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

• 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
• 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

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.

总结 淋巴管平滑肌瘤病（LAM）是一种罕见的疾病与毁灭性的后果，对年轻妇女 被诊断出患有这种疾病。我们观察到糖蛋白gp 100和其他黑色素瘤的隐匿性表达， 相关抗原在结节性肺肿瘤病变中的表达。LAM细胞携带功能失调的TSC复合物， 表现出组成性mTOR激活。虽然雷帕霉素可以提供缓解，但仍然非常需要开发一种新的药物。 真正治愈女性LAM。我们评估了合适抗原的表达和相关的浸润 免疫细胞。在这里，我们建议利用黑色素瘤相关抗原的隐匿性表达， 开发安全有效的基于T细胞的LAM免疫疗法。首先，我们将生成针对 LAM抗原与CD 4 T细胞结合并制备用于过继转移的细胞。这些建筑物配备有或 没有归巢受体来驱动过继转移的T细胞到LAM肺，利用了一致的 在受影响的组织中趋化因子配体CCL 2的过度表达，以减少肿瘤的影响。 转基因T细胞产生的干细胞样属性，以促进长寿和持续的功能。 在靶向TCR转基因和HLA非依赖性CAR T细胞之间进行功效和安全性比较 LAM表面抗原。基于由构建体编码的天然受体表位的表达，产生T 细胞很容易被分类和追踪，并将在这种疾病的小鼠模型中进行测试。我们会委聘 免疫活性疾病模型，以及PDX植入小鼠，以探索 过继转移的LAM反应性T细胞。在PDX小鼠中，LAM微环境是很保守的。 LAM肿瘤抗原的表达可以随时间维持，而治疗剂可以在统计学上进行测试。 有生物学意义的方式。最后，我们将探索LAM和PDX中的免疫微环境 暴露于过继转移或未暴露于过继转移的组织，以了解T细胞是否由LAM肺携带或由 可以教导过继转移以清除现有病变。接下来，我们的合作小组旨在制定一个双赢的 免疫疗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T细胞的体外测试;和（2）测量过继性免疫抑制剂的抗肿瘤功效。 在LAM的免疫活性以及PDX模型中转移的T细胞，以及（1）深入分析 过继转移前后LAM病变所处的免疫环境。临床前数据 然后，可以在后续研究中设计临床试验，并验证LAM中的良性肿瘤 可通过过继转移组织归巢LAM反应性T细胞进行治疗。