Phase I study of B7-H3 targeting CAR-T cells administered by local delivery in paediatric high risk brain tumour patients.

不能手术切除或对化疗或放疗不敏感的儿童脑肿瘤是儿科肿瘤学临床未满足的主要需求。近几十年来，尽管对新疗法进行了大量临床试验，但这些患者的预后几乎没有改善。在这项研究计划中，我们正在寻求通过I期临床试验来评估一种针对这一高危患者群体的新方法，在缺乏其他治疗选择的患者中，评估一种新的治疗方法（嵌合抗原受体：CAR-T细胞）和新的给药途径（直接向肿瘤区域注射细胞）。CAR-T细胞技术的基本原理是，从患者身上提取血液样本，在实验室对免疫系统的杀伤细胞（T细胞）进行基因改造，从而特异性地识别癌细胞，而不是正常细胞。这些基因修饰的治疗细胞构成了一种“细胞疗法”，我们称它们为“杀伤t细胞”。经过安全性和质量测试后，基因修饰的杀伤t细胞可以被送回患者体内，通过连续肿瘤成像以及收集和分析患者样本来评估对肿瘤生长的影响。在拟议的临床试验中，特别的创新主要体现在三个方面。首先，要试验的特定基因改造是新的；即在杀伤t细胞表面上编码新分子结构的新DNA序列。这种新结构包含了一种新的癌细胞识别成分，还包含了一个分子开关，允许使用药物打开和关闭杀伤t细胞的活动。因此，试验首先需要测试这种方法的安全性。其次，我们将评估这些基因修饰的杀伤细胞是否在没有事先给病人化疗的情况下起作用。化疗前治疗被认为对注射的杀伤T细胞的功能至关重要。然而，化疗也会增加患者的总体毒性，并可能限制可以安全地给予单个患者的治疗次数。第三，我们将使用一种新的递送方式，即将基因修饰的杀伤t细胞直接注射到浸泡在大脑中的液体（脑脊液）中。这将作为另一种有效的递送系统，并有可能克服将杀伤T细胞递送到脑肿瘤的传统方法的局限性，即注射到血液中。每位患者将接受最多三次预定输注，如果有临床益处，允许进一步输注。计划共招募18名患者。

Childhood brain tumours that cannot be surgically removed or are insensitive to chemotherapy or radiotherapy represent a major clinical unmet need in paediatric oncology. There has been little improvement in outcome for these patients in recent decades despite numerous clinical trials of new treatments. In this research proposal we are seeking to evaluate a new approach to this high-risk patient group through a phase I clinical trial in which a new treatment (chimeric antigen receptor: CAR-T cells) and new route of administration (direct injection of cells into the region of the tumour) is evaluated in patients lacking other treatment options.The principle underlying CAR-T cell technology is that a blood sample is taken from the patient, and the killer cells of the immune system (T cells) are genetically modified in the lab, so as to specifically recognise cancer cells, but not normal cells. These genetically-modified therapeutic cells constitute a "cellular therapy", and we term them "killer T-cells". Following safety and quality testing, the gene-modified killer T-cells can be administered back to the patient, and the effect on tumour growth can be evaluated by serial tumour imaging, and by collection and analysis of patient samples. In the proposed clinical trial, particular innovation lies in three main areas. Firstly, the particular genetic modification to be trialled is new; ie a new DNA sequence encoding a new molecular structure on the surface of the killer T-cells. This novel structure incorporates a new recognition component for the cancer cells, and also incorporates a molecular switch allowing the activity of the killer T-cells to be switched on and off by use of a drug. Hence the trial needs first and foremost to test the safety of this approach. Secondly, we will evaluate if these gene-modified killer cells work without giving prior chemotherapy treatments to the patients. Chemotherapy pre-treatment has been previously considered essential for function of injected killer T cells. However, the chemotherapy also can increase overall toxicity for the patient, and can limit the number of treatments that can be safely given to an individual patient. Thirdly, we will use a novel mode of delivery, which is direct injection of the gene modified killer T-cells into the fluid that bathes the brain (cerebrospinal fluid). This will act as an alternate efficient delivery system and potentially will overcome the limitations of delivering killer T cells to brain tumours by the traditional approach of injection into the bloodstream. Each patient will receive up to three scheduled infusions, with further infusions allowed if there is clinical benefit. It is planned that a total of 18 patients will be recruited.