Development of an integrated and scalable platform process for the robust manufacture of allogeneic iPSC immunotherapies

现代疗法经常使用人体细胞作为治疗方式。最近在白血病和淋巴瘤治疗方面的突破与患者自身分离的t淋巴细胞的管理有关，这些t淋巴细胞在实验室经过修饰以识别和杀死肿瘤细胞。然而，这种疗法有很强的副作用，需要时间来生产用于治疗的细胞，而且由于成本高，并不总是负担得起。免疫肿瘤学的一种新方法是利用另一种类型的淋巴细胞——自然杀伤细胞（NK）。这些细胞可以变得活跃，有效地消灭癌细胞，包括实体瘤，副作用最小。重要的是，它们可以从外周血或脐带血中获得，对匹配供体没有严格的要求。下一代疗法源于人类诱导多能干细胞（iPSC）作为一种通用的现成产品产生NK细胞。这种技术不仅可以创造无限的治疗剂来源，而且可以通过基因修饰起始的iPSC材料，以患者为中心的方法，将产生的NK细胞靶向特定的癌细胞类型。在拟议的合作中，Plasticell， Cell and Gene therapy Catapult和伦敦帝国理工学院的目标是开发一种用于免疫治疗的ipsc衍生的全功能NK细胞的制造工艺。Plasticell已部署其屡获殊荣的筛选平台，以生成NK细胞从iPSCs分化的协议。这项技术将被转移到细胞和基因治疗弹射器，以适应生产规模。最后，所有检测NK细胞功能的试验将在伦敦帝国理工学院NK细胞专家休·布雷迪教授的控制和指导下进行。我们的目标是在可以很容易地转化为临床实践的条件下，开发一种强大而有效的人类NK细胞生产过程。在整个项目中，所有使用的材料和方法都将是临床可接受的，目的是产生高产、高纯度的功能成熟的NK细胞。生成的NK细胞将在实验室环境中测试其与供体来源的NK细胞的相容性及其杀死癌细胞的能力。该项目的成功将导致使用先进的研究技术和基于动物的癌症模型进行全面的临床前研究，并开发下一代实体瘤治疗方法。

Modern therapies are often concerned with using human cells as therapeutic modalities. Recent breakthroughs in the treatment of leaukemia and lymphoma are associated with the administration of patient's own isolated T-lymphocyes, modified at the laboratory to recognise and kill tumour cells. However, such therapies have strong side effects, require time for producing the cells for treatment and are not always afforadable due to high costs. A new approach in immuno-oncology is to utilize another type of lymphocytes -- Natural killer (NK) cells. These cells can become active and efficiently eliminate cancer cells, including solid tumours, with minimal side effects. Importantly, they can be obtained from the peripheral or cord blood with no strict requirements for the matching donor. The next generation therapy originates from the production of NK cells from the human induced pluripotant stem cells (iPSC) as a universal off-the-shelf product. Such technology not only allows to create an unlimited source of the therapeutic agents, but to target the produced NK cells to a specific cancer cell type in a patient-centered approach by genetically modifying the starting iPSC material.In the proposed collaboration, Plasticell, Cell and Gene therapy Catapult and Imperial College London aim to develop a manufacturing procedure for iPSC-derived fully functioning NK cells for immuno-therapies. Plasticell has deployed its award-winning screening platform to generate protocols for differentiation of NK cells from iPSCs. This technology will be transferred to the Cell and Gene therapy Catapult to be adapted to a manufacturing scale. Finally, all assays to test the functionality of produced NK cells will be developed under control and guidance of the NK cell specialist Prof Hugh Brady at Imperial Colledge London. We aim at developing a process of a robust and efficient production of human NK cells in conditions that can be easily translated to the clinical practice. Throughout the project, all the materials and methods used will be clinically acceptable with the purpose to generate functionally mature NK cells in high yield and purity. The produced NK cells will be tested for their compatibility with donor-derived NK cells and their ability to kill cancer cells in the laboratory settings. The success of this project will lead to comprehensive pre-clinical studies using advanced research techniques and animal-based cancer models, and developing next generation therapies for solid tumours.