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Article ; Online: Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 18, Page(s) 3592–3602

Abstract: Purpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to ... ...

Abstract	Purpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Patients and methods: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Results: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. Conclusions: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.
MeSH term(s)	Adult ; Humans ; Protein-Arginine N-Methyltransferases/genetics ; Neoplasms/drug therapy ; Neoplasms/pathology ; Pyrimidines ; Pyrroles ; Lymphoma, Non-Hodgkin ; Carcinoma, Adenoid Cystic
Chemical Substances	JNJ-64619178 ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319) ; Pyrimidines ; Pyrroles ; PRMT5 protein, human (EC 2.1.1.319)
Language	English
Publishing date	2023-07-25
Publishing country	United States
Document type	Multicenter Study ; Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-0092
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Article ; Online: Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes.

Leukemia research

2023 Volume 134, Page(s) 107390

Abstract: Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated ...

Abstract	Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.
MeSH term(s)	Humans ; Protein-Arginine N-Methyltransferases/genetics ; Protein-Arginine N-Methyltransferases/therapeutic use ; Myelodysplastic Syndromes/drug therapy ; Myelodysplastic Syndromes/genetics ; Anemia/drug therapy ; Bone Marrow ; Treatment Outcome
Chemical Substances	JNJ-64619178 ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319) ; PRMT5 protein, human (EC 2.1.1.319)
Language	English
Publishing date	2023-09-20
Publishing country	England
Document type	Multicenter Study ; Clinical Trial, Phase I ; Journal Article
ZDB-ID	752396-8
ISSN	1873-5835 ; 0145-2126
ISSN (online)	1873-5835
ISSN	0145-2126
DOI	10.1016/j.leukres.2023.107390
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Article ; Online: Eltrombopag modulates reactive oxygen species and decreases acute myeloid leukemia cell survival.

Kalota, Anna / Selak, Mary A / Garcia-Cid, Laura A / Carroll, Martin

PloS one

2015 Volume 10, Issue 4, Page(s) e0126691

Abstract: Previous studies have demonstrated that the small molecule thrombopoietin (TPO) mimetic, eltrombopag (E), induces apoptosis in acute myeloid leukemia (AML) cells. Here, we sought to define the mechanism of the anti-leukemic effect of eltrombopag. Our ... ...

Abstract	Previous studies have demonstrated that the small molecule thrombopoietin (TPO) mimetic, eltrombopag (E), induces apoptosis in acute myeloid leukemia (AML) cells. Here, we sought to define the mechanism of the anti-leukemic effect of eltrombopag. Our studies demonstrate that, at a concentration of 5 μM E in 2% serum, E induces apoptosis in leukemia cells by triggering PARP cleavage and activation of caspase cascades within 2-6 hours. The induction of apoptotic enzymes is critically dependent on drug concentration and the concentration of serum. This effect is not associated with an alteration in mitochondrial potential but is associated with a rapid decrease in a reactive oxygen species (ROS) in particular hydrogen peroxide (H2O2). Interestingly, E also decreases mitochondrial maximal and spare respiratory capacities suggesting an induced mitochondrial dysfunction that may not be readily apparent under basal conditions but becomes manifest only under stress. Co-treatment of MOLM14 AML cells with E plus Tempol or H2O2 provides a partial rescue of cell toxicity. Ferric ammonioum citrate (FAC) also antagonized the E induced toxicity, by inducing notable increase in ROS level. Overall, we propose that E dramatically decreases ROS levels leading to a disruption of AML intracellular metabolism and rapid cell death.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Adult ; Aged ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Blotting, Western ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Female ; Humans ; Hydrogen Peroxide/antagonists & inhibitors ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/metabolism ; Male ; Middle Aged ; Oxygen Consumption/drug effects ; Reactive Oxygen Species/antagonists & inhibitors ; Thyroxine/therapeutic use ; Tumor Cells, Cultured ; Young Adult
Chemical Substances	Antineoplastic Agents ; Reactive Oxygen Species ; Adenosine Triphosphate (8L70Q75FXE) ; Hydrogen Peroxide (BBX060AN9V) ; Thyroxine (Q51BO43MG4)
Language	English
Publishing date	2015-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0126691
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Article ; Online: A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells.

Kalota, Anna / Gewirtz, Alan M

Blood

2009 Volume 115, Issue 1, Page(s) 89–93

Abstract: Biologic characterization of SB-559457 (SB), a nonpeptidyl hydrazone class of thrombopoietin receptor (Mpl) agonist, revealed toxicity toward human leukemia cells. Antiproliferative effects followed by significant, nonapoptotic, cell death within 72 ... ...

