Durable clinical and immunologic response to an off-the-shelf EWSR1-FLI1 peptide vaccine in metastatic Ewing sarcoma

Area of Science:

• Oncology
• Immunotherapy
• Genetics

Background:

• Ewing sarcoma is a rare, aggressive cancer with poor outcomes, especially when metastatic.
• Current treatments lack effective immunotherapy options for this fusion-driven malignancy.
• Fusion breakpoints are potential targets for precision immunotherapy, but their immunogenicity is not well-established.

Purpose of the Study:

• To evaluate the safety and immunogenicity of a novel multi-peptide vaccine targeting the EWSR1-FLI1 fusion breakpoint in a patient with metastatic Ewing sarcoma.
• To assess the clinical response and immune system changes following vaccination.

Main Methods:

• An off-the-shelf multi-peptide vaccine targeting the EWSR1-FLI1 fusion was administered to one patient with high-burden metastatic Ewing sarcoma.
• Vaccinations were given alongside granulocyte-macrophage colony-stimulating factor (GM-CSF) and topical imiquimod.
• Immune monitoring involved in vitro peptide stimulation and intracellular cytokine staining to detect T-cell responses.

Main Results:

• The patient developed de novo polyfunctional CD4+ T-cell responses against all four fusion-derived peptides.
• These immune responses were first detected at 7 months and persisted for over two years.
• The treatment was well-tolerated with only mild local reactions, and durable disease stability was maintained for over 26 months.

Conclusions:

• This first-in-human study demonstrates the feasibility, safety, and immunogenicity of a fusion-derived peptide vaccine in Ewing sarcoma.
• Precision immunotherapy targeting gene fusions shows promise for treating sarcomas.
• Further research is warranted to explore this therapeutic approach in fusion-driven sarcomas.