Data from a Phase I investigator-sponsored trial of the investigational cancer vaccine vitespen (Oncophage®, Antigenics Inc, 3 Forbes Rd, Lexington, MA 02421), an investigational patient-specific vaccine designed to treat cancer with the intent of minimizing adverse events of toxicities in recurrent, high-grade glioma, showed a considerable survival advantage for patients with this disease.
Vaccination with the new cancer vaccine following brain cancer surgery increased overall median survival to approximately 10.5 months with four patients surviving beyond 12 months and one patient surviving almost 2.5 years. This is compared to a historical median survival of only 6.5 months post surgery. All patients enrolled into the trial had at least one recurrence of brain cancer.
The trial was conducted at the Brain Tumor Research Center at the University of California, San Francisco, CA, a center which is internationally recognized as a major research and treatment center for adults and children with tumors of the brain and spinal cord. The data was presented in November 2008 during the Society for Neuro-Oncology’s 13th Annual Scientific Meeting in Las Vegas.
‘These are the most challenging patients to treat because their survival is typically three to six months,’ explained Andrew T. Parsa, MD, PhD, associate professor in the department of neurological surgery at the University of California, San Francisco. ‘These preliminary results suggest a possible impact on survival as well as a very favorable safety profile.’
In addition to survival data, the study also observed a correlation between immune response and overall survival as a result of vaccination with vitespen (n=12; P < .001). These responses were validated by using three separate immune techniques and showed that vitespen evoked a tumor-specific immune response by producing activated T-cells and natural killer cells that can destroy tumor cells. ‘Gliomas develop built-in immunoresistant pathways which play an important role in tumor progression,’ Parsa explained. ‘This study demonstrated significant tumor-specific immune responses leading to a proliferation of T-cells which did not exist in these patients before vaccination with Oncophage. We look forward to completing the Phase II portion of this study and presenting results next year.’
Study Design and Findings
This investigator-sponsored Phase I/II study was designed to evaluate the feasibility, safety and activity of vaccination with vitespen in patients with recurrent, high-grade glioma. Patients were monitored for immune response before and after vitespen treatment using three different techniques.
According to investigators, no adverse events or toxicities identified were considered attributable to the vaccine. A tumor-specific immune response was detected after vaccination in all 12 patients.
Current Regulatory Status
Vitespen is approved in Russia for the adjuvant treatment of kidney cancer patients at intermediate risk for disease recurrence. Outside Russia, vitespen is being evaluated in clinical trials. The drug has been granted fast track and orphan drug status from multiple regulatory bodies, including the US Food and Drug Administration and the European Medicines Agency (EMEA), for the treatment of renal cell carcinoma and metastatic melanoma.
Gliomas are the most common type of brain tumor and is currently a fatal disease impairing areas such as thinking, personality and movement. The National Cancer Institute estimates that about 19,000 cases are diagnosed every year in the U.S and according to historical estimates, the median survival of patients with previously treated glioma is typically three to six months.
The outlook for patients with gliomas is generally poor. The median survival for patients with moderately severe or grade III gliomas is 3 - 5 years. The median survival for patients with grade IV glioma, the most severe and aggressive form of the disease also called glioblastoma multiforme, is less than a year.
Vitespen offers a unique, personalized, opportunity for the treatment of individual patients.
Derived from each individual’s tumor, the vaccine consists of purified complexes of tumor-derived HSPs linked to tumor antigen peptides which consists the ‘antigenic fingerprint’ of the patient’s particular cancer. This ‘antigenic fingerprint’ is designed to reprogram the body’s immune system to target only cancer cells bearing this specific fingerprint.
When these purified complexes are re-administered to a patient antigenic tumor peptides are expressed on the surface of potent antigen-presenting cells of the immune system, such as macrophages and dendritic cells. This stimulates a more powerful anti-tumor immune response than that generated by expression of the same antigens by the tumor cell. The result is that activated T-cells directly target and destroy cancer cells bearing the specific ‘fingerprint’.
Vitespen is designed to target only cancerous cells and to leave healthy tissue unaffected. As a result, vaccination with this cancer drug limits the toxicities and debilitating side effects typically associated with traditional cancer treatments such as broad-acting cancer chemotherapy and radiation therapy.
Mode of Action
Heat-shock proteins (HSPs) also called stress proteins, are the most abundant and ubiquitous soluble intracellular proteins. They are present in all cells in all life forms and induced when a cell undergoes various types of environmental stresses like heat, cold and oxygen deprivation.
Despite the obvious importance of stress responses, heat shock proteins have only recently been examined for the role they play in the control of disease pathology and in the survival and virulence of pathogens. For example, research has shown that a number of heath shock proteins protect against oxidative damage, conveys peptide antigens for presentation to the immune system, and can protect against cardiac failure.
Various forms of heat shock proteins are involved in binding and stabilizing proteins at intermediate stages of folding (essential for protein function), assembly and translocation and degradation. They interact with antigen-presenting cells (APCs) through CD91 and other receptors, eliciting a cascade of events that includes representation of HSP-chaperoned peptides MHC, translocation of NF-kappaB into the nuclei, and maturation of dendritic cells. The key role heath shock proteins play in fundamental immunologic phenomena allow them to be used for immunotherapy of cancers and infections in new and exciting ways.