Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2021 Jun 1;27(11):3039-3049. doi: 10.1158/1078-0432.CCR-21-0163. Epub 2021 Apr 2.
Despite the prognostic importance of immune infiltrate in colorectal cancer, immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch-repair (pMMR) colorectal cancer. This study explores combining anti-CTLA-4 and an anti-PD-L1 therapy in the preoperative management of resectable colorectal cancer liver metastases with the intent to improve immune responses in this disease setting.
Patients with resectable colorectal cancer liver-only metastases received one dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety.
A total of 24 patients were enrolled between November 2016 and November 2019. Twenty-three patients received treatment [21 pMMR and 2 deficient mismatch-repair (dMMR)] and subsequently 17 (74%; 95% CI: 53%-88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95% CI: 10%-44%) and 2/17 (12%; 95% CI: 2%-38%) patients. The median relapse-free survival (RFS) was 9.7 (95% CI: 8.1-17.8) months, and overall survival was 24.5 (95% CI: 16.5-28.4) months. Four patients demonstrated complete pathologic response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T-cell infiltration, but did demonstrate evidence of CD8 and CD4 activation posttreatment. An increase in B-cell transcriptome signature and B-cell density was present in posttreatment samples from patients with prolonged RFS.
This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to colorectal cancer liver resection. Evidence for T- and B-cell activation following this therapy was seen in pMMR metastatic colorectal cancer.
尽管免疫浸润在结直肠癌中具有预后意义，但免疫疗法在难治性转移性错配修复充分（pMMR）结直肠癌中的临床活性有限。本研究探讨了在可切除结直肠癌肝转移患者的术前管理中联合使用抗 CTLA-4 和抗 PD-L1 治疗，以改善这种疾病环境中的免疫反应。
仅患有结直肠癌肝转移的患者术前接受一次 tremelimumab 和 durvalumab 治疗，然后术后单独使用 durvalumab。主要目的是确定可行性和安全性。
2016 年 11 月至 2019 年 11 月期间共纳入 24 例患者。23 例患者接受了治疗[21 例 pMMR 和 2 例缺陷错配修复（dMMR）]，随后 17 例（74%；95%CI：53%-88%）接受了手术切除。23 例患者中有 5 例（22%；95%CI：10%-44%）和 17 例患者中的 2 例（12%；95%CI：2%-38%）出现 3/4 级治疗相关免疫毒性和术后 3/4 级毒性。中位无复发生存期（RFS）为 9.7 个月（95%CI：8.1-17.8），总生存期为 24.5 个月（95%CI：16.5-28.4）。4 例患者表现出完全病理缓解，2 例 dMMR 患者和 2 例 POLE 突变患者。通过流式细胞术、免疫荧光和 RNA 测序对术前和术后肿瘤组织进行分析，发现 T 细胞浸润水平相似，但治疗后确实显示出 CD8 和 CD4 激活的证据。在 RFS 延长的患者的治疗后样本中，B 细胞转录组特征和 B 细胞密度增加。
本研究表明在结直肠癌肝切除术前使用 tremelimumab 和 durvalumab 的新辅助联合治疗是安全的。在 pMMR 转移性结直肠癌中，这种治疗后观察到 T 细胞和 B 细胞激活的证据。
