Evaluating gamma-delta T cell therapy for osteosarcoma

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Cells in the immune system usually protect the body from infection. Cancer immunotherapy uses genetically modified immune cells to attack cancer - this approach works well for leukaemia, but less well for cancers that form solid lumps. Immune cells are like machines - their anti-cancer behaviour can be changed by adding engineered modules to give or remove particular characteristics from the cellular "chassis". This project will evaluate three kinds of engineered module in the context of gamma-delta T cells, an immune cell type which already has powerful anti-cancer activity and which is therefore a strong candidate for enhancement. My laboratory recently developed and patented a new combination of modules specifically designed for the gamma-delta T cell chassis. Engineered cells survive longer and kill cancer cells more quickly than regular gamma-delta T cells, and because the modules are released from the cell, they confer these benefits on their neighbours. I will pit these cells against osteosarcoma, a type of bone cancer that affects teenagers and is particularly hard to cure, especially in the relapsed setting. To simulate this realistically in the lab I will use 3D cultures of patient-derived osteosarcoma cells which we have already established and used to show that gamma-delta T cells can seek out and kill a bone tumour sitting in a "bony" context. I will test ways of making these 3D models more realistic, to better mimic what might happen in a patient tumour.Two of the modules to be tested already exist but need improvement. One allows the gamma-delta T cells to label cancer cells to be killed by the immune system - I will compare different formats for this module to maximise the killing of labelled cancer cells. The second module provides a constant stimulus to keep the gamma-delta T cells healthy. Some extra stimulus is helpful, but giving too much could have the opposite effect. I will therefore investigate ways of using drug-controlled switches to control the level of stimulus released; this will also have the benefit of improving safety because the stimulus could be turned off if a patient had side-effects.The third module is new, and is aimed at the therapeutic ideal of an "off the shelf" immunotherapy which will be much cheaper to manufacture than current options and also quicker to obtain for patients. To achieve this, the immunotherapy must a) not attack the patient's healthy cells and b) not be rejected by the patient's own immune system. Gamma-delta T cells don't attack healthy cells even if they're from another person; their inbuilt properties provide half of the answer already. I will explore modules aimed at hiding the cells from the recipient immune system, allowing them to provide a longer lasting benefit. Novel engineering must be grounded in purpose - in this case to deliver new treatments to improve outcomes for osteosarcoma patients. The technology is a platform however, with relevance to many cancer types and one of many in development worldwide which harness the properties of gamma-delta T cells. There is pressing need for consensus about how to evaluate the benefits and behaviour of gamma-delta T cells when they are given to patients. Alongside the developments in the laboratory I have therefore started an international consortium of gamma-delta T cell experts with the aim of developing this consensus. I am to develop this group further, so that we can evaluate current evidence and make recommendations to help others measure the right things at the right time for the benefit of everyone bringing gamma-delta T cells to the clinic.