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Since their first production in 2007, human induced pluripotent stem cells (iPSCs) have provided a novel platform for the development of various cell therapies targeting a spectrum of diseases, ranging from rare genetic eye disorders to cancer treatment. However, several challenges must be tackled for iPSC-based cell therapy to enter the market and achieve broader global adoption. This white paper, authored by the Japanese Society for Regenerative Medicine (JSRM) - International Society for Cell Therapy (ISCT) iPSC Committee delves into the hurdles encountered in the pursuit of safe and economically viable iPSC-based therapies, particularly from the standpoint of the cell therapy industry. It discusses differences in global guidelines and regulatory frameworks, outlines a series of quality control tests required to ensure the safety of the cell therapy, and provides details and important considerations around cost of goods (COGs), including the impact of automated advanced manufacturing. [ABSTRACT FROM AUTHOR]

The article discusses the interaction of regulatory frameworks associated with approval of global medicinal product and unproven cellular therapies to evaluate their benefits and risks.

The successful commercialization of cell therapies requires thorough planning and consideration of product quality, cost and scale of the manufacturing process. The implementation of automation can be central to a robust and reproducible manufacturing process at industrialized scales. There have been a number of wash-and-concentrate devices developed for cell manufacturing. These technologies have arisen from transfusion medicine, hematopoietic stem cell and biologics manufacturing where operating mechanisms are distinct from manual centrifugation. This review describes the historical origin and fundamental technologies underlying each currently available wash-and-concentrate device as well as their relative advantages and disadvantages in cell therapy applications. Understanding the specific attributes and limitations of these technologies is essential to optimizing cell therapy manufacturing. [Display omitted] [ABSTRACT FROM AUTHOR]

The article discusses views of the 2015 International Society for Cellular Therapy (ISCT) on the issue of unproven cellular therapies for patients, which are not recognized on medical grounds.

In a phase I study of autologous chimeric antigen receptor (CAR) anti-LeY T-cell therapy of acute myeloid leukemia (AML), we examined the safety and postinfusion persistence of adoptively transferred T cells. Following fludarabine-containing preconditioning, four patients received up to 1.3 × 109 total T cells, of which 14-38% expressed the CAR. Grade 3 or 4 toxicity was not observed. One patient achieved a cytogenetic remission whereas another with active leukemia had a reduction in peripheral blood (PB) blasts and a third showed a protracted remission. Using an aliquot of In111-labeled CAR T cells, we demonstrated trafficking to the bone marrow (BM) in those patients with the greatest clinical benefit. Furthermore, in a patient with leukemia cutis, CAR T cells infiltrated proven sites of disease. Serial PCR of PB and BM for the LeY transgene demonstrated that infused CAR T cells persisted for up to 10 months. Our study supports the feasibility and safety of CAR-T-cell therapy in high-risk AML, and demonstrates durable in vivo ­persistence.Molecular Therapy (2013); 21 11, 2122-2129. doi:10.1038/mt.2013.154 [ABSTRACT FROM AUTHOR]

The role of the peripheral blood (PB) CD34+ cell count in predicting the CD34+ cell yield in hematopoietic progenitor cell apheresis collections is well established. However, sometimes unexpectedly poor CD34+ cell yields are obtained. To determine the effect, if any, of a range of factors on the ability of the PB CD34+ count to predict collection CD34+ cell count, we performed a retrospective analysis on consecutive hematopoietic progenitor cell apheresis collections between 2004 and 2008. Factors investigated included mobilization regimen, PB white blood cell count, body weight, and disease. After exclusion of collections involving apheresis complications, a total of 1,225 PB CD34+ cell results with corresponding collection CD34+ cell results from 458 patients were analyzed. Although differences in the median PB CD34+ cell counts and collection CD34+ cell counts were seen between mobilized collections with chemotherapy plus granulocyte colony-stimulating factor and those with granulocyte colony-stimulating factor alone, the predictive capability of the PB CD34+ cell count for the collection CD34+ cell yield remained similar. Although poorer collection efficiencies were observed in the myelodysplastic syndrome/myeloproliferative disorder diagnostic subgroup, our findings confirm that PB CD34+ cell analysis remains a powerful and irreplaceable tool for predicting hematopoietic progenitor cell apheresis CD34+ cell yield. [Copyright &y& Elsevier]

Background & Aims: HCV patients who fail conventional interferon-based therapy have limited treatment options. Dendritic cells are central to the priming and development of antigen-specific CD4+ and CD8+ T cell immunity, necessary to elicit effective viral clearance. The aim of the study was to investigate the safety and efficacy of vaccination with autologous dendritic cells loaded with HCV-specific cytotoxic T cell epitopes. Methods: We examined the potential of autologous monocyte-derived dendritic cells (MoDC), presenting HCV-specific HLA A2.1-restricted cytotoxic T cell epitopes, to influence the course of infection in six patients who failed conventional therapy. Dendritic cells were loaded and activated ex vivo with lipopeptides. In this phase 1 dose escalation study, all patients received a standard dose of cells by the intradermal route while sequential patients received an increased dose by the intravenous route. Results: No patient showed a severe adverse reaction although all experienced transient minor side effects. HCV-specific CD8+ T cell responses were enumerated in PBMC by ELIspot for interferon-γ. Patients generated de novo responses, not only to peptides presented by the cellular vaccine but also to additional viral epitopes not represented in the lipopeptides, suggestive of epitope spreading. Despite this, no increases in ALT levels were observed. However, the responses were not sustained and failed to influence the viral load, the anti-HCV core antibody response and the level of circulating cytokines. Conclusions: Immunotherapy using autologous MoDC pulsed with lipopeptides was safe, but was unable to generate sustained responses or alter the outcome of the infection. Alternative dosing regimens or vaccination routes may need to be considered to achieve therapeutic benefit. [ABSTRACT FROM AUTHOR]

Infusions of ex vivo-expanded (EXE) mobilized blood cells have been explored to enhance haematopoietic recovery following high dose chemotherapy (HDT). However, prior studies have not consistently demonstrated improvements in trilineage haematopoietic recovery. Three cohorts of three patients with breast cancer received three cycles of repetitive HDT supported by either unmanipulated (UM) and/or EXE cells. Efficacy was assessed by an internal comparison of each patient's consecutive HDT cycles, and to 106 historical UM infusions. Twenty-one cycles were supported by EXE cells and six by UM cells alone. Infusions of EXE cells resulted in fewer days with an absolute neutrophil count (ANC) <0·1 × 109/l (median 2 vs. 4 d, P = 0·002) and 3 d faster ANC recovery to >0·1 × 109/l (median 5 vs. 8 d, P = 0·0002). This resulted in a major reduction in the incidence of febrile neutropenia compared with UM cycles (0% vs. 83%; P = 0·008) and in 66% of historical UM cycles ( P = 0·01) and a marked reduction in hospital re-admission. There were also fewer platelet transfusions required (43% vs. 100%; P = 0·009). We conclude that EXE cells enhance both neutrophil and platelet recovery and reduce febrile neutropenia, platelet transfusion and hospital re-admission. [ABSTRACT FROM AUTHOR]