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

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Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) developing in persons exposed to DNA-damaging agents for a prior cancer are often referred to as treatment- or therapy-related myeloid neoplasms (t-MN)[1,2]. t-MN constitute approximately 10-20% of all cases of AML and MDS[3], a proportion that may increase in the future with an increasing prevalence of cancer survivors[4,5]. Hematopoietic cell transplants (HCT) use high doses of drugs and/or ionizing radiations and can also lead to t-MN[6,7].
Source: Leukemia Research - Category: Hematology Authors: Source Type: research
Downregulation of microRNA‑21 expression inhibits proliferation, and induces G1 arrest and apoptosis via the PTEN/AKT pathway in SKM‑1 cells. Mol Med Rep. 2018 Jul 05;: Authors: Li G, Song Y, Li G, Ren J, Xie J, Zhang Y, Gao F, Mu J, Dai J Abstract Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and may progress to acute myeloid leukemia (AML). MicroRNAs (miRNA/miRs) as oncogenes or tumor suppressors regulate a number of biological processes including cell proliferation, cell cycle and apoptosis in different types of cancer cells. Recently, it has been reported that m...
Source: Molecular Medicine Reports - Category: Molecular Biology Tags: Mol Med Rep Source Type: research
Publication date: Available online 17 July 2018Source: The Lancet HaematologyAuthor(s): Mark P Little, Richard Wakeford, David Borrego, Benjamin French, Lydia B Zablotska, M Jacob Adams, Rodrigue Allodji, Florent de Vathaire, Choonsik Lee, Alina V Brenner, Jeremy S Miller, David Campbell, Mark S Pearce, Michele M Doody, Erik Holmberg, Marie Lundell, Siegal Sadetzki, Martha S Linet, Amy Berrington de GonzálezSummaryBackgroundSubstantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (
Source: The Lancet Haematology - Category: Hematology Source Type: research
In conclusion, incidence of breakthrough IFI was low among patients receiving posaconazole prophylaxis, and not significantly different between patients receiving the tablet versus oral suspension formulations. PMID: 30012757 [PubMed - as supplied by publisher]
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
Therapy related myeloid neoplasm (t-MN) is an emerging challenge in the current era given that newer therapies are improving the life expectancy of patients diagnosed with cancer. This condition arises as a result of exposure to prior chemotherapy or radiotherapy used to treat malignant or non-malignant conditions. The World Health Organization (WHO) 2001 classification of tumors of hematopoietic and lymphoid tissues had initially described this disorder with two subtypes – therapy related acute myeloid leukemia (t-AML) and therapy related myelodysplastic syndrome (t-MDS) 1.
Source: Leukemia Research - Category: Hematology Authors: Tags: Research paper Source Type: research
Enumeration of blasts in the bone marrow is critical for diagnostic, prognostic, and therapeutic response evaluation in myelodysplastic syndromes, myeloproliferative neoplasms and acute leukemias. However, few studies have examined the accuracy and precision of marrow blast counting using standard microscopic procedures. In our study, four experienced hematopathologists evaluated blast percentages in marrow using either differential counts on aspirate smears or visual estimates on CD34-stained trephine biopsies.
Source: Seminars in Hematology - Category: Hematology Authors: Source Type: research
Ludwig Boltzmann Cluster Oncology (LBC ONC): first 10 years and future perspectives. Wien Klin Wochenschr. 2018 Jul 13;: Authors: Valent P, Hadzijusufovic E, Grunt T, Karlic H, Peter B, Herrmann H, Eisenwort G, Hoermann G, Schulenburg A, Willmann M, Hubmann R, Shehata M, Selzer E, Gleixner KV, Rülicke T, Sperr WR, Marian B, Pfeilstöcker M, Pehamberger H, Keil F, Jäger U, Zielinski C Abstract In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previous Ludwig Boltzmann Institutes working in the field of hematology and cancer research. The gene...
Source: Wiener Klinische Wochenschrift - Category: General Medicine Authors: Tags: Wien Klin Wochenschr Source Type: research
Application of next-generation sequencing (NGS) panels is usually limited to diagnosis, prognosis, and development of personalized treatment strategies/targeted therapies for patients with myeloid malignancies e.g., Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and acute myelogenous leukemia (AML). Here we present a case of 3 year old male that presented with pancytopenia and splenomegaly. His initial bone marrow revealed mild to moderate fibrosis (normocellular; no increase in blasts).
Source: Cancer Genetics and Cytogenetics - Category: Genetics & Stem Cells Authors: Source Type: research
We report a myelodysplastic syndrome (MDS) patient who presented Fusarium solani infection associated with granulocytic sarcoma as an initial presentation of acute myeloid leukemia (AML) transformation. We performed histological examination, immunohistochemistry analysis, culture of the biopsy tissue and DNA sequencing to make a conclusive diagnosis of F. solani and granulocytic sarcoma, reinforcing the necessity of performing complete evaluation of skin lesions in immunocompromised patients.
Source: Journal of Medical Mycology - Category: Biology Source Type: research
Myelodysplastic syndrome (MDS) is rare in the pediatric age group and it may be associated with inheritable bone marrow failure (BMF) such as Fanconi anemia (FA). FA is a rare multi-system genetic disorder, ch...
Source: Molecular Cytogenetics - Category: Molecular Biology Authors: Tags: Case Report Source Type: research
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