Adoptive T Cell Therapy Following CD25 Lymphodepletion

描述(由申请人提供)：采用T细胞疗法是治疗癌症患者的一种很有前途的策略。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，通过延长转移的T细胞在体内的持久性和扩大免疫反应的范围以限制抗原缺失肿瘤变异体的生长，可以增强其有效性。调节性T细胞(以CD25hi CD4表型为特征)在癌症患者中被发现水平升高，并可能通过抑制T细胞的激活和效应器功能而阻碍有效的抗肿瘤T细胞反应。我们推测，减少调节性T细胞数量的预输注调节方案将导致过继转移的T细胞在体内持续时间延长，并促进针对更广泛的肿瘤相关抗原的内源性T细胞反应的产生。在这项研究中，我们建议检验一种联合生物学方法的好处：过继转移抗原特异性CTL克隆和使用DAB389-IL-2(也称为去IL-2或Ontak)去除CD25淋巴。我们假设，给DAB389-IL-2去除调节性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肿瘤相关抗原的产生，这些抗原是在转移的抗原特异性CTL溶解肿瘤后在Treg耗尽的促炎环境中释放的。我们建议评估CD25淋巴去除作为过继T细胞治疗的辅助手段，其目的如下：1.评估在CD25淋巴去除后使用自体CD8+抗原特异性T细胞克隆的黑色素瘤患者细胞过继免疫治疗的安全性和抗肿瘤效果2.确定CD25淋巴去除对过继转移的CD8+抗原特异性CTL克隆体内存留时间的影响3.评估过继转移CD8+抗原特异性CTL和CD25淋巴去除后T细胞对非靶向肿瘤相关抗原(抗原扩散)的诱导作用与公共卫生相关：对标准化疗和放射耐药的癌症可能可以使用免疫系统的组件进行治疗。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。通过分离和扩增这种T细胞并将它们注入患者体内，我们可以跟踪这些细胞的生存和功能，并希望找到一种安全的治疗方法，将提高黑色素瘤特异性T细胞的有效性。

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.