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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA158186-02
Application #
8300098
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Song, Min-Kyung H
Project Start
2011-07-12
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$332,000
Indirect Cost
$124,500
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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; Glennie, Martin J (2013) Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res 19:1035-43
Byrne, Katelyn T; Vonderheide, Robert H (2013) CD40 therapy and surgery: a potential immunologic partnership. J Immunother 36:359-61
Vonderheide, Robert H; Bajor, David L; Winograd, Rafael et al. (2013) CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother 62:949-54
Bajor, David L; Vonderheide, Robert H (2012) Rehabilitation for oncogene addiction: role of immunity in cellular sobriety. Clin Cancer Res 18:1192-4