Antileukemic Effort Of NK Cells In HCT For Pediatric AML
Wing Leung
St. Jude Children´s Research Hospital
memphis, Tn 38105
Grant 5R01CA120583-02 from National Cancer Institute IRG: ZRG1
Abstract: Acute myeloid leukemia (AML) is the second most frequent leukemia diagnosed in children, and natural killer (NK) cells have clinically important antileukemic effects. Children with AML who either do not enter remission after induction chemotherapy or who relapse despite standard chemotherapy have an extremely poor prognosis. Although unrelated donor (URD) hematopoietic cell transplantation (HCT) can cure some of these patients, their probability of survival is less than 25%. Our long-term goal is to elucidate the determinants of beneficial alloreactivity of human NK cells in URD HCT for childhood AML. Our central hypothesis is that NK- cell effects are determined by the expression of activating and inhibitory receptors. Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) on donor NK cells will be the key focus of this proposal, because we have shown that the expression of KIRs significantly affects patient outcome, is minimally influenced by the donor HLA type, is highly variable among individuals with the same KIR gene content, and may be undetectable, even if genotyping indicates its presence. This project will take advantage of the availability of a prospective cohort of patients enrolled in Children´s Oncology Group (COG) AAML05P1 study and will receive a uniform transplantation regimen. The following Specific Aims will be addressed Specific Aim 1. To assess NK-cell development after URD HCT in patients with poor prognosis AML. NK-cell reconstitution and receptor-acquisition pattern will be evaluated in 160 HCT recipients by blood tests using flow cytometry, RT-PCR, RQ-PCR, and cytotoxicity analyses. We hypothesize that NK-cell development after HCT is primarily affected by the compatibility of donor KIRs and recipient KIR-ligands and by the number of CD34+ cells and CD3+ T cells in the graft. Specific Aim 2 To define the relationship between the status of donor NK-cell receptor and patient outcomes after unrelated donor (URD) HCT in patients with poor prognosis AML. We will correlate the relationships between factors affecting NK receptor status and clinical events in 160 HCT recipients. The testable hypotheses are that clinical outcomes are better if there is KIR incompatibility between donor and recipient and if NK-cell reconstitution and receptor-acquisition occurs early after HCT. Relevance to public health Natural killer cells are blood cells that have antileukemic properties. We will investigate these properties in patients with acute myelogenous leukemia (AML) who are enrolled on Children´s Oncology Group (COG) studies and will undergo hematopoietic cell transplantation (HCT) and in their unrelated donors. Our goal is to optimize the pairing of unrelated donors and recipients of HCT, thereby improving survival of pediatric patients with AML who typically have a poor prognosis
Keywords: cell acute myelogenous leukemia, blood cell, blood test, cell transplantation, chemotherapy, children, cytotoxicity, emotion, flow cytometry, gene, genotype, human, immunoglobulin, killer cell, leukemia, ligand, natural killer cell, oncology, prognosis, public health, receptor, transplantation clinical research
Project start date: 2007-08-01
Project end date: 2012-06-30
5R01CA120583-02 (2008): $364712
Sponsored Links Excellgen http://Excellgen.com
ANTILEUKEMIC EFFORT OF NK CELLS IN HCT FOR PEDIATRIC AML
Wing Leung, Member & Professor
St. Jude Children´s Research Hospital, Memphis, Tn 38105
Grant 5R01CA120583-04 from National Cancer Institute
