Objectives, benefits and challenges of bioreactor systems for the clinical-scale expansion of T lymphocyte cells.

Cell therapies based on T cell have gathered interest over the last decades for treatment of cancers, becoming recently the most investigated lineage for clinical trials. Although results of adoptive cell therapies are very promising, obtaining large batches of T cell at clinical scale is still challenging nowadays. We propose here a review study focusing on how bioreactor systems could increase expansion rates of T cell culture specifically towards efficient, reliable and reproducible cell therapies. After describing the specificities of T cell culture, in particular activation, phenotypical characterization and cell density considerations, we detail the main objectives of bioreactors in this context, namely scale-up, GMP-compliance and reduced time and costs. Then, we report recent advances on the different classes of bioreactor systems commonly investigated for non-adherent cell expansion, in comparison with the current "gold standard" of T cell culture (flasks and culture bag). Results obtained with hollow fibres, G-Rex® flasks, Wave bioreactor, multiple-step bioreactors, spinner flasks as well as original homemade designs are discussed to highlight advantages and drawbacks in regards to T cells' specificities. Although there is currently no consensus on an optimal bioreactor, overall, most systems reviewed here can improve T cell culture towards faster, easier and/or cheaper protocols. They also offer strong outlooks towards automation, process control and complete closed systems, which could be mandatory developments for a massive clinical breakthrough. However, proper controls are sometimes lacking to conclude clearly on the features leading to the progresses regarding cell expansion, and the field could benefit from process engineering methods, such as quality by design, to perform multi parameters studies and face these challenges.