FY25 Macrophage Derived Engineered Vesicles for Prevention C4938

Osteosarcoma is the most common bone cancer in children. The five-year survival for patients with localized disease is currently 66%, while survival for patients with metastatic disease at diagnosis remains unacceptably low at 20%. Since the addition of chemotherapy to wide surgical excision of osteosarcoma tumors in the 1980’s, little progress has occurred in improving outcomes for osteosarcoma patients. Multiple attempts at intensifying conventional cytotoxic agents only increased toxicity without improving outcomes and responses to targeted agents and checkpoint inhibitors have been disappointing. There are few if any promising new agents in the pipeline for osteosarcoma, leading to a desperate need for innovative approaches to this frustratingly difficult to treat tumor. 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 the M2-type, 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, with support of the Pediatric Cancer Research Trust, we have already; 1) developed Macrophage derived Engineered Vesicles (MEVs) engineered from cancer eliminating M1 mouse macrophages; 2) show in our preliminary data these MEVs are able to convert M2 macrophages to M1 macrophages and that MEVs target specifically to cancers; 3) MEVs have anticancer activity in cell lines and in mouse models; 4) identified candidate surface proteins critical for macrophage re-polarization; 5) established a mouse osteosarcoma xenograft model which reliably develops pulmonary metastases; 6) developed MEVs made from human M1 macrophages and demonstrated their ability to target cancers and re-polarize macrophages. In this application, we propose to further develop MEVs as a clinically useful anticancer agent. This work will lay the foundation for a first in human clinical trial of MEVs for the treatment of osteosarcoma.