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

急性髓性白血病（AML）是成人中最常见的侵袭性白血病，并且随着年龄的增长而增加。尽管在治疗方面取得了进步，但总的来说，只有不到三分之一的成年人能长期存活，尽管年轻年龄组和某些亚型的预后更好。最有效的治疗方法是强化化疗和有毒性的骨髓移植。一小部分患者因治疗无效而无法存活（三分之一），一小部分患者因毒性而死亡，在某些情况下，疾病有反应但随后又复发（约一半）。在这一点上，病人经常达到某些化疗药物的剂量上限，这限制了治疗的选择。一种新的癌症免疫疗法被称为嵌合抗原受体（CAR） T细胞。这需要我们免疫系统的一部分细胞，通过某种形式的基因重新编程，使它们能够识别并杀死癌细胞。这在另一种罕见的白血病（急性淋巴细胞白血病）中是有效的，我们正试图将这种方法扩展到治疗急性髓性白血病。这是具有挑战性的，因为基因重编程的CAR - t细胞也能识别并杀死健康细胞，如正常骨髓细胞，因为它们不能区分这些细胞类型。由于骨髓移植是复发性AML患者标准治疗的一部分，但通常需要高剂量的化疗来清除宿主骨髓，为供体系统有效地种子“腾出空间”，我们建议研究CAR - T细胞对AML有效，并研究利用其“骨髓清除”特性，为骨髓移植建立一个有效的平台，使用低剂量的预备化疗。如果我们的CAR - T细胞疗法效果良好，这将是开发有效的CAR - T细胞疗法并将其用于AML患者的道路上迈出的一步

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