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）：过继性 T 细胞疗法代表了治疗癌症患者的一种有前途的策略。使用过继转移的抗原特异性 T 细胞克隆进行的 I 期和 II 期研究得出的结论是，可以通过延长转移 T 细胞的体内持久性并扩大免疫反应范围以限制抗原丢失的发展来增强其有效性肿瘤变异体。调节性 T 细胞（以 CD25hi CD4 表型为特征）在癌症患者中水平升高，并可能通过抑制 T 细胞激活和效应功能来阻碍有效的抗肿瘤 T 细胞反应。我们假设减少调节性 T 细胞群的输注前预处理方案将导致过继转移 T 细胞在体内的持久性延长，并促进针对更广泛的肿瘤相关抗原产生内源性 T 细胞反应。在本研究中，我们建议检查组合生物方法的益处：使用 DAB389-IL-2（也称为 denileukin diftitox 或 Ontak）过继转移抗原特异性 CTL 克隆和 CD25 淋巴细胞清除。我们假设给予 DAB389-IL -2 消耗调节性 T 细胞 (Treg) 不仅可以增强过继转移的 T 细胞反应，还可以促进针对更广泛的群体的 T 细胞反应的产生转移的抗原特异性 CTL 裂解肿瘤后，在 Treg 耗尽的促炎环境中释放肿瘤相关抗原。我们建议评估 CD25 淋巴细胞清除作为过继性 T 细胞治疗的辅助手段的使用，具体目标如下： 1. 评估使用自体 CD8+ 抗原特异性 T 细胞克隆对黑色素瘤患者进行细胞过继性免疫治疗的安全性和抗肿瘤功效CD25 淋巴细胞清除 2. 确定 CD25 淋巴细胞清除对过继转移的 CD8+ 抗原特异性 CTL 克隆体内持续时间的影响3. 评估过继转移 CD8+ 抗原特异性 CTL 和 CD25 淋巴细胞清除后 T 细胞对非靶向肿瘤相关抗原（抗原扩散）的诱导 公共卫生相关性：对标准化疗和放疗具有抗性的癌症可以使用以下方法治疗：免疫系统的组成部分。我们建议使用免疫细胞（识别肿瘤细胞靶点的 T 细胞）作为治疗晚期（转移性）黑色素瘤患者的一种手段。通过分离和扩增此类 T 细胞并将其注入患者体内，我们可以追踪这些细胞的存活和功能，并且我们希望找到一种安全的治疗方法，并提高黑色素瘤特异性 T 细胞的有效性。