Scale up of Platelet Production from Human Pluripotent Stem Cells for Developing Targeted Therapies: Advances and Challenges
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CELL & GENE THERAPY INSIGHTS STRATEGIES FOR SCALE-UP & SCALE-OUT EXPERT INSIGHT Scale up of platelet production from human pluripotent stem cells for developing targeted therapies: advances and challenges Jonathan N Thon & Sven M Karlsson Without question, the future of regenerative medicine is in the scalable production of transfusable human tissues for therapeutic use. Platelets will be among the first of these stem-cell based therapeutic tissues to be developed and adopted for clinical use, most notably because they are anucleate and can be safely irradiated to substantially reduce the risk of teratoma development and other cell contaminants. Furthermore, plate- lets are short-lived, well characterized, easily transplanted, are not re- quired to be autologous, and support a larger than $20 billion per year global market that relies entirely on human volunteer donors. While we are within a decade of realizing the potential of stem cell-based therapeu- tics, this was not obvious only several years ago. This article identifies the major logistical challenges associated with commercially scaling platelet production for therapeutic use and our experiential insights into translat- ing this technology to the clinic. Submitted for review: Sep 6 2017 u Published: Nov XX 2017 While platelets are primarily re- immunity [1–6]. Among the stem be safely irradiated to kill any con- sponsible for clot formation at sites cell-based therapeutic landscape, taminating nucleated cells, thereby of active hemorrhage, it is becom- platelets are an ideal early entrant reducing the risk of teratoma devel- ing increasingly apparent that they because they: are in high clinical de- opment [8,9]; do not require HLA or also play significant roles in wound mand due to their short inventory blood type matching for the major- healing, angiogenesis and innate shelf-life [7]; are anucleate and can ity (>90%) of platelet transfusions, www.insights.bio 701 CELL & GENE THERAPY INSIGHTS which will facilitate large-scale for cell culture, tissue regenera- manufacture of allogeneic human tion, wound healing, drug delivery, pluripotent stem cells (hPSCs) for and there is even work in the cos- off-the-shelf therapy (Box 1); are metics industry using platelets for short-lived and well characterized, skin rejuvenation [16–28]. Platelet which will simplify projected clin- BioGenesis is addressing this need ical trials [10]; are easily transplant- by establishing a scalable, current ed [11]; and would benefit tremen- good manufacturing practice (cG- dously from sterile manufacture, as MP)-compliant commercial plat- current donor-based platelet trans- form to make safe and functional fusions are inherently susceptible to human platelets [29]. In this arti- bacterial and viral contamination cle, we describe the challenges in [12,13]. bringing hPSC-platelets from the Current platelet demand exceeds research phase through to com- supply by ~20% [14], and unmet mercially viable products. We lay demand is expected to more than out best practices for overcoming double by 2022 due to a growing these obstacles, ensuring regulatory and aging population requiring compliance, establishing a scalable more platelet-based procedures, process, and securing freedom to new medications that reduce plate- operate. We conclude with trans- let counts, and the expansion of lational insights into the future of existing uses of platelet transfusions regenerative medicine and the mar- to improve healing time [15]. In the ket expansion of stem cell-derived USA, the blood market effectively platelet products. operates as an oligopoly, with the While all platelets are hPSC-de- American Red Cross and Ameri- rived, for the purposes of this article ca’s Blood Centers each controlling hPSC-derived platelets will refer to a little less than half of the market platelets generated outside the hu- and HemeXcel as the third major man body by industrial cell culture. blood provider. There are numerous other potential markets for plate- lets and their growth factors that are currently constrained by lack COMMERCIALIZATION of access to platelets. For example, CHALLENGES platelet growth factors can be used There is a tremendous amount of f BOX 1 variability among donated plate- lets and the various quality assess- Platelets synthesize class I HLA (but not class II). While platelets ab- ment metrics that are used to gauge sorb soluble HLA antigens from plasma, leading to relatively high- platelet function [30]. Despite this er numbers of class I HLA antigens on their surface as compared to red cells and granulocytes, the incidence of HLA antibodies follow- fact, there has been a historical pre- ing platelet