Tumour Immunology Group, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
J Immunother. 2013 Sep;36(7):365-72. doi: 10.1097/CJI.0b013e31829fb856.
Postresection recurrences of cancer arising from occult tumor deposits, either local or metastatic, represent major causes of death in patients with operable solid tumors. Thus, new therapies are required that complement existing treatments to eradicate these occult deposits. Agonistic anti-CD40 antibody is one of the most powerful new cancer immunotherapies, enhancing immune priming of effector CD8 T cells by dendritic cells, leading to increased antitumor activity. We investigated the use of anti-CD40 antibody for the treatment of postoperative recurrence and metastasis, with regional lymphadenectomy, in a murine model of cancer. Subcutaneous AB1-HA mesothelioma tumors were induced in BALB/c mice. Established tumors were surgically excised on day 16, with or without sentinel lymph node removal. On the day of surgery, animals were rechallenged with AB1-HA tumor cells at the surgical site (local recurrence) or the opposite flank (metastasis). Postoperative tumors were treated with anti-CD40 (FGK45) on emergence, delivered either intratumorally, peritumorally, or systemically. Local or systemic anti-CD40 treatment slowed postsurgical metastatic growth relative to untreated controls (P = 0.020) and improved survival from metastasis. Anti-CD40 also retarded the growth of local recurrences (P = 0.004) and improved survival from recurrence. Sentinel lymph node dissection did not impair efficacy (P > 0.05). This study demonstrates that anti-CD40 therapy, given either locally or systemically, may be a powerful and readily translatable adjuvant to cancer surgery, including in cases where regional lymphadenectomy is indicated.
术后复发的癌症起源于隐匿性肿瘤沉积，无论是局部的还是转移性的，是可手术实体瘤患者死亡的主要原因。因此，需要新的治疗方法来补充现有的治疗方法，以根除这些隐匿性沉积物。激动性抗 CD40 抗体是最强大的新型癌症免疫疗法之一，通过树突状细胞增强效应 CD8 T 细胞的免疫启动，从而增加抗肿瘤活性。我们研究了在癌症的小鼠模型中，使用抗 CD40 抗体与区域淋巴结切除术联合治疗术后复发和转移。在 BALB/c 小鼠中诱导皮下 AB1-HA 间皮瘤肿瘤。在第 16 天，手术切除已建立的肿瘤，无论是否切除前哨淋巴结。在手术当天，动物在手术部位（局部复发）或对侧侧翼（转移）用 AB1-HA 肿瘤细胞重新挑战。手术后，在肿瘤出现时用抗 CD40（FGK45）治疗，通过肿瘤内、肿瘤周围或全身给药。局部或全身抗 CD40 治疗相对于未治疗的对照组（P = 0.020）可减缓术后转移的生长并提高转移的生存率。抗 CD40 还可延缓局部复发的生长（P = 0.004）并提高复发的生存率。前哨淋巴结清扫术不会影响疗效（P > 0.05）。这项研究表明，抗 CD40 治疗，无论是局部还是全身给药，都可能是癌症手术的一种强大且易于转化的辅助治疗方法，包括在需要区域淋巴结切除术的情况下。
