Immunotherapy for Chronic Myelogenous Leukemia

慢性粒细胞白血病的免疫治疗

• 批准号: 8448304
• 负责人: EMMANUEL KATSANIS
• 金额: $ 24.89万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448304
• 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.

描述（由申请人提供）：当前申请是一项竞争性更新，旨在继续我们对慢性粒细胞白血病（CML）新型疗法（特别是癌症疫苗）开发的研究。此次更新将重点关注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CML化学免疫治疗方法中的应用。这种药物已成为CML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。这促使了对新的酪氨酸激酶抑制剂如达沙替尼或舒尼替尼的评估，以及对联合治疗如化学免疫疗法的检查。肿瘤免疫学领域最近出现了重大突破，其中之一是CD 4 + CD 25+调节性T细胞（Treg）作为癌症诱导的耐受性的建立和持续的关键贡献者的出现。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分子伴侣的细胞裂解物疫苗（CRCL）联合治疗已建立的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，我们已经产生了重要的数据，表明这种药物可能会负面调节CD 4 + CD 25+调节性T细胞（Treg）的抑制功能。这是一个新的尚未探索的概念。因此，本提案中待检验的中心假设是，甲磺酸伊马替尼不仅可能直接作用于BCR-ABL+白血病细胞，而且还可能通过下调Treg抑制活性使免疫细胞对肿瘤疫苗敏感。为了解决这个假设，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CD 4 + CD 25- T细胞转化为CD 4 + CD 25 + FoxP 3 + Treg。2.确定BCR-ABL酪氨酸激酶抑制剂抑制Treg的分子机制。将检查Treg和常规T细胞中BCR-ABL酪氨酸激酶抑制剂对特定细胞信号转导途径的调节和对关键转录因子的调节。3.优化结合Treg消除或失活与特异性肿瘤疫苗接种的化学免疫治疗策略。为了验证伊马替尼在化学免疫治疗方法中的使用，我们建议（1）评估BCR-ABL酪氨酸激酶抑制剂的差异效率和目前使用的体内耗尽/消除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接种治疗小鼠BCR-ABL+或BCR-ABL-白血病的化学免疫治疗方法。4.评价BCR-ABL酪氨酸激酶抑制剂对CML患者Treg数量、表型和功能的影响。这部分提案对于验证甲磺酸伊马替尼作为潜在Treg抑制剂在人类化学免疫治疗策略中的应用至关重要。将在甲磺酸伊马替尼治疗前和治疗期间对CML患者进行Treg频率、表型和抑制活性分析。这些研究是基于一个新的概念，由令人信服的初步数据支持，使用FDA批准的药物消耗/消除肿瘤诱导耐受的主要细胞成分。这些结果不仅有助于阐明BCR-ABL酪氨酸激酶抑制剂的作用机制，而且可能进一步改善白血病的化学免疫治疗。因此，我们的建议是及时的，高度相关的和重要的发展，改善治疗慢性粒细胞白血病。

项目成果

The dendritic cell-regulatory T lymphocyte crosstalk contributes to tumor-induced tolerance.

• DOI: 10.1155/2011/430394
• 发表时间: 2011
• 期刊: Clinical & developmental immunology
• 作者: Janikashvili N;Bonnotte B;Katsanis E;Larmonier N
• 通讯作者: Larmonier N

Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL- tumors.

• DOI: 10.4049/jimmunol.181.10.6955
• 发表时间: 2008-11-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Larmonier, Nicolas;Janikashvili, Nona;LaCasse, Collin James;Larmonier, Claire Billerey;Cantrell, Jessica;Situ, Elaine;Lundeen, Tamara;Bonnotte, Bernard;Katsanis, Emmanuel
• 通讯作者: Katsanis, Emmanuel

Chaperone-rich cell lysate embedded with BCR-ABL peptide demonstrates enhanced anti-tumor activity against a murine BCR-ABL positive leukemia.

嵌入 BCR-ABL 肽的富含分子伴侣的细胞裂解物表现出增强的针对小鼠 BCR-ABL 阳性白血病的抗肿瘤活性。

• DOI: 10.1096/fj.06-7843com
• 发表时间: 2007
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Kislin,KerriL;Marron,MarilynT;Li,Gang;Graner,MichaelW;Katsanis,Emmanuel
• 通讯作者: Katsanis,Emmanuel

Signaling pathways induced by a tumor-derived vaccine in antigen presenting cells.

• DOI: 10.1016/j.imbio.2009.09.006
• 发表时间: 2010-07
• 期刊: IMMUNOBIOLOGY
• 影响因子: 2.8
• 作者: Cantrell, Jessica;Larmonier, Claire;Janikashvili, Nona;Bustamante, Sara;Fraszczak, Jennifer;Herrell, Amanda;Lundeen, Tamara;LaCasse, Collin J.;Situ, Elaine;Larmonier, Nicolas;Katsanis, Emmanuel
• 通讯作者: Katsanis, Emmanuel

Induction of BCR-ABL-specific immunity following vaccination with chaperone-rich cell lysates derived from BCR-ABL+ tumor cells.

• DOI: 10.1182/blood-2004-05-1915
• 发表时间: 2005-03
• 期刊: Blood
• 影响因子: 20.3
• 作者: Yi Zeng;M. Graner;S. Thompson;M. Marron;Emmanuel Katsanis