Therapeutic Targeting of Immune Dysfunction in Langerhans Cell Histiocytosis
Abstract
Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder with similar incidence and overall survival as pediatric Hodgkins Lymphoma. The current therapeutic standard of care fails in over 50% of patients, and treatment failure is associated with significant long-term morbidity and mortality. Translational research resources and efforts to study LCH have been relatively sparse due to challenging samples and the lack of reliable pre-clinical models. To address this issue the Histiocytosis Program at Texas Childrens Cancer Center has developed an unprecedented research resource of ~1000 viably preserved LCH lesions and paired peripheral blood mononuclear cells, along with associated clinical data. In addition, we generated the first mouse models of LCH-like disease, allowing us to characterize the molecular mechanisms that drive LCH. LCH lesions histology reveals a universal feature of accumulation of Langerin positive dendritic cells along with a large inflammatory infiltrate. To improve outcomes for patients, we not only need to define the mechanisms driving LCH, but also to translate these discoveries into improved therapeutic strategies. The objective of this project is to develop pre-clinical models to determine the most effective therapeutic strategies for patients with LCH. We hypothesize that combination therapeutic strategies targeting MAPK activation and dysfunctional Tcells can overcome the immune suppressive microenvironment in LCH, leading to better clinical outcomes than chemotherapy or MAPK inhibition alone. Aim1: To define the impact of specific MAPK pathway mutations on initial treatment failure and immune evasion in patients with LCH; Aim 2: To test novel therapeutic salvage strategies in mutation-specific in vitro and in vivo models of LCH. In the first year, we have obtained the HRPO and ACURO approval to complete the proposed studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1117650
Entities
People
- Rikhia C. Chakraborty
Organizations
- Baylor College of Medicine