Potentiating Adoptive T Cell Therapy by Immunomodulation

描述（由申请人提供）：涉及抗原特异性T细胞的离体分离和扩增的连续治疗产生了肿瘤根除和免疫保护的希望，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。将在I期研究中实施的环磷酰胺剂量范围（300 - 4，000 mg/m2）基于既往临床试验，证明环磷酰胺具有免疫增强作用。输注后低剂量和高剂量IL-2的剂量和时间表已经涉及过继性T细胞疗法的先前临床试验以影响体内T细胞存活。在一项扩展的II期研究中，将评价在该初始I期研究中确定的环磷酰胺预处理方案和输注后IL-2方案的临床疗效，该方案被认为是安全的，并且可最大限度地提高T细胞持久性。公共卫生研究中心（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): 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. The dosing range for cyclophosphamide that will be implemented in the Phase I study, 300 to 4,000 mg/m2, is grounded in previous clinical trials demonstrating an immunopotentiating effect of cyclophosphamide. The dose and schedule of post-infusion low-dose and high-dose IL-2 have been implicated in previous clinical trials of adoptive T cell therapy to impact T cell survival in vivo. A cyclophosphamide conditioning regimen and post-infusion IL-2 schedule identified in this initial Phase I study that is deemed to be safe and that maximizes T cell persistence will be evaluated for clinical efficacy in an extended Phase II study. 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.