Department of Radiation Oncology, University of California Davis, Comprehensive Cancer Center, Sacramento, California.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Clin Cancer Res. 2021 May 1;27(9):2470-2480. doi: 10.1158/1078-0432.CCR-20-4632. Epub 2021 Feb 10.
Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.
We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink.
Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8 and CD8/PD-1/Ki-67 T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood.
We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.
缺乏关于联合 PD-L1/CTLA-4 阻断给予不同辐射剂量的安全性、疗效和免疫影响的前瞻性人体数据。
我们进行了一项多中心 II 期研究，随机分配转移性微卫星稳定结直肠癌患者接受重复低剂量分割放疗（LDFRT）或低分割放疗（HFRT）联合 PD-L1/CTLA-4 抑制。主要终点是辐射野外的反应。使用多重免疫荧光（IF）、免疫组化（IHC）、RNA/T 细胞受体（TCR）测序、飞行时间（CyTOF）流式细胞术和 Olink 分析相关样本。
18 例患者可评估反应。中位既往治疗线数为 4 条（范围，1-7 条）。16 例患者出现与治疗相关的毒性（84%），8 例患者出现 3-4 级毒性（42%）。1 例患者出现野外肿瘤缩小的稳定疾病，最佳反应为稳定疾病。中位总生存期为 3.8 个月（90%置信区间，2.3-5.7 个月）。IF 和 RNA 测序（RNA-seq）的相关性分析显示，HFRT 后辐射野中 CD8 和 CD8/PD-1/Ki-67 T 细胞浸润增加。LDFRT 在两名患者中增加了微核/原发性核破裂的焦点。CyTOF 和 RNA-seq 显示多种循环免疫群体显著下降，尤其是接受 HFRT 的患者。TCR 测序显示肿瘤和外周血中 T 细胞 repertoire 存在与治疗相关的变化。
我们证明了在 PD-L1/CTLA-4 阻断的基础上加入 LDFRT 和 HFRT 的可行性和安全性。尽管稳定疾病的最佳反应不支持在该人群中同时使用 HFRT 或 LDFRT 联合 PD-L1/CTLA-4 抑制，但生物标志物支持 LDFRT 和 HFRT 均能影响局部免疫微环境和全身免疫原性，这有助于指导未来的研究。
