National Blood Foundation 2021 Research and Development summit: Discovery, innovation, and challenges in advancing blood and biotherapies

Over the last 75 years, the Association for the Advancement of Blood and Biotherapies (AABB) has been advancing blood and biotherapies through professional development, the establishment of standards, and the accreditation of facilities. In 1983, AABB expanded its vision and contribution to advance research, through its National Blood Foundation (NBF). Its early-career grant program has funded more than 200 investigators, many of whom have blazed the trail to become subject matter experts in the field of transfusion medicine, cellular therapies, and regenerative medicine science. Industry contributors represented by the Council on Research and Development (CORD) and other partners are key for financial contribution, engagement, and direction. There have been significant discoveries and innovations over the last 40 years that have impacted the state of the science in immunohematology, transfusion medicine, and biotherapies (see Table 1). Prevention of transfusion-transmitted infectious diseases (TTID) through donor screening has driven safety advancements in blood, organ, tissue, and cellular therapies.1-3 Development and public health advocacy of hepatitis B virus (HBV) vaccine, as well as the identification of human immunodeficiency virus (HIV), and hepatitis C virus (HCV) have significantly impacted blood safety. First tackled through non-renumerated whole blood donations and high-risk donor interview questions, testing significantly reduced TTIDs. Generational advancements in serological detection and development of polymerase chain reaction (PCR) amplification methodology closed the gap between infection and detection.4 Nobel Laurates have been honored for the HBV vaccine, PCR development, HIV as the etiological agent of acquired immunodeficiency syndrome (AIDS), and the discovery of HCV as the etiologic agent of non-A, non-B hepatitis.5-8 1969 1981 1972 1985 1990 1997 1980's 1990's 2019 Advancements in the use of Rh immune globulin (Rh Ig) and pre-storage universal leukoreduction (ULR) are worth noting. At first, Rh Ig was used as a postpartum therapy in eligible women at risk of Rh alloimmunization from an Rh-positive fetus or newborn.9 Protocol modification to include antepartum administration has been significant to reduce Rh alloimmunization and the risk of hemolytic disease of the fetus and newborn (HDFN).10, 11 Likewise, the use of pre-storage leukoreduction, though slow to achieve universal acceptance, has significant benefit to reduced adverse events of transfusion at an incremental cost.12, 13 Advances in the 21st century have been primarily attributed to scientific knowledge at the molecular level of cells.14-18 This has contributed to early advancements of recombinant growth factors, gene manipulation for cellular therapies, and molecular interrogation of blood systems.19, 20 Process improvements in apheresis have also contributed to the ability to collect human peripheral blood progenitor cells and other starting materials for biotherapies.21 Incrementally these discoveries continue to advance the safety and availability of blood and biotherapies. Cell surface modification with designer epitopes has potential as diagnostic, therapeutic, and R&D tools. Such modification to the erythrocyte has been done by Kode technology using Functional head, Spacer, and Lipid (FSL) constructs.22-25 The lipid is necessary for integration into the cell membrane while the different spacers facilitate a variety of conformational and functional properties. The functional head of peptide epitopes is typically less than 20 amino acids and specifically selected to represent the most antigenic regions of a protein; which improves both sensitivity and specificity. Intriguingly kodecyte with peptide epitopes react better with IgG than with IgM antibodies. Over 200 functional Kode constructs have been created using carbohydrates, peptides/proteins, and labels (such as biotin, fluorophores, metals, DNA, and radiolabels). In immunohematology, kodecytes have been used to quality control weak expression of A and B antigens using FSL-A and FSL-B and are suitable for quantification ABO antibodies in undiluted plasma.26 Glycan and peptides kodecyte panels have also been developed for the identification of various blood groups (i.e. Lewis, FORS, and Miltenberger) and as indicators for diagnostic detection of organisms (Treponema pallidum, leptospira, babesia protozoa, cytomegalovirus, Trypanosoma cruzi, and SARS-CoV-2).27, 28 Human platelet lysates (HPL) from outdated platelet concentrates are an animal-origin-free substitute for fetal bovine serum (FBS) in manufacturing a variety of cell-based products for regenerative medicine.29 Large-scale pooling of HPL and use in good manufacturing practice (GMP) laboratories for human primary cell propagation of mesenchymal stem cells and other cells, highlights the requirement for standardization in cell expansion to support safety, efficiency, efficacy, and potency. Since pooled HPLs are not routinely subjected to robust viral removal steps like plasma-derived medicinal products (PDMP), there is a risk that expanded cells propagated in HPL may be contaminated with pathogens that could be transmitted to the recipient of cellular therapy. As pooled HPL is increasingly used as a substitute for FBS, it is evident that similar safety nets such as those used for PDMP need to be established. This includes a GMP environment with donor epidemiology, donor screening, pathogen reduction of the platelet concentrates, when implemented, manufacturing pool testing, viral inactivation, or removal during the HPL process, and traceability. A solvent/detergent (S/D) treatment process for HPL, capable of inactivating lipid-enveloped viruses, was reported over a decade ago.30 Expansion of adipose tissue-derived mesenchymal stromal cells (AT-MSC) using S/D-treated HPL has been reported as good as or better than FBS based on the International Society of Cell and Gene Therapy (CGT) criteria.31, 32 Nanofiltration, similar to that used in plasma fractionation has also been reported to provide over 5 log reduction of non-enveloped viruses as well as the removal of extracellular vesicles.33, 34 Table 2 highlights the numerous trophic factors associated with viral-inactivated HPL. To pursue the regenerative concept of HPL, a tailor-made purified human platelet pellet lysate (HPPL) has been developed for neurologic treatment and is in pre-clinical testing as an intranasal or intracerebroventricular drug.35, 36 This requires a target HPPL product profile with low protein, fibrinogen-depleted, free of coagulation and thrombogenic factors, no proteolytic activities, and virally-reduced.37 This HPPL provides strong neuroprotection of Lund human mesencephalic (LUHMES) cells against various neurotoxins, as well as in a mouse model of Parkinson's disease.37 The use of pathogen-reduced platelet concentrates to produce HPPL has been investigated as