Clinical-scale, modular manufacturing of tumor-reactive TILs using a closed and automated culture system.

Recent studies have revealed the potential of tumor-infiltrating lymphocytes (TILs) to treat solid tumors effectively and safely. However, the translation of TIL therapy for patients is still hampered by non-standardized and laborious manufacturing procedures that are expensive and produce highly variable cellular products. To address these limitations, the CliniMACS Prodigy Tumor Reactive T cell (TRT) Process has been developed.

Maintenance therapy with trofosfamide, idarubicin and etoposide in patients with rhabdomyosarcoma and other high-risk soft tissue sarcomas (CWS-2007-HR): a multicentre, open-label, randomised controlled phase 3 trial.

Background: Rhabdomyosarcoma and other soft tissue sarcomas (STS) with high-risk features are still associated with an unsatisfactory outcome. We evaluated the efficacy of oral maintenance therapy added at the end of standard therapy in patients with high-risk rhabdomyosarcoma and STS.

Methods: CWS-2007-HR was a multicentre, open-label, randomised controlled, phase 3 trial done at 87 centers in 5 countries.

Ecto-NOX Disulfide-Thiol Exchanger 2 (ENOX2/tNOX) Is a Potential Prognostic Marker in Primary Malignant Melanoma and May Serve as a Therapeutic Target.

With an increasing incidence of malignant melanoma, new prognostic biomarkers for clinical decision making have become more important. In this study, we evaluated the role of ecto-NOX disulfide-thiol exchanger 2 (ENOX2/tNOX), a cancer- and growth-associated protein, in the prognosis and therapy of primary malignant melanoma. We conducted a tissue microarray analysis of immunohistochemical ENOX2 protein expression and The Cancer Genome Atlas (TCGA) RNA expression analysis, as well as viability assays and Western blots of melanoma cell lines treated with the ENOX2 inhibitor phenoxodiol (PXD) and BRAF inhibitor (BRAFi) vemurafenib.

An evaluation of exagamglogene autotemcel for the treatment of sickle cell disease and transfusion-dependent beta-thalassaemia.

Introduction: Sickle cell disease is the most common hereditary hemoglobinopathy followed by beta-thalassemia. Until recently, allogeneic stem cell transplantation was the only curative approach. Based on the Crispr-Cas9-technology enabling targeting specific genes of interest, fetal hemoglobin which is normally shut-off after birth can be switched on and sufficient levels can alleviate symptoms in sickle cell disease and avoid transfusions in beta-thalassemia.

No evidence on infectious DNA-based agents in pediatric acute lymphoblastic leukemia using whole metagenome shotgun sequencing.

The etiology of pediatric acute lymphatic leukemia (ALL) is still unclear. Whole-metagenome shotgun sequencing of bone marrow samples in patients with treatment-naïve ALL (n=6) was performed for untargeted investigation of bacterial and viral DNA. The control group consisted of healthy children (n=4) and children with non-oncologic diseases (n=2) undergoing bone marrow sampling.

Immune reconstitution after transplantation of autologous peripheral stem cells in children: a comparison between CD34+ selected and nonmanipulated grafts.

Background And Aims: High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) improves the prognosis in pediatric patients with several solid tumors and lymphomas. Little is known about the reconstitution of the immune system after ASCT and the influence of CD34+ cell selection on the reconstitution in pediatric patients.

Methods: Between 1990 and 2001, 94 pediatric patients with solid tumors and lymphomas received autologous CD34+ selected or unmanipulated peripheral stem cells after HDC.

A novel approach to guide GD2-targeted therapy in pediatric tumors by PET and [Cu]Cu-NOTA-ch14.18/CHO.

The tumor-associated disialoganglioside GD2 is a immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease.

Influence of ATLG serum levels on CD3/CD19-depleted hematopoietic grafts and on immune recovery in pediatric haplo-HSCT.

Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplant (HSCT) but hampers posttransplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts, these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T-cell-specific ATLG in pediatric patients treated with 3 established dosing regimens (15, 30, or 60 mg/kg).

Targeting GD2 after allogeneic SCT: effector cell composition defines the optimal use of ch14.18 and the bispecific antibody construct NG-CU (GD2-CD3).

We investigated whether T cell-recruiting bispecific anti-CD3/GD2 antibody NG-CU might be an alternative to therapeutic anti-GD2 monoclonal antibody (mAb) ch14.18, mediating complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) through natural killer (NK) cells for immunotherapy in high-risk/relapsed neuroblastoma after autologous/allogeneic stem cell transplantation (auto/alloSCT). Different antibody concentrations and effector-to-target ratios (E:T) were evaluated using xCELLigence RTCA system, peripheral blood mononuclear cells (PBMCs) (healthy donors and patients after alloSCT), and neuroblastoma cell lines (LS/LAN-1).

