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

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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