Harnessing global HLA data for enhanced patient matching in iPSC haplobanks.

Background: Several countries have either developed or are developing national induced pluripotent stem cell (iPSC) banks of cell lines derived from donors with HLA homozygous genotypes (two identical haplotypes) prevalent in their local populations to provide immune matched tissues and cells to support regenerative medicine therapies. This 'haplobank' approach relies on knowledge of the HLA genotypes of the population to identify the most beneficial haplotypes for patient coverage, and ultimately identify donors or cord blood units carrying two copies of the target haplotype.

Aims: A potentially more efficient alternative to a national bank approach is to assess the haplotypes required to provide global patient coverage and to produce a single, global haplobank.

The infected blood inquiry report-lessons for gamete donation.

Donation of substances of human origin (SoHO) is essential for the treatment of many patients and ranges from the donation of whole organs to the donation of tissue or cell products, including also gamete donation. In order to ensure the safety of recipients of SoHOs there are multiple steps taken in the donation pathway of all such substances to ensure the quality and safety of the donation. However, despite this, there is always a residual risk associated with SoHOs.

EBV T-cell immunotherapy generated by peptide selection has enhanced effector functionality compared to LCL stimulation.

Adoptive immunotherapy with Epstein-Barr virus (EBV)-specific T cells is an effective treatment for relapsed or refractory EBV-induced post-transplant lymphoproliferative disorders (PTLD) with overall survival rates of up to 69%. EBV-specific T cells have been conventionally made by repeated stimulation with EBV-transformed lymphoblastoid cell lines (LCL), which act as antigen-presenting cells. However, this process is expensive, takes many months, and has practical risks associated with live virus.

Long-range inhibition synchronizes and updates prefrontal task activity.

Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates and humans to update their behaviour to adapt to changes in the environment-for example, during cognitive tasks. Parvalbumin-expressing inhibitory neurons in the medial prefrontal cortex are important for learning new strategies during a rule-shift task, but the circuit interactions that switch prefrontal network dynamics from maintaining to updating task-related patterns of activity remain unknown. Here we describe a mechanism that links parvalbumin-expressing neurons, a new callosal inhibitory connection, and changes in task representations.

Subclinical infection occurs frequently following low dose exposure to prions by blood transfusion.

Infectious prion diseases have very long incubation periods, and the role that subclinical infections play in transmission, persistence and re-emergence of these diseases is unclear. In this study, we used a well-established model of vCJD (sheep experimentally infected with bovine spongiform encephalopathy, BSE) to determine the prevalence of subclinical infection following exposure by blood transfusion from infected donors. Many recipient sheep survived for years post-transfusion with no clinical signs and no disease-associated PrP (PrP) found in post mortem tissue samples by conventional tests.

Recommendations for procurement of starting materials by apheresis for advanced therapy medicinal products.

Activities involved in the production of certain advanced therapy medicinal products (ATMPs) require standardized approaches to mononuclear cell procurement to ensure the highest product quality, safety and process efficiency. These aims must be achieved while meeting regulatory and accreditation requirements for the procurement of mononuclear cells as starting materials. Mononuclear cells constitute the starting materials for many ATMPs, and this article sets out recommendations for procurement by clinical apheresis, addressing the variation among existing working practices and different manufacturers' requirements that currently poses a challenge when managing multiple different protocols.

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses.

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes.

Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH).

Introduction: Liver cirrhosis is a growing global healthcare challenge. Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and complications related to portal hypertension. There are no licensed antifibrotic or proregenerative medicines and liver transplantation is a scarce resource.

Cytometric analysis of T cell phenotype using cytokine profiling for improved manufacturing of an EBV-specific T cell therapy.

Adoptive immunotherapy using Epstein-Barr Virus (EBV)-specific T cells is a potentially curative treatment for patients with EBV-related malignancies where other clinical options have proved ineffective. We describe improved good manufacturing practice (GMP)-compliant culture and analysis processes for conventional lymphoblastoid cell line (LCL)-driven EBV-specific T cell manufacture, and describe an improved phenotyping approach for analysing T cell products. We optimized the current LCL-mediated clinical manufacture of EBV-specific T cells to establish an improved process using xenoprotein-free GMP-compliant reagents throughout, and compared resulting products with our previous banked T cell clinical therapy.

Preclinical transmission of prions by blood transfusion is influenced by donor genotype and route of infection.

Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease resulting from zoonotic transmission of bovine spongiform encephalopathy (BSE). Documented cases of vCJD transmission by blood transfusion necessitate on-going risk reduction measures to protect blood supplies, such as leucodepletion (removal of white blood cells, WBCs). This study set out to determine the risks of prion transmission by transfusion of labile blood components (red blood cells, platelets, plasma) commonly used in human medicine, and the effectiveness of leucodepletion in preventing infection, using BSE-infected sheep as a model.

Estimation of manufacturing development costs of cell-based therapies: a feasibility study.

Background Aims: Cell-based therapies (CBTs) provide opportunities to treat rare and high-burden diseases. Manufacturing development of these innovative products is said to be complex and costly. However, little research is available providing insight into resource use and cost drivers.

Rapid GMP-Compliant Expansion of SARS-CoV-2-Specific T Cells From Convalescent Donors for Use as an Allogeneic Cell Therapy for COVID-19.

COVID-19 disease caused by the SARS-CoV-2 virus is characterized by dysregulation of effector T cells and accumulation of exhausted T cells. T cell responses to viruses can be corrected by adoptive cellular therapy using donor-derived virus-specific T cells. One approach is the establishment of banks of HLA-typed virus-specific T cells for rapid deployment to patients.

Haplobanking induced pluripotent stem cells for clinical use.

The development of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and colleagues in 2006 has led to a potential new paradigm in cellular therapeutics, including the possibility of producing patient-specific, disease-specific and immune matched allogeneic cell therapies. One can envisage two routes to immunologically compatible iPSC therapies: using genetic modification to generate a 'universal donor' with reduced expression of Human Leukocyte Antigens (HLA) and other immunological targets or developing a haplobank containing iPSC lines specifically selected to provide HLA matched products to large portions of the population. HLA matched lines can be stored in a designated physical or virtual global bank termed a 'haplobank'.

The Global Alliance for iPSC Therapies (GAiT).

The Global Alliance for iPSC Therapies (GAiT) is a new initiative to support the implementation and clinical application of therapies derived from pluripotent stem cells to the benefit of patients globally. GAiT's mission is to serve as a central, international resource for those organisations developing therapies from clinical-grade induced pluripotent stem cells, and to support the expansion of this nascent field. With the support of its international partners, GAiT already has an early position on manufacturing, regulatory and quality standards.

Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020.

BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.

Pancreas-derived mesenchymal stromal cells share immune response-modulating and angiogenic potential with bone marrow mesenchymal stromal cells and can be grown to therapeutic scale under Good Manufacturing Practice conditions.

Background Aims: Mesenchymal stromal cells (MSCs) isolated from various tissues are under investigation as cellular therapeutics in a wide range of diseases. It is appreciated that the basic biological functions of MSCs vary depending on tissue source. However, in-depth comparative analyses between MSCs isolated from different tissue sources under Good Manufacturing Practice (GMP) conditions are lacking.

What does cell therapy manufacturing cost? A framework and methodology to facilitate academic and other small-scale cell therapy manufacturing costings.

Background Aims: Recent technical and clinical advances with cell-based therapies (CBTs) hold great promise in the treatment of patients with rare diseases and those with high unmet medical need. Currently the majority of CBTs are developed and manufactured in specialized academic facilities. Due to small scale, unique characteristics and specific supply chain, CBT manufacturing is considered costly compared to more conventional medicinal products.

Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants.

Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b).

Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization.

Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation.

Safety profile of autologous macrophage therapy for liver cirrhosis.

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 10, 10 or up to 10 cells.

Microcircuit Mechanisms through which Mediodorsal Thalamic Input to Anterior Cingulate Cortex Exacerbates Pain-Related Aversion.

Hyperexcitability of the anterior cingulate cortex (ACC) is thought to drive aversion associated with chronic neuropathic pain. Here, we studied the contribution of input from the mediodorsal thalamus (MD) to ACC, using sciatic nerve injury and chemotherapy-induced mouse models of neuropathic pain. Activating MD inputs elicited pain-related aversion in both models.

A Report from a Workshop of the International Stem Cell Banking Initiative, Held in Collaboration of Global Alliance for iPSC Therapies and the Harvard Stem Cell Institute, Boston, 2017.

This report summarizes the recent activity of the International Stem Cell Banking Initiative held at Harvard Stem Cell Institute, Boston, MA, USA, on June 18, 2017. In this meeting, we aimed to find consensus on ongoing issues of quality control (QC), safety, and efficacy of human pluripotent stem cell banks and their derivative cell therapy products for the global harmonization. In particular, assays for the QC testing such as pluripotency assays test and general QC testing criteria were intensively discussed.