Potentiating Adoptive T Cell Therapy by Immunomodulation

描述（由申请人提供）：项目总结/摘要免疫治疗涉及抗原特异性T细胞的离体分离和扩增，有望实现肿瘤根除和免疫保护，毒性最小。近年来，这种方式已经产生了治疗转移性黑色素瘤患者的有希望的结果。然而，有助于转移的T细胞的体内存活和功能以及最终患者中的肿瘤消退的因素尚未被定义和优化。据信，输注前调节和输注后细胞因子施用有助于过继转移的T细胞的功效。我们假设，使用T细胞克隆的定义的大小，表型和特异性过继治疗将允许一个精确和严格的检查免疫调节方案的影响，并促进识别的元素负责一个成功的战略。我们建议在I期剂量探索研究中确定输注前环磷酰胺预处理方案和输注后IL-2剂量，其是安全的并且支持过继转移的T细胞的体内存活和功能。在进行本试验的过程中，我们观察到T细胞持续时间显著（30至300天），伴有RECIST标准的部分和完全应答。作为一项剂量递增研究，该研究最初设计的患者数量有限（n=6）。鉴于这些发现，我们建议将这项研究扩展到另外6例患者，并更严格地评估过继转移T细胞的分化表型，从而在体内产生这些高度持久的群体。为了响应通知编号（NOT-OD-09-058）“NIH宣布恢复法案资金用于竞争性修订申请的可用性”，我们建议评估这些高度持久的过继转移T细胞克隆的遗传和表型特征，希望这些T细胞可以前瞻性地鉴定和富集用于过继细胞治疗。 公共卫生相关性：研究与公共卫生的相关性（外行语言）：对标准化疗和放疗有抵抗力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，T细胞，识别肿瘤细胞上的靶点，作为治疗晚期（转移性）黑色素瘤患者的一种手段。通过分离和扩增这些T细胞并将其注入患者体内，我们可以跟踪这些细胞的存活和功能，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。

DESCRIPTION (provided by applicant): Project Summary/Abstract Adoptive therapy involving the ex vivo isolation and expansion of antigen-specific T cells yields the promise of tumor eradication and immunoprotection with minimal toxicity. In recent years, this modality has produced promising results for the treatment of patients with metastatic melanoma. However, factors contributing to the in vivo survival and function of transferred T cells and ultimately, tumor regression in patients, have yet to be defined and optimized. It is believed that pre-infusion conditioning and post-infusion cytokine administration contribute to the efficacy of adoptively transferred T cells. We postulate that the use of T cell clones of defined magnitude, phenotype and specificity for adoptive therapy will permit a precise and rigorous examination of the influence of immunomodulatory regimens and facilitate the identification of elements responsible for a successful strategy. We propose to identify in a Phase I, dose-finding study, a cyclophosphamide conditioning regimen pre- infusion and a dose of IL-2 post-infusion that is safe and that supports the in vivo survival and function of adoptively transferred T cells. In the course of performing this trial we observed T cell persistence of significant duration (from 30 to 300 days) accompanied by RECIST-criteria partial and complete responses. As a dose escalation study, the study was initially designed with a limited number of patients (n=6). In light of these findings, we propose to extend this study to include an additional 6 patients and to more rigorously evaluate the differentiation phenotype of adoptively transferred T cells giving rise to these highly persistent populations in vivo. In response to Notice Number (NOT-OD-09-058) " NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications," we propose to evaluate the genetic and phenotypic signature of these highly persistent adoptively transferred T cell clones in the hope that such T cells can be prospectively identified and enriched for adoptive cellular therapy. PUBLIC HEALTH RELEVANCE: Relevance of Research to Public Health (lay language): 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.