Part 3: Understanding the manufacturing of unproven cellular therapy products

Abstract

As stated in the other parts of this guide, the delivery of cells to patients requires transparent, rigorous manufacturing steps that are clearly defined and well understood. What raises a concern is the manufacturing of cellular-therapy products that seem to originate in an engineering “black box.” Tissues go in to the black box, and cells emerge ready for use despite the fact that there is little clarity about what has occurred. Production for clinical use encompasses a wide array of possible manufacturing approaches ranging from essentially no processing or manipulation to extensive procedures including ex vivo culture and gene modification [ 1 Abbasalizadeh S. Baharvand H. Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies. Biotechnol Adv. 2013; 31: 1600-1623 Crossref PubMed Scopus (63) Google Scholar , 2 Eaker S. Armant M. Brandwein H. et al. Concise review: guidance in developing commercializable autologous/patient-specific cell therapy manufacturing. Stem Cells Transl Med. 2013; 2: 871-883 Crossref PubMed Scopus (44) Google Scholar ]. Similar to the concerns of how to evaluate the appropriate use and clinical indication of cellular therapy products, it is of utmost importance to consider cell manufacturing to properly assess the risk factors in certain treatments [ [3] von Tigerstrom B. Product regulation and the clinical translation of stem cell research. Stem Cell Rev. 2009; 5: 135-139 Crossref PubMed Scopus (15) Google Scholar ]. In recent years, there have been instances of safety concerns about cell therapy products [ 4 Dlouhy B.J. Awe O. Rao R.C. Kirby P.A. Hitchon P.W. Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient: case report. J Neurosurg Spine. 2014; 21: 618-622 Crossref PubMed Scopus (118) Google Scholar , 5 Amariglio N. Hirshberg A. Scheithauer B.W. et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009; 6: e1000029https://doi.org/10.1371/journal.pmed.1000029 Crossref PubMed Scopus (739) Google Scholar , 6 Kawarai T. Tsuda R. Taniguchi K. et al. Spinal myoclonus resulting from intrathecal administration of human neural stem cells. Mov Disord. 2011; 26: 1358-1360 Crossref PubMed Scopus (3) Google Scholar , 7 Jones S.D. Levine H.L. McKee S. Emerging Challenges in Cell Therapy Manufacturing. 2012 Google Scholar ] and their manufacturing steps [ 7 Jones S.D. Levine H.L. McKee S. Emerging Challenges in Cell Therapy Manufacturing. 2012 Google Scholar , 8 Stephenson E. Ogilvie C.M. Patel H. et al. Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells. J R Soc Interface. 2010; 7: S677-88 Crossref PubMed Scopus (30) Google Scholar , 9 Borgonovo T. May Vaz I. Senegaglia A.C. Kuniyoshi Rebelatto C.L. Slud Brofman P.R. Genetic evaluation of mesenchymal stem cells by G-banded karyotyping in a Cell Technology Center. Rev Bras Hematol Hemoter. 2014; 36: 202-207 Crossref PubMed Scopus (34) Google Scholar ], particularly within unproven cellular therapy approaches. Although these concerns can be independent of the broader question of the product efficacy, they contribute to the controversy of unproven cellular therapy products.