Perspectives on Manufacturing of High-Quality Cell Therapies

摘要

Cell therapies are taking center stage in medicine spanning cancer immunotherapy, stem cell engineering, and regenerative medicine. Recently, the first ex vivo hematopoietic stem cell (HSC) gene therapy for the treatment of adenosine deaminase deficiency-severe combined immunodeficiency (ADA-SCID) received marketing approval.1Ylä-Herttuala S. ADA-SCID gene therapy endorsed by European medicines agency for marketing authorization.Mol. Ther. 2016; 24: 1013-1014Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar By now, the majority of the 150 plus patients who have received HSC gene therapy to treat monogenic diseases have demonstrated clinical benefits.2Wang X. Riviere I. Genetic engineering and manufacturing of hematopoietic stem cells.Mol. Ther. Methods Clin. Dev. 2017; 5: 96-105Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Promising clinical outcomes in phase I/II trials based on T cells engineered to express T cell chimeric antigen receptors (CARs)3Sadelain M. CAR therapy: the CD19 paradigm.J. Clin. Invest. 2015; 125: 3392-3400Crossref PubMed Scopus (171) Google Scholar against hematological malignancies have also spurred unprecedented interest from pharmaceutical and biotechnology companies. As a result, CD19-targeted CAR T cells may soon receive marketing approval.4Walker A. Johnson R. Commercialization of cellular immunotherapies for cancer.Biochem. Soc. Trans. 2016; 44: 329-332Crossref PubMed Scopus (20) Google Scholar As living drugs, cell therapies pose unique commercialization challenges in terms of manufacturing, standardization, and distribution.4Walker A. Johnson R. Commercialization of cellular immunotherapies for cancer.Biochem. Soc. Trans. 2016; 44: 329-332Crossref PubMed Scopus (20) Google Scholar, 5Wang X. Riviere I. Clinical manufacturing of CAR T cells: foundation of a promising therapy.Mol. Ther. Oncolytics. 2016; 3: 16015Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 6Roh K.H. Nerem R.M. Roy K. Biomanufacturing of therapeutic cells: state of the art, current challenges, and future perspectives.Annu. Rev. Chem. Biomol. Eng. 2016; 7: 455-478Crossref PubMed Scopus (45) Google Scholar Automated, robust, and cost-effective production platforms compliant with current good manufacturing practices (cGMP) coupled with robust analytics, which ensure reproducible cell quality, are needed to broaden the availability and realize the commercialization potential of these complex, predominantly personalized, therapeutic modalities. HSC and CAR-T cell engineering processes commonly start from an autologous or donor apheresis. The inter-institution and inter-patient variability that are inherent to apheresis collection and composition, the paucity of well-defined and quantifiable critical quality attributes (CQAs), and the requirement for cGMP-grade culture media components and ancillary genetic modifiers, such as viral vectors and CRISPR/Cas9 components, add to the complexity of these therapeutic modalities.5Wang X. Riviere I. Clinical manufacturing of CAR T cells: foundation of a promising therapy.Mol. Ther. Oncolytics. 2016; 3: 16015Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 6Roh K.H. Nerem R.M. Roy K. Biomanufacturing of therapeutic cells: state of the art, current challenges, and future perspectives.Annu. Rev. Chem. Biomol. Eng. 2016; 7: 455-478Crossref PubMed Scopus (45) Google Scholar, 7Eyquem J. Mansilla-Soto J. Giavridis T. van der Stegen S.J. Hamieh M. Cunanan K.M. Odak A. Gönen M. Sadelain M. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection.Nature. 2017; 543: 113-117Crossref PubMed Scopus (963) Google Scholar To decrease the production scale and shorten the time in culture, cell subsets known to provide optimal therapeutic effects and limited toxicities may be selected to initiate manufacturing8Sommermeyer D. Hudecek M. Kosasih P.L. Gogishvili T. Maloney D.G. Turtle C.J. Riddell S.R. Chimeric antigen r