Strategies to improve the adoptive transfer of T cells

描述（由申请人提供）：诱导性T细胞疗法，其涉及已经离体分离或工程化的肿瘤特异性T细胞的扩增群体的再输注，已经在患有晚期黑色素瘤和白血病的患者亚组中实现了显著的抗肿瘤应答。然而，只有一小部分患者从过继性T细胞疗法中受益，部分原因是难以从患者中鉴定和扩增高亲和力肿瘤反应性T细胞，以及难以在过继性转移后维持患者中T细胞的数量和抗肿瘤活性。通过基因转移将肿瘤靶向受体引入T细胞以赋予肿瘤反应性提供了一种有希望的方法来克服必须从每个患者分离肿瘤反应性T细胞以治疗其恶性肿瘤的障碍，但没有解决通过离体培养在数量上扩增并过继转移到患者的抗原特异性T细胞的体内存活持续时间是不可预测的问题，而且常常很短。因此，确定T细胞在转移后持续存在的能力的T细胞特征的鉴定，以及可应用于人的增强存活和/或体内扩增转移的T细胞的策略可以改善治疗结果。这项资助支持的研究利用非人灵长类动物（NHP）模型来解决过继性T细胞治疗的这一重要障碍。这项工作已经确定了TE细胞的遗传品质，这些品质决定了它们在体内的命运和建立持久T细胞记忆的能力，并确定了白细胞介素15（IL-15）在支持转移T细胞长期持久性方面的作用。NHP模型中使用的技术概括了人类过继治疗中使用的技术，该模型的发现正在转化为T细胞治疗癌症的临床试验。本竞争性更新中的研究将利用该模型优化IL-15给药策略和细胞疫苗接种策略，该细胞疫苗由展示同源抗原的活化T细胞组成，以增强通过TE细胞过继转移实现的T细胞免疫的幅度和持久性，并评价靶向在人B细胞恶性肿瘤上选择性表达的新型分子的安全性。这些研究因其直接相关性和快速转化为人类过继性T细胞治疗的潜力而被选中。具体目标是：1.确定皮下IL-15用于改善过继转移的TE细胞存活及其向记忆细胞转化的安全性和有效性。2.为了优化使用T细胞抗原呈递细胞（T-APC）的全身疫苗接种来驱动过继转移的TE细胞的体内扩增。3.确定过继转移TE细胞的安全性，TE细胞经遗传修饰以表达ROR 1特异性嵌合抗原受体，ROR 1是一种在人B-CLL和套细胞淋巴瘤上表达的表面分子，在M.穆拉塔。

DESCRIPTION (provided by applicant): Adoptive T cell therapy, which involves the reinfusion of expanded populations of tumor-specific T cells that have been isolated or engineered ex vivo, has achieved dramatic antitumor responses in a subset of patients with advanced melanoma and leukemia. However, only small subsets of patients have benefited from adoptive T cell therapy, in part because of the difficulty identifying and expanding high avidity tumor-reactive T cells from patients, and of maintaining the number and anti-tumor activity of the T cells in the patient after adoptive transfer. The introduction of tumor-targeting receptors into T cells by gene transfer to confer tumor reactivity provides a promising approach to overcome the obstacle of having to isolate tumor-reactive T cells from each patient to treat their malignancy, but does not solve the problem that the duration of in vivo survival of antigen-specific T cells that have been numerically expanded by culture ex vivo and adoptively transferred to patients is unpredictable, and often short. Thus, the identification of characteristics of T cells that determine their capacity to persist after transfer, and strategies to enhance survival and/or to expand transferred T cells in vivo that can be applied to humans could improve therapeutic outcome. Studies supported by this grant have utilized a nonhuman primate (NHP) model to address this important impediment to adoptive T cell therapy. This work has identified heritable qualities of TE cells that determine their fate in vivo and ability to establish durable T cell memory, and identified a role for interleukin 15 (IL-15) for supporting the long-term persistence of transferred T cells. The techniques used in the NHP model recapitulate those used in human adoptive therapy, and findings from this model are being translated into clinical trials of T cell therapy for cancer. The studies in this competing renewal will utilize the model to optimize strategies for administering IL-15 and for vaccination with a cellular vaccine comprised of an activated T cell that displays the cognate antigen, to enhance the magnitude and durability of T cell immunity achieved by adoptive transfer of TE cells, and evaluate the safety of targeting a novel molecule that is selectively expressed on human B cell malignancies. These studies have been selected for their immediate relevance and potential for rapid translation to human adoptive T cell therapy. The specific aims are: 1. To determine the safety and efficacy of subcutaneous IL-15 for improving the survival of adoptively transferred TE cells and their conversion to memory cells. 2. To optimize the use of systemic vaccination with T-cell antigen presenting cells (T-APC) for driving the in vivo expansion of adoptively transferred TE cells. 3. To determine the safety of adoptively transferring TE cells genetically modified to express a chimeric antigen receptor specific for ROR1, a surface molecule expressed on human B-CLL and mantle cell lymphoma, and conserved in M. mullata.