Targeting complement to enhance antitumor immunity and control malignant effusions in patients with recurrent epithelial ovarian cancer
靶向补体增强复发性上皮性卵巢癌患者的抗肿瘤免疫并控制恶性积液
基本信息
- 批准号:10689822
- 负责人:
- 金额:$ 64.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-24 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AnaphylatoxinsAscitesBiologyBloodBlood VesselsCancer PatientCause of DeathChemotactic FactorsCirculationComplementComplement 3aComplement 5aComplement component C4aCyclophosphamideCytometryCytotoxic T-LymphocytesDataDiagnosisDiseaseDisseminated Malignant NeoplasmEpithelial ovarian cancerExposure toFDA approvedFRAP1 geneFoundationsGenetic TranscriptionGoalsGranulopoiesisGuidelinesHumanImmune checkpoint inhibitorImmune responseImmunosuppressionImmunotherapyInfiltrationInflammatoryLeadLiquid substanceLymphocyteMalignant - descriptorMalignant Female Reproductive System NeoplasmMalignant NeoplasmsMalignant neoplasm of ovaryMemoryMitochondriaModelingMorphologyMusMyeloid-derived suppressor cellsNADPH OxidaseNational Comprehensive Cancer NetworkNeutrophil InfiltrationNewly DiagnosedOralPathway interactionsPatientsPeptidesPhase II Clinical TrialsPhenotypeProgression-Free SurvivalsProliferatingQuality of lifeRandomizedRecurrenceRefractoryRegimenRelapseResearchResponse GeneralizationSafetySamplingSignal PathwaySignal TransductionSpecific qualifier valueSuppressor-Effector T-LymphocytesT cell infiltrationT memory cellT-Cell ActivationT-LymphocyteTestingTherapeutically TargetableTimeTumor ImmunityUnited StatesWorkanti-PD-1armbevacizumabcancer immunotherapycell injurychemokinecohortcytokinedisorder controlefficacy evaluationefficacy testingeffusionglucose uptakegranulocyteimmunogenicimmunoregulationinhibitorneutrophilnovelnovel strategiesnuclear factors of activated T-cellsobjective response rateparoxysmal nocturnal hemoglobinuriapembrolizumabphase II trialprimary endpointrandomized trialresponseresponse to injurysecondary endpointstandard of caresurvival predictiontumortumor microenvironmenttumor progression
项目摘要
Abstract
Epithelial ovarian cancer (OC) is the leading cause of death from gynecological malignancies in the United
States. While OC is immunogenic and increased infiltration of cytotoxic T lymphocytes (CTL) correlates with
longer survival, single agent checkpoint inhibitors are largely ineffective in the relapsed/refractory setting. Our
long-term goal is to develop novel approaches to overcome obstacles to durable antitumor immunity to make
immunotherapy more effective. Our results point to previously unrecognized mechanisms for mature
neutrophils acquiring a suppressor phenotype within the tumor microenvironment (TME). Neutrophil
suppressors inhibited stimulated proliferation of circulating naïve, central memory, and effector memory T cells,
and of tumor-associated lymphocytes (TAL) from patients with newly diagnosed OC. Induction of the neutrophil
suppressor phenotype required complement signaling and NADPH oxidase activation. A similar complement-
dependent neutrophil suppressor phenotype was induced by ascites from patients with recurrent OC and from
malignant effusions from patients with a number of metastatic cancers, underscoring the generalizability of our
findings. These results in human samples and work by others in tumor-bearing mice support targeting
complement to enhance anti-tumor immunity. We will evaluate APL-2, a peptide C3 inhibitor, in a randomized
phase 2 clinical trial in patients with recurrent OC and persistent malignant effusions. APL-2 was safe and
superior to eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) and is FDA-approved for this
indication; it’s use in cancer is novel. Following a safety lead-in, patients will be randomized to the following
cohorts: (i) bevacizumab (anti-VEGF); (ii) APL-2 + pembrolizumab (anti-PD1); and (iii) APL-2 + pembrolizumab
+ bevacizumab. Specific Aim 1: To evaluate safety and control of malignant effusions as primary endpoints
and progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall
survival (OS), and quality of life (QoL) as secondary endpoints. Specific Aim 2: To determine the effects of
APL-2-based therapy in modulation of immune responses in the TME. Patient samples (blood, effusion, tumor)
will be collected at baseline and at pre-specified time points during the trial. We will test the extent that APL-2
will abrogate neutrophil suppressor activity and expand activated T cells in the TME. A combination of
functional studies and transcriptional and mass cytometry profiling of circulating and ascites neutrophils and T
cells will be performed. The impact of our proposal is to gain safety and preliminary efficacy data on APL-2-
based regimens in recurrent OC with malignant effusions and a detailed understanding of how these regimens
modulate the immune landscape in the TME. This research is expected to establish the foundation for larger
randomized trials to definitively test the efficacy of C3 inhibition in enhancing cancer immunotherapy.
摘要
项目成果
期刊论文数量(1)
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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Brahm H Segal其他文献
Tratamiento de la Aspergilosis: Guías para la práctica clínica de la Sociedad de Enfermedades Infecciosas de los Estados Unidos de América (IDSA)
曲霉病治疗:美国联合感染协会 (IDSA) 临床实践指南
- DOI:
10.1086/590225 - 发表时间:
2008 - 期刊:
- 影响因子:11.8
- 作者:
Thomas J. Walsh;E. Anaissie;David W. Denning;Raoul Herbrecht;Dimitrios P. Kontoyiannis;Kieren A. Marr;Vicki A. Morrison;Brahm H Segal;William J. Steinbach;David A. Stevens;Jo;John R. Wingard;Thomas F. Patterson - 通讯作者:
Thomas F. Patterson
Brahm H Segal的其他文献
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{{ truncateString('Brahm H Segal', 18)}}的其他基金
Targeting complement to enhance antitumor immunity and control malignant effusions in patients with recurrent epithelial ovarian cancer
靶向补体增强复发性上皮性卵巢癌患者的抗肿瘤免疫并控制恶性积液
- 批准号:
10530911 - 财政年份:2022
- 资助金额:
$ 64.57万 - 项目类别:
Role of NADPH Oxidase in Regulating Inflammation
NADPH 氧化酶在调节炎症中的作用
- 批准号:
8213585 - 财政年份:2009
- 资助金额:
$ 64.57万 - 项目类别:
Role of NADPH Oxidase in Regulating Inflammation
NADPH 氧化酶在调节炎症中的作用
- 批准号:
7915353 - 财政年份:2009
- 资助金额:
$ 64.57万 - 项目类别:
Role of NADPH Oxidase in Regulating Inflammation
NADPH 氧化酶在调节炎症中的作用
- 批准号:
8012832 - 财政年份:2009
- 资助金额:
$ 64.57万 - 项目类别:
Role of NADPH Oxidase in Regulating Inflammation
NADPH 氧化酶在调节炎症中的作用
- 批准号:
8417735 - 财政年份:2009
- 资助金额:
$ 64.57万 - 项目类别:
Role of NADPH Oxidase in Regulating Inflammation
NADPH 氧化酶在调节炎症中的作用
- 批准号:
7662998 - 财政年份:2009
- 资助金额:
$ 64.57万 - 项目类别:
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