Abstract:
:Chimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.
journal_name
Leukemiajournal_title
Leukemiaauthors
Jiang Z,Liao R,Lv J,Li S,Zheng D,Qin L,Wu D,Chen S,Long Y,Wu Q,Wang S,Lin S,Huang X,Tang Z,Shi P,Zhou H,Liu Q,Zhao R,Li Y,Jie Y,Wei W,Lai P,Du X,Cui S,Weinkove R,Liu P,Pei D,Yao Y,Li Pdoi
10.1038/s41375-020-01085-1subject
Has Abstractpub_date
2020-11-09 00:00:00eissn
0887-6924issn
1476-5551pii
10.1038/s41375-020-01085-1pub_type
杂志文章相关文献
LEUKEMIA文献大全abstract::A poorly defined transforming event(s) affects the pluripotential bone marrow (BM) stem cell in myelodysplastic syndromes (MDS), conferring a growth advantage upon it which leads eventually to monoclonal hematopoiesis. The progeny of this transformed ancestor undergo recognizable albeit dysplastic maturation. We propo...
journal_title:Leukemia
pub_type: 杂志文章,评审
doi:
更新日期:1996-10-01 00:00:00
abstract::Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally define...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2014.93
更新日期:2014-10-01 00:00:00
abstract::Three cell populations with different DNA indices were demonstrated in a case of biphenotypic terminal transferase (TdT)/myeloid-positive acute leukemia which had developed from a pre-leukemic diploid population also expressing biphenotypic features. At the time of development of acute leukemia, flow-cytometric analys...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1989-01-01 00:00:00
abstract::We investigated the effect of ubenimex on the growth and differentiation of U937 cells, a histiocytic lymphoma cell line. Ubenimex is a dipeptide ((2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl-L-leucine) and an inhibitor of aminopeptidase B produced by Streptomyces olivoreticuli. Ubenimex inhibited the proliferation of U9...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1994-12-01 00:00:00
abstract::Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AML) characterized by the presence of the t(15;17) translocation and the resulting PML/RAR alpha fusion proteins. To date APL is the only AML which is sufficiently sensitive to all-trans retinoic acid (ATRA) differentiating effect...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1994-10-01 00:00:00
abstract::We analyzed mRNA expression of the flt3 gene in 30 patients with acute myeloid leukemia (AML) and 50 with acute lymphoblastic leukemia (ALL). Using reverse transcriptase-polymerase chain reaction (RT-PCR), expression of flt3 was observed in 61 patients; 22 (73%) with AML and 39 (78%) with ALL. Among these, five patien...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1996-12-01 00:00:00
abstract::Self-renewal, as defined by the capacity to yield new colonies following replating, is an important function of leukemic progenitors (L-CFU) to originate self-maintaining clones. In this work, we studied the effect of hyperthermia (41-44 degrees C) on the growth of human L-CFU derived primary colonies and of secondary...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1991-04-01 00:00:00
abstract::The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34+CD38- fraction. To understand the origin of malignant cells in primary human B-pre...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2008.83
更新日期:2008-06-01 00:00:00
abstract::Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a larg...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2016.362
更新日期:2017-07-01 00:00:00
abstract::The high efficacy of the standard treatment of chronic myeloid leukemia (CML) with imatinib has prompted the need for accurate methods to monitor response at levels below the landmark of complete cytogenetic remission. Quantification of BCR-ABL transcripts has proven to be the most sensitive method available, and has ...
journal_title:Leukemia
pub_type: 杂志文章,评审
doi:10.1038/leu.2009.168
更新日期:2009-11-01 00:00:00
abstract::In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade ...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/s41375-018-0038-8
更新日期:2018-07-01 00:00:00
abstract::Despite improved prognosis in acute myelogenous leukaemia (AML) children with Down syndrome (DS), therapy-related toxicity remained a problem. We compared 67 DS patients from study AML-BFM 98 with 51 DS patients of the previous study AML-BFM 93, and the non-DS groups of both studies. Compared to non-DS patients, DS pa...
journal_title:Leukemia
pub_type: 临床试验,杂志文章
doi:10.1038/sj.leu.2403814
更新日期:2005-08-01 00:00:00
abstract::The clinical and cell growth characteristics of 11 children with monosomy 7 presenting as preleukemia (eight cases) or acute nonlymphoblastic leukemia (three cases) were studied. Anemia was common to all patients, with nine showing leukocytosis, seven thrombocytopenia, and one thrombocytosis. There was a striking pred...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1987-02-01 00:00:00
abstract::The Brazilian Cooperative Group for Treatment of Childhood Acute Lymphocytic Leukemia (GBTLI) has started clinical activities trials in 1980. Three consecutive multicenter studies in children with unprevious treated ALL have been completed including 994 patients. The first GBTLI-80 accrued 203 children from 1980 to 19...
