Exploring adjuvant immunotherapy to treat lymphangioleiomyomatosis
Awardee: Katharina Maisel
Institution: University of Maryland, College Park
Grant Amount: $75,110.00
Funding Period: February 1, 2023 - January 31, 2024
Summary:
Lymphangioleiomyomatosis (LAM) is a rare lung diseases that causes cystic destruction of the lungs caused by the abnormal growth of smooth-muscle-like LAM cells that have cancer-like features. To date, rapamycin is the only FDA approved treatment for LAM and this treatment is not a cure. Additionally, about 30% of patients do not respond to the treatment. Therefore, new therapeutic avenues are desperately needed. We and other have recently shown that LAM may cause suppression of the local immune response, similar to cancer, and that re-activating this immune response through checkpoint inhibitor or CAR T cell therapies can enhance survival in a murine model of LAM. Immune adjuvants are another immunotherapy currently under investigation for cancer treatments. We have found that one particular adjuvant, CpG, which activates toll-like receptor 9 (TLR9) on antigen presenting cells can enhance survival in murine LAM. However, this survival is incomplete and thus further investigation is necessary. We have found that repeated dosing of CpG causes an overall reduction of immune cell recruitment to the lungs but does not reduce immunosuppressive regulatory T cells. Repeated TLR stimulation on immune cells can lead to ‘TLR tolerance’, in which the cells become less responsive to the stimulus over time. We hypothesize that TLR tolerance is one of the reasons for incomplete survival after CpG treatment in LAM. Research has also shown that spacing out TLR stimulating treatments or alternating the specific TLR that is stimulated may reduce TLR tolerance. Thus, we will investigate the mechanisms of TLR tolerance in LAM and explore alternative treatments to further increase survival. Overall, this proposal will shed new light onto mechanisms of immunosuppression in LAM and also define new treatment avenues for LAM. Furthermore, this work is the first to use adjuvant immunotherapies as treatments for neoplastic growths with loss of TSC expression and could thus open up the use of these treatments for diseases beyond LAM. Finally, understanding the interplay of immune cells, LAM cells, adjuvant immunotherapies, and loss of TSC expression could lead to new treatment targets/strategies for LAM and other diseases for which adjuvant immunotherapies is used.