Abstract: Acute myeloid leukemia (AML) is the second most frequent leukemia diagnosed in children, and natural killer (NK) cells have clinically important antileukemic effects. Children with AML who either do not enter remission after induction chemotherapy or who relapse despite standard chemotherapy have an extremely poor prognosis. Although unrelated donor (URD) hematopoietic cell transplantation (HCT) can cure some of these patients, their probability of survival is less than 25%. Our long-term goal is to elucidate the determinants of beneficial alloreactivity of human NK cells in URD HCT for childhood AML. Our central hypothesis is that NK- cell effects are determined by the expression of activating and inhibitory receptors. Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) on donor NK cells will be the key focus of this proposal, because we have shown that the expression of KIRs significantly affects patient outcome, is minimally influenced by the donor HLA type, is highly variable among individuals with the same KIR gene content, and may be undetectable, even if genotyping indicates its presence. This project will take advantage of the availability of a prospective cohort of patients enrolled in Children´s Oncology Group (COG) AAML05P1 study and will receive a uniform transplantation regimen. The following Specific Aims will be addressed Specific Aim 1. To assess NK-cell development after URD HCT in patients with poor prognosis AML. NK-cell reconstitution and receptor-acquisition pattern will be evaluated in 160 HCT recipients by blood tests using flow cytometry, RT-PCR, RQ-PCR, and cytotoxicity analyses. We hypothesize that NK-cell development after HCT is primarily affected by the compatibility of donor KIRs and recipient KIR-ligands and by the number of CD34+ cells and CD3+ T cells in the graft. Specific Aim 2 To define the relationship between the status of donor NK-cell receptor and patient outcomes after unrelated donor (URD) HCT in patients with poor prognosis AML. We will correlate the relationships between factors affecting NK receptor status and clinical events in 160 HCT recipients. The testable hypotheses are that clinical outcomes are better if there is KIR incompatibility between donor and recipient and if NK-cell reconstitution and receptor-acquisition occurs early after HCT. Relevance to public health Natural killer cells are blood cells that have antileukemic properties. We will investigate these properties in patients with acute myelogenous leukemia (AML) who are enrolled on Children´s Oncology Group (COG) studies and will undergo hematopoietic cell transplantation (HCT) and in their unrelated donors. Our goal is to optimize the pairing of unrelated donors and recipients of HCT, thereby improving survival of pediatric patients with AML who typically have a poor prognosis
Keywords: 0-11 years old; AML - Acute Myeloid Leukemia; Address; Affect; Blood (Leukemia); Blood Cells; Blood Tests; CD3; CD3 Antigens; CD3 Complex; CD3 molecule; CD34; CD34 gene; Cell Transplantation; Cells; Child; Child Youth; Childhood; Childhood AML; Childhood Acute Granulocytic Leukemia; Childhood Acute Myeloblastic Leukemia; Childhood Acute Myelocytic Leukemia; Childhood Acute Myelogenous Leukemia; Childhood Acute Myeloid Leukemia; Children (0-21); Children`s Oncology Group; Clinical; Cytofluorometry, Flow; Cytotoxic cell; Development; Diagnosis; Disease remission; Enrollment; Event; Flow Cytofluorometries; Flow Cytometry; Flow Microfluorimetry; Forecast of outcome; Genotype; Goals; HPCA1; Hematologic Tests; Hematological Tests; Hematology Testing; Hematopoietic; Human; Human, Child; Human, General; Immune Globulins; Immunoglobulins; Immunoglobulins / Antibodies; Individual; Investigators; K Cells; K lymphocyte; Killer Cells; Leukemia, Myelocytic, Acute; Leukemias, General; Ligands; Lytotoxicity; Man (Taxonomy); Man, Modern; Microfluorometry, Flow; Myeloblastic Leukemia, Acute; Myelogenous Leukemia, Acute; NK Cells; Natural Killer Cells; OKT3 antigen; Outcome; Patients; Pattern; Pediatric AML; Pediatric Acute Myeloblastic Leukemia; Pediatric Acute Myelocytic Leukemia; Pediatric Acute Myelogenous Leukemia; Pediatric Acute Myeloid Leukemia; Peripheral Blood Cell; Probability; Prognosis; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Public Health; RMSN; RT-PCR; RTPCR; Receptor Gene; Receptor Protein; Regimen; Relapse; Remission; Research Personnel; Researchers; Reverse Transcriptase Polymerase Chain Reaction; T-Cells; T-Lymphocyte; T3 Antigens; T3 Complex; T3 molecule; Thymus-Dependent Lymphocytes; Transplantation; Wing; acute granulocytic leukemia; acute myeloid leukemia; acute nonlymphocytic leukemia; chemotherapy; children; cohort; cytotoxicity; enroll; flow cytophotometry; improved; leukemia; outcome forecast; pediatric; programs; prospective; public health medicine (field); receptor; reconstitute; reconstitution; reverse transcriptase PCR; thymus derived lymphocyte; transplant; youngster
