West China Hospital of Sichuan University Chengdu, Sichuan
R. Luo1,2, M. Yu1, Y. Wu1,3, Z. Su1, K. Kang1,3, Z. Yao1,3, W. Xiu1, X. Zhang1, Y. Xu1, Y. Liu1, B. Zou1,2, Y. Gong1,2, M. Huang1, J. Xue1, and Y. Lu1,2; 1Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China, 2Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China, 3Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Purpose/Objective(s): Bulky tumors remain challenging to be treated. Stereotactic body radiation therapy (SBRT) is effective against radioresistant tumor cells and triggers immunogenic cell death (ICD), leading to T-cell-mediated antitumor effects. Low-dose radiation (LDRT) can inflame the tumor microenvironment (TME) by recruiting T cells. We developed a novel radiotherapy technique (EclipseRT, ERT) whose dose distribution map resembles the “eclipse” by concurrently delivering LDRT to the whole tumor, meanwhile SBRT to only a part of the same tumor. This study evaluated the safety and efficacy of ERT to bulky lesions with PD-1 inhibitors (iERT)in mice and patients. Materials/
Methods: In mice with CT26 colon or LLC1 lung bulky tumors (400–700 mm3), the whole tumor was irradiated by LDRT (2 Gy x 3), while SBRT (10 Gy x 3) targeted the tumor center; aPD-1 was given weekly. The dependence of therapeutic effects on CD8+ T cells and NK cells was determined using depleting antibodies. Changes in immune cell frequencies were determined by flow cytometry. Multiplex Immunohistochemistry (mIHC) was applied to analyze the number and the location of CD8+ T cells and their subpopulations, as well as the phospho-eIF2a level (the ICD marker) of tumor cells in TME. Single-cell sequencing (scRNA-seq) was applied to analyze the TME upon iERT. Patients with advanced lung or liver bulky tumors who failed standard treatment or with oncologic emergencies were treated. Results: iERT demonstrated superior efficacy over SBRT/aPD-1 or LDRT/aPD-1 in controlling bulky tumors in both mouse models in a CD8+ T-cell dependent manner. In the CT26 model, iERT resulted in complete tumor regression in 3/11 mice and induced more tumor-specific CD8+ T cells in TME compared to other groups. mIHC analysis revealed enhanced CD8+ T cell infiltration, including stem-like (TCF1+ TIM3- PD-1+), and more differentiated (TCF1- TIM3+ PD-1+) subpopulations. Phospho-eIF2a levels were elevated in tumor centers irradiated with ERT or SBRT compared to untreated or LDRT-treated centers, accompanied by increased dendritic cell infiltration. scRNA-seq data showed increased cytotoxic (granzymes) and cytokine (CCL5) secreting NK cells post-iERT. Depleting NK cells or blocking CCL5 using specific antibodies diminished iERT efficacy. In total, 39 advanced cancer patients were treated with iERT. Radiation-induced pneumonitis occurred in 1 of 26 patients receiving thoracic ERT. No toxicity above grade III was observed. The objective response rate was 38.5%. The median progression-free and overall survival was 5.6 and 23.0 months, respectively. Conclusion: iERT displayed superior efficacy in controlling bulky tumors in two mouse models, relying on CD8+ T cells and NK cells for its effectiveness. Further investigation is needed to understand how iERT-induced ICD activates both innate NK cell and adaptive CD8+ T cell immunity. The new therapeutic strategy was safe and effective in patients with bulky tumors. Further clinical trials are warranted.
