MICA: Immunotherapy for oral cancer prevention and treatment

在世界范围内，口腔癌（OSCC）是第八大最常见的癌症，也是全球主要的健康问题，全球每年的发病率约为39.8万，死亡人数超过22.2万。OSCC通常难以治疗；手术和放疗仍然是标准的治疗方法，但尽管有所改善，但与显著的发病率和相对稳定的约50-60%的5年生存率相关。约15-80%的OSCC由前体病变（OPL）发展而来，最常见的是白色斑块（白斑）。目前确定白斑管理的金标准是异常增生的病理诊断，据报道严重异常增生的转化率为24.1%。目前，唯一有效的治疗方法是手术切除。然而，研究表明，这不太可能降低复发或恶性变化的风险。很明显，对于癌前病变和已建立的OSCC都需要更有效的治疗。免疫疗法是几十年来最有前途的新癌症疗法。这些治疗方法利用病人免疫系统的力量来对抗癌症，就像免疫系统对抗病毒一样。癌症被免疫系统识别为“外来”，因为它们表达的蛋白质（抗原）通常在正常组织中找不到。有些病人对癌症有很强的免疫反应；这可以在肿瘤组织中看到免疫细胞（淋巴细胞）攻击癌细胞。然而，大多数癌症不能被免疫系统很好地识别，免疫系统需要刺激才能做出反应。如果我们识别出癌细胞上的异常蛋白质，那么我们就可以设计出针对这些抗原的疫苗来产生针对癌细胞的免疫反应（就像针对病毒的疫苗一样）；最近的研究表明，宫颈的癌前病变可以通过接种疫苗成功清除。这种类型的癌症是由一种病毒（人类乳头瘤病毒）引起的，疫苗是针对病毒蛋白质设计的。相比之下，在大多数癌症和癌前病变中，靶向抗原是未知的。该建议旨在确定在OPL和OSCC中表达的常见肿瘤相关抗原（TAA；癌睾丸抗原和其他抗原），作为开发治疗和预防这种疾病的疫苗的治疗策略的一部分。癌睾丸抗原的表达已经在OPL中被描述，马来西亚癌症研究（CRM）团队的初步工作已经确定了两种抗原，MADGED4B和FJX1，它们通常在OPL和OSCC中表达。我们将扩展这一分析，检查不典型增生病例中的整体基因表达，并使用OSCC识别常见的肿瘤抗原，重点关注那些在疾病过程早期发现的抗原，在癌症发展之前。我们将使用南安普顿大学团队（UoS）开发的一种新型疫苗设计来使用这些抗原制造疫苗，并在人源化的小鼠癌症模型中进行测试。这种疫苗基于一种植物病毒，它能产生与人类病毒类似的强大免疫反应；但它安全、廉价且易于在工厂中大量生产。这对马来西亚等中低收入经济体很有吸引力，因为那里的OSCC特别普遍，但许多患者无法获得常规治疗。一种具有成本效益的疫苗策略可以在癌症发展之前针对OPL并治疗OSCC，这将改变全球对这种疾病的管理。

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.