IFN-γ-Induced CD317 Tethers Extracellular Vesicles to Mesenchymal Stromal Cells Interfering With Immune Modulation.

In spite of the numerous clinical trials conducted on mesenchymal stromal cells and their extracellular vesicles (MSC-EVs) across a wide range of diseases, the field faces challenges in reaching a consensus on crucial parameters such as source, marker definition, and culture conditions, adding to heterogeneous efficiencies. Nevertheless, there is widespread acceptance of the pro-inflammatory activation of MSCs with IFN-γ and TNF-α to enhance immune modulation. Our study highlights the impact of activation duration on MSC-EV-mediated immune modulation of macrophages.

Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodies.

Background: Since the onset of the COVID-19 pandemic, SARS-CoV-2 neutralising monoclonal antibodies (mAbs) are being developed for clinical use. With the appearance of new virus variants, most mAbs lost their virus-neutralising activity, highlighting the complexity of mAb development under conditions of continuous SARS-CoV-2 evolution.

Methods: Hamsters were treated with SARS-CoV-2 neutralising mAbs and then challenged with SARS-CoV-2.

Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.

Background: The β common integrin subunit CD18 is essential for leukocyte-endothelial adhesion and extravasation to inflamed or infected tissue. Damaging variants in , which encodes CD18, cause leukocyte adhesion deficiency type I (LAD-I), an inborn error of immunity that leads to frequent life-threatening infections and a high risk of death among affected children. Allogeneic hematopoietic stem-cell transplantation (HSCT) represents a curative treatment but is limited by donor availability, a high incidence of graft-versus-host disease, and graft failure.

Dual Topoisomerase Inhibitor Is Highly Potent and Improves Antitumor Response to Radiotherapy in Cervical Carcinoma.

Despite advances in vaccination and early detection, the total number of cases and deaths from cervical cancer has risen steadily in recent decades, making it the fourth most common type of cancer in women worldwide. Low-income countries in particular struggle with limited resources and treatment limitations for cervical cancer. Thus, effective medicines that are simple to manufacture are needed.

Meta-Analysis and Optimization of the Immortalization Assay for Safety Assessment of Retroviral Vectors in Gene Therapy.

The underlying risk of retroviral vector-induced insertional oncogenesis in gene therapies requires a reliable preclinical safety assessment. Dysregulation of genes neighboring the vector's integration sites has triggered hematopoietic malignancies in patients treated with different vector genera and designs. With ca.

Corrigendum: Anti-Mesothelin CAR-NK cells as a novel targeted therapy against cervical cancer.

[This corrects the article DOI: 10.3389/fimmu.2024.

Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity.

Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B (BCL11B) propagates CAR-induced killer (CARiK) cell development from lymphoid progenitors. Here, we show that CRISPR-Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors distinctively modulates this process either alone or in combination with a CAR. Upon adoptive transfer into hematopoietic stem cell recipients, Bcl11b-edited progenitors mediated innate-like antigen-independent anti-leukemic immune responses.

Engineering a bacterial toxin deaminase from the DYW-family into a novel cytosine base editor for plants and mammalian cells.

Base editors are precise editing tools that employ deaminases to modify target DNA bases. The DYW-family of cytosine deaminases is structurally and phylogenetically distinct and might be harnessed for genome editing tools. We report a novel CRISPR/Cas9-cytosine base editor using SsdA, a DYW-like deaminase and bacterial toxin.

Anti-Mesothelin CAR-NK cells as a novel targeted therapy against cervical cancer.

Resistance to the currently available treatment paradigms is one of the main factors that contributes to poor outcomes in patients with advanced cervical cancer. Novel targeted therapy approaches might enhance the patient's treatment outcome and are urgently needed for this malignancy. While chimeric-antigen receptor (CAR)-based adoptive immunotherapy displays a promising treatment strategy for liquid cancers, their use against cervical cancer is largely unexplored.

Engineered packaging cell line for the enhanced production of baboon-enveloped retroviral vectors.

The baboon endogenous retrovirus (BaEV) glycoprotein is superior to the commonly used vesicular stomatitis virus glycoprotein (VSVg) for retroviral gene transfer into resting hematopoietic stem cells and lymphocyte populations. The derivative BaEVRLess (lacking the R domain) produces higher viral titers compared with wild-type BaEV, but vector production is impaired by syncytia formation and cell death of the HEK293T cells due to the high fusogenic activity of the glycoprotein. This lowers viral titers, leads to increased batch-to-batch variability, and impedes the establishment of stable packaging cell lines essential for the economical production of viral supernatants.

