Development of experimentally-integrated process models for adaptive CAR-T cell therapy manufacturing

新一代基因编辑细胞疗法已经开发出来，有可能治愈某些侵袭性癌症。Autolus是该领域领先的生物制药公司，在体外对患者自身的免疫细胞（t细胞）进行基因工程改造，以识别和靶向癌细胞。在体外工程之后，患者的t细胞在其表面表达“嵌合抗原受体”（CARs），这些嵌合抗原受体经过精心构建，使t细胞能够绕过癌细胞的防御机制。最近FDA批准的两种自体CAR-T疗法显示出显著的临床效果，大多数患者接受治疗后缓解（一些患者在给药后5年或更长时间）。然而，昂贵的、固有的可变的、次优的、人工的和开放的制造过程限制了患者对这些变革性治疗的可及性。为了解决这些制造挑战，有必要补偿患者起始材料的固有变化并优化生产。一个实时测量和适应过程测量的自适应生产系统可以实现这一目标。这样一个系统将需要相关的、实验推导的过程模型。然而，由于缺乏可靠的实验数据、支持结构化方法的工具、实现计算可处理（低参数）但现实的模型的困难以及所需的专业技能，这种模型的使用受到限制。该工业奖学金将专注于在Autolus和伦敦大学学院（UCL）的联合专业知识和设施的帮助下，建立实验驱动的自适应自体CAR-T细胞治疗制造过程模型。拟议的项目将加强对CAR-T制造工艺和产品特性的理解，并为工艺开发提供有效的预测过程工具。工业研究员将开发一套专业技能，这将是未来在细胞和基因治疗方面的职业生涯的宝贵基础。

A new generation of gene-edited cell therapies have been developed which have the potential to cure certain aggressive types of cancer. Autolus, a leading biopharmaceutical company within this field, are genetically engineering patient's own immune cells (T-cells) in vitro to recognise and target cancerous cells. Following in vitro engineering, patient's T-cells express 'chimeric antigen receptors' (CARs) on their surface, which have been carefully constructed to allow the T-cells to by-pass cancerous cells' defence mechanisms. Recently two FDA approved autologous CAR-T therapies have shown remarkable clinical outcomes, with most patients receiving therapy in remission (some for 5 or more years post-administration).However, the costly, inherently variable, sub-optimal, manual, and open manufacturing processes limit patient accessibility to these transformative therapies. To resolve these manufacturing challenges, it is necessary to compensate for the inherent variation in patient starting material and optimise production. An adaptive production system which measures and adapts to in-process measurements in real-time can achieve this. Such a system will require relevant, experimentally-derived process models. However, the use of such models is limited due to lack of robust experimental data, tools to support a structured approach, the difficulty of realising computationally tractable (low parameter) yet realistic models, and the specialised skill sets required. This Industrial Fellowship will focus on establishing experimentally-driven process models for adaptive autologous CAR-T cell therapy manufacture with the aid of combined expertise and facilities at Autolus and University College London (UCL). The proposed project will enhance understanding of the CAR-T manufacturing process and product characteristics, as well as providing effective predictive in-process tools for process development. The Industrial Fellow will develop a specialised skillset that will be a valuable foundation for a future career in cell and gene therapies.