Combined CD40 activation and CTLA4 blockade in melanoma

描述（由申请人提供）：T淋巴细胞是肿瘤免疫监测的主要介质，特别是对于黑色素瘤患者，T细胞浸润到肿瘤中可以预测临床结果，并且免疫治疗策略在某些情况下显示出临床效用。在这里，我们建议评估同时靶向CD40和CTLA-4在黑色素瘤患者中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因子，可以用于治疗。CD40是一种介导抗原提呈细胞活化的细胞表面受体，在建立肿瘤免疫中起重要作用。CTLA-4是T细胞活化的负调节因子，用CTLA-4单克隆抗体（mAb）阻断CD80/86-CTLA-4通路可增强抗肿瘤T细胞反应并导致肿瘤排斥反应。在小鼠中，与激动剂CD40 mAb和阻断CTLA-4 mAb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。该建议的中心假设是，通过将CD40激活与CTLA-4阻断相结合，可以在黑色素瘤患者中实现更高效力的T细胞激活和改善的临床活性。为了验证这一假设，我们建议将激动剂CD40 mAb CP-870,893与阻断CTLA-4 mAb tremelimumab联合用于转移性黑色素瘤患者。虽然每一种完全的人类单克隆抗体已经单独测试，并显示出对黑色素瘤患者的希望，但联合使用却没有。我们的方法代表了一种“踩油门”同时“切断刹车”的新策略。此外，该方法源于肿瘤学的基本原则，即优先组合两种或两种以上具有不同作用机制、无重叠临床毒性和明确的单药反应率的药物。临床前毒理学研究表明，在非人灵长类动物中，CP-870,893/tremelimumab联合治疗具有可接受的安全性。我们的研究者赞助的CP-870,893和tremelimumab的I期研究已获得完全监管批准并开放入组（NCT01103635）。3例患者已开始治疗，无重大毒性，表明治疗的可行性。如果获得资助，我们将(1)确定转移性黑色素瘤患者每3周给药一次的CP-870,893联合每12周给药一次的tremelimumab的最大耐受剂量；(2)通过评估治疗相关的抗原提呈细胞的激活和功能、T细胞亚群的调节和肿瘤抗原特异性T细胞的诱导，确定CP-870,893 /tremelimumab在患者中的免疫机制。

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.