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.

概括淋巴血管肌瘤病（LAM）是一种罕见的疾病，对年轻女性造成了毁灭性后果被诊断出患有这种疾病。我们观察到糖蛋白GP100和其他黑色素瘤的神秘表达结节性肺部肿瘤病变中的相关抗原。 LAM细胞带有功能失调的TSC复合物，并且展示本构的MTOR激活。尽管雷帕霉素可以提供缓解，但很需要开发一个真正治愈妇女的妇女。我们评估了合适的抗原的表达和相关的浸润通过免疫细胞。在这里，我们建议利用黑色素瘤相关抗原的神秘表达为LAM开发安全有效的，基于T细胞的免疫疗法。首先，我们将生成定位的构造 lam抗原可转导T细胞并制备细胞以进行过继转移。这些结构配备了或不带有归巢受体来将收养的T细胞驱动到肺肺，从而利用一致的为了最大程度地减少肿瘤作用，趋化组织中趋化因子配体CCL2的过表达。转基因T细胞用干细胞样属性产生，以促进寿命和持续功能。在靶向TCR转基因和HLA独立的CAR T细胞之间进行疗效和安全性比较 LAM表面抗原。基于由构建体编码的天然受体表位的表达，导致t 细胞很容易分类和追踪，并将在疾病的小鼠模型中进行测试。我们将参与免疫能力的疾病模型以及PDX植入小鼠，以探索治疗潜力采用转移的LAM反应性T细胞。在PDX小鼠中，LAM微环境良好。可以随着时间的推移保持LAM肿瘤抗原的表达，而治疗药可以在统计上进行测试和生物学上有意义的方式。最后，我们将探索LAM和PDX中的免疫微环境暴露于收养转移的组织，以了解是否由Lam肺含有或由可以教授收养转移以清除现有的病变。接下来，我们的协作小组旨在发展获胜治疗毁灭性疾病的免疫治疗方法。因此，该项目将涵盖（1）生成和体外测试转基因小鼠和人类T细胞；（2）测量采用的抗肿瘤功效在免疫胜任和LAM的PDX模型以及（1）深入分析中，T细胞转移了T细胞收养后和之后，在LAM病变中遇到的免疫环境。产生的临床前数据然后可以在后续研究中设计一项临床试验并检验假设，即良性肿瘤在LAM中通过通过组织归巢，LAM反应性T细胞的过继转移来接受治疗。