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视的主要介质，特别是对于T细胞浸润到肿瘤中可预测临床结局的黑素瘤患者，并且在某些情况下免疫策略已显示出临床实用性。在这里，我们建议评估同时靶向CD 40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剂，可以用于治疗。CD 40是介导抗原呈递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细胞活化的负调节剂，并且用CTLA-4单克隆抗体（mAb）阻断CD 80/86-CTLA-4途径增强抗肿瘤T细胞应答并导致肿瘤排斥。在小鼠中，激动剂CD 40 mAb和阻断剂CTLA-4 mAb的联合治疗增强了肿瘤特异性T细胞的诱导和肿瘤排斥反应，而没有毒性。该提议的中心假设是，通过在黑素瘤患者中将CD 40活化与CTLA-4阻断相结合，可以实现更高效力的T细胞活化和改善的临床活性。为了验证这一假设，我们建议在转移性黑色素瘤患者中联合使用联合收割机激动剂CD 40 mAb CP-870，893和阻断剂CTLA-4 mAb曲美木单抗。尽管每种完全人源单克隆抗体都已分别进行了测试，并显示出对黑色素瘤患者的治疗前景，但这种组合并没有。我们的方法代表了一种新的策略，即“踩油门”，同时“踩刹车”。此外，该方法源于基本的肿瘤学原则，即优先组合具有不同作用机制、非重叠临床毒性和确定的单药反应率的两种或多种药物。临床前毒理学研究证明CP-870，893/曲美木单抗联合治疗在非人灵长类动物中具有可接受的安全性特征。我们的制药商申办的CP-870，893和曲美木单抗的I期研究已获得监管机构的全面批准，并开放招募（NCT 01103635）。三名患者已开始治疗，无重大毒性，表明可行性。如果获得资助，我们将（1）在转移性黑色素瘤患者中建立CP-870，893每3周给药一次与曲美木单抗每12周给药一次联合给药的最大耐受剂量，以及（2）通过评估治疗相关的抗原呈递细胞活化和功能、T细胞亚群调节，以及使用一组最先进的免疫评估测定法诱导肿瘤抗原特异性T细胞。

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.