well with similar results.38 These were non-toxic, non-inflammatory, and promote wound healing of neuronal cells and neuronal differentiation.39 In traumatic brain injury (TBI) mouse models using topical and intranasal delivery, the HPPL improved motor and cognitive functions while decreasing neuroinflammation and oxidative stress in the injured cortex.40 This implies protection against the loss of cortical synaptic proteins. Using HPPL treatment it was noted that 60% of the genes upregulated by TBI were significantly downregulated. Taken together, these data suggest potential applications of platelet lysates in the treatment of various neurological diseases. Linking research and discovery into the routine blood operation requires a flexible environment to bridge the gap between a creative research environment and the controlled, regulated manufacturing environment. Canadian Blood Services (CBS) representing the national blood service to a majority of Canadian Provinces and Vitalant, the largest independent non-profit blood supplier in the United States have developed an incubator or “sandbox” to translate projects to a process-controlled manufacturing procedure. The incubator or “sandbox” concept is key to bridging from the less regulated environment of the research laboratory to the far more stringently regulated environment of formal preclinical development, controlled manufacturing, and clinical trials (see Figure 1). Independent investigators doing basic and applied research and development are subject to less extensive regulations and in general have more flexibility in designing, executing, and documenting studies. As discoveries and development progress, however, there is a need to transition to the more controlled, regulated environment of preclinical development, manufacturing, and clinical trials. The extent and types of control needed are defined by Good Laboratory Practices (GLPs), which cover formal preclinical animal studies, Good Manufacturing Practices (GMPs) which define manufacturing process control and product characterization, and Good Clinical Practices (GCP), which specify requirements for clinical trials. To facilitate innovation, CBS established a network of Centers for Applied Development (netCAD) linking research and discovery with routine operations and creating a mutual support process among university-based laboratories. Initially, a developmental laboratory was designed as a miniature blood center to explore various processes for buffy coat platelet production supporting the design, development, and validation of the new product and processes without compromising operations. This has been extremely beneficial for CBS operations and research as well as commercial companies to develop a next-generation product for Transfusion Medicine. The “sandbox” concept has enabled CBS to create and validate new standard operating procedures (SOP) as well as a means of monitoring the quality of components to ensure these processes hold to accepted standards. Directing and encouraging deferred donors to the developmental laboratory added a significant contribution for the donor and provided a wealth of information from these deferred donors to inform policy, especially those deferred for men having sex with other men (MSM). Figure 2 focuses on the significant contribution of the developmental laboratory within Canada. It is interesting to note that the developmental lab has a bioregistry of 1200 deferred donors and has provided blood products both internally to CBS and blood researchers in Canada. Vitalant has long valued blood research through its research institute founded by Dr. Herb Perkins in 1959. The evolution of the research laboratory today is the Vitalant Research Institute (VRI) and the newly established Vitalant Innovation Center (VIC). While the VRI “is dedicated to advancing blood safety worldwide through scientific research, education and the promotion of evidence-based policies,” the VIC is focused on translational science (see Figure 3). The VIC, acting as a “sandbox,” bridges innovation from research discovery or customer requirements, process improvements, or changes implemented by regulatory mandates into a safe environment for evaluation and migration into a regulatory controlled process. This enables Vitalant to develop and validate products and procedures while monitoring quality and training before launching the product in the operational environment. Similar to netCAD, the VIC can provide cell sourcing to support preclinical and basic research, perform preclinical and clinical testing of investigational devices for regulatory submissions, manufacture for clinical trials, and provide a biorepository for biological sample storage. Since the launch of the Sputnik 1 satellite in 1957, the Defense Advanced Research Projects Agency (DARPA) of the U.S. Department of Defense (DoD) has been investing in breakthrough technologies for U.S. national security. The high-risk-high reward objectives are aimed for transformational versus incremental advances as it works within an innovation ecosystem that includes the collaboration of academic, corporate, and government partners for pushing boundaries in its research programs. Seeing the need for specific biologic programs, in 2014 DARPA stood up the Biological Technologies Office (BTO), although programming with biological elements continues in other offices. The blood and biotherapy communities have a great opportunity to tap into DARPA's BTO to sharpen the research focus. Brainstorming with and proposing research opportunities to BTO has the potential to bring new solutions to problems within blood and biotherapies, embracing big risks with great reward. Careful evaluation of risks and focusing on risks worth taking are integral to DARPA's approach. George H. Heilmeier, former DARPA Director (1975–1977), established a set of questions known as the “Heilmeier Catechism” to evaluate proposed research programs (see Table 3).41 This evaluation starts with a description of why the new approach will be successful based on the current limit of practice and those of the new approach. The “who cares” factor must also be asked and answered to understand the impact and relevancy of the success of the new approach. Through this process, the risk is identified as well mitigations to help establish cost, timelines, and milestones with quantitative metrics of success. DARPA funding opportunities are made through Broad Agency Announcements (BAAs) for specific programs and for a range of technical areas of interest to each office and can be found with timelines on the DARPA website (https://www.darpa.mil/work-with-us/opportunities). In addition, many DARPA programs include independent verification and validation by US Government partners, which enables testing in additional relevant settings and technology transitions. As well, funded research may be identified to support offshoots or “seedlings” to explore gaps such as the evaluation of technological potential. 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