Liu Jing, O'Donnell Jake S, Yan Juming, Madore Jason, Allen Stacey, Smyth Mark J, Teng Michele W L
Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
Oncoimmunology. 2019 Mar 1;8(5):e1581530. doi: 10.1080/2162402X.2019.1581530. eCollection 2019.
Adjuvant immunotherapies targeting CTLA4 or PD-1 recently demonstrated efficacy in the treatment of earlier stages of human cancer. We previously demonstrated using mouse spontaneous metastasis models that neoadjuvant immunotherapy and surgery was superior, compared to surgery and adjuvant immunotherapy, in eradicating the lethal metastatic disease. However, the optimal scheduling between neoadjuvant immunotherapy and surgery and how it impacts on efficacy and development of immune-related adverse events (irAEs) remains undefined. Using orthotopic 4T1.2 and E0771 mouse models of spontaneously metastatic mammary cancer, we varied the schedule and duration of neoadjuvant immunotherapies and surgery and examined how it impacted on long-term survival. In two tumor models, we demonstrated that a short duration (4-5 days) between first administration of neoadjuvant immunotherapy and resection of the primary tumor was necessary for optimal efficacy, while extending this duration (10 days) abrogated immunotherapy efficacy. However, efficacy was also lost if neoadjuvant immunotherapy was given too close to surgery (2 days). Interestingly, an additional 4 adjuvant doses of treatment following a standard 2 doses of neoadjuvant immunotherapy, did not significantly improve overall tumor-free survival regardless of the combination treatment (anti-PD-1+anti-CD137 or anti-CTLA4+anti-PD-1). Furthermore, biochemical immune-related adverse events (irAEs) increased in tumor-bearing mice that received the additional adjuvant immunotherapy. Overall, our data suggest that shorter doses of neoadjuvant immunotherapy scheduled close to the time of surgery may optimize effective anti-tumor immunity and reduce severe irAEs.
靶向CTLA4或PD-1的辅助免疫疗法最近在人类癌症早期治疗中显示出疗效。我们之前使用小鼠自发转移模型证明，与手术和辅助免疫疗法相比，新辅助免疫疗法和手术在根除致死性转移性疾病方面更具优势。然而，新辅助免疫疗法与手术之间的最佳时间安排及其对疗效和免疫相关不良事件（irAEs）发生发展的影响仍不明确。利用原位4T1.2和E0771自发转移性乳腺癌小鼠模型，我们改变了新辅助免疫疗法和手术的时间安排及持续时间，并研究其对长期生存的影响。在两种肿瘤模型中，我们证明新辅助免疫疗法首次给药与原发性肿瘤切除之间的短时间间隔（4 - 5天）对于达到最佳疗效是必要的，而延长这个间隔时间（10天）会消除免疫疗法的疗效。然而，如果新辅助免疫疗法给药时间离手术太近（2天），疗效也会丧失。有趣的是，在标准的2剂新辅助免疫疗法之后额外给予4剂辅助治疗，无论联合治疗方案（抗PD-1 + 抗CD137或抗CTLA4 + 抗PD-1）如何，都不会显著提高总体无瘤生存率。此外，接受额外辅助免疫疗法的荷瘤小鼠中生化免疫相关不良事件（irAEs）增加。总体而言，我们的数据表明，在接近手术时间安排较短剂量的新辅助免疫疗法可能会优化有效的抗肿瘤免疫并减少严重的irAEs。