Abstract	Biologic characterization of SB-559457 (SB), a nonpeptidyl hydrazone class of thrombopoietin receptor (Mpl) agonist, revealed toxicity toward human leukemia cells. Antiproliferative effects followed by significant, nonapoptotic, cell death within 72 hours occurred in 24 of 26 acute myeloid leukemia, 0 of 6 acute lymphoblastic leukemia, and 3 of 6 chronic myeloid leukemia patient samples exposed to SB, but not recombinant human thrombopoietin (rhTpo), in liquid suspension culture. Further investigation revealed increased phosphorylation of p70S6/S6 kinases in SB-, but not in rhTpo-, treated cells. Expression profiling of cells exposed to SB versus rhTpo revealed statistically significant, more than 2-fold changes in GAPDH and REDD1 gene expression, confirmed by quantitative reverse-transcribed polymerase chain reaction. These genes, induced in energy or hypoxia stressed cells, have been implicated in cell death pathways, and may provide important clues to the mechanism of SB-induced, leukemic cell death. These results suggest that nonpeptidyl, hydrazone class Mpl agonists may be clinically useful antileukemic agents by virtue of their combined thrombopoietic and antileukemic effects.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/toxicity ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Hydrazones/chemistry ; Hydrazones/pharmacology ; Hydrazones/toxicity ; Leukemia, Myeloid/enzymology ; Leukemia, Myeloid/genetics ; Leukemia, Myeloid/pathology ; Peptides/pharmacology ; Phosphorylation/drug effects ; Receptors, Thrombopoietin/agonists ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Cells, Cultured
Chemical Substances	Antineoplastic Agents ; DDIT4 protein, human ; Hydrazones ; Peptides ; Receptors, Thrombopoietin ; SB-559457 ; Transcription Factors ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1)
Language	English
Publishing date	2009-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2009-06-227751
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Article: Design of antisense oligonucleotides and short interfering RNA duplexes (siRNA) targeted to BCL6 mRNA: towards rational drug development for specific lymphoma subsets.

Kalota, Anna / Opalinska, J B

Blood cells, molecules & diseases

2007 Volume 38, Issue 3, Page(s) 199–203

Abstract: Many algorithms based on computational analysis and thermodynamic parameters have been developed to predict the secondary structure of RNA. Still, many antisense oligodeoxynucleotides (AS ODNs), or siRNA molecules designed according to these predictions ... ...

Abstract	Many algorithms based on computational analysis and thermodynamic parameters have been developed to predict the secondary structure of RNA. Still, many antisense oligodeoxynucleotides (AS ODNs), or siRNA molecules designed according to these predictions fail to silence the intended target, whereas other, not fulfilling those criteria prove highly active. We have developed a reliable mapping strategy, which allows us to predict the sites accessible for hybridization within target mRNA in vitro and in vivo. Our mapping experiments employed self-quenching reporter molecules (SQRMs) and were first carried out in a cell free system, and later confirmed in vivo.
MeSH term(s)	Blotting, Western/methods ; Cell Line, Tumor ; DNA-Binding Proteins/genetics ; Drug Design ; Genetic Therapy ; Humans ; Lymphoma/genetics ; Lymphoma/therapy ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/genetics ; Polymerase Chain Reaction/methods ; Proto-Oncogene Proteins c-bcl-6 ; RNA, Messenger/genetics ; RNA, Small Interfering/chemistry ; RNA, Small Interfering/genetics ; Sequence Analysis
Chemical Substances	BCL6 protein, human ; DNA-Binding Proteins ; Oligonucleotides, Antisense ; Proto-Oncogene Proteins c-bcl-6 ; RNA, Messenger ; RNA, Small Interfering
Language	English
Publishing date	2007-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1237083-6
ISSN	1096-0961 ; 1079-9796
ISSN (online)	1096-0961
ISSN	1079-9796
DOI	10.1016/j.bcmd.2006.11.007
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Zs.A 1138: Show issues

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Article ; Online: Intrinsic resistance to JAK2 inhibition in myelofibrosis.

Kalota, Anna / Jeschke, Grace R / Carroll, Martin / Hexner, Elizabeth O

Clinical cancer research : an official journal of the American Association for Cancer Research

2013 Volume 19, Issue 7, Page(s) 1729–1739

Abstract: Purpose: Recent results have shown that myeloproliferative neoplasms (MPN) are strongly associated with constitutive activation of the Janus-activated kinase (JAK)2 tyrosine kinase. However, JAK2 inhibitors currently approved or under development for ... ...

