Combinatorial PD-1 Blockade and CD137 Activation Has Therapeutic Efficacy in Murine Cancer Models and Synergizes with Cisplatin

There is an urgent need for improved therapy for advanced ovarian carcinoma, which may be met by administering immune-modulatory monoclonal antibodies (mAbs) to generate a tumor-destructive immune response. Using the ID8 mouse ovarian cancer model, we investigated the therapeutic efficacy of various mAb combinations in mice with intraperitoneal (i.p.) tumor established by transplanting 3 × 106 ID8 cells 10 days previously. While most of the tested mAbs were ineffective when given individually or together, the data confirm our previous finding that 2 i.p. injections of a combination of anti-CD137 with anti-PD-1 mAbs doubles overall survival. Mice treated with this mAb combination have a significantly increased frequency and total number of CD8+ T cells both in the peritoneal lavage and spleens, and these cells are functional as demonstrated by antigen-specific cytolytic activity and IFN-γ production. While administration of anti-CD137 mAb as a single agent similarly increases CD8+ T cells, these have no functional activity, which may be attributed to up-regulation of co-inhibitory PD-1 and TIM-3 molecules induced by CD137. Addition of the anti-cancer drug cisplatin to the 2 mAb combination increased overall survival >90 days (and was probably curative) by a mechanism which included a systemic CD8+ T cell response with tumor specificity and immunological memory. Strikingly, combined treatment of cisplatin and CD137/PD-1 mAb also gave rise to the long-term survival of mice with established TC1 lung tumors. A similar combination of the 2 mAbs and cisplatin should be considered for clinical ‘translation’.

晚期卵巢癌亟需更优化的治疗方案，而通过给予免疫调节型单克隆抗体（monoclonal antibodies, mAbs）以诱导肿瘤破坏性免疫应答，或可满足这一需求。本研究采用ID8小鼠卵巢癌模型，对10日前经腹腔接种3×10⁶个ID8细胞、已建立腹腔内（intraperitoneal, i.p.）肿瘤的小鼠，测试了多种单克隆抗体联合方案的治疗效果。尽管多数受试单克隆抗体无论单独给药还是联合给药均未显现疗效，但本研究数据证实了我们此前的发现：两次腹腔注射抗CD137与抗PD-1单克隆抗体的联合方案，可使小鼠总生存期翻倍。接受该联合抗体方案治疗的小鼠，其腹腔灌洗液与脾脏中的CD8+ T细胞频率及总细胞数均显著升高，且这些细胞具备功能——这一点可通过抗原特异性细胞溶解活性与干扰素-γ（IFN-γ）的产生得以证实。尽管单独给予抗CD137单克隆抗体同样可升高CD8+ T细胞数量，但此类细胞并无功能活性，这一现象或可归因于CD137诱导的共抑制性PD-1与TIM-3分子的上调表达。在上述两种单克隆抗体的联合方案中加入抗癌药物顺铂（cisplatin）后，小鼠总生存期延长至90天以上（且大概率实现治愈），其作用机制包括介导具备肿瘤特异性与免疫记忆能力的系统性CD8+ T细胞应答。值得注意的是，顺铂与CD137/PD-1单克隆抗体的联合治疗，还可使已建立TC1肺肿瘤的小鼠实现长期存活。此类由两种单克隆抗体与顺铂组成的联合方案，有望推进至临床转化阶段。