Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS

Wilms’ tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR–gene transduced T-cell (TCR–T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and ...
Source: Blood - Category: Hematology Authors: Tags: Immunobiology and Immunotherapy, Myeloid Neoplasia, Clinical Trials and Observations, Gene Therapy Source Type: research

Related Links:

Purpose of review Myelodysplastic syndromes (MDSs) are rare disorders in children, showing peculiar clinical manifestations and biological features. This review will summarize biological, genetic and clinical features of childhood MDS and will provide an update of the algorithm of treatment of the different disease variants. Recent findings The most recent classification of MDS includes refractory cytopenia of childhood (RCC), advanced and therapy-related MDS. Importantly, in children, these clonal hematopoietic disorders may be often associated with inherited bone marrow failure syndromes, this representing a challen...
Source: Current Opinion in Oncology - Category: Cancer & Oncology Tags: HEMATOLOGIC MALIGNANCIES: Edited by Miguel A. Sanz Source Type: research
Purpose of review The present review focuses on the current management of patients with chronic myelomonocytic leukemia (CMML) and the most recent developments in the field. Recent findings CMML is a heterogeneous malignant myeloid disorder sharing features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms and characterized by peripheral blood monocytosis and increased risk of progression to acute leukemia. Its natural course is highly variable and use of CMML-specific prognostic scoring systems is strongly recommended for tailoring treatment. Multiple recent studies have showed that somatic mutation...
Source: Current Opinion in Oncology - Category: Cancer & Oncology Tags: HEMATOLOGIC MALIGNANCIES: Edited by Miguel A. Sanz Source Type: research
Relative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studiesRelative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studies, Published online: 12 October 2018; doi:10.1038/s41375-018-0275-xRelative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studies
Source: Leukemia - Category: Hematology Authors: Source Type: research
The integration of genetic data into the clinical and pathological assessment of myeloid neoplasms underscores the expanding role of genomic changes in the diagnosis, prognosis, classification and therapeutic implications of precision medicine. Myeloid neoplasms include myelodysplastic syndrome (MDS), myelodysplastic/ myeloproliferative neoplasm (MDS/MPN), myeloproliferative neoplasm (MPN) and acute myeloid leukemia (AML). The myelodysplastic syndromes (MDS) comprise a very heterogeneous group of clonal myeloid disorders characterized by peripheral blood cytopenias, a bone marrow aspirate/biopsy showing dysplasia in one or...
Source: Cancer Genetics and Cytogenetics - Category: Genetics & Stem Cells Authors: Tags: Review Article Source Type: research
Conclusions: G-CSF for patients with AA is not associated with a higher occurrence of secondary malignant neoplasm, mainly MDS/AML, or PNH.Acta Haematol 2018;140:141 –145
Source: Acta Haematologica - Category: Hematology Source Type: research
Purpose of review The monitoring of minimal residual disease (MRD) has important clinical implications in both the pre and postallogeneic stem cell transplant (SCT) setting in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Next-generation sequencing (NGS) is a rapidly improving technology whose application to the monitoring of MRD is an active area of research. We aim to describe existing methods of MRD in AML and MDS, with a focus on the utility of NGS in patients undergoing SCT. Recent findings Flow cytometry and quantitative PCR have been recommended by the European Leukemia Net as the preferred m...
Source: Current Opinion in Hematology - Category: Hematology Tags: HEMATOPOIETIC STEM CELL TRANSPLANTATION: Edited by Armand Keating Source Type: research
(University of Texas M. D. Anderson Cancer Center) The University of Texas MD Anderson Cancer Center and Cyclacel Pharmaceuticals, Inc., today announced a three-year strategic alliance agreement that will enable clinical evaluation for safety and efficacy of three Cyclacel medicines in patients with hematological malignancies, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and other advanced leukemias.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
In this study, genetic mouse models and patient-derived xenografts (PDX) demonstrated that Jarid2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either reduced overall survival of MPN, or drove transformation to sAML, depending on the timing and context of co-operating mutations. Mechanistically, Jarid2 recruits PRC2 to epigenetically repress self-renewal pathways in hematopoietic progenitor cells. These studies establish Jarid2 as a bona fide hematopoietic tumor suppressor and highlight new therapeutic targets.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing Mus musculus Source Type: research
International Journal of Urology, EarlyView.
Source: International Journal of Urology - Category: Urology & Nephrology Authors: Source Type: research
AbstractPurpose of ReviewTo review the diagnosis of individuals with hereditary hematopoietic malignancies (HHMs) that predispose to myelodysplastic syndrome and acute myeloid leukemia, barriers to HHM diagnosis, and unaddressed questions and controversies within the HHM field.Recent FindingsPathogenic germline mutations in approximately a dozen genes predispose to HHMs, and many more genes are likely to be involved. Many of these HHM genes have only been identified recently. HHM phenotypes are diverse, but may be categorized as “purely” myeloid syndromes, syndromes with abnormal platelet number/function, and H...
Source: Current Hematologic Malignancy Reports - Category: Hematology Source Type: research
More News: Acute Leukemia | Clinical Trials | Gene Therapy | Genetics | Immunotherapy | Leukemia | Myelodysplastic Syndrome | Study | Vaccines