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中未满足的主要临床需求。尽管进行了大量新疗法的临床试验，但近几十年来这些患者的预后几乎没有改善。在本研究提案中，我们寻求通过 I 期临床试验来评估治疗这一高危患者群体的新方法，其中采用新的治疗方法（嵌合抗原受体：CAR-T 细胞）和新的给药途径（直接注射细胞）在缺乏其他治疗选择的患者中进行评估。CAR-T 细胞技术的原理是从患者身上采集血液样本，并对免疫系统的杀伤细胞（T 细胞）进行基因改造在实验室中，从而特异性识别癌症细胞，但不是正常细胞。这些基因改造的治疗细胞构成了“细胞疗法”，我们将它们称为“杀伤性T细胞”。经过安全性和质量测试后，可以将基因修饰的杀伤性 T 细胞回输给患者，并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，特别的创新在于三个主要领域。首先，所试验的特定基因改造是新的；即在杀伤性T细胞表面编码新分子结构的新DNA序列。这种新颖的结构结合了一种新的癌细胞识别成分，并且还结合了一个分子开关，允许通过使用药物来打开和关闭杀伤性 T 细胞的活性。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未对患者进行事先化疗的情况下发挥作用。化疗预处理以前被认为对于注射的杀伤性 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个体患者的治疗次数。第三，我们将使用一种新颖的输送方式，即将基因修饰的杀伤性 T 细胞直接注射到沐浴大脑的液体（脑脊液）中。这将作为一种替代的高效输送系统，并有可能克服通过注射到血流中的传统方法将杀伤性 T 细胞输送到脑肿瘤的局限性。每位患者将接受最多 3 次预定输注，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。