Immunotherapy for Chronic Myelogenous Leukemia

慢性粒细胞白血病的免疫治疗

• 批准号: 8088191
• 负责人: EMMANUEL KATSANIS
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088191
• 关键词: Address; Affect; Antigen-Presenting Cells; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell Count; Cell physiology; Cells; Chronic Myeloid Leukemia; Clinical Trials; Dasatinib; Data; Dendritic Cells; Development; Evaluation; FDA approved; Frequencies; Generations; Goals; Grant; Human; IL2RA gene; Imatinib; Imatinib mesylate; Immune; Immune Tolerance; Immune response; Immunization; Immunobiology; Immunotherapy; In Vitro; Laboratories; Lead; Light; Lymphocyte; Malignant Neoplasms; Molecular; Molecular Chaperones; Mus; Patients; Pharmaceutical Preparations; Phenotype; Play; Protein Tyrosine Kinase; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Resistance; Role; Signal Transduction; Signal Transduction Pathway; Spleen; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tyrosine Kinase Inhibitor; Uncertainty; Vaccination; Vaccines; Work; base; bcr-abl Fusion Proteins; cancer immunotherapy; clinically relevant; combat; design; improved; in vivo; inhibitor/antagonist; leukemia; lymph nodes; novel; public health relevance; response; transcription factor; tumor; tumor immunology; tumor progression

DESCRIPTION (provided by applicant): The current application is a competing renewal designed to pursue our studies on the development of novel therapies, specifically cancer vaccines, for chronic myelogenous leukemia (CML). This renewal will focus on the immunomodulatory role of the BCR-ABL tyrosine kinase inhibitor imatinib mesylate (STI-571 or GleevecTM) and its application in chemoimmunotherapy approaches for CML. This drug has become the therapy of choice for patients with CML, but the emergence of imatinib resistant leukemia remains a major challenge. This has prompted the evaluation of newer tyrosine kinase inhibitors such as dasatinib or sunitinib, and the examination of combination treatments such as chemoimmunotherapy. The field of tumor immunology has recently seen major breakthroughs, one of which is the emergence of CD4+CD25+ regulatory T cells (Treg) as critical contributors in the establishment and persistence of cancer- induced tolerance. During our current grant cycle we have reported that imatinib mesylate can be efficiently combined with a chaperone rich cell lysate vaccine (CRCL), developed in our laboratory, to treat established BCR-ABL+ leukemia. In an attempt to elucidate the mechanism of action of imatinib mesylate on immune cells, we have generated significant data indicating that this agent may negatively modulate the suppressive function of CD4+CD25+ regulatory T cells (Treg). This is a novel yet unexplored concept. Therefore, the central hypothesis to be tested in this proposal is that imatinib mesylate may not only act directly on BCR-ABL+ leukemia cells but may also sensitize immune cells to tumor vaccines by down-modulating Treg suppressive activity. To address this hypothesis, we propose the following specific aims: 1. Study the negative modulation of Treg by BCR-ABL tyrosine kinase inhibitors. We will (1) investigate how BCR-ABL tyrosine kinase inhibitors affect the immunobiology of Treg and non-Treg lymphocytes in vivo and in vitro, and (2) determine whether these drugs influence the conversion CD4+CD25- T cells into CD4+CD25+FoxP3+ Treg. 2. Determine the molecular mechanisms underlying BCR-ABL tyrosine kinase inhibitor suppression of Treg. The modulation of specific cell signalling transduction pathways and regulation of key transcription factors by BCR-ABL tyrosine kinase inhibitors in Treg and conventional T cells will be examined. 3. Optimize a chemoimmunotherapy strategy combining Treg elimination or inactivation with specific tumor vaccination. To validate the use of imatinib in chemo-immunotherapy approaches, we propose to (1) evaluate the differential efficiency of BCR-ABL tyrosine kinase inhibitors and the currently used strategies to deplete/inactivate Treg in vivo, and (2) further optimize a chemoimmunotherapy approach using BCR-ABL inhibitors and tumor specific vaccination to treat BCR-ABL+ or BCR-ABL- leukemia in mice. 4. Evaluate the effects of BCR-ABL tyrosine kinase inhibitors on Treg number, phenotype and function in CML patients. This part of the proposal is critical in order to validate the application of imatinib mesylate as a potential Treg inhibitory agent in human chemoimmunotherapy strategies. Analysis of Treg frequency, phenotype and suppressive activity will be performed in CML patients before and during imatinib mesylate therapy. These studies are based on a novel concept supported by convincing preliminary data to deplete/inactivate a major cellular component of tumor-induced tolerance using FDA approved agents. They will not only shed light on the mechanisms of action of BCR-ABL tyrosine kinase inhibitors, but may also lead to further improvement in chemo-immunotherapy of leukemia. Our proposal is therefore timely, highly relevant and significant for the development of improved treatments for CML. PUBLIC HEALTH RELEVANCE: This proposal is based on two clinically relevant challenges in combating chronic myelogenous leukemia: the resistance of leukemia to imatinib mesylate, and the establishment of leukemia-induced immune tolerance with regulatory T cells as the likely contributors. The proposed studies will investigate how BCR-ABL tyrosine kinase inhibitors may be used more effectively to impede the suppressive function of regulatory T lymphocytes and promote the function of anti-tumoral T cells, thereby working synergistically with leukemia- based vaccination. Results from these studies will help shed light on how to improve chemo-immunotherapic approaches not only for CML but also for other (BCR-ABL-) cancers.

