Ovarian cancer represents the sixth most commonly diagnosed cancer among women worldwide and causes more deaths per year than any other cancer of the female reproductive system (Permuth-Wey 2009). The median age at diagnosis is 58 years with 90% of diagnoses occurring in women over the age of 40 years.
Epithelial ovarian cancer is the fifth leading cause of cancer death among women in the United States and Northern and Western Europe and is the leading cause of death from gynecological cancer (Runnebaum 2001). Standard management of ovarian cancer involves surgery followed by chemotherapy. One study found the mean age adjusted 5-year survival for ovarian cancer to be 36.3% (Berrino 2007). Despite the high incidence and mortality rates, the etiology of this disease is poorly understood. There is a clear need to develop novel approaches to treatment to increase the survival of patients.
The CVac™ cancer vaccine approach stimulates the patient's own immune system to target and destroy tumours.
CVac™ is a cancer vaccine product consisting of an adjuvant, mannan, attached to a tumour cell surface protein, mucin 1. The product is known as MFP or mannan fusion protein. The treatment is patient-specific and delivered to patients via autologous dendritic cell therapy. The patient's dendritic cells are isolated from their blood after which MFP is mixed with the cells so as to introduce the protein mucin-1 into and expressed on the surface of the cells.
Dendritic cells are a subset of white blood cells whose primary role is to educate the immune system to recognise infection and cancer. When the dendritic cell encounters foreign material it generates a recognition signal and triggers the immune system to respond by activating another subset of blood cells called cytotoxic or killer T cells. These cells then respond by killing the foreign material.
Manipulating the dendritic cells outside of the patient's own body allows the cells to overcome the evasive mechanisms of the tumour and the immune system is educated to recognise and fight the tumour.
At Prima BioMed the tumour antigen being targeted is called mucin-1. This is a molecule expressed by a variety of tumours including breast, ovarian, prostate, lung and colon cancers. Mucin-1 is expressed by normal tissue in the body but changes conformation on tumour cells so the immune response will be specific to the tumour tissue and will not damage normal tissue. We also use a proprietary immune adjuvant called mannan (oxidised mannose). Mannan assists in activating the immune system and ensures preferential expression of the production of killer T cells that will target mucin-1.
Dendritic Cell Therapy offers a number of advantages over other practised and experimental treatments for cancer. First, by targeting a protein that sits on tumour cells in a form not on normal cells, the side effects are minimal which is in stark contrast to cytotoxic agents which kill cells indiscriminately. Second, the process activates the immune system to recognise the tumour and once the immune system is activated it will continue to fight the tumour, unlike antibody based therapies that need to be administered at frequent intervals to affect tumours.
Dendritic cells can be isolated from a cancer patient and manipulated to trigger recognition of a cancer by T cells. Isolation of the dendritic cells from the blood takes place via a process not dissimilar to donating blood, called leukopheresis. Once the dendritic cells have been removed from the patient they are then manipulated in the laboratory to express a tumour associated protein or antigen. These cells are then injected back into the cancer patient where they activate the killer T cells to fight the tumour. Tumours have sophisticated mechanisms of avoiding the cells and thus evade the immune system. This evasion allows tumours to grow.
A successful phase I trial was completed which examined the safety of the product in patients with various adenocarcinomas. All patients produced an immune response to the product. A phase IIa study was completed in May 2006 with final results reported in March 2007. CVac™ demonstrated a positive clinical response or stabilisation of disease in four of the 21 patients, based on changes in CA125.
A third trial is ongoing in the US and Australia and recently to completed enrollment. A pivotal study is planned to commence enrollment, initially recruiting in Australia and subsequently in the US and Europe.