Immunomodulatory Therapy of Multiple Myeloma with SMAC Mimetics
使用 SMAC 模拟物对多发性骨髓瘤进行免疫调节治疗
基本信息
- 批准号:9152284
- 负责人:
- 金额:$ 26.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AgonistAnemiaApoptosisApoptosis InhibitorBone MarrowBone Marrow CellsBortezomibCCL2 geneCD47 geneCSF1R geneCell LineCell TransplantationCellsChemotactic FactorsClinicClinicalClinical TrialsCoculture TechniquesCyclophosphamideDexamethasoneDichloromethylene DiphosphonateDiseaseDose-LimitingEnrollmentEvaluationGenetic HeterogeneityGenetically Engineered MouseGenomic InstabilityGoalsGrowthHeterogeneityHumanIL8 geneImmuneImmune responseImmune systemImmunomodulatorsImmunosuppressionImmunosuppressive AgentsIn VitroInterleukin-12LiposomesMalignant NeoplasmsMediatingMediator of activation proteinModelingMolecularMolecular ProfilingMolecular TargetMultiple MyelomaMusOxidesPathway interactionsPatientsPhase II Clinical TrialsPlasmaPlasma CellsPre-Clinical ModelReportingRoleSamplingSerumSignal TransductionSolid NeoplasmSyndromeTNFRSF5 geneTherapeuticToll-like receptorsTransplantationXenograft ModelXenograft procedureadaptive immunityangiogenesisantitumor effectbonecIAP1 proteincellular targetingchemotherapyclinically relevantcytokinein vivoinhibitor-of-apoptosis proteinmacrophagemimeticsmonocytemouse modelneoplastic cellnovelphase I trialresearch studysynergismtargeted treatmenttumortumorigenic
项目摘要
PROJECT SUMMARY—ABSTRACT
Multiple myeloma (MM) is a genetically heterogeneous disease, with varying levels of genomic instability and
intra-tumor clonal heterogeneity. Both levels of heterogeneity pose challenges for directed anti-tumor targeted
therapy, which may be overcome by harnessing the power of the immune system. LCL161 is a SMAC mimetic
targeting the cellular inhibitor of apoptosis proteins cIAP1 and -2 (cIAP1/2). We previously reported that bi-
allelic deletions of cIAP1/2 in MM result in activation of the non canonical NFkB pathway, and consistently
LCL161 has little direct anti-tumor activity, against primary MM cells, MM cell lines, or xenograft models where
it induces even higher levels of NFkB. However, LCL161 has dramatic activity in vivo against MM that
develops spontaneously in the immuno-competent and clinically predictive Vk*MYC mouse model, but not in
vitro against these same tumor cells, suggesting an important role for the host in mediating the anti-tumor
effect. Transplantation and cell depletion experiments in Vk*MYC mice implicated macrophages as mediator of
LCL161 anti-MM activity that does not depend on adaptive immunity. MΦ are a crucial component of the MM
niche and support MM growth by providing survival signals and promoting immunosuppression. However
macrophages can be re-educated to acquire tumoricidal activity by CSF1R inhibition, anti-CD47 treatment or
combinations of Toll-like-receptor (TLR) agonists + IFNg, TLRa + CD40 agonist or chemotherapy. We found
that the SMAC mimetic compound (SMC) LCL161 also promotes macrophages M1 polarization and potent
anti-MM activity in vivo. Specifically, LCL161 treatment induced M1 polarization and tumoricidal activity in BM
derived macrophages co-cultures experiments, and induction of M1 cytokines in plasma from MM patients
enrolled in the clinical trial.
The goal of this proposal is to define the mechanisms implicated in LCL161 anti-MM activity in Vk*MYC mice
and in samples obtained from MM patients enrolled in a phase II clinical trial of LCL161 at the Mayo Clinic.
项目SUMMARY-ABSTRACT
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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Marta Chesi其他文献
Marta Chesi的其他文献
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{{ truncateString('Marta Chesi', 18)}}的其他基金
Credentialing a Genetically Engineered Clinically-Relevant Mouse Model of Multiple Myeloma
认证基因工程临床相关的多发性骨髓瘤小鼠模型
- 批准号:
10527365 - 财政年份:2018
- 资助金额:
$ 26.33万 - 项目类别:
Credentialing a Genetically Engineered Clinically-Relevant Mouse Model of Multiple Myeloma
认证基因工程临床相关的多发性骨髓瘤小鼠模型
- 批准号:
10053331 - 财政年份:2018
- 资助金额:
$ 26.33万 - 项目类别:
Credentialing a Genetically Engineered Clinically-Relevant Mouse Model of Multiple Myeloma
认证基因工程临床相关的多发性骨髓瘤小鼠模型
- 批准号:
10310482 - 财政年份:2018
- 资助金额:
$ 26.33万 - 项目类别:
Project 3: Early detection and prevention of MM progression
项目3:早期发现和预防MM进展
- 批准号:
10706331 - 财政年份:2015
- 资助金额:
$ 26.33万 - 项目类别:
PQD2 Rational Combination of Standard Agents and Immunotherapy to Treat Myeloma
PQD2 标准药物与免疫疗法的合理组合治疗骨髓瘤
- 批准号:
8791848 - 财政年份:2014
- 资助金额:
$ 26.33万 - 项目类别:
PQD2 Rational Combination of Standard Agents and Immunotherapy to Treat Myeloma
PQD2 标准药物与免疫疗法的合理组合治疗骨髓瘤
- 批准号:
9335305 - 财政年份:2014
- 资助金额:
$ 26.33万 - 项目类别:
Immunomodulatory Therapy of Multiple Myeloma with SMAC Mimetics
使用 SMAC 模拟物对多发性骨髓瘤进行免疫调节治疗
- 批准号:
9331584 - 财政年份:
- 资助金额:
$ 26.33万 - 项目类别:
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