Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot
使用新型放射免疫进行骨髓移植治疗血液系统恶性肿瘤
基本信息
- 批准号:8403556
- 负责人:
- 金额:$ 33.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-09 至 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:90YAblationAcuteAcute Myelocytic LeukemiaAcute leukemiaAllogenicAntibodiesAntigensAttenuatedBerylliumBiodistributionBiotinBone MarrowBone Marrow TransplantationCellsCharacteristicsClinicalClonal DeletionCombination Drug TherapyCyclophosphamideDOTA-biotinDiseaseDisease modelDisease remissionDoseDysmyelopoietic SyndromesEngraftmentExhibitsGoalsGranulocyte Colony-Stimulating FactorGuidelinesHLA AntigensHaplotypesHematologic NeoplasmsHematopoieticHumanImmuneImmunosuppressionImmunosuppressive AgentsInfusion proceduresInternationalIsotopesKineticsLabelLengthLeukemic CellLiverLungMajor Histocompatibility ComplexMalignant NeoplasmsMarrowMethodsMinority GroupsModelingModificationMonoclonal AntibodiesMusOrganOutcomePTPRC genePalpablePatientsProceduresProphylactic treatmentRadiationRadiation therapyRadioRadioactivityRadioimmunotherapyRadioisotopesRadiolabeledReagentRegimenRelative (related person)Research ProposalsResidual NeoplasmSCID MiceSiteSpleenStem cellsStreptavidinT-LymphocyteTechnologyTestingTherapeuticTimeTissuesToxic effectTranslationsTransplantationTreatment EfficacyUnited States National Institutes of HealthWhole-Body IrradiationXenograft procedureabstractingbiotin 2chemotherapyclinically relevantcomparativeconditioningdisorder controldosimetryethnic minority populationfludarabinegraft vs host diseasehematopoietic cell transplantationhigh riskimprovedin vivokeratinocyte growth factorkillingsleukemianovelpre-clinicalprogramspublic health relevanceradiotracerreconstitutionresearch studyresponsetransplant registrytumor
项目摘要
ABSTRACT
Project summary: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) currently kill the
majority of afflicted patients despite treatment with combination chemotherapy and hematopoietic cell
transplantation (HCT). The option of HCT for potential therapy of acute leukemias must be further extended to
patients who do not have a readily available HLA-matched donor, such as patients in ethnic minority groups.
Radiolabeled anti-CD45 monoclonal antibodies (Ab) have been shown to improve outcomes for AML and MDS
in the setting of HCT, but toxicity remains high and cure rates are suboptimal. The objective of this research
proposal is to develop a strategy to improve the cure rate of AML and MDS using radioimmunotherapy (RIT)
pretargeted to the CD45 cell antigen. In Aim 1 we will optimize the therapeutic efficacy and toxicities of the
pretargeted RIT approach by comparing the relative merits of 90Y- and 177Lu-labeled biotin in comparative
biodistribution, dosimetry and therapy experiments to determine if the shorter path length b emissions of 177Lu
afford more favorable tumor-to-normal organ ratios than those achievable with 90Y. In Aim 2 we will assess the
relative merits of HCT employing MHC-haploidentical stem cells utilizing myeloablative pretargeted RIT with an
anti-CD45 Ab (30F11)-streptavidin (SA) conjugate followed by either 90Y- or 177Lu-labeled DOTA-biotin (as
determined from aim 1 the best radionuclide will be used), compared to conventional RIT using a directly
radiolabeled anti-CD45 Ab (30F11) in clinically relevant disseminated AML murine leukemia model in which
both leukemic cells and normal hematopoietic cells express CD45. We anticipate that the results from this aim
will demonstrate that pretargeted RIT is superior to conventional RIT and will allow us to improve the
therapeutic efficacy of haploidentical BMT, with tolerable toxicity. In Aim 3 we will characterize and maximize
the myelosuppressive and immunosuppressive effects of radiation delivered to lymphohematopoietic tissues
via either 90Y- or 177Lu-labeled biotin (as determined from aim 1) in combination with optimized supplemental
doses of total body irradiation (TBI) and Fludarabine (FLU) in a preclinical murine haploidentical HCT model
employing cyclophosphamide (CY) post-transplant graft-vs-host disease prophylaxis. Reducing the TBI and
FLU doses, while administering high doses of pretargeted 90Y- or 177Lu-biotin as part of a preparative regimen
for marrow HCT, would depend upon the demonstration of the ability of such an approach to: 1) ablate the
marrow space, and 2) produce adequate immunosuppression. Thus, in aim 3 we will also evaluate the kinetics
and durability of hematopoietic and immune cell reconstitution using an anti-mCD45 Ab-SA conjugate (30F11
Ab-SA) and radiobiotin, followed by reduced doses of TBI and/or FLU and infusion of MHC-haploidentical BM
and post-transplantation CY in a murine leukemia model. We hypothesize that the pretargeted RIT strategy
defined in this proposal will amplify the amount of radiation delivered to leukemia cells, decrease the radiation
delivered to the liver, lungs, and other normal organs, improve remission and cure rates, prolong survival, and
markedly attenuate toxicities compared to conventional RIT combined with standard conditioning reagents.
