Aak1 to increase infiltration of adoptively transferred cells into solid tumors

Aak1 增加过继转移细胞向实体瘤的浸润

• 批准号: 10558244
• 负责人: Laura Marie Rogers
• 金额: $ 45.76万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-16 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558244
• 关键词: Adaptor Signaling Protein; Adoptive Cell Transfers; Adoptive Transfer; B lymphoid malignancy; Binding; Biochemical; CXC chemokine receptor 3; CXCL10 gene; CXCR3 gene; Cell Signaling Process; Cell surface; Cells; Chemotaxis; Clathrin; Clinical; Data; Development; Dominant-Negative Mutation; Endocytic Vesicle; Endocytosis; Engineering; Evaluation; Flow Cytometry; Gene Mutation; Genes; Genetic; Genetic Screening; Goals; Hela Cells; Human; Image; In Vitro; Individual; Infiltration; Knock-out; Knockout Mice; Ligands; Malignant Neoplasms; Measures; Mediating; Microscopy; Modeling; Modification; Molecular; Mus; Mutate; Mutation; Phosphotransferases; Play; Process; Proteins; Receptor Signaling; Regulation; Regulatory Pathway; Reporting; Role; Series; Sleeping Beauty; Solid Neoplasm; Surface; System; T cell infiltration; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Tissues; Treatment Efficacy; Xenograft procedure; cancer immunotherapy; cell motility; chemokine; chemokine receptor; chimeric antigen receptor; chimeric antigen receptor T cells; cytotoxic; design; enhancer-binding protein AP-2; experimental study; genome wide screen; immune checkpoint; improved; in vivo; innovation; melanoma; migration; mutant; new therapeutic target; novel; overexpression; pharmacologic; pre-clinical; receptor; receptor expression; standard care; success; targeted treatment; therapeutic target; trafficking; translational potential; treatment strategy; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Insufficient T cell infiltration is a major challenge in adoptive transfer therapies like CAR-T. Therefore, one strategy to improve therapy is to enhance T cell trafficking into tumors. However, current therapies targeting T cell activities largely consist of immune checkpoint modulators, and very little innovation has occurred in therapeutic design targeting T cell intrinsic regulators of intratumoral accumulation. This is due, in part, to an incomplete understanding of the regulatory pathways involved in T cell trafficking. We recently identified Adapter protein 2 associated kinase 1 (Aak1) as an important regulator of T cell chemotaxis into tumors in an in vivo forward genetic screen. The primary objective of this project is to measure the translational potential of AAK1 as a therapeutic target in cancer to augment adoptive transfer therapies, with the additional goal of better understanding molecular functions of Aak1 as a regulator of chemokine receptor Cxcr3 internalization. These goals will be accomplished in three aims. Aim 1 will quantify the impact of genetic modification of Aak1 on tumor infiltration of adoptively transferred T cells in a preclinical solid tumor model. Aim 2 will determine whether Aak1 kinase activity is required for chemokine-induced internalization of Cxcr3 in primary T cells. Aim 3 will measure the degree to which Aak1 modification impacts therapeutic efficacy in adoptive transfer therapies. This proposal has several innovative aspects, including characterization of a novel, T cell specific Aak1 knockout mouse, functional and mechanistic testing of a novel Aak1 mutant construct, and evaluation of Aak1 as a novel therapeutic target to limit T cell chemotaxis into inflamed tissue. Successful completion of this project will benefit development of novel treatment strategies for solid tumors, and findings can broadly be applied to any T cell adoptive transfer approach and is not limited to individual CAR or TCR engineered platforms.

项目总结/摘要 T细胞浸润不足是CAR-T等过继转移疗法的主要挑战。因此，一 改善治疗的策略是增强T细胞向肿瘤中的运输。然而，目前针对T 细胞活动主要由免疫检查点调节剂组成，而且几乎没有创新 靶向肿瘤内积累的T细胞内在调节因子的治疗设计。这在一定程度上是由于 对参与T细胞运输的调节途径的不完全理解。我们最近发现适配器 蛋白2相关激酶1（Aak 1）作为体内T细胞趋化性进入肿瘤的重要调节因子， 遗传筛查该项目的主要目的是测量AAK 1的翻译潜力， 癌症的治疗靶点，以增强过继转移治疗，其额外目标是更好地 了解Aak 1作为趋化因子受体Cxcr 3内化调节剂的分子功能。这些 目标将在三个方面实现。目的1：量化Aak 1基因修饰对肿瘤的影响 在临床前实体瘤模型中过继转移的T细胞的浸润。目标2将决定Aak 1是否 激酶活性是趋化因子诱导的Cxcr 3在原代T细胞中内化所必需的。目标3将衡量 Aak 1修饰在何种程度上影响过继转移治疗的疗效。这项建议 具有几个创新方面，包括表征一种新的T细胞特异性Aak 1敲除小鼠， 新的Aak 1突变体构建体的功能和机制测试，以及Aak 1作为新的 治疗靶点，以限制T细胞趋化性进入发炎组织。该项目的成功完成将使 开发新的实体瘤治疗策略，研究结果可广泛应用于任何T细胞 本发明的CAR或TCR工程化平台可以是过继转移方法，并且不限于单独的CAR或TCR工程化平台。