Main Text In this issue of Stem Cell Reports two

Main Text In this issue of Stem Cell Reports, two critically important studies describe negative results of a neural stem cell (NSC) product (HuCNS-SC) intended for clinical use in a model of cervical spinal cord injury (SCI) (Anderson et al., 2017) and in a model of Alzheimer’s disease (Marsh et al., 2017). Anderson et al. reported that they relayed their negative results to the company 6 months ahead of the first patient dosing, and yet the decision was made to continue with a cervical SCI clinical trial. Data obtained from the first six patients in this clinical Pathway Study showed an initial small improvement that did not persist at later study time points (up to 1 year), and a decision was made to terminate the trial in May 2016; for business reasons, the company providing HuCNS-SC, StemCells Inc., folded. The two reports raise several important questions. Why did research grade NSCs show benefit in pre-clinical models of cervical SCI whereas a comparable clinical lot did not (Anderson et al., 2017)? Was the preclinical failure predictive of failure for the clinical Pathway Study? And how should stakeholders—regulatory officials, physicians, and participants—be best informed about failed efficacy data in order to decide whether to continue with or participate in a clinical study? The need for discussion about how cell products are characterized and tested for comparability and how these data are used is heightened by the drive to accelerate the approval process for regenerative therapy products, already accomplished in several countries and expected to result from the US 21st Century Cures Act. After demonstrating efficacy of research-grade HuCNS-SC tak1 inhibitor in murine thoracic spinal cord injury models, the Cummings lab was excited to explore the application of this product to the more severe cervical injury. Anderson et al. (2017) performed a controlled, masked study to assess the efficacy of HuCNS-SC for cervical SCI using a clinical cell line (CCL) supplied by StemCells Inc. A “comparable” research grade cell line (RCL) was also provided by StemCells Inc. All the cell preparations were shipped overnight with appropriate monitoring and transplanted on day of receipt. The RCL product showed efficacy for SCI in immunodeficient Rag2γ mice injected with 75,000 cells at 9 days or 60 days post injury. Locomotor function was significantly improved at 12 weeks when RCL NSCs were transplanted at 9 days post injury, with less effect for 60 day post-injury transplants. The CCL groups, however, showed no locomotor improvement at either time point and, in fact, a possible worsening of outcomes associated with more extensive CCL engraftment. Based on the lack of efficacy in the CCL studies, these results might explain the lack of efficacy in the Pathway Study. In a companion study aimed at demonstrating the therapeutic potential of StemCells Inc.’s HuCNS-SC in an Alzheimer’s disease animal model, clinical-grade cells were transplanted into the brain of Rag-5xfAD mice. Despite robust engraftment, treated animals did not improve cognition, increase BDNF, or increase synaptic density at 5 months after transplantation. This was in contrast to prior studies using a research grade HuCNS-SC preparation provided by StemCells Inc. that showed promising results in an Alzheimer’s disease model at 1 month post transplantation (Ager et al., 2015). In addition, the longer duration study found periventricular cell clusters in a subset of animals—clusters resembling rare neurocytoma tumors according to one of the pathologists. This study amplifies concern about differences between the test cell preparations and points to the importance of performing longer-term functional and safety studies in pre-clinical models of central nervous system repair. With the increasing use of pluripotent-derived cell types for CNS repair, it has become possible to generate sufficient FCP to allow both pre-clinical testing and clinical study on the same lot. This resolves uncertainty regarding FCP potency and provides a fully tested “off-the-shelf” product, albeit one limited by having to directly transplant cryopreserved product and to start with a single stem cell source capable of generating lots of adequate size. Furthermore, the approach does not resolve the longer-term problem, as eventually even a large lot of FCP will run out. Moreover, in the case of individualized iPSC-based treatment or the use of HLA-matched iPSC banks, it may not be feasible to test every FCP in definitive pre-clinical animal studies. Given the possibility for variation demonstrated by the papers in this issue, should each new cell line be given a unique identifier that is disclosed to investigators and participants in the clinical trial so that they understand which cells are provided and the levels of functional characterization performed on those cells? When the cell product is labeled the same (in this case all are labeled HuCNS-SC), how can patients and physicians know the extent of testing that has been performed on a particular line and understand the risks contributed by product variability in order to make an informed decision on whether to participate in a trial? This point is discussed along with further background to their studies on StemCells Inc.’s products and implications for clinical advancement of cell therapies (Anderson and Cummings, 2016).