Haematopoietic gene therapy of non-conditioned patients with Fanconi anaemia-A: results from open-label phase 1/2 (FANCOLEN-1) and long-term clinical trials.

Background: Allogeneic haematopoietic stem-cell transplantation is the standard treatment for bone marrow failure (BMF) in patients with Fanconi anaemia, but transplantation-associated complications such as an increased incidence of subsequent cancer are frequent. The aim of this study was to evaluate the safety and efficacy of the infusion of autologous gene-corrected haematopoietic stem cells as an alternative therapy for these patients.

Methods: This was an open-label, investigator-initiated phase 1/2 clinical trial (FANCOLEN-1) and long-term follow-up trial (up to 7 years post-treatment) in Spain.

Blood-generating heart-forming organoids recapitulate co-development of the human haematopoietic system and the embryonic heart.

Despite the biomedical importance of haematopoietic stem cells and haematopoietic progenitor cells, their in vitro stabilization in a developmental context has not been achieved due to limited knowledge of signals and markers specifying the multiple haematopoietic waves as well as ethically restricted access to the human embryo. Thus, an in vitro approach resembling aspects of haematopoietic development in the context of neighbouring tissues is of interest. Our established human pluripotent stem cell-derived heart-forming organoids (HFOs) recapitulate aspects of heart, vasculature and foregut co-development.

Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy.

Rationale And Objective: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CFTR modulators offer significant improvements, but ∼10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.

Alpharetroviral Vector-Mediated Gene Therapy for IL7RA-Deficient Severe Combined Immunodeficiency.

Severe combined immunodeficiency (SCID) encompasses rare primary immunodeficiency disorders characterized by deficient T-cell development, which leads to a severely compromised immune system and susceptibility to life-threatening infections. Among SCID subtypes, IL7RA-SCID is caused by mutations in the interleukin 7 receptor alpha chain (IL7RA) and represents a significant subset of patients with limited treatment options. This study investigated the efficacy of a self-inactivating (SIN) alpharetroviral vector (ARV) engineered to deliver a codon-optimized cDNA to restore T-cell development in -knockout mice.

The caspase-inhibitor Emricasan efficiently counteracts cisplatin- and neomycin-induced cytotoxicity in cochlear cells.

Cisplatin is a chemotherapeutic agent widely used to treat solid tumors. However, it can also be highly ototoxic, resulting in high-frequency hearing loss. Cisplatin causes degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear, which are essential components of the hearing process and cannot be regenerated in mammals.

Graft-Specific Regulatory T Cells for Long-Lasting, Local Tolerance Induction.

Background: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent models.

Methods: To enhance the efficacy of adoptive Treg therapy, we investigated different immune interventions in the recipients.

Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo.

Aims: Understanding the molecular identity of human pluripotent stem cell (hPSC)-derived cardiac progenitors and mechanisms controlling their proliferation and differentiation is valuable for developmental biology and regenerative medicine.

Methods And Results: Here, we show that chemical modulation of histone acetyl transferases (by IQ-1) and WNT (by CHIR99021) synergistically enables the transient and reversible block of directed cardiac differentiation progression on hPSCs. The resulting stabilized cardiovascular progenitors (SCPs) are characterized by ISL1pos/KI-67pos/NKX2-5neg expression.

Diversification of the VH3-53 immunoglobulin gene segment by somatic hypermutation results in neutralization of SARS-CoV-2 virus variants.

COVID-19 induces re-circulating long-lived memory B cells (MBC) that, upon re-encounter with the pathogen, are induced to mount immunoglobulin responses. During convalescence, antibodies are subjected to affinity maturation, which enhances the antibody binding strength and generates new specificities that neutralize virus variants. Here, we performed a single-cell RNA sequencing analysis of spike-specific B cells from a SARS-CoV-2 convalescent subject.

Preclinical Development of CAR T Cells with Antigen-Inducible IL18 Enforcement to Treat GD2-Positive Solid Cancers.

Purpose: Cytokine-engineering of chimeric antigen receptor-redirected T cells (CAR T cells) is a promising principle to overcome the limited activity of canonical CAR T cells against solid cancers.

Experimental Design: We developed an investigational medicinal product, GD2IL18CART, consisting of CAR T cells directed against ganglioside GD2 with CAR-inducible IL18 to enhance their activation response and cytolytic effector functions in the tumor microenvironment. To allow stratification of patients according to tumor GD2 expression, we established and validated immunofluorescence detection of GD2 on paraffin-embedded tumor tissues.