We therefore anticipate rapid translation of the optimized promising pretargeted RIT into our clinical RIT HCT
program for AML and MDS.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN M PAGEL其他文献
JOHN M PAGEL的其他文献
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{{ truncateString('JOHN M PAGEL', 18)}}的其他基金
Alpha Radioimmunotherapy for Lymphoma Treatment
淋巴瘤治疗的阿尔法放射免疫疗法
- 批准号:
8420091 - 财政年份:2013
- 资助金额:
$ 33.3万 - 项目类别:
Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot
使用新型放射免疫进行骨髓移植治疗血液系统恶性肿瘤
- 批准号:
8631547 - 财政年份:2013
- 资助金额:
$ 33.3万 - 项目类别:
Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot
使用新型放射免疫进行骨髓移植治疗血液系统恶性肿瘤
- 批准号:
8042689 - 财政年份:2010
- 资助金额:
$ 33.3万 - 项目类别:
Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot
使用新型放射免疫进行骨髓移植治疗血液系统恶性肿瘤
- 批准号:
7897177 - 财政年份:2010
- 资助金额:
$ 33.3万 - 项目类别:
Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot
使用新型放射免疫进行骨髓移植治疗血液系统恶性肿瘤
- 批准号:
8209292 - 财政年份:2010
- 资助金额:
$ 33.3万 - 项目类别:
RADIOLABELED BC8, FLU, TBI AND PBSC TRANSPLANT FOR ELDERLY AML OR MDS PATIENTS
为老年 AML 或 MDS 患者进行放射性标记 BC8、FLU、TBI 和 PBSC 移植
- 批准号:
7603447 - 财政年份:2007
- 资助金额:
$ 33.3万 - 项目类别:
RADIOLABELED BC8, FLUDARABINE, TBI FOLLOWED BY PBSC TRANSPLANT FOR ADVANCED AML
放射性标记 BC8、氟达拉滨、TBI,随后进行 PBSC 移植治疗晚期 AML
- 批准号:
7379338 - 财政年份:2006
- 资助金额:
$ 33.3万 - 项目类别:
RADIOLABELED BC8, FLU, TBI AND PBSC TRANSPLANT FOR ELDERLY AML OR MDS PATIENTS
为老年 AML 或 MDS 患者进行放射性标记 BC8、FLU、TBI 和 PBSC 移植
- 批准号:
7379339 - 财政年份:2006
- 资助金额:
$ 33.3万 - 项目类别:
PHASE I STUDY: ELDERLY PATIENTS WITH MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROM
第一阶段研究:患有粒细胞白血病或骨髓增生异常综合征的老年患者
- 批准号:
7198848 - 财政年份:2005
- 资助金额:
$ 33.3万 - 项目类别:
RADIOLABELED BC8 (ANTI-CD45) ANTIBODY TREATMENT FOR ACUTE MYELOID LEUKEMIA
放射性标记 BC8(抗 CD45)抗体治疗急性髓系白血病
- 批准号:
7198847 - 财政年份:2005
- 资助金额:
$ 33.3万 - 项目类别:
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