MICA: Immunotherapy for oral cancer prevention and treatment

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Worldwide, oral cancer (OSCC) is the eighth most common cancer and a major global health concern, with an annual incidence of around 398,000 and more than 222,000 deaths worldwide. OSCC is often difficult to treat; surgery and radiotherapy remain the standard treatments but, despite improvements, are associated with significant morbidity and a relatively static 5-year survival rate of around 50-60%. Around 15-80% of OSCC develop from a precursor lesion (OPL), most commonly a white patch (leukoplakia). The current gold standard for determining leukoplakia management is pathological diagnosis of dysplasia, with transformation rates of 24.1% being reported in severe dysplasia. At present, the only effective treatment is surgical excision. However, studies indicate that this is not likely to reduce the risk of recurrence or malignant change. It is clear that more effective treatments are required for both premalignant lesions and established OSCC.Immunotherapy represents the most promising new cancer therapy for several decades. These treatments harness the power of the patient's immune system to fight the cancer, in the same way that the immune system might fight a virus. Cancers are recognised by the immune system as "foreign' because they express proteins (antigens) not usually found in normal tissues. Some patients have a strong immune response against their cancer; this can be seen in the tumour tissue as immune cells (lymphocytes) attacking the cancer cells. However, most cancers are not well recognised by the immune system, and the immune system needs to be stimulated to respond. If we identify the abnormal proteins on the cancer cells, then we can design vaccines against these antigens to generate an immune response against the cancer cell (just like vaccinating against a virus); recent studies have shown that premalignant lesions in the cervix can be successfully cleared through vaccination. This type of cancer is caused by a virus (human papillomavirus) and vaccines are designed to target viral proteins. By contrast, in most cancers and premalignant lesions targetable antigens are unknown.This proposal aims to identify common tumour associated antigens (TAA; cancer testis antigens and others) expressed in OPL and OSCC as part of a therapeutic strategy to develop vaccines to treat and prevent this disease. Expression of cancer testis antigens have been described in OPL, and preliminary work by the Cancer Research Malaysia (CRM) team have identified two antigens, MADGED4B and FJX1 that are commonly expressed in both OPL and OSCC. We will extend this analysis, examining global gene expression in cases of dysplasia and with OSCC to identify common tumour antigens, focusing on those found early in the disease process, before cancer develops. We will use these antigens to make vaccines using a novel vaccine design developed by the University of Southampton team (UoS), and test these in a humanised mouse cancer models. The vaccine is based on a plant virus that produces a powerful immune response in a similar way to human viruses; but is safe, cheap and readily mass-produced in plants. This is attractive for low-to-middle income economies such as Malaysia, where OSCC is especially prevalent, but conventional treatment is unattainable for many patients. A cost-effective vaccine strategy that can target OPL before cancer develops and also treat OSCC would transform the management of this disease worldwide.