Striking effect of low-dose radiotherapy combined with PD-1 blockade on small cell lung cancer in mice and refractory patients (Achilles Study).
Authors: Wang Hui , Yu Min , Na Feifei , Yin Limei , Zhou Lin , Yao Zhuoran , Pan Xiangyu , Zhang Xuanwei , Chen Lin , Li Yanying , Zou Bingwen , Gong Youling , Zhu Jiang , Liu Yongmei , Yi Linglu , Tong Ruizhan , Xue Jianxin , Huang Meijuan , Chen Chong , Lu You 
Published: June 2022

e20608

Background: Immune checkpoint inhibitors (ICIs) provide a durable and long-term benefit but still unsatisfactory clinical efficacy for extensive-stage small cell lung cancer (ES-SCLC). An optimized dose and schedule of radiotherapy for ES-SCLC remain to be studied. We hypothesized that the addition of low-dose radiotherapy (LDRT) to ICI could improve the efficacy of ES-SCLC. Methods: In SCLC bearing mice, the tumor was irradiated with LDRT in dose-escalation starting at 3Gy×1 fractions (f) up to 3Gy×7f, and combined with PD-1 antibody injection (0.2mg/mouse, i.p, every 3 days). Mice were followed for tumor growth and survival. The tumor microenvironment was dynamically analyzed every 3 days till day 18 by flow cytometry and immunofluorescence. 15 patients (pts) with relapsed ES-SCLC who received the treatment with LDRT and PD-1 blockade were retrospectively reviewed. Results: LDRT with 3Gy×5f delivered over 5 days (LDRT15Gy/5f) was determined to be the optimized dose when combined with PD-1 blockade. Combined group exhibited obvious growth retardation and prolonged survival compared to either monotherapy.The most robust infiltration of T cells in combined group was observed on day 9 after start of treatment. Bulk and single-cell RNA-seq showed significant immune cells infiltration, predominately CD8+ T cells and M1 macrophage. The activation and degranulation of CD8+ T cells in combination group were enhanced. Intra-tumoral CD8+ T cells were mainly assigned to effector memory (Tem) cells, then exhausted precursor (Texp) cells and exhausted (Tex) cells. Pseudo-time analysis supported a state evolution model that CD8+ Tem cells differentiate into intra-tumoral CD8+ Tex cells through an intermediate CD8+ Texp state. Tumor cells were divided into clusters 0, 1, and 2. Cluster 0 nearly disappeared while the proportion of cluster 1 increased in combination therapy. Cluster 1 enriched inflammatory response pathways and higher expression of MHC class I versus clusters 0 and 2. Additionally, the density of intra-tumoral microvessel was decreased, while vascular perfusion and the number of pericyte-covered vessels increased in combined group. Correspondingly, 15 recurrent ES-SCLC pts who treated with up-front LDRT15Gy/5f plus PD-1 blockade showed an ORR of 80%. Median PFS and OS were 4.3 months and 10.9 months. PFS rates at 6, 12 and 24 months were 40%, 20% and 6.7%, and OS rates were 60%, 40% and 24%, respectively. No patient experienced above grade 4 radiation- and immunotherapy-related toxicity. Conclusions: Our study is the first report of the synergistic effect of LDRT15Gy/5f and PD-1 blockade in SCLC mice model and recurrent ES-SCLC pts. The LDRT15Gy/5f demonstrates both immunologic adjuvant and cytotoxic effect on SCLC, and is safe and feasible in clinical pts. Further translational research, Match trial (NCT04622228), is ongoing.