197P Combining stereotactic body radiation and low-dose radiation (EclipseRT) with PD-1 inhibitor in mice models and patients with bulky tumor

Bulky tumors remain challenging to treat. Stereotactic body radiation therapy (SBRT) can induce immunogenic cell death (ICD), thus causing T-cell-mediated antitumor effects. Low-dose radiation (LDRT) can inflame the tumor microenvironment (TME) by recruiting T cells. We designed a new radiotherapeutic method (Eclipse RT, E-RT) that combines partial SBRT and LDRT to the same large tumor with αPD-1 and examined it in mice with bulky colon CT26 or Lewis lung carcinoma. The safety and efficacy of ERT/αPD-1 in patients with bulky tumors were also retrospectively analyzed. In mice with bulky tumors (about 400 cm3), the whole tumor was irradiated by LDRT (2 Gy × 3 fractions) and/or the tumor center was irradiated by SBRT (10 Gy × 3); αPD1 was given weekly. The dependence of therapeutic effects on CD8+ T cells was determined using depleting antibodies. Frequencies of CD8+ T cells and M1 macrophages (Mϕ) were determined by FACS. Multiplex IHC was applied to analyze CD8+ T cells and p-eIF2α (ICD marker) in TME. Kaplan-Meier method was applied to estimate the patients’ progression-free survival (PFS) and overall survival (OS). ERT/αPD-1 is superior to SBRT/αPD-1 or LDRT/αPD-1 in controlling bulky tumors in both mouse models and it depended on CD8+ T cells. In the CT26 model, ERT/αPD-1 cured 3 of 11 mice and induced more CD8+ T cells and M1 Mϕ compared to other groups. Multiplex IHC analysis showed that ERT/αPD-1 induced higher infiltration of CD8+ T cells into the tumor center and periphery compared to other groups, and ERT/αPD-1 induced stronger ICD in the tumor center compared to LDRT/αPD-1. In 39 patients with bulky tumors treated with ERT/αPD-1, 30 patients were diagnosed with stage IV NSCLC and failed lines of therapy. Radiation-induced pneumonitis occurred in 1 of 26 patients receiving thoracic ERT. The overall response rate and the median estimated PFS are 46.9% and 5.6 months, respectively. The minimum estimated OS is 16.8 months and the median estimated OS does not reach yet. ERT/αPD-1 showed superior efficacy in controlling bulky tumor in two mouse models. ERT/αPD-1 was safe and effective in patients with bulky tumors and it might become a new strategy to treat these patients.