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

B7-H3 靶向 CAR-T 细胞的 I 期研究通过局部递送在儿科高危脑肿瘤患者中进行。

• 批准号: MR/X030199/1
• 负责人: William Anderson
• 金额: $ 485.21万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX030199%2F1
• 关键词: Phase; study; B7; H3; targeting

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.

无法通过手术切除或对化学疗法或放射疗法不敏感的儿童脑肿瘤代表了小儿肿瘤学的主要临床需求。尽管有许多新治疗的临床试验，但最近几十年来，这些患者的结果几乎没有改善。在这项研究建议中，我们正在寻求通过I期临床试验评估该高风险患者组的新方法，在该试验中，新的治疗方法（嵌合抗原受体：CAR-T细胞：CAR-T细胞）和新的给药途径（将细胞直接注入肿瘤区域）在患者缺乏其他治疗方案的患者中评估。在实验室中进行了修饰，以便特别识别癌细胞，而不是正常细胞。这些遗传改性的治疗细胞构成了一种“细胞疗法”，我们将其称为“杀手T细胞”。经过安全性和质量测试，可以将基因改性的杀手T细胞送回患者，并且可以通过串行肿瘤成像以及对患者样品的收集和分析来评估对肿瘤生长的影响。在拟议的临床试验中，特定的创新位于三个主要领域。首先，要试用的特定遗传修饰是新的。即一个新的DNA序列，编码杀手T细胞表面上的新分子结构。这种新颖的结构结合了癌细胞的新识别成分，还结合了一个分子开关，允许通过使用药物打开和关闭杀手T细胞的活性。因此，该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起作用，而无需对患者进行事先化疗治疗。化学疗法预处理先前被认为是注射杀伤T细胞功能至关重要的。但是，化学疗法也可以增加患者的总体毒性，并且可以限制可以安全地接受的患者的治疗次数。第三，我们将使用一种新型的传递方式，即将基因修饰的杀伤剂T细胞直接注射到沐浴大脑的液体中（脑脊液）。这将充当替代的有效递送系统，并有可能通过传统的注射到血液中的传统方法来克服将杀手T细胞传递给脑肿瘤的局限性。每个患者最多将收到三个预定的输注，如果有临床益处，则允许进一步输注。计划总共招募18名患者。