Project start date: 2007-08-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
5R01CA120583-04 (2010): $362276
5R01CA120583-03 (2009): $357812
Grants awarded to Wing Leung
Antileukemic Effort Of NK Cells In HCT For Pediatric AML
Wing Leung
St. Jude Children´s Research Hospital
memphis, Tn 38105
Grant 1R01CA120583-01A2 from National Cancer Institute IRG: ZRG1
Abstract: Acute myeloid leukemia (AML) is the second most frequent leukemia diagnosed in children, and natural killer (NK) cells have clinically important antileukemic effects. Children with AML who either do not enter remission after induction chemotherapy or who relapse despite standard chemotherapy have an extremely poor prognosis. Although unrelated donor (URD) hematopoietic cell transplantation (HCT) can cure some of these patients, their probability of survival is less than 25%. Our long-term goal is to elucidate the determinants of beneficial alloreactivity of human NK cells in URD HCT for childhood AML. Our central hypothesis is that NK- cell effects are determined by the expression of activating and inhibitory receptors. Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) on donor NK cells will be the key focus of this proposal, because we have shown that the expression of KIRs significantly affects patient outcome, is minimally influenced by the donor HLA type, is highly variable among individuals with the same KIR gene content, and may be undetectable, even if genotyping indicates its presence. This project will take advantage of the availability of a prospective cohort of patients enrolled in Children´s Oncology Group (COG) AAML05P1 study and will receive a uniform transplantation regimen. The following Specific Aims will be addressed Specific Aim 1. To assess NK-cell development after URD HCT in patients with poor prognosis AML. NK-cell reconstitution and receptor-acquisition pattern will be evaluated in 160 HCT recipients by blood tests using flow cytometry, RT-PCR, RQ-PCR, and cytotoxicity analyses. We hypothesize that NK-cell development after HCT is primarily affected by the compatibility of donor KIRs and recipient KIR-ligands and by the number of CD34+ cells and CD3+ T cells in the graft. Specific Aim 2 To define the relationship between the status of donor NK-cell receptor and patient outcomes after unrelated donor (URD) HCT in patients with poor prognosis AML. We will correlate the relationships between factors affecting NK receptor status and clinical events in 160 HCT recipients. The testable hypotheses are that clinical outcomes are better if there is KIR incompatibility between donor and recipient and if NK-cell reconstitution and receptor-acquisition occurs early after HCT. Relevance to public health Natural killer cells are blood cells that have antileukemic properties. We will investigate these properties in patients with acute myelogenous leukemia (AML) who are enrolled on Children´s Oncology Group (COG) studies and will undergo hematopoietic cell transplantation (HCT) and in their unrelated donors. Our goal is to optimize the pairing of unrelated donors and recipients of HCT, thereby improving survival of pediatric patients with AML who typically have a poor prognosis
Keywords: cell acute myelogenous leukemia, blood cell, blood test, cell transplantation, chemotherapy, children, cytotoxicity, emotion, flow cytometry, gene, genotype, human, immunoglobulin, killer cell, leukemia, ligand, natural killer cell, oncology, prognosis, public health, receptor, transplantation clinical research
Project start date: 2007-08-01
Project end date: 2012-06-30
1R01CA120583-01A2 (2007): $359055