描述(由申请人提供)：目前的申请是一个竞争性的续展，旨在继续我们对慢性粒细胞白血病(CML)的新疗法，特别是癌症疫苗的开发研究。这次更新将集中在BCR-ABL酪氨酸激酶抑制剂甲磺酸伊马替尼(STI-571或GleevecTM)的免疫调节作用及其在慢性粒细胞白血病化疗免疫治疗中的应用。这种药物已经成为慢性粒细胞白血病患者的首选治疗方法，但伊马替尼耐药白血病的出现仍然是一个重大挑战。这促使人们评估较新的酪氨酸激酶抑制剂，如达沙替尼或舒尼替尼，并检查联合治疗，如化学免疫治疗。肿瘤免疫学领域最近取得了重大突破，其中之一是CD4+CD25+调节性T细胞(Treg)的出现，它在癌症诱导耐受的建立和持续中起着关键作用。在我们目前的资助周期中，我们已经报道了甲磺酸伊马替尼可以有效地与我们实验室开发的富含伴侣蛋白的细胞裂解疫苗(CRCL)相结合，用于治疗已确定的bcr-abl+白血病。为了阐明甲磺酸伊马替尼对免疫细胞的作用机制，我们产生了大量数据表明，该药可能对CD4+CD25+调节性T细胞(Treg)的抑制功能产生负面调节。这是一个新的但尚未探索的概念。因此，这项建议要检验的中心假设是，甲磺酸伊马替尼不仅可能直接作用于BCR-ABL+白血病细胞，还可能通过下调Treg抑制活性而使免疫细胞对肿瘤疫苗敏感。针对这一假说，我们提出了以下具体目标：1.研究BCR-ABL酪氨酸激酶抑制剂对Treg的负性调节作用。我们将(1)研究BCR-ABL酪氨酸激酶抑制剂如何在体内和体外影响Treg和非Treg淋巴细胞的免疫生物学，以及(2)确定这些药物是否影响CD4+CD25-T细胞向CD4+CD25+FoxP3+Treg的转化。2.确定BCR-ABL酪氨酸激酶抑制剂抑制Treg的分子机制。本课程将研究BCR-ABL酪氨酸激酶抑制剂对Treg和传统T细胞中特定细胞信号转导通路的调节和对关键转录因子的调节。3.优化Treg消除或灭活与特异性肿瘤疫苗接种相结合的化疗免疫治疗策略。为了验证伊马替尼在化学免疫治疗方法中的应用，我们建议(1)评估BCR-ABL酪氨酸激酶抑制剂的不同效率和目前使用的在体内耗尽/灭活Treg的策略，以及(2)进一步优化使用BCR-ABL抑制剂和肿瘤特异性疫苗治疗BCR-ABL+或BCR-ABL-白血病的化疗免疫方法。4.评价bcr-abl酪氨酸激酶抑制剂对CML患者Treg数、表型和功能的影响。该提案的这一部分对于验证甲磺酸伊马替尼作为潜在的Treg抑制剂在人类化学免疫治疗策略中的应用至关重要。在甲磺酸伊马替尼治疗前和治疗期间，将对CML患者进行Treg频率、表型和抑制活性的分析。这些研究基于一个新的概念，由令人信服的初步数据支持，使用FDA批准的药物来耗尽/灭活肿瘤诱导耐受的一个主要细胞成分。他们不仅将阐明BCR-ABL酪氨酸激酶抑制剂的作用机制，而且还可能导致白血病的化学免疫治疗的进一步改进。因此，我们的建议对于CML改进治疗的发展是及时的、高度相关的和重要的。公共卫生相关性：这项建议是基于抗击慢性粒细胞白血病的两个临床相关挑战：白血病对甲磺酸伊马替尼的耐药性，以及建立白血病诱导的免疫耐受，调节性T细胞可能是贡献者。拟议的研究将探讨如何更有效地使用BCR-ABL酪氨酸激酶抑制剂来阻止调节性T淋巴细胞的抑制功能，促进抗肿瘤T细胞的功能，从而与基于白血病的疫苗协同工作。这些研究的结果将有助于阐明如何改进化学免疫治疗方法，不仅适用于CML，也适用于其他(BCR-ABL-)癌症。