Production and Application of CAR T Cells: Current and Future Role of Europe

Abstract

Rapid developments in the field of CAR T cells offer important new opportunities while at the same time increasing numbers of patients pose major challenges. This review is summarizing on the one hand the state of the art in CAR T cell trials with a unique perspective on the role that Europe is playing. On the other hand, an overview of reproducible processing techniques is presented, from manual or semi-automated up to fully automated manufacturing of clinical-grade CAR T cells. Besides regulatory requirements, an outlook is given in the direction of digitally controlled automated manufacturing in order to lower cost and complexity and to address CAR T cell products for a greater number of patients and a variety of malignant diseases.

Review: Sustainable Clinical Development of CAR-T Cells – Switching From Viral Transduction Towards CRISPR-Cas Gene Editing

“…A major challenge for academic institutions, such that CAR-T cells become a standard clinical strategy, is to scale out the GMP-compliant manufacturing (38)(39)(40)(41). The entire manufacturing process for semi-automated or automated processes requires 12 days (range 6-22 days) (39,42).…”

“…Since LV gene transfer is usually robust in actively replicating T cells, manual manufacturing methods can be efficiently replaced with closed automated systems (42,43). Importantly, digitally controlled automated manufacturing systems can potentially improve the practicability and lower the costs associated with clean rooms and highly trained personnel for production of CAR-T cells for a broader patient usage (41). Thus, in sum, although the upstream production and testing of clinical grade RVs/LVs still remains complex and expensive, the downstream T cell transduction procedures are relatively straightforward, particularly with the launching of powerful automated cell manufacturing systems allowing consistent gene transfer efficacy, cell recovery and viability (Table 1).…”

“…The current challenge is to further optimize and standardize the gene editing procedures to improve CAR T cell yields and manufacturing stability. Subsequently, virus-free knock-in methods should be adopted for automated manufacturing systems to accommodate future clinical scaling (41,59).…”

Influence of Culture Conditions on Ex Vivo Expansion of T Lymphocytes and Their Function for Therapy: Current Insights and Open Questions

“…According to the European Medicines Agency’s Committee for Advanced Therapies, CAR T cells are an advanced therapy medicinal product (ATMP) ( Buechner et al, 2018 ; Vucinic et al, 2021 ). Industrial production of CAR T cells requires standardization of multi-process manufacturing steps in order to reduce the variability of the final product and meet the efficacy observed in clinical studies ( Wang and Rivière, 2016 ; Stroncek et al, 2019 ; Abou-El-Enein et al, 2021 ).…”

Underlying mechanisms of evasion from NK cells as rationale for improvement of NK cell-based immunotherapies

“…During the last two decades, the CAR technology has been developed as next generation immunotherapeutic approach reaching impressive clinical results in two hematological disorders, the acute lymphoblastic leukemia and diffuse large B cell lymphoma. This led to more than 800 clinical trials worldwide (clinicaltrials.gov) ( 133 ) as well as to five approved CAR T cell products, the first four targeting CD19 and the last one directed against BCMA, respectively ( 134 ). In a similar way, engineered CAR NK cells redirected against several cancer epitopes including hematological and tumor targets resulted in improved NK cell cytotoxicity ( 135 – 138 ).…”