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细胞克隆的I期和II期研究已经得出结论，其有效性可以通过延长转移的T细胞的体内持久性和扩大免疫应答的库以限制抗原丢失肿瘤变体的生长来增强。调节性T细胞（以CD 25 hi CD 4表型为特征）在癌症患者中的水平增加，并且可能通过抑制T细胞活化和效应子功能来阻碍有效的抗肿瘤T细胞应答。我们假设，一个预输注调节方案，减少调节性T细胞的人口将导致延长体内持久的过继转移的T细胞，并促进产生内源性T细胞反应，对更广泛的面板的肿瘤相关抗原。在这项研究中，我们建议检查联合生物方法的益处：使用DAB 389-IL-2过继转移抗原特异性CTL克隆和CD 25淋巴细胞清除我们假设施用DAB 389-IL-2以耗尽调节性T细胞（Treg）可能不仅增强过继转移的T细胞应答，而且还促进产生针对更广泛的肿瘤相关抗原的T细胞应答，所述肿瘤相关抗原在Treg耗尽的促炎环境中在肿瘤被转移的抗原特异性CTL裂解后释放。我们建议评估使用CD 25淋巴细胞清除作为过继性T细胞治疗的辅助手段，具体目的如下：1.评估细胞过继免疫疗法在黑色素瘤患者中的安全性和抗肿瘤疗效，在CD 25淋巴细胞耗竭后使用自体CD 8+抗原特异性T细胞克隆2。确定CD 25淋巴细胞耗竭对过继转移的CD 8+抗原特异性CTL克隆体内持续时间的影响3.评价过继转移CD 8+抗原特异性CTL和CD 25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：对标准化疗和放疗耐药的癌症可以使用免疫系统的成分进行治疗。我们建议使用免疫细胞，即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。通过分离和扩增这样的T细胞并将其输注到患者体内，我们可以跟踪这些细胞的存活和功能，我们希望，确定一种安全的治疗方法，并将提高黑色素瘤特异性T细胞的有效性。