Novel Combination Therapy for Treatment and Prevention of PulmonaryLymphangioleiomyomatosis (LAM) and Tuberous Sclerosis Complex (TSC)

治疗和预防肺淋巴管平滑肌瘤病 (LAM) 和结节性硬化症 (TSC) 的新型联合疗法

基本信息

批准号：
10697901
负责人：
VERA P KRYMSKAYA
金额：
$ 30万
依托单位：
BIOSPUTNIK LLC
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：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10697901
关键词：
Acceleration Adverse event Affect Age Animals Antibodies Benign Biological Products Brain Bronchoalveolar Lavage C57BL/6 Mouse Cancer Model Categories Cell Count Cell Culture Techniques Cell Line Cells Clinic Clinical Code Combined Modality Therapy Complex Control Groups Cyst Cytoplasm Data Development Disadvantaged Disease Dose Ensure Environment Eye FDA approved FRAP1 gene Female of child bearing age Fibroblasts Flow Cytometry Genetic Genetic Diseases Goals Grant Growth Heart Human Immune Immune Evasion Immunocompetent Immunoglobulins Immunohistochemistry Immunologic Surveillance Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Incubated Inherited Injections Investigation Kidney Laboratories Lesion Libraries Life Literature Lung Lung Lymphangioleiomyomatosis Lung Transplantation Lung diseases Lymphangioleiomyomatosis Lymphatic Obstruction Malignant Neoplasms Medical Mesenchymal Modeling Morphology Mus Mutation Neoplasms Nodule Organ PD-1 blockade Pathway interactions Patients Pattern Pennsylvania Persons Pharmaceutical Preparations Pneumothorax Pregnancy Preparation Prevention Preventive treatment Proliferating Property Publishing Quantitative Reverse Transcriptase PCR Rare Diseases Recurrence Regimen Reporting Research Safety Sequential Treatment Shortness of Breath Signal Transduction Sirolimus Skin Smooth Muscle Myocytes Structure Surface Suspensions System TSC1 gene TSC1/2 gene TSC2 gene Tail Testing Therapeutic Tissues Translating Transplant Recipients Tuberous Sclerosis Tumor Suppressor Genes United States Universities Up-Regulation Veins Western Blotting Woman Work anti-PD-1 anti-PD1 antibodies anti-PD1 therapy checkpoint inhibition child bearing clinical development clinical translation comparison group curative treatments efficacy evaluation experimental study gene function immune checkpoint blockade immunoregulation improved improved outcome in vivo intraperitoneal lung lesion mTOR Inhibitor mouse model mutant neoplastic novel novel therapeutics pembrolizumab programmed cell death ligand 1 standard of care time use tumor

项目摘要

1 ABSTRACT 2 Tuberous sclerosis (TS), also called tuberous sclerosis complex, is a rare, multi-systemic genetic and often life- 3 threatening disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, 4 heart, eyes, lungs, and skin. Lymphangioleiomyomatosis (LAM) is a TS-related tumor-like disorder. Both occur 5 as a consequence of an inherited or sporadic mutation in either the TSC1 or TSC2 gene, which function as 6 negative regulators of the mTOR pathway. Uncontrolled mTORC1 activity leads to the neoplastic proliferation of 7 abnormal smooth muscle cells (LAM cells) in the lungs, progressive shortness of breath, recurrent 8 pneumothoraxes, and loss of pulmonary tissue structure and function. In addition, published data suggests that 9 LAM cells may evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 10 (PD-L1). LAM is a rare disease affecting women in childbearing age. The first and only FDA-approved treatment 11 for LAM is the immunosuppressant Rapamycin. It is the current standard-of-care and acts by inhibiting mTORC1. 12 Rapamycin has several clinical disadvantages, including a considerable number of non-responders, severe 13 adverse events due to its immunosuppressive properties and pregnancy category C, limiting its use in women of 14 childbearing age. Thus, there is a high unmet medical need to develop alternative and safer treatment options for 15 LAM and TS. We have identified Anti-PD1 checkpoint blockade as a potential novel therapy for LAM/TS. Using 16 our recently developed immunocompetent mouse model, the Co-PI Prof. Krymskaya was able to show that 17 treatment with an Anti-PD1 antibody significantly improved mouse surival. To advance immunetherapy for LAM, 18 our goal for this grant is the investigation of the mechanistic interplay between Rapamyin and Anti-PD1 antibodies 19 to harness the potential of a combination therapy in vitro and in vivo. Aim 1 will cover a set of in vitro studies, 20 investigating immune-relevant expression patterns and underlying cellular effects on mTOR and related signaling 21 pathways, since the relationship between the former and checkpoint blockade is not fully understood yet. We will 22 use immortalized TSC2-null 101, 102 and TSC2-expressing 103 cells before moving on to our expanded library 23 of primary human LAM-derived AML (LAMD) cells, originating from over 25 LAM patients. Investigating the effect 24 of Rapamycin and mTOR/Akt signalling will increase our understanding of the connection between those pathways 25 and PD-L1 upregulation, before moving on to Aim 2. The in vivo proof of concept will compare preventative and 26 therapeutic co-treatment with Anti-PD1 and Rapamying in an immunocompetent TSC2-null murine model 27 developed at the laboratory of Prof. Krymskaya at the University of Pennsylvania. We will evaluate prevention of 28 TSC2-null lesion growth, immunohistochemical and lung morphology changes and animal survival. This project 29 aims to develop a novel therapy for patients with the devastating diseases of LAM/TS. Based on Pembrolizumab’s 30 favorable safety profile in its approved indications, positive efficacy results in our studies would enable an 31 accelerated clinical development under FDA BPIC act for biologics and orphan disease designation for LAM/TS. 32

