Abstract：
:Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here we isolated a high-affinity (HA) folate receptor beta (FRβ)-specific single-chain variable fragment (2.48 nm KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ(+) AML in vitro and in vivo compared with a low-affinity FRβ CAR (54.3 nm KD). Using the HA-FRβ immunoglobulin G, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34(+) hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T cells lysed mature CD14(+) monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T cells retained effective antitumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T cells is highly effective against AML and reduces the risk for long-term myeloid toxicity.
journal_name
Leukemiajournal_title
Leukemiaauthors
Lynn RC,Feng Y,Schutsky K,Poussin M,Kalota A,Dimitrov DS,Powell DJ Jrdoi
10.1038/leu.2016.35subject
Has Abstractpub_date
2016-06-01 00:00:00pages
1355-64issue
6eissn
0887-6924issn
1476-5551pii
leu201635journal_volume
30pub_type
杂志文章相关文献
LEUKEMIA文献大全abstract：:Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the ben...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/leu.2017.88
更新日期：2017-11-01 00:00:00
abstract：:Although dephosphorylation of tyrosine containing proteins is considered a necessary step in the induction of leukemia cell differentiation by hybrid polar compounds (HPC), the crucial actors in this step remain unknown. We present evidence that tyrosine phosphorylation of JAK1 and JAK2 is down-regulated in murine ery...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/sj.leu.2401936
更新日期：2000-12-01 00:00:00
abstract：:The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in t...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/leu.2017.257
更新日期：2018-02-01 00:00:00
abstract：:The unbalanced translocation, der(1;7)(q10;p10), is one of the characteristic cytogenetic abnormalities found in myelodysplastic syndromes (MDS) and other myeloid neoplasms. Although described frequently with very poor clinical outcome and possible relationship with monosomy 7 or 7q- (-7/7q-), this recurrent cytogenet...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/sj.leu.2404619
更新日期：2007-05-01 00:00:00
abstract：:Identification of rearrangements in the immunoglobulin heavy chain (IgH), T cell receptor (TCR) and other genes assists in the classification of hemopoietic disorders. This study reviews a 5 year experience of genotyping as an assessment of clonality in a central referral laboratory. Patients were referred for assessm...
journal_title：Leukemia
pub_type： 杂志文章,评审
doi：10.1038/sj.leu.2400678
更新日期：1997-06-01 00:00:00
abstract：:The purpose of this study was to determine the incidence of and pharmacokinetic parameters associated with the development of transient encephalopathy following the administration of high-dose methotrexate and intrathecal chemotherapy in children with acute lymphoblastic leukemia (ALL). Two hundred and fifty-nine chil...
journal_title：Leukemia
pub_type： 临床试验,杂志文章
doi：10.1038/sj.leu.2401098
更新日期：1998-08-01 00:00:00
abstract：:Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combin...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/leu.2010.218
更新日期：2010-12-01 00:00:00
abstract：:Multiple myeloma (MM) is the second most common blood malignancy. Epidemiological family studies going back to the 1920s have provided evidence for familial aggregation, suggesting a subset of cases have an inherited genetic background. Recently, studies aimed at explaining this phenomenon have begun to provide direct...
journal_title：Leukemia
pub_type： 杂志文章,评审
doi：10.1038/s41375-019-0703-6
更新日期：2020-03-01 00:00:00
abstract：:Many genes are involved in cell cycle control, DNA repair and induction of cell death. Alterations in these genes have been responsible for the development of cancer as well as for resistance to cancer therapy. Recently, an emerging family of bcl2-like genes has been identified that plays a role in the regulation of c...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1995-11-01 00:00:00
abstract：:The long-term results in 130 patients with newly diagnosed acute myelogenous leukemia treated with continuous infusion high-dose ara-C (1.5 gm/m2/day x 4 days, CIHDAC) were compared with those in 264 patients treated in previous studies with standard dose ara-C (70-90 mg/m2/d x 7 days) plus either adriamycin (Ad-OAP),...
journal_title：Leukemia
pub_type： 临床试验,杂志文章
doi：
更新日期：1994-08-01 00:00:00
abstract：:The blast cells of acute myeloblastic leukemia may be considered as a renewal population maintained by stem cells that are capable of both self-renewal and differentiation. Blast stem cells grow in culture usually when stimulated by growth factors normally active on myelopoietic cells. Two culture methods permit an ev...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1988-06-01 00:00:00
abstract：:The discovery of EGFR gene amplification in glioblastoma multiforme has prompted interest in experimental therapies to target the receptor on brain tumor cells. To develop an animal model for in vivo study of such strategies, we transfected C6 glioma cells with a plasmid containing the neomycin resistance gene and the...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1995-10-01 00:00:00
abstract：:The mechanisms by which non-oncogene bearing, slowly transforming T-cell-tropic retroviruses induce leukemia is not well understood. Viruses such as the murine radiation leukemia virus (RadLV) induce oncogenic transformation of T-cells in the thymus only in vivo and after a long latency. The capacity of RadLV to induc...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1992-04-01 00:00:00
abstract：:In a European BIOMED-2 collaborative study, multiplex PCR assays have successfully been developed and standardized for the detection of clonally rearranged immunoglobulin (Ig) and T-cell receptor (TCR) genes and the chromosome aberrations t(11;14) and t(14;18). This has resulted in 107 different primers in only 18 mul...
