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

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

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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复合物，是一种罕见的，多系统的遗传，通常是生命的 3威胁性疾病，导致良性肿瘤在大脑和其他重要器官（例如Kidsneys）中生长 4心，眼睛，肺和皮肤。淋巴管肌瘤病（LAM）是一种与TS相关的肿瘤样疾病。两者都发生 5由于TSC1或TSC2基因中的遗传或零星突变，其功能充当 6 MTOR途径的负调节剂。不受控制的MTORC1活性导致肿瘤增殖 7个异常的平滑肌细胞（LAM细胞），肺部逐渐短，反复发作 8个气胸，以及肺组织结构和功能的丧失。此外，已发布的数据表明 9个LAM细胞可以通过上调编程死亡配体的表面表达1来逃避免疫监视1 10（PD-L1）。林是一种罕见的疾病，影响育龄年龄的妇女。第一次也是唯一的FDA批准治疗 11对于林是免疫抑制剂雷帕霉素。它是当前的护理标准，并通过抑制MTORC1来起作用。 12雷帕霉素有几次临床灾难，包括考虑的非反应数量，严重 13个不良事件由于其免疫抑制特性和C类C，限制了其在女性中的使用 14个生育年龄。这是有很高的未满足医疗需要开发替代和安全的治疗选择 15 lam和ts。我们已经确定了抗PD1检查点封锁是对LAM/TS的潜在新疗法。使用 16我们最近开发的免疫功能小鼠模型，Co-Pi教授Krymskaya能够证明这一点 17抗PD1抗体的治疗可显着改善小鼠的刺激。为了推进林的免疫疗法， 18我们的这笔赠款目标是雷帕敏和抗PD1抗体之间机械相互作用的投资 19为了利用体外和体内组合疗法的潜力。 AIM 1将涵盖一组体外研究， 20研究与免疫相关的表达模式以及对MTOR和相关信号的潜在细胞效应 21个途径，因为尚未完全理解前者和检查站封锁之间的关系。我们将 22使用永生的TSC2-NULL 101、102和表达TSC2的103个单元 23个原代人LAM衍生的AML（LAMD）细胞，起源于25多名LAM患者。研究效果雷帕霉素和MTOR/AKT信号的24号将增加我们对这些途径之间联系的理解 25和PD-L1上调，然后继续进行目标2。 26与抗PD1的治疗性共同治疗，并在免疫能力的TSC2无鼠模型中遭到apagamying 27在宾夕法尼亚大学的Krymskaya教授实验室开发。我们将评估预防 28 TSC2无效病变生长，免疫组织化学和肺形态变化和动物存活。这个项目 29旨在为LAM/TS毁灭性疾病的患者开发一种新的疗法。基于Pembrolizumab的 30个有利的安全性概况在其批准的指示中，我们的研究中的阳性效率会导致 31在FDA BPIC生物制剂和LAM/TS的孤儿疾病设计下加速了临床发展。 32