Abstract 197P
Background
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.
Methods
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).
Results
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.
Conclusions
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.
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China (NSFC).
Disclosure
All authors have declared no conflicts of interest.