Umbilical Cord Blood-Derived Therapies as a Treatment for Graft-Versus-Host Disease

Umbilical cord blood (UCB) has been increasingly used as a source of haematopoietic stem cells (HSCs) for transplantation. UCB transplantation (UCBT) has some advantages such as less stringent human leucocyte antigen (HLA) matching and lower impact of graft-versus-host disease (GvHD). UCBT is also characterised by a high rate of infections, graft failure, delayed engraftment and slow recovery of the immune system. UCB contains HSC as well as immune cells that could be considered to develop new treatments for the main complications post-UCBT but also to treat other diseases. GvHD remains a major complication post-CBT and post-haematopoietic stem cell transplantation (HSCT). In view of their ability to induce tolerance and suppress the functions of effector T cells, regulatory T (Treg) cells have been proposed as an adoptive therapy to modulate GvHD post-HSCT. In addition, we showed that UCB contains soluble NKG2D ligands that can modulate the functions of NKG2D expressing cells, making UCB plasma a product of interest to modulate inflammation and in particular skin GvHD. Here, we aim to describe some of the therapies currently developed using UCB, focusing on Treg cells and UCB plasma for the treatment of GvHD

512 the cytokine release syndrome crucially contributes to the anti leukemic effects of cd44v6 car t cells

Background: Despite the remarkable clinical results of CD19 CAR-T cells in B-cell leukemias, their long-term efficacy is limited by the emergence of CD19-loss escape variants. Moreover, whether the cytokine release syndrome (CRS) is necessary for durable remissions is a matter of debate. Currently available xenograft models in NSG mice are not suited for studying the antitumor effects of CAR-T cells beyond 3-4 weeks, because of xenograft-versus-host disease (X-GVHD). Moreover, since NSG mice lack functional myeloid cells, the CRS does not develop. Aim: To verify whether the CRS contributes to the antileukemic effects of CAR in an innovative xenotolerant mouse model.Results: NSG mice triple transgenic for human IL-3, GM-CSF and SCF (NSG-3GS) were sub-lethally irradiated and injected intra-liver with human HSCs soon after birth, enabling an accelerated and better balanced lympho-hematopoietic reconstitution compared with NSG mice. Reconstituting human T cells were single CD4+/CD8+ T cells, representing all memory sub-populations. After ex vivo isolation and activation with CD3/CD28-beads and IL-7/IL-15, NSG-3GS T cells were transduced with a CD44v6 CAR, retaining an early-differentiated (stem-cell/central-memory) phenotype and full antitumor functionality against acute myeloid leukemia (AML). NSG-3GS-derived CD44v6 CAR T cells were subsequently infused in tumor-bearing secondary recipients previously humanized with autologous HSCs. CAR-T cells persisted in vivo for at least 6 months and mediated durable leukemia remissions (P<0.001 vs controls) in the absence of X-GVHD. Tumor clearance associated with an acute malaise syndrome, characterized by high fevers and a surge in human IL-6 levels, which was lethal in 30% of the mice. Differently from CD19 CAR-T cells, the CRS by CD44v6 CAR-T cells was significantly anticipated (3 vs 8 days), coinciding with human CD44v6+ monocyte depletion. In humanized mice, previous myeloid-cell depletion by clodronate administration completely prevented this syndrome, but associated with late leukemia relapses. Conversely, mice developing the CRS entered a state of durable and profound remission, as demonstrated by prolonged observation times and secondary transplantation. Conclusions: By using an innovative xenotolerant mouse model, we have demonstrated that the CRS is needed for sustained antileukemic effects by CD44v6 CAR-T cells

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Développement d'une approche de thérapie génique des leucémies aiguës myéloblastiques

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Développement d'une approche de thérapie génique des leucémies aiguës myéloblastiques

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Current Status of Gene Engineering Cell Therapeutics

Ex vivo manipulations of autologous patient’s cells or gene-engineered cell therapeutics have allowed the development of cell and gene therapy approaches to treat otherwise incurable diseases. These modalities of personalized medicine have already shown great promises including product commercialization for some rare diseases. The transfer of a chimeric antigen receptor or T cell receptor genes into autologous T cells has led to very promising outcomes for some cancers, and particularly for hematological malignancies. In addition, gene-engineered cell therapeutics are also being explored to induce tolerance and regulate inflammation. Here, we review the latest gene-engineered cell therapeutic approaches being currently explored to induce an efficient immune response against cancer cells or viruses by engineering T cells, natural killer cells, gamma delta T cells, or cytokine-induced killer cells and to modulate inflammation using regulatory T cells

Functional Characterisation and Analysis of the Soluble NKG2D Ligand Repertoire Detected in Umbilical Cord Blood Plasma

We previously reported that cord blood plasma (CBP) contains significantly more soluble NKG2D ligands (sNKG2DLs), such as sMICB and sULBP1, than healthy adult plasma. Viral infection or malignant transformation upregulates expression of NKG2D ligand on affected cells, leading to NK group 2, member D (NKG2D)-mediated natural killer (NK) cell lysis. Conversely, sNKG2DL engagement of NKG2D decreases NK cell cytotoxicity leading to viral or tumour immune escape. We hypothesised that sNKG2DLs detected in CBP may represent an additional fetal–maternal tolerance mechanism. To further understand the role of sNKG2DL in pregnancy and individual contributions of the various ligand types, we carried out functional analysis using 181 CBP samples. To test the ability of CBP to suppress the function of NK cells in vitro, we measured expression of NKG2D, CD107a, and IFN-γ in NK cells from control donors after exposure to 181 individual CBP samples and characterised the sMICA, sMICB, and sULBP1 content of each one. Furthermore, to detect possible allelic differences between samples that may also affect function, we carried out umbilical cord blood typing for MHC class I-related chain A (MICA) and MHC class I-related chain B (MICB) coding and promoter allelic types. Strongest functional correlations related to increasing concentration of exosomal sULBP1, which was present in all CBP samples tested. In addition, common MICB alleles, such as MICB*005:02, resulted in increased concentration of sMICB. Interestingly, MICB*005:02 uniquely associated with eight different promoter types. Among promoter polymorphisms, P2 resulted in the highest expression of sMICB and P9 the least and was confirmed using luciferase reporter assays. Higher levels of sMICB associated with lower IFN-γ production, indicating that sMICB also suppressed NK cell function. We also examined the MICA functional dimorphism encoding methionine (met) or valine (val) at residue 129 associated with strong or weak NKG2D binding, respectively. Most sMICA associated with val/val, some with met/val but none with met/met and, counter-intuitively, the presence of sMICA in CBP increased NK cell cytotoxicity. We propose a model for fetal–maternal tolerance, whereby NK cell activity is limited by sULBP1 and sMICB in CBP. The release of 129val sMICA with weak NKG2D signalling may reduce the overall net suppressive signal and break tolerance thus allowing fetal NK cells to overcome immunological threats in utero