Base edited T cell therapy against T-ALL (TvT)

在过去的几年里，利用病人自身的免疫细胞来对抗某些类型的血癌已经成为可能。一般来说，收集被称为T细胞的白细胞，并将其带到一个特殊的洁净室，在那里使用一种失效的病毒对它们进行修饰。这增加了额外的DNA代码，使细胞能够对抗白血病。我们之前已经证明，在没有任何匹配的情况下，使用捐赠者的T细胞是可能的。这些步骤最初使用名为TALENs的分子剪刀，2015年我们在英国成功治疗了两名婴儿，然后开始了儿童和成人的临床试验，最近发表了这些试验。在GOS，我们现在正在使用新版本的策略，在制造出现成的CAR - T细胞后，我们使用一种叫做CRISPR的新版本的剪刀来剪断T细胞中的两个基因，使它们能够不匹配地使用。在这个新的应用中，我们希望将这种方法扩展到使用供体T细胞的其他血癌，包括T细胞白血病。到目前为止，这是不可能的，因为武装起来对抗其他T细胞的T细胞很难生长，因为它们最终会互相攻击。在最近的实验中，我们使用基因组编辑技术去除T细胞上的标记，使它们变得不可见，并且在工程步骤中不会成为目标。我们使用了一种更新版本的CRISPR，而不是切割DNA，它改变了一个字母（或碱基），告诉细胞停止显示它们的标记，也允许它们在不匹配的情况下使用。作为计划中的骨髓移植（BMT）的一部分，一项为期两年的临床试验将治疗来自英国各地的10名儿童。如果T细胞可以用来消除可测量的白血病，那么BMT后白血病复发的几率就会大大降低。我们将仔细跟踪副作用和抗癌活性，特别是在治疗后的头4周，但将持续一年，以确保治疗既安全又有效。

Over the past few years it's become possible to use a patient's own immune cells to fight certain types of blood cancer. Generally, white blood cells called T cells are collected and taken to a special clean room, where they are modified using a disabled virus. This adds extra DNA code that programs he cells to fight leukaemia. We have previously shown that it's possible to use additional steps to allow T cells to be used from donors without any matching. These steps originally used molecular scissors called TALENs, and in 2015 we successfully treated two infants in the UK and then started clinical trials in children and adults, which were recently published. At GOS, we are now using a next version of the strategy after making ready-made CAR T cells using new versions of the scissors called CRISPR to snip two genes in T cells that allow them to used without matching. In this new application, we want to extend the approach to used donor T cells other blood cancers, including T cell leukaemia. Up to now, this hasn't been possible because T cells armed to fight other T cells have been difficult to grow because they end up fighting each other. In recent experiments we have used genome-editing to remove markings on T cells so they become invisible and are not targeted during the engineering steps. Rather than cutting DNA, we have used an even newer version of CRISPR that changes a single letter (or base) to tell cells to stop showing their markings, also to allow them to be used without matching. A clinical trial is proposed to treat 10 children from a cross the UK over a two year period, as part of planned bone marrow transplantation (BMT). If T cells can be used to eliminate measurable leukaemia, the chances of it coming back after BMT are very much reduced. Careful tracking of side effects and anti-cancer activity will be provided, especially in the first 4 weeks after treatment, but will continue for a year to make sure the treatment is both safe and effective.