Phase-I-II Study of DAB389 (ONTAK) in Patients with Adv. Refractory Breast Cancer
DAB389 (ONTAK) 在 Adv. 患者中的 I-II 期研究
基本信息
- 批准号:7282692
- 负责人:
- 金额:$ 25.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-08 至 2010-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino Acid SequenceAutoantigensBedsBindingCD4 Positive T LymphocytesCD8B1 geneCell DeathCellsChemotherapy-Oncologic ProcedureChimeric ProteinsClinicalClinical ResearchCutaneousDAB389 Interleukin-2 ImmunotoxinDenileukin DiftitoxDiphtheria ToxinDiseaseDisease remissionEffector CellGenerationsHumanIL2RA geneImmuneImmune responseImmunityImmunologicsImmunosuppressive AgentsIn VitroInterleukin 2 ReceptorInterleukin-2LeadMalignant - descriptorMalignant NeoplasmsMammary NeoplasmsNormal CellOutcomePatientsPeripheralPharmaceutical PreparationsPhasePopulationProductionProtein BiosynthesisProtein OverexpressionProtein Synthesis InhibitionRefractoryRenal Cell CarcinomaSafetySiteStagingT-Cell LymphomaT-LymphocyteTherapeuticTherapeutic AgentsToxinTumor AntigensTumor ImmunityWorkcancer cellcell killingchemotherapycytokinecytotoxicdesignhuman dataimmunogenicin vivomalignant breast neoplasmmelanomamouse modelneoplastic cellnovelperipheral bloodreceptorresponsetumoruptake
项目摘要
DESCRIPTION (provided by applicant): Combination chemotherapy regimens for advanced breast cancer usually result in objective responses as first line treatment. However, complete remissions occur in fewer than 20% of patients, and median survival is limited. Therapeutic strategies that would elicit a clinical response in refractory advanced stage breast cancer are needed. ONTAK, a cytotoxic fusion protein composed of diptheria toxin (DT) fragments and amino acid sequences of IL-2, is designed to direct the cytocidal action of DT to malignant cells that express the high affinity form of the IL-2 receptor (CD25) while minimizing damage to normal cells that do not express the receptor. Clinical studies have shown ONTAK to be a safe and effective agent in the treatment of cutaneous T cell lymphomas (CTCL) that express CD25. Its putative mechanism of action in CTCL is to bind to the interleukin-2 receptor (IL-2R) and induce uptake of the drug with subsequent inhibition of protein synthesis by the diptheria toxin. Studies have clearly shown the capacity of the drug to block protein synthesis and induce cell death. Breast cancer, like CTCL, has been shown to express CD25, and this increased expression of CD25 is associated with the malignant potential of the tumor. Thus, we propose that, similar to its action in CTCL, ONTAK may have direct anti-tumor activity in breast cancers that overexpress IL-2R. Accumulating evidence suggests that a population of CD4+ T cells that constitutively express the IL-2Ra chain may function as "professional" suppressor or T regulatory cells (Tregs). Tregs are potent suppressors of CD4+ and CD8+ T cells and have been shown to down-regulate immune responses to self antigens, such as tumor antigens. Additionally, Tregs have been shown to be increased in the peripheral blood of patients with breast cancer. We hypothesize that depletion of Tregs by ONTAK may result in generation of functional immune effector cells and enhancement of endogenous tumor-specific immunity. This proposal is a phase I-II study of ONTAK administered to patients with advanced refractory breast cancer. The specific aims of this study are to (i) evaluate the safety of ONTAK administration in patients with advanced refractory breast cancer, (2) determine whether administration of ONTAK in patients with advanced stage breast cancer will decrease circulating T regulatory cells and augment endogenous immunity, and (3) evaluate an association between IL-2R expression in breast cancer and any clinical response induced by ONTAK administration.
描述(由申请人提供):晚期乳腺癌的联合化疗方案作为一线治疗通常会产生客观缓解。然而,完全缓解发生在不到20%的患者中,并且中位生存期有限。需要在难治性晚期乳腺癌中引起临床反应的治疗策略。ONTAK是一种由白喉毒素(DT)片段和IL-2氨基酸序列组成的细胞毒性融合蛋白,旨在将DT的细胞杀伤作用导向表达高亲和力形式IL-2受体(CD 25)的恶性细胞,同时最大限度地减少对不表达该受体的正常细胞的损伤。临床研究表明,ONTAK是治疗表达CD 25的皮肤T细胞淋巴瘤(CTCL)的安全有效药物。其在CTCL中的假定作用机制是与白细胞介素-2受体(IL-2 R)结合并诱导药物摄取,随后通过白喉毒素抑制蛋白质合成。研究已经清楚地表明了药物阻断蛋白质合成和诱导细胞死亡的能力。乳腺癌,如CTCL,已被证明表达CD 25,并且这种CD 25表达的增加与肿瘤的恶性潜能相关。因此,我们提出,与其在CTCL中的作用相似,ONTAK可能在过表达IL-2 R的乳腺癌中具有直接的抗肿瘤活性。越来越多的证据表明,组成性表达IL-2 Ra链的CD 4 + T细胞群体可能作为“专业”抑制或T调节细胞(Tcells)发挥作用。T细胞是CD 4+和CD 8 + T细胞的有效抑制剂,并且已经显示下调对自身抗原(例如肿瘤抗原)的免疫应答。此外,已显示TdR在患有乳腺癌的患者的外周血中增加。我们假设ONTAK对TcB的消耗可能导致功能性免疫效应细胞的产生和内源性肿瘤特异性免疫的增强。本提案是一项ONTAK治疗晚期难治性乳腺癌患者的I-II期研究。本研究的具体目的是(i)评价晚期难治性乳腺癌患者接受ONTAK给药的安全性,(2)确定晚期乳腺癌患者接受ONTAK给药是否会减少循环调节性T细胞并增强内源性免疫,(3)评价乳腺癌中IL-2 R表达与ONTAK给药诱导的任何临床应答之间的相关性。
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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{{ truncateString('LUPE G SALAZAR', 18)}}的其他基金
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7603452 - 财政年份:2007
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- 批准号:
7603486 - 财政年份:2007
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Phase-I-II Study of DAB389 (ONTAK) in Patients with Adv. Refractory Breast Cancer
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7158826 - 财政年份:2006
- 资助金额:
$ 25.29万 - 项目类别:
HER-2/NEU (HER2) ICD MEMORY IMMUNITY AFTER VACCINATION HER2-ICD
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