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A7104 - PD-L1 as a Notential Therapeutic Target for Patients with Advanced or Refractory-to-Rapamycin Pulmonary Lymphangioleiomyomatosis (LAM)
Author Block: V. P. Krymskaya; Pulmonary, Allergy and Critical Care Division,, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.
PD-L1 as a potential therapeutic target for patients with advanced or refractory-to-rapamycin pulmonary lymphangioleiomyomatosis (LAM)
Lurong Lian1, Katharina Maisel2, Ryan Rue1, Mervyn J. Merrilees3, Kseniya Obraztsova1, Elena N. Atochina-Vasserman1, Ning Zuo3, Luis F. Angel4, Inkyung Kang6, Thomas N. Wight6, Melody A. Swartz2, Evgeniy Eruslanov7, and Vera P. Krymskaya1
LAM is a devastating rare genetic lung disease of women of childbearing age caused by TSC1/2 mutations, characterized by proliferation of neoplastic LAM cells, progressive shortness of breath, recurrent pneumothoraces, chylous effusions, and irreversible respiratory failure. The only currently approved FDA treatment of LAM, Sirolimus, does not cure the disease and only stabilizes lung functions. Thus, there remains an urgent unmet need to identify novel molecular targets for the treatment of LAM, especially patients who are refractory to treatment with rapamycin. To date, there have been no reports that have extensively evaluated the composition of immune cells and their heterogeneity in human LAM lungs at the cellular level. Thus, to develop an extensive phenotypical description of immune cell profile in human LAM, we analyzed lung LAM tissue and peripheral blood compared to control lung rejected for transplantation. We found that LAM lung does not dramatically accumulate inflammatory cells such as T cells and myeloid cells. However, the frequency of B cells in LAM lung is significantly higher compared to controls. While myeloid cell numbers are not increased in LAM lungs, LAM lung infiltrating CD14+ cells are activated and express T cell co-inhibitory and co-stimulatory receptors, suggesting that these cells possess the potential to modulate T cell responses to LAM. We have identified that LAM lungs express the T cell co-inhibitory molecule PD-L1, specifically in LAM lesions, both in human LAM lungs and in our murine model of LAM. To test if the PD-L1/PD-1 axis may be a potentially novel treatment, we performed an in vivo survival study using mice treated with either anti-PD-1 antibody or IgG isotype control. Treatment was begun 10 days after injection of TSC2-null LAM cells. At the time when 50% of the control IgG-treated mice had died, 100% the anti-PD1-treated mice were still alive, showing an overall significantly increased survival rate in mice treated with anti-PD-1 therapy. These data demonstrate that anti-PD1 antibody significantly prolongs the survival of the mouse LAM model, and suggests a novel immunotherapeutic approach for treatment of LAM.
Funded by: NHLBI RO1HL114085, RO1HL131626, The LAM Foundation.