TCR diversity evaluation as a predictive biomarker of response to immunotherapy

TCR 多样性评估作为免疫治疗反应的预测生物标志物

• 批准号: 971444
• 金额: $ 19.11万
• 依托单位: IMMUNID
• 依托单位国家: 英国
• 项目类别: Small Business Research Initiative
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=971444
• 关键词: TCR; diversity; evaluation; predictive; biomarker

TCR diversity evaluation as a predictive biomarker of response to immunotherapy After decades of disappointing results, the recent success of immunotherapy in clinical oncology confirms the relevance of the immune system activation in the defence against the tumour. For the first time in metastatic melanoma, Ipilimumab (BMS, Yervoy®), a monoclonal antibody stimulating T cells, increased the life expectancy of patients. Furthermore, the FDA recently approved other monoclonal antibodies with similar mechanisms of action in metastatic melanoma and other solid tumours, confirming that targeting the immune system could promote the development of an effective anti-tumour adaptive immune response, sometimes leading to a complete remission of the patients and long survival. The emerging checkpoint inhibitors are without doubt an exciting development for patients with metastatic melanoma. Nevertheless response rates amongst unselected patients are low – sadly the majority of treated patients do not benefit from these treatments. By contrast the rate of adverse events is high, and can be life-threatening or life-altering. Additionally the drug cost (£75k for a course of Ipilimumab) for all the checkpoint inhibitors is very high, as are the fiscal- and opportunity-costs of the adverse events when they occur. Consequently, the study of the mechanisms of action and especially the validation of relevant biomarkers are key urgent requirements in order to help identify patients’ likelihood to respond, and to prevent non-responders from being exposed to such toxic drugs. ImmunID’s ImmunTraCkeR test is a molecular diagnostics test, performed on the blood of the patient, to evaluate his/her immune status. ImmunTraCkeR analyzes combinatorial diversity of T lymphocytes receptors, i.e. the cell population targeted by immune checkpoint inhibitors, which is why the test will help determine whether the patient is immunologically fitted for a specific immunotherapy. This project follows the results obtained by ImmunID in 40 metastatic melanoma patients treated by ipilimumab using ImmunTraCkeR to demonstrate a significant correlation between the patient immune diversity profile at baseline and response to immunotherapy (Fisher test p-value= 0.016). Most importantly, the ImmunTraCkeR assay could be used to predict absence of response to ipilimumab with a 100% specificity (Negative Predictive Value = 100%). In line with these results, the project’s clinical trial will include a further 40 patients from centres in the UK. As a predictive test, ImmunTraCkeR will help physicians and patients make informed clinical decisions by identifying people likely to benefit from immunotherapies. A health economics study , to model the impact that a successful test would have on the NHS, will be conducted to evaluate the benefits for the healthcare system and prioritise further research.By identifying non-responders before commencing treatment we estimate immediate cost savings for the NHS of ~£19M/year in melanoma alone, from unnecessary drug costs and toxicities. Furthermore, we anticipate QALY gains in untreated patients, through harm spared and earlier more appropriate treatment. Considering the wider applications of checkpoint inhibitors in multiple cancers, ImmunTraCkeR therefore has huge potential socioeconomic benefits for the UK and globally.

TCR多样性评估作为免疫治疗反应的预测生物标志物经过数十年令人失望的结果，免疫治疗最近在临床肿瘤学中的成功证实了免疫系统激活在防御肿瘤中的相关性。在转移性黑色素瘤中，伊匹单抗（BMS，Yerimumab ®），一种刺激T细胞的单克隆抗体，首次增加了患者的预期寿命。此外，FDA最近批准了在转移性黑色素瘤和其他实体瘤中具有类似作用机制的其他单克隆抗体，证实靶向免疫系统可以促进有效的抗肿瘤适应性免疫反应的发展，有时导致患者的完全缓解和长期生存。对于转移性黑色素瘤患者来说，新出现的检查点抑制剂无疑是一个令人兴奋的进展。尽管如此，未经选择的患者的缓解率很低--遗憾的是，大多数接受治疗的患者并没有从这些治疗中受益。相反，不良事件的发生率很高，可能危及生命或改变生命。此外，所有检查点抑制剂的药物成本（伊匹单抗疗程为7.5万英镑）非常高，不良事件发生时的财政和机会成本也很高。因此，研究作用机制，特别是验证相关生物标志物是关键的迫切要求，以帮助确定患者的反应可能性，并防止无反应者接触此类有毒药物。ImmunID的ImmunTraCkeR测试是一种分子诊断测试，对患者的血液进行，以评估他/她的免疫状态。ImmunTraCkeR分析T淋巴细胞受体的组合多样性，即免疫检查点抑制剂靶向的细胞群，这就是为什么该测试将有助于确定患者是否在免疫学上适合特定的免疫疗法。该项目遵循ImmunID在使用ImmunTraCkeR接受伊匹单抗治疗的40例转移性黑色素瘤患者中获得的结果，以证明基线时患者免疫多样性特征与对免疫治疗的应答之间的显著相关性（Fisher检验p值= 0.016）。最重要的是，ImmunTraCkeR测定可用于预测对伊匹单抗无应答，特异性为100%（阴性预测值= 100%）。根据这些结果，该项目的临床试验将包括来自英国中心的另外40名患者。作为一种预测性测试，ImmunTraCkeR将帮助医生和患者通过识别可能从免疫治疗中受益的人来做出明智的临床决策。将进行一项卫生经济学研究，以模拟成功的测试对NHS的影响，以评估医疗保健系统的益处，并优先考虑进一步的研究。通过在开始治疗前识别无应答者，我们估计仅在黑色素瘤方面，NHS的直接成本节省约1900万英镑/年，不必要的药物成本和毒性。此外，我们预计未经治疗的患者，通过避免伤害和更早更适当的治疗，QALY收益。考虑到检查点抑制剂在多种癌症中的广泛应用，ImmunTraCkeR因此对英国和全球具有巨大的潜在社会经济效益。