Development of a 'humanised' model for renal cancer

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Immune checkpoint inhibitors (ICPIs) are a type of cancer treatment that boosts the body's immune system to fight cancer. ICPIs are revolutionising cancer treatment as they can lead to years of control of cancers in up to 50% of patients. However, unfortunately less than 50% of kidney cancer patients benefit from treatment with these costly drugs (1year treatment up to £90,000), yet up to 80% of patients experience side effects relating to 'over-activation' of their immune system which can attack their normal organs. Therefore, there is an urgent need to accurately predict which patients will benefit from treatment whilst providing alternative treatment options for patients who do not. Normally such studies can be performed using laboratory models to prevent patients being unnecessarily exposed to sub-optimal drugs (and combinations) and their side effects, but models for testing ICPIs in kidney cancer are limited as they lack immune cells that work like a human immune system. However, a new genetically engineered mouse has been developed (called a NSG MHC I/II knockout (KO) mouse) which can grow a human immune system when immune cells from patients' blood (called peripheral blood mononuclear cells; PBMCs) are injected into the mouse, to generate a so-called 'humanised' mouse. The goal of my project is to develop a new 'humanised' mouse model for kidney cancer. The specific objectives are:1) To generate 'humanised' mice by injecting PBMCs from kidney cancer patients into NSG MHC I/II KO mice, plus transplant RCC and normal kidney tissue from patients having surgery to remove their kidney cancer to generate a new 'humanised' mouse model for RCC2) To test the new model to determine the extent to which it reflects patient responses by comparing immune and cancer responses in kidney cancer patients vs 'humanised' mice treated with ICPIs3) To provide preliminary (pilot) data for a future large grant (called a Clinician Scientist grant) To do this I will inject PBMCs from kidney cancer patients into the new strain of mice to create 'humanised' mice. I will also implant kidney and normal kidney tissue (obtained when those patients have surgery to remove their kidney cancer) into the mice. This will create the new 'humanised' model for kidney cancer which has both the immune system and kidney cancer that the patient has (acting like an 'avatar'). We will do this for up to 30 patients as some work will be needed to optimise the procedures to make sure that the PBMCs, cancer and normal kidney cells grow properly in the mice. I will then test the model and see how well it mirrors patient responses to ICPI treatment. The mice will be treated with ICPI for 4 weeks and their immune, tumour and normal tissue responses will be compared to the same responses in kidney cancer patients who receive the same drugs in the clinic as part of their normal treatment. This data will form essential pilot data for my future Clinician Scientist application which will aim to fully assess and validate the model with arrange of different drugs for a longer time period. It could then be used to identify the most effective novel therapies and combinations of different drugs (with the least side effects) for kidney cancer patients which can then be tested in clinical trials, rather than testing all treatments and combinations in patients as currently happens. This would save significant time and cost. It could also identify markers from blood or tumours that could predict which patients are likely to respond or have very serious side effects to new treatments so those patients who would not benefit from a particular treatment could be spared treatment or side effects and offered an alternative treatment. The model will also be useful to many academic and commercial researchers worldwide who can use it to streamline drug development (as above) but also to investigate how the immune system interacts with kidney cancer (and vice versa).