journal_title：Leukemia
pub_type： 杂志文章,多中心研究,评审
doi：10.1038/sj.leu.2403202
更新日期：2003-12-01 00:00:00
abstract：:Monitoring of BCR-ABL transcripts has become established practice in the management of chronic myeloid leukemia. However, nucleic acid amplification techniques are prone to variations which limit the reliability of real-time quantitative PCR (RQ-PCR) for clinical decision making, highlighting the need for standardizat...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/sj.leu.2404716
更新日期：2007-07-01 00:00:00
abstract：:We previously demonstrated that the EVI-1 gene was transcriptionally activated in the 3q21q26 syndrome and chromosomal breakpoints at 3q26 were clustered within 400 Kb of the EVI-1 gene. Since thrombocytosis is often observed in the 3q21q26 syndrome, we first mapped the thrombopoietin (TPO) gene and then we examined f...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1995-08-01 00:00:00
abstract：:This report summarizes recent findings in the field of basic and translational apoptosis research which were presented at the 1st Conference on 'Mechanisms of Cell Death and Disease: Advances in Therapeutic Intervention' organized by the European School of Hematology and the University of Texas MD Anderson Cancer Cent...
journal_title：Leukemia
pub_type： 杂志文章,评审
doi：10.1038/sj.leu.2401940
更新日期：2000-12-01 00:00:00
abstract：:Hematopoietic stem cells (HSCs) are uniquely capable of self-renewal and provision of all of the mature elements of the blood and immune system throughout the lifetime of an individual. HSC self-renewal is regulated by both intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments or 'niche...
journal_title：Leukemia
pub_type： 杂志文章,评审
doi：10.1038/leu.2011.236
更新日期：2012-01-01 00:00:00
abstract：:Previous studies in pediatric patients with acute myelogenous leukemia (AML) have suggested that 2-chlorodeoxyadenosine (2CdA) is an effective therapeutic agent. Santana et al (J Clin Oncol 1992; 10: 364-370) reported a CR rate of 8/17 (95% Cl 23-72%) in children with relapsed AML and a median first CR of 21 months. T...
journal_title：Leukemia
pub_type： 临床试验,杂志文章
doi：
更新日期：1996-10-01 00:00:00
abstract：:Interferon-alpha produces a complete hematologic and cytogenetic remission in approximately 20% of patients with chronic myelogenous leukemia (CML). In this study, we applied fluorescent in situ hybridization (FISH) methodology to examine the possibility that a low level of proliferating Philadelphia-chromosome-positi...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1993-02-01 00:00:00
abstract：:Four randomized prospective studies on interferon alpha (IFN) in CML report varying degrees of prolongation of the chronic phase of CML and of survival as compared to conventional therapies. There is agreement that IFN prolongs survival as compared to standard busulfan. There is disagreement, however, as to which degr...
journal_title：Leukemia
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
doi：
更新日期：1997-04-01 00:00:00
abstract：:An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title：Leukemia
pub_type： 已发布勘误
doi：10.1038/s41375-020-0968-9
更新日期：2020-11-01 00:00:00
abstract：:In order to further define the role of the MDR1 gene in acute myeloid leukemia (AML), we determined the association between the presence of P-glycoprotein on leukemic cells and the efficacy of therapy in patients with AML. Immunocytochemistry with monoclonal antibody C219 was performed to demonstrate the presence of P...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1994-06-01 00:00:00
abstract：:Human DNA ligase was purified from different kinds of immunocompetent cells: thymocytes, normal and stimulated lymphocytes, blasts from ALL (Burkitt and non-T, non-B) and ANLL (M1, M2, and M5). Based upon the protocol for the treatment of these leukemias, the purified enzymes were assayed in the presence of routinely ...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1988-06-01 00:00:00
abstract：:Microarrays for gene expression profiling are rapidly becoming important research tools for the identification of novel markers, for example, for novel classification of leukemias and lymphomas. Here, we review the considerations and infrastructure for microarray experiments. These considerations are illustrated via a...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/sj.leu.2402974
更新日期：2003-07-01 00:00:00
abstract：:The efficacy of antifungal prophylaxis with itraconazole capsules and its serum concentrations were evaluated in patients intensively treated for acute leukaemia. A consecutive group of patients without systemic antifungal prophylaxis (January 1993 to August 1994, period 1) was compared with another consecutive group ...
journal_title：Leukemia
pub_type： 杂志文章
doi：10.1038/sj.leu.2401137
更新日期：1998-09-01 00:00:00
abstract：:We have previously reported that constitutive expression of c-fos oncogene allows long-term proliferation of primary mouse bone marrow stromal cells favoring the granulocytic differentiation of myeloid precursors in an in vitro assay. Retrovirus-mediated gene transfer of the human c-fos gene was used here for immortal...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1996-03-01 00:00:00
abstract：:Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, af...
journal_title：Leukemia
pub_type： 杂志文章,多中心研究
doi：10.1038/leu.2013.219
更新日期：2013-10-01 00:00:00
abstract：:This paper describes seven patients with ALL and a hypodiploid karyotype with less than 40 chromosomes. A consideration of these and 15 previously published cases indicates that they may be divided into two groups depending on chromosome number, i.e., less than 30 and 30-39. The less than 30 group are younger and pred...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1989-10-01 00:00:00
abstract：:The molecular events which confer cellular resistance to cytotoxic drugs such as cytosine arabinoside (ara-C) are poorly understood. Nevertheless, in a proportion of patients with acute leukemia, such events will be responsible for the failure of therapy. Mutations which cause ara-C resistance in a chinese hamster ova...
journal_title：Leukemia
pub_type： 杂志文章
doi：
更新日期：1994-02-01 00:00:00
