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Abstract
Background Inoperable bulky tumors remain challenging to treat with chemotherapy, radiotherapy (RT) or immune checkpoint inhibitors (ICIs). We developed a novel RT technique with eclipse-shaped dose distribution (EclipseRT, ERT) by embedding partial-tumor stereotactic body radiation therapy (SBRT, immunogenic) into a whole-tumor low-dose radiation (LDRT, immunomodulatory) field.
Methods ERT plus PD-1 inhibitors (immuno-ERT, iERT) was tested in mice with CT26 or LLC1 bulky tumors. The entire mouse tumor and its center were irradiated by LDRT (2 Gy × 3 fractions) and SBRT (10 Gy × 3 fractions), respectively. The safety and effectiveness of iERT were assessed in patients with bulky refractory tumors.
Results iERT was superior to partial SBRT/αPD-1 or LDRT/αPD-1 therapy in controlling bulky tumors in both mouse models. Impressively, iERT eradicated 3 of 11 established large CT26 tumors and its efficacy was CD8+ T cell dependent. iERT induced stronger infiltration of stem-like (TCF1+TIM3-) and more differentiated (TCF-TIM3+) CD8+ T cells into large tumors. Tumor centers irradiated by ERT or SBRT showed elevated phospho-eIF2α, an immunogenic cell death marker, accompanied by higher dendritic cell infiltration. In 39 patients with advanced bulky lung or liver tumors, iERT was feasible with acceptable toxicity. The objective response rate was 38.5%. Median progression-free survival and overall survival were 5.6 and 21.1 months, respectively (figure 1).
Conclusions iERT induced whole-tumor immunostimulatory effects and effectively controls bulky mouse tumors. It was also well-tolerated and effective in patients. This novel strategy may expand the indications for RT and change current practices in patients with advanced bulky tumors.
Ethics Approval Patients with advanced disease who underwent iERT at West China Hospital of Sichuan University between May, 2020 to April, 2023, were retrospectively reviewed. The patient study protocol was approved by the ethics committee of West China Hospital of Sichuan University (no. 2023–403). All patients provided written informed consent before the commencement of treatment.
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