ICF: Chimeric antigen receptor T cells targeting CD123, CD33 and CLL1 for therapy of Acute Myeloid Leukaemia

急性髓系白血病(AML)是成人最常见的侵袭性白血病，其发病率随年龄增长而增加。尽管在治疗方面取得了进展，但总的来说，只有不到三分之一的成年人长期存活，尽管年轻年龄组和某些亚型的预后较好。最有效的治疗方法是强化化疗和骨髓移植，这些都是有毒的。较小比例的患者无法存活，因为疾病对治疗没有反应(三分之一)，一小部分人死于毒性，在某些情况下，疾病有反应，但随后复发(约一半)。在这一点上，患者通常已经达到了某些化疗药物的剂量上限，这限制了治疗选择。一种新的癌症免疫疗法被称为嵌合抗原受体(CAR)T细胞。这需要细胞，这些细胞是我们免疫系统的一部分，通过某种形式的基因重新编程，可以使它们识别和杀死癌细胞。这对另一种更罕见的白血病(急性淋巴细胞性白血病)有效，我们正试图将这种方法推广到治疗AML。这是具有挑战性的，因为基因重新编程的CAR T细胞也识别和杀死健康细胞，如正常的骨髓细胞，因为它们无法区分这些细胞类型。由于骨髓移植是适合复发AML患者的标准护理的一部分，但通常需要大剂量化疗来清除宿主骨髓，并为供者系统有效地植入种子腾出空间，因此我们建议研究对AML有效的CAR T细胞，并利用其‘骨髓清除’特性来建立一个有效的平台，以较低剂量的预备化疗进行骨髓移植。如果我们的CAR T细胞疗法效果良好，它将在开发有效的CAR T细胞疗法并使其适用于AML患者的道路上向前迈进一步

Acute myeloid leukaemia (AML) is the commonest aggressive leukaemia in adults and has an increasing frequency with age. Despite advances made in treatments, in general, less than a third of adults survive long-term, though prognosis is better in younger age groups and certain subtypes. The most effective treatments are intensive chemotherapy and bone marrow transplantation which are toxic. A smaller proportion of patients do not survive because the disease does not respond to treatment (a third), a small proportion die due to toxicity and in some the disease responds but then comes back (about half). At this point, patients have often reached the ceiling of doses of certain chemotherapy agents which limits therapy options.A new form of immune therapy for cancer called chimeric antigen receptor (CAR) T cells has been developed. This takes cells which are part of our immune system and through a form of genetic re-programming, can enable them to recognise and kill cancer cells. This is effective in another rarer form of leukaemia (acute lymphoblastic leukaemia) and we are trying to extend this approach to treat AML. This is challenging because the genetically- reprogrammed CAR T-cells also recognise and kill healthy cells such as normal bone marrow cells because they cannot distinguish these cell types. Since bone marrow transplantation is part of the standard care for a fit patient with relapsed AML, but normally involves high dose chemotherapy to clear the host bone marrow and 'make space' for the donor system to seed effectively, we propose to study CAR T cells which are effective against AML and investigate using their 'bone marrow-clearing' properties to set up an effective platform for bone marrow transplantation with lower doses of preparatory chemotherapy. If our CAR T cell therapy works well, it will be a step forward on the path to developing effective CAR T cell treatments and making them available for patients with AML