1 摘要 2 结节性硬化症 (TS)，也称为结节性硬化症，是一种罕见的多系统遗传性疾病，通常是终身性的。 3 导致大脑和其他重要器官（例如肾脏）良性肿瘤生长的威胁疾病， 4 心脏、眼睛、肺和皮肤淋巴管平滑肌瘤病 (LAM) 是一种与 TS 相关的肿瘤样疾病。 5 是 TSC1 或 TSC2 基因遗传性或散发性突变的结果，该基因的功能为 mTOR 通路的 6 个负调节因子不受控制的 mTORC1 活性导致肿瘤增殖。 7 肺部平滑肌细胞（LAM细胞）异常，进行性呼吸短促，反复发作 8 气胸以及肺组织结构和功能丧失此外，已发表的数据表明。 9 LAM细胞可能通过上调程序性死亡配体1的表面表达来逃避免疫监视 10 (PD-L1) 是一种影响育龄妇女的罕见疾病第一个也是唯一一个获得 FDA 批准的治疗方法。 LAM 的 11 是免疫抑制剂雷帕霉素，它是当前的治疗标准，通过抑制 mTORC1 发挥作用。 12 雷帕霉素有一些临床缺点，包括相当多的无反应者、严重的由于其免疫抑制特性和妊娠 C 类，导致 13 种不良事件，限制其在女性中的使用 14 因此，开发替代且更安全的治疗方案的医疗需求尚未得到满足。 15 LAM 和 TS。我们已确定抗 PD1 检查点阻断是一种潜在的 LAM/TS 新型疗法。 16 我们最近开发的免疫活性小鼠模型，Co-PI Krymskaya 教授能够证明： 17 使用抗 PD1 抗体治疗可显着提高小鼠存活率为了推进 LAM 的免疫治疗， 18 我们这笔资助的目标是研究雷帕霉素和抗 PD1 抗体之间的机制相互作用 19 为了利用体外和体内联合疗法的潜力，目标 1 将涵盖一系列体外研究， 20 研究免疫相关表达模式以及对 mTOR 和相关信号传导的潜在细胞影响 21 条路径，因为前者和检查站封锁之间的关系尚未完全了解。 22 在继续使用我们的扩展库之前，使用永生化的 TSC2 缺失 101、102 和表达 TSC2 的 103 细胞 23 个原代人 LAM 衍生的 AML (LAMD) 细胞，源自超过 25 名 LAM 患者，正在研究其效果。 24 雷帕霉素和 mTOR/Akt 信号传导将增加我们对这些途径之间联系的理解 25 和 PD-L1 上调，然后再进行目标 2。体内概念验证将比较预防性和 26 在免疫功能正常的 TSC2 缺失小鼠模型中使用抗 PD1 和 Rapamying 进行联合治疗 27 是由宾夕法尼亚大学 Krymskaya 教授实验室开发的，我们将评估预防措施。 28 TSC2 缺失病灶生长、免疫组织化学和肺形态学变化以及动物存活。 29 旨在为患有 LAM/TS 毁灭性疾病的患者开发一种基于 Pembrolizumab 的新疗法。 30 在其批准的适应症中具有良好的安全性，我们研究中的积极疗效结果将使 31 根据 FDA BPIC 法案加速了 LAM/TS 生物制品和孤儿疾病指定的临床开发。 32