Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM

ATTAC 时间：针对 gp100 细胞的 T 细胞过继转移来治疗 LAM

基本信息

批准号：
10682121
负责人：
I. Caroline Le Poole
金额：
$ 60.51万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2023-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682121
关键词：
Adoptive Cell Transfers Adoptive Transfer Affect Alleles Antibodies Antigens Automobile Driving Benign CCL2 gene Cell Compartmentation Cells Cellular immunotherapy Clinical Trials Complex Data Development Diagnosis Diagnostic Disease Disease model Distant Educational process of instructing Environment Epitopes Exhibits Exposure to FRAP1 gene Female of child bearing age Follow-Up Studies Gene Expression Profile Genes Glycoproteins Homing Human Immune Immunocompetent Immunologic Monitoring Immunosuppression Immunotherapeutic agent Immunotherapy Implant Infiltration Investigation Learning Lesion Life Expectancy Ligands Longevity Lung Lung Lymphangioleiomyomatosis Lung Transplantation Lymphangioleiomyomatosis Macrophage Malignant Neoplasms Measures Memory Modality Modeling Monitor Mus Mutation Nature Neoplasm Metastasis Nodule Outcome Patients Predisposition Rare Diseases Reaction Reagent Regulatory T-Lymphocyte Renal Tissue Reproducibility SILV gene Safety Signal Transduction Sirolimus Site Solid Sorting Source Specificity Surface Surface Antigens T cell response T cell therapy T-Cell Homing Receptors T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Testing Therapeutic Time Tissues Transgenic Mice Transgenic Organisms Treatment Efficacy Tumor Antigens Woman cell preparation chemokine chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells cytokine cytotoxicity design effective therapy effector T cell efficacy testing gp100 Antigen human model immune cell infiltrate immunogenic improved in vitro activity in vitro testing in vivo insight melanoma melanoma-associated antigen migration monocyte chemoattractant protein 1 receptor mouse model neoantigens neoplasm immunotherapy neoplastic cell overexpression patient derived xenograft model permissiveness pre-clinical receptor side effect stem-like cell tool trafficking tumor tumor progression tumor-immune system interactions vector young woman

项目摘要

SUMMARY Lymphangioleiomyomatosis (LAM) is a rare disorder with devastating consequences for the young women diagnosed with this disease. We observed occult expression of the glycoprotein gp100 and other melanoma associated antigens in nodular, pulmonary tumor lesions. LAM cells carry a dysfunctional TSC complex and exhibit constitutive mTOR activation. Though rapamycin can provide relief, there is a great need to develop a true cure for women with LAM. We evaluated the expression of suitable antigens and the associated infiltration by immune cells. Here we propose to capitalize on the occult expression of melanoma associated antigens to develop safe and effective, T cell-based immunotherapy for LAM. First, we will generate constructs targeting LAM antigens to transduce T cells and prepare the cells for adoptive transfer. These constructs are equipped or not with a homing receptor to drive the adoptively transferred T cells to LAM lung, exploiting the consistent overexpression of the chemokine ligand CCL2 within affected tissues., in order to minimize off tumor effects. Transgenic T cells are generated with stem cell-like attributes to promote longevity and continued functionality. Efficacy and safety comparisons are made between TCR transgenic and HLA-independent CAR T cells targeting a LAM surface antigen. Based on expression of a natural receptor epitope encoded by the construct, resulting T cells are readily sorted and traced, and will be put to the test in mouse models of the disease. We will engage an immunocompetent disease model, as well as PDX implanted mice to explore the treatment potential of adoptively transferred, LAM reactive T cells. Within PDX mice, the LAM microenvironment is well conserved. Expression of LAM tumor antigens can be maintained over time, while therapeutics can be tested in a statistically and biologically meaningful way. Finally, we will explore the immune microenvironment in LAM and in PDX tissues exposed to adoptive transfer or not, to learn whether T cells harbored by LAM lung or supplied by adoptive transfer can be taught to clear existing lesions. Next, our collaborative group aims to develop a winning immunotherapeutic approach to treat the devastating disease. The project will thus cover (1) generating and in vitro testing of transgenic mouse and human T cells; and (2) measuring the anti-tumor efficacy of adoptively transferred T cells in immune competent as well as PDX models of LAM as well as (1) in-depth analysis of the immune environment encountered in LAM lesions before and after adoptive transfer. Resulting preclinical data can then serve to design a clinical trial in follow-up studies and test the hypothesis, that benign tumors in LAM are amenable to treatment by adoptive transfer of tissue homing, LAM reactive T cells.

概括淋巴管平滑肌瘤病 (LAM) 是一种罕见疾病，对年轻女性造成毁灭性后果诊断患有这种疾病。我们观察到糖蛋白 gp100 和其他黑色素瘤的隐匿表达结节性肺部肿瘤病变中的相关抗原。 LAM 细胞携带功能失调的 TSC 复合体表现出组成型 mTOR 激活。尽管雷帕霉素可以提供缓解作用，但仍然非常需要开发一种真正治愈患有 LAM 的女性。我们评估了合适抗原的表达和相关的浸润由免疫细胞。在这里，我们建议利用黑色素瘤相关抗原的隐匿表达来为 LAM 开发安全有效的基于 T 细胞的免疫疗法。首先，我们将生成目标构建体 LAM 抗原转导 T 细胞并为细胞过继转移做好准备。这些结构配备或不使用归巢受体来驱动过继转移的 T 细胞至 LAM 肺，利用一致的趋化因子配体 CCL2 在受影响的组织内过度表达，以尽量减少肿瘤效应。转基因 T 细胞具有干细胞样属性，可延长寿命并持续发挥功能。 TCR 转基因和 HLA 独立 CAR T 细胞靶向的功效和安全性进行了比较 LAM 表面抗原。基于构建体编码的天然受体表位的表达，产生 T 细胞很容易分类和追踪，并将在该疾病的小鼠模型中进行测试。我们将参与免疫活性疾病模型以及 PDX 植入小鼠以探索治疗潜力过继转移的 LAM 反应性 T 细胞。在 PDX 小鼠中，LAM 微环境保存完好。 LAM 肿瘤抗原的表达可以随着时间的推移而维持，而治疗方法可以通过统计方法进行测试。和具有生物学意义的方式。最后，我们将探讨 LAM 和 PDX 中的免疫微环境暴露于过继转移或未暴露的组织，以了解 T 细胞是否由 LAM 肺携带或由可以教导过继转移来清除现有的病变。接下来，我们的合作小组旨在开发一个获胜的免疫治疗方法来治疗这种毁灭性的疾病。因此，该项目将涵盖 (1) 发电和转基因小鼠和人类 T 细胞的体外测试； (2) 测量过继性的抗肿瘤功效在 LAM 的免疫活性和 PDX 模型中转移 T 细胞以及 (1) 深入分析 LAM 病变在过继转移前后遇到的免疫环境。临床前数据结果然后可以在后续研究中设计临床试验并测试 LAM 良性肿瘤的假设适合通过组织归巢 LAM 反应性 T 细胞过继转移进行治疗。