Combined CD40 activation and CTLA4 blockade in melanoma

描述(申请人提供)：T淋巴细胞是肿瘤免疫监测的主要媒介，特别是对于黑色素瘤患者，T细胞向肿瘤中的渗透预测临床结果，免疫治疗策略在某些情况下已显示出临床实用。在这里，我们建议评估同时靶向CD40和CTLA-4对黑色素瘤患者的临床和免疫学影响。这两种分子都是癌症免疫反应的关键调节器，可以用于治疗。CD40是一种细胞表面受体，介导抗原提呈细胞的激活，在建立肿瘤免疫中发挥重要作用。CTLA-4是T细胞活化的负性调节因子，用CTLA-4单抗阻断CD80/86-CTLA-4通路可增强抗肿瘤T细胞应答，导致肿瘤排斥反应。在小鼠中，激动剂CD40单抗和阻断CTLA-4单抗联合治疗可增强肿瘤特异性T细胞的诱导和肿瘤排斥反应，且无毒性。这一建议的中心假设是，通过联合CD40激活和CTLA-4阻断治疗黑色素瘤患者，可以实现更高效力的T细胞激活和改善临床活动。为了验证这一假设，我们建议将激动剂CD40单抗CP-870,893与阻断CTLA-4单抗雷利单抗联合应用于转移性黑色素瘤患者。尽管每一种完全人源性的单抗都已经单独进行了测试，并在黑色素瘤患者身上显示出了希望，但这种组合还没有。我们的方法代表了一种新颖的战略，即“踩油门”，同时“踩刹车”。此外，该方法源于肿瘤学的基本原则，即优先结合两种或多种具有不同作用机制、不重叠的临床毒性和明确的单一药物应答率的药物。临床前毒理学研究表明，CP-870,893/temlimumab联合治疗在非人类灵长类动物中具有可接受的安全性。我们的研究人员赞助的CP-870,893和temlimumab的第一阶段研究已经获得完全的监管批准，并开放注册(NCT01103635)。三名患者已经开始治疗，没有出现重大毒性反应，这表明可行。如果获得资金，我们将(1)确定转移性黑色素瘤患者每3周服用一次CP-870,893与每12周给予一次temlimumab的最大耐受量，(2)通过一系列最先进的免疫评估分析，通过评估与治疗相关的抗原提呈细胞的激活和功能、T细胞亚群的调节以及肿瘤抗原特异性T细胞的诱导，确定CP-870,893/temlimumab在患者中的免疫机制。 公共卫生相关性：我们的目标是在转移性黑色素瘤患者的I期研究中，确定激动剂CD40抗体CP-970,893与阻断CTLA-4抗体temlimumab联合使用的临床和免疫学影响。长期目标是开发一种基于增强抗肿瘤免疫反应的转移性黑色素瘤患者的新疗法。

DESCRIPTION (provided by applicant): T lymphocytes are prime mediators of tumor immune surveillance, particularly for patients with melanoma in whom T cell infiltration into tumors predicts clinical outcome and for whom immunotherapeutic strategies have in some cases shown clinical utility. Here, we propose to evaluate the clinical and immunological impact of simultaneously targeting CD40 and CTLA-4 in patients with melanoma. Both molecules are critical regulators of the cancer immune response that can be exploited therapeutically. CD40 is a cell-surface receptor that mediates activation of antigen presenting cells and plays an important role in establishing tumor immunity. CTLA-4 is a negative regulator of T cell activation, and blockade of the CD80/86-CTLA-4 pathway with CTLA-4 monoclonal antibody (mAb) enhances anti-tumor T cell responses and leads to tumor rejection. In mice, combination therapy with agonist CD40 mAb and blocking CTLA-4 mAb enhances the induction of tumor-specific T cells and tumor rejection without toxicity. It is the central hypothesis of this proposal that higher potency T cell activation and improved clinical activity can be achieved by combining CD40 activation with CTLA-4 blockade in patients with melanoma. To test this hypothesis, we propose to combine the agonist CD40 mAb CP-870,893 with the blocking CTLA-4 mAb tremelimumab in patients with metastatic melanoma. Although each fully human mAb has been tested separately and shown promise in patients with melanoma, the combination has not. Our approach represents a novel strategy to "step on the gas" while "cutting the brakes". Moreover, the approach emanates from the fundamental oncological tenet that prioritizes combining two or more agents that have distinct mechanisms of action, non-overlapping clinical toxicities, and a definite single-agent response rate. Preclinical toxicology studies demonstrate an acceptable safety profile of combined CP-870,893/tremelimumab therapy in non-human primates. Our investigator-sponsored phase I study of CP-870,893 and tremelimumab has received full regulatory approval and is open to enrollment (NCT01103635). Three patients have begun treatment without major toxicity indicating feasibility. If funded, we will (1) Establish the maximum tolerated doses of CP-870,893 given every 3 weeks in combination with tremelimumab given every 12 weeks in patients with metastatic melanoma, and (2) Determine the immunological mechanism of CP- 870,893/tremelimumab in patients by assessing treatment-related activation and function of antigen presenting cells, modulation of T cell subsets, and induction of tumor antigen-specific T cell using a panel of state-of-the-art immune assessment assays. PUBLIC HEALTH RELEVANCE: We aim to determine the clinical and immunological impact of combining the agonist CD40 antibody CP-970,893 with the blocking CTLA-4 antibody tremelimumab in a phase I study of patients with metastatic melanoma. The long-term goal is to develop a new therapy for patients with metastatic melanoma based on enhancement of anti-tumor immune responses.