Abstract	Purpose: Recent results have shown that myeloproliferative neoplasms (MPN) are strongly associated with constitutive activation of the Janus-activated kinase (JAK)2 tyrosine kinase. However, JAK2 inhibitors currently approved or under development for treating myeloproliferative neoplasms do not selectively deplete the malignant clone, and the inhibition of activity of the drug target (JAK2) has not been rigorously evaluated in the clinical studies. Therefore, in this study we developed an in vitro assay to gain insight into how effectively JAK2 activity is inhibited in the samples of patients. Experimental design: We treated primary cells from normal donors and patients with MPN with JAK2 inhibitors and measured phosphorylation of downstream targets STAT5 and STAT3 by flow cytometry. Obtained results were next correlated with JAK2 V617F allele burden and plasma cytokine level. Results: We observed a dose-dependent decrease in pSTAT5 and pSTAT3 in ex vivo treated granulocytes. However, phosphorylation of STAT3 and STAT5 in cells from patients with myelofibrosis was significantly less inhibited when compared with cells from patients with polycythemia vera, essential thrombocythemia, and normal donors. Sensitivity to inhibition did not correlate with JAK2 V617F clonal burden. Mixing studies using plasma from patients with myelofibrosis did not transfer resistance to sensitive cells. Likewise, no single cytokine measured seemed to account for the observed pattern of resistance. Conclusions: Taken together, these observations suggest that there are cell intrinsic mechanisms that define a priori resistance to JAK2 inhibition in myelofibrosis, and the lesion is localized upstream of STAT3 and STAT5.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Alleles ; Carbazoles/pharmacology ; Cytokines/pharmacology ; Drug Resistance ; Female ; Gene Frequency ; Humans ; Janus Kinase 2/antagonists & inhibitors ; Janus Kinase 2/genetics ; Janus Kinase 2/metabolism ; Male ; Middle Aged ; Mutation ; Neutrophils/drug effects ; Neutrophils/metabolism ; Phosphorylation ; Primary Myelofibrosis/genetics ; Primary Myelofibrosis/metabolism ; Protein Kinase Inhibitors/pharmacology ; STAT3 Transcription Factor/metabolism ; STAT5 Transcription Factor/metabolism
Chemical Substances	Carbazoles ; Cytokines ; Protein Kinase Inhibitors ; STAT3 Transcription Factor ; STAT5 Transcription Factor ; lestaurtinib (DO989GC5D1) ; Janus Kinase 2 (EC 2.7.10.2)
Language	English
Publishing date	2013-02-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-12-1907
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Article ; Online: Short hairpin RNA screen reveals bromodomain proteins as novel targets in acute myeloid leukemia.

Blobel, Gerd A / Kalota, Anna / Sanchez, Patricia V / Carroll, Martin

Cancer cell

2011 Volume 20, Issue 3, Page(s) 287–288

Abstract: Targeting chromatin regulators for the treatment of malignancies has shown great promise, but also revealed significant challenges. By employing an elegant shRNA screen and a selective pharmacological inhibitor, a recent study published in Nature ... ...

Abstract	Targeting chromatin regulators for the treatment of malignancies has shown great promise, but also revealed significant challenges. By employing an elegant shRNA screen and a selective pharmacological inhibitor, a recent study published in Nature establishes the bromodomain protein Brd4 as novel target in acute myeloid leukemia (AML).
Language	English
Publishing date	2011-08-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccr.2011.08.019
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Article ; Online: Eltrombopag modulates reactive oxygen species and decreases acute myeloid leukemia cell survival.

Anna Kalota / Mary A Selak / Laura A Garcia-Cid / Martin Carroll

PLoS ONE, Vol 10, Iss 4, p e

2015 Volume 0126691

Abstract	Previous studies have demonstrated that the small molecule thrombopoietin (TPO) mimetic, eltrombopag (E), induces apoptosis in acute myeloid leukemia (AML) cells. Here, we sought to define the mechanism of the anti-leukemic effect of eltrombopag. Our studies demonstrate that, at a concentration of 5 μM E in 2% serum, E induces apoptosis in leukemia cells by triggering PARP cleavage and activation of caspase cascades within 2-6 hours. The induction of apoptotic enzymes is critically dependent on drug concentration and the concentration of serum. This effect is not associated with an alteration in mitochondrial potential but is associated with a rapid decrease in a reactive oxygen species (ROS) in particular hydrogen peroxide (H2O2). Interestingly, E also decreases mitochondrial maximal and spare respiratory capacities suggesting an induced mitochondrial dysfunction that may not be readily apparent under basal conditions but becomes manifest only under stress. Co-treatment of MOLM14 AML cells with E plus Tempol or H2O2 provides a partial rescue of cell toxicity. Ferric ammonioum citrate (FAC) also antagonized the E induced toxicity, by inducing notable increase in ROS level. Overall, we propose that E dramatically decreases ROS levels leading to a disruption of AML intracellular metabolism and rapid cell death.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Fears and Health Needs of Patients with Diabetes: A Qualitative Research in Rural Population.

