FY22 Macrophage derived Engineered Vesicles for Preventing Metastases in Pediatric Osteosarcoma

Osteosarcoma is the most common bone cancer in children. The five year survival is currently 70%, and metastases is the most common complication in the 30% of patients that die of their disease. Preventing and treating metastases more effectively could significantly reduce the deaths caused by osteosarcoma. Emerging evidence suggests tumor-associated macrophages are critical to the development of metastases in osteosarcoma. Usually macrophages are the M1 type and help eliminate cancer cells and prevent metastasis, however, often these macrophages are re-polarized to M2, cancer promoting macrophages. Our hypothesis is that re-polarizing M2 macrophages back to cancer eliminating M1 macrophages would prevent metastases. To re-polarize the macrophages, we have already developed Macrophage derived EngineereD vesicles (MEDs) from cancer eliminating M1 mouse macrophages and show in our preliminary data these MEDs are able to convert M2 macrophages to M1 macrophages and that MEDs target specifically to cancers. Since little is understood about the mechanism underlying macrophage re-polarization by MEDs we will use both experimental and computational approaches to determine how MEDs interact with macrophages and use this information to program our next generation of MEDs to have enhanced macrophage re-polarizing properties. These MEDs will then be tested in our osteosarcoma mouse xenograft models which reliably develop pulmonary metastases to determine if MEDs can re-polarize tumor associated macrophages in vivo, and if macrophage re-polarization is an effective strategy for reducing metastases in osteosarcoma. We have also developed human MEDs and will perform proof of concept studies to assess whether human MEDs can specifically target cancers and re-polarize macrophages. This work will lay the foundation for a first in human clinical trial of MEDs for the treatment of osteosarcoma.