transfusion is low (10–20%) [71,72]. Interestingly, >50% sumption that donor-derived plate- of patients with HLA antibodies fail to manifest refractoriness, such lets ‘work’, and there is no single that the incidence of HLA-mediated refractoriness following platelet gold-standard assay to assess donor transfusion is only 3–5% [71]. platelet unit quality and function Serum-free production of platelets should result in lower num- ex vivo ahead of transfusion. Instead, cur- bers of class I HLA antigens on their surface potentially resulting in a lower incidence of HLA-refractoriness still. While this prediction will rent US Food and Drug Admin- need to be borne out in the data, it argues strongly against the need to istration (FDA) requirements re- invest in the production of HLA-null (universal) platelets as a first-tier garding platelet unit preparation product. focus on storage temperature, pH, 702 DOI: 10.18609/cgti.2017.068 expert INSIGHT residual leukocyte count and bac- f Establishing a consistent terial/viral contamination rate. To differentiation protocol that avoids serum or feeder-cells, license platelets based on post-stor- which would likely make age radiolabeled autologous platelet regulatory approval substantially viability measurements in normal more challenging and add variability and contamination risk subjects, the FDA requires that the to the product. lower post-storage 95% confidence f Developing an industrial limits (LCLs) for platelet recoveries process during early stages of are ≥66% and survivals are ≥58% of development that will scale to the same subject’s radiolabeled fresh meet future clinical and then commercial demand for hPSC- recoveries and survivals, respectively derived platelets, so that the [31]. While donors volunteer plate- process does not need to be lets, procurement of platelet units is redeveloped at each stage. not free. Blood bankers, who are the f Prioritizing first quality and key decision makers for platelet or- then cost, so that hPSC-derived platelets will meet regulatory ders and distribution, choose their requirements and result in a platelet supplier based on availabil- product that is commercially ity and price (Box 2). Therefore, in viable. addition to demonstrating non-in- The tradeoff between focusing feriority relative to donor platelets, on quality and cost is the principal hPSC-derived platelets need to be challenge for regenerative medicine cost-competitive to warrant com- and a significant barrier to creating mercial adoption. a scalable and profitable business The improved safety, projected in this space. While regenerative ‘on-demand’ availability, function- medicine is expected to ultimately al definition of product, and low- improve patient safety and reduce er inter-unit variability constitute overall costs, PSC-derived prod- the major value propositions that ucts are likely to be more expensive will drive market adoption of hP- in the short term. It will therefore SC-derived platelets over donor require all stakeholders working platelets. Additionally, the reduced together to support a commercial inter-unit variability will substan- path to market for early regenera- tially empower physicians to begin tive medicine technologies such as predicting how donors will respond platelets, by supporting transforma- to platelet transfusions. Commer- tive advancements in this space and cial development of hPSC-derived providing reimbursement rates that platelets should therefore strive to reflect these long-term benefits. leverage the value propositions of donor independence (sterile, safe, and scalable products) and on-de- mand manufacturing capability by: REGULATORY f Advancing a donor-independent, COMPLIANCE cGMP-compliant hPSC line Current Good Manufacturing Prac- rather than developing processes around research grade or animal tice comprises a set of standards lines that cannot be advanced that are set forth by the FDA that clinically, or relying on primary describe ways that manufacturing CD34+ stem cells that carry the same availability, sterility and processes and facilities must be cost limitations as donor-derived designed, overseen, and operated. platelets. Observation of cGMP during the Cell & Gene Therapy Insights - ISSN: 2059-7800 703 CELL & GENE THERAPY INSIGHTS f BOX 2 f Clinical development plan, A leukoreduced, irradiated apheresis platelet unit in the United States including: costs approximately $1000 when accounting for the cost of discard- f Phase 1 clinical study synopsis ed units. Leukoreduced (non-irradiated) platelet units are marginally f Phase 2 clinical study synopsis cheaper, averaging just under $750 per unit and comprising an addi- tional ~50% of all platelets transfused. Prices vary greatly depending While this is an ever-changing on supply and demand [73–76]. landscape, there are guiding prin- ciples that will need to