Stereotactic Body Radiation Therapy Augmented Checkpoint Inhibitor Immunotherapy Response in Heavily Pretreated Metastatic Osteosarcoma.
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PURPOSE: Immunotherapy for relapsed/refractory (R/R) osteosarcoma has shown limited success because of its immunosuppressive microenvironment. Recent evidence suggests stereotactic body radiation therapy (SBRT) as not only a local therapy but also a modality with an immunomodulatory role. However, combining SBRT with immune checkpoint inhibitors (ICIs) is yet to be explored in osteosarcoma. METHODS AND MATERIALS: We retrospectively reviewed patients with R/R osteosarcoma (n = 62) receiving ICIs with concurrent SBRT radiation therapy (ICI+SBRT, n = 18), conventional radiation therapy (CRT) (ICI+CRT, n = 23), or without radiation therapy (ICI-only, n = 21) as a late-line therapy in our institution from January 2020 to March 2024. The therapeutic efficacy, toxicity, and potential abscopal effect were explored by measuring the radiological response of radiated and nonradiated lesions. Peripheral blood flow cytometry and immune intratumoral lymphocyte infiltration were investigated for the correlative biomarker of therapeutic efficacy. RESULTS: Although the local control did not differ significantly between 2 radiation therapy modalities, patients receiving ICI+SBRT demonstrated significantly better systemic tumor response compared with ICI-only or ICI+CRT, with a median progression-free survival of 5.68 months and a median overall survival (OS) of 12.0 months. Interestingly, nonradiated lesions showed a significantly better response in the ICI+SBRT group than that of the CRT, suggesting a potential abscopal effect. In 8 patients receiving second or more course of SBRT because of disease oligoprogression, we observed a continued clinical benefit of ICIs beyond tumor progression. Common grade 3-4 toxicity of ICI+SBRT included pneumonitis (n = 4, 22.2%), bronchopleural fistula (n = 1, 5.6%), and lymphopenia (n = 1, 5.6%). Flow cytometry analysis suggested that higher baseline CD3 lymphocytes and lower neutrophil-to-lymphocyte ratio were associated with better abscopal effect in patients with ICI+SBRT. Furthermore, higher intratumoral immune infiltration of CD8 lymphocyte and PD-L1 expression were seen in post-SBRT tumor specimens than the pre-SBRT counterpart. CONCLUSIONS: SBRT emerges as an attractive combination strategy to augment the efficacy of ICI-based immunotherapy in R/R osteosarcoma.