971444TCR diversity evaluation as a predictive biomarker of response to immunotherapyClosedSmall Business Research InitiativeInnovate UKTCR 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.