportive-care arm, and the median overall survival time for patients in the L-BLP25 arm was 17.2 months compared with 13.0 months in the best-supportive-care arm. The greatest survival difference was noted in patients with stage IIIB locoregional disease, in whom survival was longer for those randomly assigned to the L-BLP25 arm compared with the best-supportive-care arm (Figure 3). At 34 months, the survival rate was 48.6% for the L-BLP25 arm vs 26.7% for the best-supportive-care arm, and median survival was 30.6 months among the L-BLP25 vaccine recipients compared with 13.3 months among those in the best-supportive-care group. No clinically significant survival advantage was noted in patients with stage IIIB pleural effusion or stage IV disease.
No significant toxicity was associated with the L-BLP25 vaccine, and quality of life was maintained longer in patients who received the vaccine.
Planning for a phase III trial of the L-BLP25 vaccine is nearing completion. It is a double-blind, placebo-controlled trial of L-BLP25 vaccine in patients with unresectable stage III NSCLC, with planned enrollment of over 1,300 patients. The primary endpoint will be overall survival; secondary endpoints include time to symptom progression, time to tumor progression, and safety. The study will also include a cost-effectiveness evaluation.
Medical Oncologist
Cross Cancer Institute
Edmonton, Alberta, Canada
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Pedro Romero, MD
Håkan Mellstedt, MD, PhD
David Carbone, MD, PhD
David Jablons, MD
Charles A. Butts, MD
Philip Bonomi, MD
Survival in patients with stage IIIB locoregional NSCLC who received L-BLP25 vaccine (Stimuvax). Graph is from the final analysis (unpublished), with permission from Charles Butts, MD.
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Clinical Development of L-BLP25 (Stimuvax®) Vaccine for Lung CancerCharles A. Butts, MD |
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