MICA: Immunotherapy for oral cancer prevention and treatment

MICA：预防和治疗口腔癌的免疫疗法

• 批准号: MR/P024351/1
• 负责人: Christian Ottensmeier
• 金额: $ 77.64万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP024351%2F1
• 关键词: MICA; Immunotherapy; oral; cancer; prevention

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.

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，全球每年发病率约为398，000，死亡人数超过222，000。口腔鳞状细胞癌通常难以治疗;手术和放疗仍然是标准治疗方法，但尽管有所改善，但仍与显著的发病率和相对稳定的5年生存率（约50- 60%）相关。大约15-80%的口腔鳞状细胞癌发展自前驱病变（OPL），最常见的是白色斑（白斑）。目前确定白斑治疗的金标准是异型增生的病理诊断，据报道重度异型增生的转化率为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，对于癌前病变和已确诊的口腔鳞状细胞癌都需要更有效的治疗。免疫治疗是几十年来最有前途的癌症治疗新方法。这些治疗利用患者免疫系统的力量来对抗癌症，就像免疫系统可以对抗病毒一样。癌症被免疫系统识别为“外来的”，因为它们表达的蛋白质（抗原）通常在正常组织中找不到。一些患者对癌症有强烈的免疫反应;这可以在肿瘤组织中看到，因为免疫细胞（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，需要刺激免疫系统才能做出反应。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针对这些抗原的疫苗，以产生针对癌细胞的免疫反应（就像接种病毒疫苗一样）;最近的研究表明，宫颈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病毒（人乳头瘤病毒）引起的，疫苗旨在靶向病毒蛋白。相比之下，在大多数癌症和癌前病变的靶向抗原是unknown.This建议的目的是确定共同的肿瘤相关抗原（TAA，癌睾丸抗原和其他）表达OPL和OSCC作为治疗策略的一部分，开发疫苗来治疗和预防这种疾病。癌症睾丸抗原的表达已在OPL中描述，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MADGED 4 B和FJX 1，它们通常在OPL和OSCC中表达。我们将扩展这一分析，检查异型增生和OSCC病例中的全球基因表达，以确定常见的肿瘤抗原，重点是在癌症发展之前，在疾病过程的早期发现的抗原。我们将使用这些抗原来制造疫苗，使用由南安普顿大学团队（UoS）开发的新型疫苗设计，并在人源化小鼠癌症模型中测试这些疫苗。这种疫苗是基于一种植物病毒，它能产生与人类病毒类似的强大免疫反应;但它安全、廉价，而且容易在植物中大规模生产。这对于中低收入经济体（如马来西亚）具有吸引力，在那里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靶向OPL，也可以治疗OSCC，这将改变全球对这种疾病的管理。

项目成果

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.

• DOI: 10.1016/j.cell.2017.10.001
• 发表时间: 2017-11-30
• 期刊: Cell
• 影响因子: 64.5
• 作者: McGranahan N;Rosenthal R;Hiley CT;Rowan AJ;Watkins TBK;Wilson GA;Birkbak NJ;Veeriah S;Van Loo P;Herrero J;Swanton C;TRACERx Consortium
• 通讯作者: TRACERx Consortium

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss.

• DOI: 10.1016/j.ejca.2017.09.033
• 发表时间: 2017-12
• 期刊: European journal of cancer (Oxford, England : 1990)
• 作者: Crabb SJ;Martin K;Abab J;Ratcliffe I;Thornton R;Lineton B;Ellis M;Moody R;Stanton L;Galanopoulou A;Maishman T;Geldart T;Bayne M;Davies J;Lamb C;Popat S;Joffe JK;Nutting C;Chester J;Hartley A;Thomas G;Ottensmeier C;Huddart R;King E
• 通讯作者: King E

Evaluating the effect of immune cells on the outcome of patients with mesothelioma.

• DOI: 10.1038/bjc.2017.269
• 发表时间: 2017-10-24
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Chee SJ;Lopez M;Mellows T;Gankande S;Moutasim KA;Harris S;Clarke J;Vijayanand P;Thomas GJ;Ottensmeier CH
• 通讯作者: Ottensmeier CH

Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer.

• DOI: 10.1038/ni.3775
• 发表时间: 2017-08
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Ganesan AP;Clarke J;Wood O;Garrido-Martin EM;Chee SJ;Mellows T;Samaniego-Castruita D;Singh D;Seumois G;Alzetani A;Woo E;Friedmann PS;King EV;Thomas GJ;Sanchez-Elsner T;Vijayanand P;Ottensmeier CH
• 通讯作者: Ottensmeier CH

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.

• DOI: 10.1016/j.immuni.2017.03.013
• 发表时间: 2017-04-18
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Arce Vargas F;Furness AJS;Solomon I;Joshi K;Mekkaoui L;Lesko MH;Miranda Rota E;Dahan R;Georgiou A;Sledzinska A;Ben Aissa A;Franz D;Werner Sunderland M;Wong YNS;Henry JY;O'Brien T;Nicol D;Challacombe B;Beers SA;Melanoma TRACERx Consortium;Renal TRACERx Consortium;Lung TRACERx Consortium;Turajlic S;Gore M;Larkin J;Swanton C;Chester KA;Pule M;Ravetch JV;Marafioti T;Peggs KS;Quezada SA
• 通讯作者: Quezada SA