Application of the National Comprehensive Cancer Network-distress thermometer in pediatric patients during autologous and allogeneic hematopoietic stem cell transplantation and relationship to blood parameters of the stress axis.

Purpose: Hematopoietic stem cell transplantations (HSCT) are extremely stressful procedures for pediatric patients. The activation of the hypothalamic pituitary adrenocortical axis (HPA) can influence the immune system negatively and therefore the overall outcome. The distress thermometer (DT) is an easy to use tool for the self-assessment of perceived distress.

Th1 cytokines in pediatric acute lymphoblastic leukemia.

Immune milieus play an important role in various types of cancer. The present study focuses on the effect of Th1 cytokines on pediatric acute lymphoblastic leukemia (ALL). The reaction of ALL cell lines and patient-derived xenografts (PDX) to the most important Th1 cytokines TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) is analyzed and correlated with the respective cytokine receptors and the intracellular signaling molecules.

Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients.

The prevalence of pathogenic and likely pathogenic (P/LP) variants in genes associated with cancer predisposition syndromes (CPS) is estimated to be 8-18% for paediatric cancer patients. In more than half of the carriers, the family history is unsuspicious for CPS. Therefore, broad genetic testing could identify germline predisposition in additional children with cancer resulting in important implications for themselves and their families.

Hybrid Molecules of Benzylguanidine and the Alkylating Group of Melphalan: Synthesis and Effects on Neuroblastoma Cells.

The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the (-iodobenzyl)guanidine [I]mIBG.

Screening for distress and quality of life in pediatric patients after allogeneic or autologous hematopoietic stem cell transplantation using a self-reporting instrument, blood stress biomarkers and an expert rating scale (PO-Bado).

Objective: Hematopoietic stem cell transplantation (HSCT) is highly distressing and potentially traumatizing for pediatric and young adult patients (PYAP). At present, there is little evidence on their individual burdens.

Methods: In this prospective cohort study, the course of the psychological and somatic distress was investigated on eight observation days (day -8/-12, -5, 0 (day of HSCT), +10, +20, and + 30 before/after HSCT), using the PO-Bado external rating scale and the EORTC-QLQ-C15-PAL self-assessment questionnaire.

Hypofibrinolysis in pediatric patients with veno-occlusive disease in hematopoietic stem cell transplantation.

Purpose: Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT) with a high incidence in pediatric patients. This study aimed to detect signs of hypofibrinolysis using thrombelastography.

Methods: In this prospective single-center study, thrombelastographic measurements (EX and TPA tests) were taken during HSCT to detect signs of impaired coagulation, clot formation, or hypofibrinolysis.

Haploidentical hematopoietic stem cell transplantation as individual treatment option in pediatric patients with very high-risk sarcomas.

Background: Prognosis of children with primary disseminated or metastatic relapsed sarcomas remains dismal despite intensification of conventional therapies including high-dose chemotherapy. Since haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of hematological malignancies by mediating a graft versus leukemia effect, we evaluated this approach in pediatric sarcomas as well.

Methods: Patients with bone Ewing sarcoma or soft tissue sarcoma who received haplo-HSCT as part of clinical trials using CD3+ or TCRα/β+ and CD19+ depletion respectively were evaluated regarding feasibility of treatment and survival.

Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial.

Purpose: Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB.

Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

Background: A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsed/refractory (R/R) B-ALL.

Methods: Data from five trials of blinatumomab for R/R B-ALL were pooled for analyses.

Automated production of specific T cells for treatment of refractory viral infections after allogeneic stem cell transplantation.

Therapy-resistant viral reactivations contribute significantly to mortality after hematopoietic stem cell transplantation. Adoptive cellular therapy with virus-specific T cells (VST) has shown efficacy in various single-center trials. However, the scalability of this therapy is hampered by laborious production methods.

Transferring measurable residual disease measurement in pediatric acute lymphoblastic leukemia from quantitative real-time PCR to digital droplet PCR.

Background: Since the measurement of measurable residual disease (MRD) is part of clinical routine examination for children affected with acute lymphoblastic leukemia (ALL), continuous efforts are made to improve its method, applicability and accuracy. Whereas quantitative real-time polymerase chain reaction (qPCR) is considered as the gold standard for MRD detection and endowed with international guidelines for implementation and evaluation, these do not yet exist for digital droplet PCR (ddPCR). However, advantages are seen in droplet partitioning for MRD measurement to allow absolute quantification without depending on reference samples.

CRISPR medicine for blood disorders: Progress and challenges in delivery.

Blood disorders are a group of diseases including hematological neoplasms, clotting disorders and orphan immune deficiency diseases that affects human health. Current improvements in genome editing based therapeutics demonstrated preclinical and clinical proof to treat different blood disorders. Genome editing components such as Cas nucleases, guide RNAs and base editors are supplied in the form of either a plasmid, an mRNA, or a ribonucleoprotein complex.