TCR diversity evaluation as a predictive biomarker of response to immunotherapy

经过几十年令人失望的结果，最近免疫治疗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，Ipilimumab （BMS, Yervoy®），一种刺激T细胞的单克隆抗体，首次提高了患者的预期寿命。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，有时会导致患者完全缓解和延长生存期。新出现的检查点抑制剂对转移性黑色素瘤患者来说无疑是一个令人兴奋的进展。然而，未选择的患者的反应率很低，可悲的是，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活。此外，所有检查点抑制剂的药物成本（Ipilimumab一个疗程7.5万英镑）都非常高，不良事件发生时的财政成本和机会成本也是如此。因此，研究其作用机制，特别是相关生物标志物的验证是关键的迫切需求，以帮助确定患者的反应可能性，并防止无反应者暴露于此类有毒药物。ImmunID的免疫追踪测试是一种分子诊断测试，对患者的血液进行检测，以评估其免疫状态。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上适合特定的免疫治疗。该项目遵循了ImmunID在40例接受ipilimumab治疗的转移性黑色素瘤患者中使用ImmunTraCkeR获得的结果，以证明患者基线免疫多样性特征与免疫治疗反应之间存在显著相关性（Fisher检验p值= 0.016）。最重要的是，ImmunTraCkeR检测可用于预测对ipilimumab无反应，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。作为一项预测性测试，免疫追踪器将通过识别可能从免疫疗法中受益的人群，帮助医生和患者做出明智的临床决策。一项健康经济学研究将模拟一项成功的测试对NHS的影响，以评估该测试对医疗系统的好处，并确定进一步研究的优先顺序。通过在开始治疗前识别无反应，我们估计仅在黑色素瘤方面，NHS每年就可以从不必要的药物成本和毒性中节省约1900万英镑。此外，我们预计通过减少伤害和更早更适当的治疗，未经治疗的患者的质量会有所提高。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。

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.