Cancer immunotherapy has emerged as the most potent and durable treatment for cancers in recent years. In some solid tumors and hematological malignancies, immunotherapy has become the standard of care, joining the ranks of conventional treatment such as surgery, chemotherapy, radiation and targeted therapy. Chimeric antigen receptor ? T (CAR-T) therapy has made impressive progress in treatment of pediatric leukemia. It is highly anticipated that checkpoint inhibitor antibody immunotherapy, such anti-PD-1, anti-PD-L1, and anti-CTLA4, will be tested in pediatric cancers in clinical trials (some Phase 1 trials are ongoing) . However, the autoimmune adverse events (irAE) associated with the immunotherapy is quite severe, with greater than 50% of patients developing grade 3 and 4 organ toxicity in adult clinical trials. The report on a Phase 1 trial of anti-CTLA4 antibody (Ipilimumab) on pediatric cancer patients suggested similar rate of irAE as observed in adult, although the observation period is too short to identify issues unique for developmental defects unique for pediatric patients. Therefore, the major challenges in research effort for pediatric cancer immunotherapy are (1) establishing mouse models to recapitulate irAE, especially the long term irAE unique for pediatric patients; (2) using mouse models to study the irAE pathogenesis (3) searching new targets to reduce irAE without impeding anti-tumor efficacy. Damage related molecular patterns (DAMPs) play an important role in regulating tissue damages, antigen presenting cells activation and effector T cell functions. Our previous work demonstrated that CD24- Siglec signaling pathway suppresses inflammation triggered by DAMPs. We have established a mouse model that faithfully recapitulates the irAEs in major organs that have been reported in anti-CTLA 4 and anti- PD-1 immunotherapy clinical trials. Here we propose to characterize the long term irAE in mouse model, and to examine the role of DAMPs-binding protein CD24 and Siglecs in irAE pathogenesis.

Public Health Relevance

Cancer immunotherapy has emerged as the most potent and durable treatment. CAR-T cellular therapy and checkpoint inhibitors immunotherapy are being tested in clinical trials for pediatric cancers. However, the immunotherapy related adverse events (irAE) are serious that warrants further investigation. We will (1) establish mouse models to recapitulate irAE, especially the long term irAE; (2) use mouse models to study the irAE pathogenesis (3) search new targets to reduce irAE without impeding anti-tumor efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA227671-03
Application #
9999525
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sommers, Connie L
Project Start
2018-09-07
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201