Adoptive T Cell Therapy Following CD25 Lymphodepletion

CD25 淋巴细胞清除后的过继 T 细胞治疗

• 批准号: 7739569
• 负责人: Cassian Yee
• 金额: $ 35.19万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739569
• 关键词: Address; Adoptive Immunotherapy; Adoptive Transfer; Antigens; Ants; Autologous; CD8 Antigens; Cell Therapy; Cell physiology; Cells; Clinical; Cytolysis; DAB389 Interleukin-2 Immunotoxin; Denileukin Diftitox; Effectiveness; Environment; Failure; Generations; IL2RA gene; Immune; Immune response; Immune system; Immunotherapy; In complete remission; Inflammatory; Infusion procedures; Lead; Malignant Neoplasms; Metastatic Melanoma; Patients; Phase; Phenotype; Population; Radiation; Reagent; Refractory; Resistance; Safety; Specificity; T-Cell Activation; T-Lymphocyte; Treatment Protocols; Tumor Antigens; Vaccines; Variant; chemotherapy; conditioning; conventional therapy; improved; in vivo; melanoma; neoplastic cell; public health relevance; response; success; treatment strategy; tumor; tumor immunology

DESCRIPTION (provided by applicant): Adoptive T cell therapy represents a promising strategy for the treatment of patients with cancer. Phase I and II studies using adoptively transferred antigen-specific T cell clones have led to the conclusion that its effectiveness may be enhanced by extending the in vivo persistence of transferred T cells and broadening the repertoire of immune responses to limit the outgrowth of antigen-loss tumor variants. Regulatory T cells (characterized by a CD25hi CD4 phenotype) are found at increased levels in patients with cancer, and may thwart an effective ant-tumor T cell response by suppressing T cell activation and effector function. We postulate that a pre-infusion conditioning regimen that decreases the regulatory T cell population will lead to extended in vivo persistence of adoptively transferred T cells and promote the generation of endogenous T cell responses against a broader panel of tumor-associated antigens. In this study we propose to examine the benefits of a combined biologic approach: adoptive transfer of antigen-specific CTL clones and CD25 lymphodepletion using DAB389-IL-2 (also known as denileukin diftitox or Ontak).We postulate that administration of DAB389-IL-2 to deplete regulatory T cells (Treg) might enhance not only the adoptively transferred T cell response, but also promote the generation of T cell responses against a broader panel of tumor-associated antigens that are released in the Treg-depleted pro-inflammatory environment following lysis of tumors by transferred antigen- specific CTL. We propose to evaluate the use of CD25 lymphodepletion as an adjunct to adoptive T cell therapy with the following Specific Aims: 1. Assess the safety and anti-tumor efficacy of cellular adoptive immunotherapy in melanoma patients using autologous CD8+ antigen-specific T cell clones following CD25 lymphodepletion 2. Determine the influence of CD25 lymphodepletion on the duration of in vivo persistence of adoptively transferred CD8+ antigen-specific CTL clones 3. Evaluate the induction of T cells to non-targeted tumor-associated antigens (antigen- spreading) following adoptive transfer of CD8+ antigen-specific CTL and CD25 lymphodepletion PUBLIC HEALTH RELEVANCE: Cancers that are resistant to standard chemotherapy and radiation may be treatable using components of the immune system. We propose to use immune cells, T cells that recognize targets on tumor cells as a means of treating patients with advanced (metastatic) melanoma. By isolating and expanding such T cells and infusing them into patients, we can track the survival and function of these cells and, we hope, identify a treatment approach that will be safe and will improve the effectiveness of melanoma- specific T cells.

描述（由申请人提供）：收养T细胞疗法代表了治疗癌症患者的有前途的策略。 I阶段和II的研究使用采用的抗原特异性T细胞克隆进行了结论，即通过扩展转移的T细胞的体内持久性并扩大免疫反应的曲目，以限制抗原 - 渗透性肿瘤变体的生长，从而提高了其有效性。在癌症患者的水平增加下，发现调节性T细胞（以CD25HI CD4表型为特征），并通过抑制T细胞激活和效应子功能来阻止有效的抗肿瘤T细胞反应。我们假设，降低调节性T细胞群体的灌注前调节方案将导致分娩T细胞的体内持续性扩大，并促进内源性T细胞反应的产生，以针对更广泛的肿瘤相关抗原。 In this study we propose to examine the benefits of a combined biologic approach: adoptive transfer of antigen-specific CTL clones and CD25 lymphodepletion using DAB389-IL-2 (also known as denileukin diftitox or Ontak).We postulate that administration of DAB389-IL-2 to deplete regulatory T cells (Treg) might enhance not only the adoptively transferred T cell response, but also promote the generation T细胞反应针对较宽的肿瘤相关抗原的较宽面板的反应，该抗原被转移的抗原特异性CTL在肿瘤裂解后释放出在Treg缺失的促炎环境中。我们建议评估CD25淋巴结ho的使用作为通过以下特定目的的辅助T细胞疗法的辅助：1。使用自体CD8+抗原特异性T细胞CLONE CD25淋巴结epplet的cd25 on cd25 limphec5 limphect5 limphem protch cd25。在通过CD8+抗原特异性CTL和CD25抗原特异性CTL和CD25淋巴管道公共健康相关的CD8+抗原特异性CTL和CD25抗原特异性的CTL和CD25抗原转移之后，使用具有抗拒的化学疗法和辐射的Impriation ranemantiation ryape and Impriation and Impriation and Impriation and CD8+抗原特异性CTL和CD25抗原特异性CTL和CD25抗原特异性CTL和CD25抗原特异性CTL和CD25抗原特异性转移后，对TARMENTIAS的持续持续进行T细胞对非靶向肿瘤相关的抗原（抗原扩散）的持续存在。我们建议使用免疫细胞，即识别肿瘤细胞靶标的T细胞作为治疗晚期（转移性）黑色素瘤患者的一种手段。通过将这些T细胞隔离和扩展并将其注入患者，我们可以跟踪这些细胞的生存和功能，我们希望确定一种将是安全的治疗方法，并将提高黑色素瘤特定T细胞的有效性。