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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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 细胞向肿瘤的运输。然而，目前针对 T 的治疗细胞活动主要由免疫检查点调节剂组成，并且在这方面几乎没有创新针对肿瘤内积累的 T 细胞内在调节因子的治疗设计。这部分是由于对 T 细胞运输中涉及的调控途径的了解不完全。我们最近确定了适配器蛋白 2 相关激酶 1 (Aak1) 作为体内 T 细胞趋化至肿瘤的重要调节因子正向遗传筛选。该项目的主要目标是衡量 AAK1 的转化潜力：癌症的治疗靶点，以增强过继转移疗法，还有一个更好的目标了解 Aak1 作为趋化因子受体 Cxcr3 内化调节剂的分子功能。这些目标将通过三个目标来实现。目标 1 将量化 Aak1 基因修饰对肿瘤的影响临床前实体瘤模型中过继转移的 T 细胞的浸润。目标2将确定Aak1是否原代 T 细胞中趋化因子诱导的 Cxcr3 内化需要激酶活性。目标 3 将测量 Aak1 修饰对过继转移疗法疗效的影响程度。这个提议具有多个创新方面，包括新型 T 细胞特异性 Aak1 敲除小鼠的表征，新型 Aak1 突变体构建体的功能和机制测试，以及 Aak1 作为新型突变体的评估限制 T 细胞趋化进入发炎组织的治疗靶点。该项目的顺利完成将受益开发实体瘤新治疗策略，其研究结果可广泛应用于任何 T 细胞采用转移方法，不限于单个 CAR 或 TCR 工程平台。