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:1993-08-01 00:00:00
abstract::We previously reported the fusion of the TEL gene to the Syk gene in myelodysplastic syndrome with t(9;12)(q22;p12). TEL-Syk fusion transformed interleukin-3 (IL-3)-dependent murine hematopoietic cell line BaF3 to growth factor independence. Here, we investigate the intracellular signal transduction of the stable tran...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2403266
更新日期:2004-03-01 00:00:00
abstract::Although reciprocal chromosomal translocations are not typical for B-cell chronic lymphocytic leukemia (B-CLL), we identified the novel t(1;6)(p35.3;p25.2) in eight patients with this disorder. Interestingly, all cases showed lack of somatically mutated IgV(H). Clinical, morphological, immunologic, and genetic feature...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2403543
更新日期:2005-01-01 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::Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma m...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2403063
更新日期:2003-09-01 00:00:00
abstract::We have investigated the direct effects of interferon (IFN) on hairy cells (HCs) isolated from patients with hairy cell leukemia using one- and two-dimensional gel electrophoresis. We have previously characterized the induction of synthesis of 10-16 specific proteins by IFN-alpha 2b in HCs, as analyzed by one-dimensio...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1987-04-01 00:00:00
abstract::To determine the frequency and prognostic significance of recently described genetic lesions in pediatric acute lymphoblastic leukemia (ALL), all cases with available leukemic cell samples treated on St Jude Study XII were analyzed by molecular techniques for alterations of the p16, MLL and ETV6 genes. Homozygous p16 ...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2400779
更新日期:1997-08-01 00:00:00
abstract::Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of pati...
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:10.1038/sj.leu.2402489
更新日期:2002-06-01 00:00:00
abstract::The interactions between haemopoietic progenitor cells and marrow stromal cells that are essential for the regulation of normal haemopoiesis are defective in chronic phase chronic myeloid leukaemia (CML). The presence of primitive progenitor cells (blast colony-forming cells, Bl-CFC) in the blood of patients with CML ...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1991-08-01 00:00:00
abstract::Toll-like receptors (TLRs) constitute a family of nonpolymorphic receptors that are devoted to pathogen recognition. In this work, we have explored the impact of TLR ligands (TLR-L) on human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We show that HSCs and HPCs have a comparable pattern ...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2009.155
更新日期:2009-11-01 00:00:00
abstract::We previously reported a strong IL4I1 gene expression in primary mediastinal B-cell lymphoma (PMBL) and recently identified the protein as a secreted L-phenylalanine oxidase, physiologically expressed by myeloid cells, which inhibits T-cell proliferation in vitro. Here, we analyzed the pattern of IL4I1 protein express...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2008.380
更新日期:2009-05-01 00:00:00
abstract::The aim of this study was to collect prospectively unselected, population-based data on young adults with acute myeloid leukaemia (AML) over a 9-year period and to evaluate the impact on survival of the introduction of allogeneic transplantation performed in first remission. The population within the Northern Region o...
journal_title:Leukemia
pub_type: 临床试验,杂志文章
doi:
更新日期:1995-07-01 00:00:00
abstract::The involvement of the BCRlABL fusion gene in patients with Philadelphia (Ph) chromosome positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) is well characterised, but the molecular events underlying the cases of Ph-negative CML and ALL that lack BCR gene involvement and those that cause t...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1992-08-01 00:00:00
abstract::Cellular stressors induce various outcomes including inhibition of cell proliferation and cell death. Sodium salicylate (SA), a plant stress hormone, can suppress the proliferation or cause apoptosis in certain mammalian cancer cells. Plant stress hormones are activators of cellular responses, including cell death, to...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2402419
更新日期:2002-04-01 00:00:00
abstract::To compare the antileukemic efficacy of idarubicin and mitoxantrone in elderly patients with acute myeloid leukemia (AML) and to evaluate the feasibility of autologous transplantation using PBSC after consolidation in those with a good performance status, 160 patients (median age 69 years), with AML at diagnosis, 118 ...
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:10.1038/sj.leu.2401445
更新日期:1999-06-01 00:00:00
abstract::The AML1/ETO fusion transcript can be detected by reverse transcription polymerase chain reaction (RT-PCR) in patients with t(8;21)-associated acute myeloid leukemia (AML) in long-term complete remission (CR). Quantitation of the amount of the fusion transcript during CR may therefore be more predictive of cure or rel...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2401128
更新日期:1998-09-01 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