Demonstrating the Manufacture of Human CAR-T Cells in an Automated Stirred-Tank Bioreactor.,Biotechnology Journal

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Demonstrating the Manufacture of Human CAR-T Cells in an Automated Stirred-Tank Bioreactor.
Biotechnology Journal ( IF 3.2 ) Pub Date : 2020-06-27 , DOI: 10.1002/biot.202000177
Elena Costariol ₁ , Marco C Rotondi ₁ , Arman Amini ₁ , Christopher J Hewitt ₂ , Alvin W Nienow _{2,

3} , Thomas R J Heathman ₄ , Qasim A Rafiq ₁

Affiliation

Chimeric antigen receptor T‐cell (CAR‐T) therapies have proven clinical efficacy for the treatment of hematological malignancies. However, CAR‐T cell therapies are prohibitively expensive to manufacture. The authors demonstrate the manufacture of human CAR‐T cells from multiple donors in an automated stirred‐tank bioreactor. The authors successfully produced functional human CAR‐T cells from multiple donors under dynamic conditions in a stirred‐tank bioreactor, resulting in overall cell yields which were significantly better than in static T‐flask culture. At agitation speeds of 200 rpm and greater (up to 500 rpm), the CAR‐T cells are able to proliferate effectively, reaching viable cell densities of >5 × 10⁶ cells ml‐1 over 7 days. This is comparable with current expansion systems and significantly better than static expansion platforms (T‐flasks and gas‐permeable culture bags). Importantly, engineered T‐cells post‐expansion retained expression of the CAR gene and retained their cytolytic function even when grown at the highest agitation intensity. This proves that power inputs used in this study do not affect cell efficacy to target and kill the leukemia cells. This is the first demonstration of human CAR‐T cell manufacture in stirred‐tank bioreactors and the findings present significant implications and opportunities for larger‐scale allogeneic CAR‐T production.

中文翻译：

演示在自动搅拌罐生物反应器中生产人类CAR-T细胞的过程。

嵌合抗原受体T细胞（CAR-T）疗法已被证明可治疗血液系统恶性肿瘤。但是，CAR-T细胞疗法的生产成本过高。作者展示了在自动搅拌罐生物反应器中由多个供体制造的人类CAR-T细胞。作者在动态条件下在搅拌罐式生物反应器中成功地从多个供体中生产了功能性人类CAR-T细胞，从而产生了比静态T瓶培养明显更好的总体细胞产量。在200 rpm和更高的搅拌速度（最高500 rpm）下，CAR-T细胞能够有效增殖，达到的活细胞密度> 5×10 ⁶7天内的ml-1细胞。这可以与当前的扩展系统相媲美，并且比静态扩展平台（T瓶和透气培养袋）要好得多。重要的是，工程化的T细胞在扩增后仍能保持CAR基因的表达并保持其溶细胞功能，即使在最高搅拌强度下生长也是如此。这证明本研究中使用的电源输入不会影响靶向和杀死白血病细胞的细胞效力。这是人类在搅拌罐式生物反应器中制造CAR-T细胞的首次证明，这一发现为大规模异体CAR-T生产提供了重要的启示和机遇。

更新日期：2020-09-02

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