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.
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.
|Benci, Joseph L; Xu, Bihui; Qiu, Yu et al. (2016) Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell 167:1540-1554.e12|
|Byrne, Katelyn T; Leisenring, Nathan H; Bajor, David L et al. (2016) CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy. J Immunol 197:179-87|
|Twyman-Saint Victor, Christina; Rech, Andrew J; Maity, Amit et al. (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373-7|
|Richman, Lee P; Vonderheide, Robert H (2014) Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol Res 2:19-26|
|Bajor, David L; Xu, Xiaowei; Torigian, Drew A et al. (2014) Immune activation and a 9-year ongoing complete remission following CD40 antibody therapy and metastasectomy in a patient with metastatic melanoma. Cancer Immunol Res 2:1051-8|
|Vonderheide, Robert H; Nathanson, Katherine L (2013) Immunotherapy at large: the road to personalized cancer vaccines. Nat Med 19:1098-100|
|Beatty, Gregory L; Torigian, Drew A; Chiorean, E Gabriela et al. (2013) A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 19:6286-95|
|Vonderheide, Robert H; Burg, Jennifer M; Mick, Rosemarie et al. (2013) Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology 2:e23033|
|Vonderheide, Robert H; Bajor, David L; Winograd, Rafael et al. (2013) CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother 62:949-54|
|Byrne, Katelyn T; Vonderheide, Robert H (2013) CD40 therapy and surgery: a potential immunologic partnership. J Immunother 36:359-61|
Showing the most recent 10 out of 12 publications