Activating Native Tumor Immunity with IL-33 Armored CARs

使用 IL-33 装甲 CAR 激活天然肿瘤免疫

基本信息

批准号：
10744438
负责人：
Yina Hsing Huang
金额：
$ 57.35万
依托单位：
DARTMOUTH COLLEGE
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：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744438
关键词：
Adoptive Transfer Antigen Receptors Antigen Targeting Antigens Antitumor Response Autoimmune Diseases CAR T cell therapy CCR5 gene CXCR6 gene Cell Survival Cells Clinic Colon Colon Carcinoma Cytokine Receptors Drug or chemical Tissue Distribution Effector Cell Flow Cytometry HIF1A gene Image Immune Immunomodulators Immunosuppression Immunotherapy Infiltration Interferon Type II Interleukin-12 Interleukin-2 Investigation Kinetics Leukocytes Liquid substance MC38 MHC Class I Genes Macrophage Malignant Epithelial Cell Malignant Neoplasms Mediating Metastatic Melanoma Methods Modeling Molecular Myeloid Cells Natural Killer Cells Nature Pathway Analysis Peptide/MHC Complex Peripheral Population Race Regulatory T-Lymphocyte Reporting Role Safety Solid Solid Neoplasm Spatial Distribution T-Lymphocyte Testing Tissues Toxic effect Tumor Immunity Tumor-associated macrophages anti-tumor immune response cancer immunotherapy cancer therapy chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells clinical translation cytokine delivery vehicle draining lymph node effector T cell immunogenic improved in vivo luminescence lung metastatic mouse model neoantigens neoplastic cell novel perforin recruit trafficking transcriptomics tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

ABSTRACT Unlike liquid cancers, current CAR T cell immunotherapies have little effect against solid cancers, largely due to the immunosuppressive nature of the tumor microenvironment. The race between administered CAR T cells and tumor associated cells to kill off and/or neutralize the other is tipped heavily in favor of the tumor. Heterogeneous tumors or tumors able to shed or downregulate CAR-targeted antigens can also escape elimination by functional CAR T cell effectors. We recently found that CAR T cells delivery of dual cytokines can enlist and activate endogenous T cells, NK cells and myeloid cells to mount an effective anti-tumor immune response. Further investigation revealed that perforin and IFNγ are dispensable in CAR T cells, supporting an accessory role for CAR T cells in mobilizing endogenous immune cells to ultimately control tumor growth. CAR T cell-mediated dual cytokine delivery was effective in controlling tumor growth with 3 different CAR T cell constructs and 4 in vivo tumor models: primary and metastatic melanoma and primary colon cell carcinoma mouse models, and importantly was impervious to antigen loss. This suggests that the dual cytokine platform has potential for universal application against multiple solid tumor types. In this application, we hypothesize that CAR T cell delivery of dual cytokines has broad application because it counteracts immunosuppressive innate and adaptive immune cells to elicit a broad endogenous anti-tumor response independent of CAR effector potential. We will test this hypothesis by identifying CAR T cell survival and distribution dynamics (Aim 1), identify the common and tumor-specific changes in immunosuppressive, immunostimulatory and effector leukocyte populations isolated from poorly and strongly immunogenic tumors pre- and post-CAR cytokine treatment (Aim 2), and determine their roles in activating endogenous tumor immunity (Aim 3). The cellular and mechanisms identified will support further improvement and clinical translation of the Super2+IL-33 platform with various CAR targeting constructs for CAR T cell therapies for solid tumors.

抽象的与液体癌不同，目前的 CAR T 细胞免疫疗法对实体癌效果甚微，很大程度上是由于肿瘤微环境的免疫抑制性质。肿瘤相关细胞杀死和/或中和其他细胞的行为在很大程度上有利于肿瘤。肿瘤或能够脱落或下调 CAR 靶向抗原的肿瘤也可以逃避功能性消除我们最近发现 CAR T 细胞递送双重细胞因子可以招募并激活。内源性 T 细胞、NK 细胞和骨髓细胞进一步发起有效的抗肿瘤免疫反应。研究表明，穿孔素和 IFNγ 在 CAR T 细胞中是可有可无的，支持辅助作用 CAR T 细胞动员内源性免疫细胞最终控制 CAR T 细胞介导的肿瘤生长。双细胞因子递送可有效控制肿瘤生长，使用 3 种不同的 CAR T 细胞构建体和 4 种体内肿瘤模型：原发性和转移性黑色素瘤和原发性结肠细胞癌小鼠模型，以及重要的是不受抗原损失的影响，这表明双细胞因子平台具有潜在的潜力。针对多种实体瘤类型的普遍应用在此应用中，我们使用了 CAR T 细胞。双重细胞因子的递送具有广泛的应用，因为它可以抵消先天性和适应性的免疫抑制免疫细胞引发广泛的内源性抗肿瘤反应，与 CAR 效应器潜力无关。通过确定 CAR T 细胞存活和分布动态（目标 1）来检验这一假设，确定常见的免疫抑制、免疫刺激和效应白细胞群的肿瘤特异性变化在 CAR 细胞因子治疗前后从免疫原性弱和强的肿瘤中分离出来（目标 2），以及确定它们在激活内源性肿瘤免疫中的作用（目标 3）。将支持具有多种CAR靶向的Super2+IL-33平台的进一步改进和临床转化用于实体瘤 CAR T 细胞疗法的构建体。