Papaspurou, Maria / Laschou, Vasiliki C / Partsiopoulou, Paraskevi / Fradelos, Evangelos C / Kleisiaris, Christos F / Kalota, Malamati A / Neroliatsiou, Anna / Papathanasiou, Ioanna V

Medical archives (Sarajevo, Bosnia and Herzegovina)

2015 Volume 69, Issue 3, Page(s) 190–195

Abstract: Introduction: Insulin-dependent patients are individuals with chronic disease who are well adapted to living and dealing with any health needs and fears arising. An important aspect in the process of adaptation to chronic illness is the provision of ... ...

Abstract	Introduction: Insulin-dependent patients are individuals with chronic disease who are well adapted to living and dealing with any health needs and fears arising. An important aspect in the process of adaptation to chronic illness is the provision of nursing care in the early stages of the disease, because this contributes to its acceptance and the early identification and management of potential complications. Purpose: To investigate the health needs and self-management problems faced by patients with diabetes daily, especially those who use insulin. Furthermore purpose of this study was to investigate the fears experienced by patients in the early stage of the disease, but also in its subsequent development and to study possible differences between sexes. Methodology: This is a qualitative study, using interpretative phenomenological approach. Fifteen (nine women and six men) insulin-dependent patients, recounted their personal fears and their needs, through semi-structured interviews, which took place in Central Greece. The method used for processing the results is the Mayering one. Results: The analysis of the narratives showed that patients have a variety of fears and needs associated with the diagnosis, treatment, expected consequences, prognosis and everyday life in the management of the disease. Most patients express the concept of need as desire. Care needs, psychological support and education to recognize and prevent hypoglycemia. Conclusions: Insulin-dependent patients express fears and needs in their daily lives. Nurses providing care aimed at enhancing the level of health, while putting self-care information and training them. Patients want the nurse next to them, so that information is continuous and permanent.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Diabetes Mellitus, Type 1/psychology ; Diabetes Mellitus, Type 1/therapy ; Female ; Greece ; Health Services Needs and Demand ; Humans ; Interviews as Topic ; Male ; Middle Aged ; Qualitative Research ; Rural Population ; Self-Management/psychology ; Sex Factors ; Social Stigma
Language	English
Publishing date	2015-06-10
Publishing country	Bosnia and Herzegovina
Document type	Journal Article
ZDB-ID	128782-5
ISSN	1986-5961 ; 0350-199X ; 0025-8083
ISSN (online)	1986-5961
ISSN	0350-199X ; 0025-8083
DOI	10.5455/medarh.2015.69.190-195
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Article ; Online: Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells.

Lynn, Rachel C / Poussin, Mathilde / Kalota, Anna / Feng, Yang / Low, Philip S / Dimitrov, Dimiter S / Powell, Daniel J

Blood

2015 Volume 125, Issue 22, Page(s) 3466–3476

Abstract: T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate receptor β (FRβ) is a myeloid-lineage antigen expressed on 70% ...

Abstract	T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate receptor β (FRβ) is a myeloid-lineage antigen expressed on 70% of acute myeloid leukemia (AML) patient samples. Here, we describe the development and evaluation of the first CARs specific for human FRβ (m909) in vitro and in vivo. m909 CAR T cells exhibited selective activation and lytic function against engineered C30-FRβ as well as endogenous FRβ(+) AML cell lines in vitro. In mouse models of human AML, m909 CAR T cells mediated the regression of engrafted FRβ(+) THP1 AML in vivo. In addition, we demonstrated that treatment of AML with all-trans retinoic acid (ATRA) enhanced FRβ expression, resulting in improved immune recognition by m909 CAR T cells. Because many cell surface markers are shared between AML blasts and healthy hematopoietic stem and progenitor cells (HSCs), we evaluated FRβ expression and recognition of HSCs by CAR T cells. m909 CAR T cells were not toxic against healthy human CD34(+) HSCs in vitro. Our results indicate that FRβ is a promising target for CAR T-cell therapy of AML, which may be augmented by combination with ATRA.
MeSH term(s)	Animals ; Cells, Cultured ; Female ; Folate Receptor 2/antagonists & inhibitors ; Folate Receptor 2/genetics ; Genetic Therapy/methods ; HEK293 Cells ; Humans ; Immunotherapy, Adoptive/methods ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/immunology ; Leukemia, Myeloid, Acute/pathology ; Leukemia, Myeloid, Acute/therapy ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Molecular Targeted Therapy ; Mutant Chimeric Proteins/metabolism ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology
Chemical Substances	Folate Receptor 2 ; Mutant Chimeric Proteins ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2015-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2014-11-612721
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