Tackling major hurdles in cell therapy translational research: Different products, common challenges

Bechara Mfarrej

Research output: ThesisDoctoral thesis 2 (Research NOT UU / Graduation UU)


Cell-based immunotherapies address a number of unmet medical needs and some have shown success. All cell-based immunotherapy products undergo extensive preclinical and proof-of-concept investigations for only a few to reach the bedside. Thus, several hurdles need to be overcome in cell therapy translational research for wider access to such innovative treatments. Major hurdles include, but are not limited to: definitive characterization of cell therapy products, feasibility of upscaling a laboratory-grade cell manufacturing protocol, automation of critical manufacturing processes, standardized quality controls, choice of therapeutic window, comparability between clinical trials and commercial success. The aim of this thesis is to tackle these common challenges faced by different products during preclinical, translational and clinical phases. With several market authorizations and withdrawals by the EMA for advanced therapy medicinal products, it is timely to evaluate the translational activity around cell-based immunotherapy products.
Adoptive transfer of ex vivo expanded T regulatory cells is currently under clinical investigation in solid organ transplantation, autoimmunity, and graft-versus-host disease, yet definitive characterization of their many modes of action remains to be identified. Such mechanisms are reviewed in Chapter 2. In Chapter 3, a preclinical investigation dissects one mechanism by which T regulatory type 1 (Tr1 cells) are therapeutically-induced in vivo in a mouse model of Tr1-induced tolerance to allogeneic islet graft transplantation, identifying macrophages as key players in this induction. In a translational context, feasibility of upscaling a laboratory-grade Tr1 cell manufacturing protocol using reagents and procedures compatible with good manufacturing practices (GMP) is reported along with data supporting the choice of therapeutic window for cell infusion in the upcoming clinical trial (Chapter 4). In an effort to reduce variations in manufacturing and cost-of-goods, feasibility of automating a critical step in hematopoietic stem cell transplantation (HSCT), washing and concentrating thawed cells is established (Chapter 5). To address the need for standardized and accredited quality controls, validation of a quantitative immune-phenotyping method is reported in Chapter 6, of relevance during collection of apheresis products, manufacturing and release of cell-based immunotherapy products. Heterogeneity in manufacturing NK cells for clinical use is reviewed in Chapter 7 while expanding on tools for harmonization of processes and quality controls to address the challenge of comparability between clinical trials. The hurdle of reaching larger patient populations and achieving commercial success is dissected for CAR-T cells in Chapter 8. Management of toxicities, investigating new indications and target tumor antigens, different manufacturing options and off-the-shelf products are addressed.
This thesis documents a unique career path covering the spectrum from bench to bedside to provide arguments to many hurdles facing cell therapy translational research. Others surely remain, for instance role of patients in product development. Activating and suppressive cell-based immunotherapies alike face these challenges nevertheless possible solutions can be extrapolated from one product to another for the benefit of larger patient populations.
Original languageEnglish
Awarding Institution
  • University Medical Center (UMC) Utrecht
  • Chabannon, C., Primary supervisor, External person
  • Prakken, Berent, Supervisor
  • Battaglia, M., Co-supervisor
Award date29 Nov 2019
Place of Publication[Utrecht]
Print ISBNs978-94-93184-17-6
Publication statusPublished - 29 Nov 2019


  • cell-based immunotherapy
  • translational research
  • Advanced therapy medicinal products


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