Evaluating gamma-delta T cell therapy for osteosarcoma

评估骨肉瘤的 γ-δ T 细胞疗法

• 批准号: MR/X033066/1
• 负责人: Jonathan Patrick Hugh Fisher
• 金额: $ 181.02万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX033066%2F1
• 关键词: Evaluating; gamma; delta; cell; therapy

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.

免疫系统中的细胞通常保护身体免受感染。癌症免疫疗法使用基因修饰的免疫细胞来攻击癌症——这种方法对白血病很有效，但对形成固体肿块的癌症就不那么有效了。免疫细胞就像机器——它们的抗癌行为可以通过添加工程模块来改变，从而赋予或移除细胞“底盘”上的特定特征。该项目将在γ - δ T细胞的背景下评估三种工程模块，γ - δ T细胞是一种免疫细胞类型，已经具有强大的抗癌活性，因此是增强的有力候选者。我的实验室最近开发了一种专门为γ - δ T细胞底盘设计的新型模块组合，并申请了专利。工程细胞比常规的γ - δ T细胞存活时间更长，杀死癌细胞的速度更快，而且由于这些模块是从细胞中释放出来的，它们将这些好处赋予了周围的细胞。我将用这些细胞对抗骨肉瘤，这是一种影响青少年的骨癌，尤其难以治愈，尤其是在复发的情况下。为了在实验室中真实地模拟这一点，我将使用我们已经建立并用于证明γ - δ T细胞可以寻找并杀死位于“骨骼”环境中的骨肿瘤的患者来源的骨肉瘤细胞的3D培养。我将测试使这些3D模型更逼真的方法，以更好地模拟患者肿瘤可能发生的情况。要测试的两个模块已经存在，但需要改进。一种允许γ - δ T细胞标记癌细胞，以便被免疫系统杀死——我将比较本模块的不同格式，以最大限度地杀死标记的癌细胞。第二个模块提供持续的刺激以保持γ - δ T细胞的健康。一些额外的刺激是有帮助的，但给予太多可能会产生相反的效果。因此，我将研究使用药物控制开关来控制刺激释放水平的方法；这也将有提高安全性的好处，因为如果病人有副作用，刺激可以被关闭。第三个模块是新的，旨在实现一种“现成的”免疫疗法的理想治疗，这种疗法的制造成本比目前的选择要低得多，而且对患者来说也更快。为了达到这个目的，免疫疗法必须a)不攻击病人的健康细胞，b)不被病人自身的免疫系统排斥。γ - δ T细胞不会攻击健康细胞，即使它们来自他人；它们的内在属性已经提供了一半的答案。我将探索旨在将细胞隐藏在受体免疫系统之外的模块，让它们提供更持久的益处。新颖的工程必须以目的为基础——在这种情况下，提供新的治疗方法来改善骨肉瘤患者的预后。然而，这项技术是一个平台，与许多癌症类型相关，也是世界上许多正在开发的利用γ - δ T细胞特性的技术之一。对于如何评估γ - δ T细胞给患者的益处和行为，迫切需要达成共识。因此，在实验室取得进展的同时，我启动了一个由γ - δ T细胞专家组成的国际联盟，旨在达成这一共识。我将进一步发展这个小组，这样我们就可以评估现有的证据，并提出建议，帮助其他人在正确的时间衡量正确的事情，让每个人都能把γ - δ T细胞带到诊所。