Enhancement of Dendritic Cell-Based Immunotherapy Using a Small Molecule TGF-beta Receptor Type I Kinase Inhibitor
Abstract
Dendritic cells (DC) have become particularly attractive candidates for cancer immunotherapy due to their potent ability to stimulate antigen specific T cells responses. A number of pre-clinical and clinical studies using tumor antigen-pulsed DCs to treat a variety of malignancies have demonstrated that DC vaccines can elicit measurable cellular anti-tumor immunity. However, despite these encouraging results, DC-based immunotherapy has demonstrated only limited clinical success in the treatment of established tumors. The limited clinical efficacy of existing DC-based cancer vaccines has been attributed in part to suppressive factors produced by the growing tumor, such as transforming growth factor-beta (TGF- ) that has been shown to impair the immunostimulatory capacity of DCs. Therefore, strategies to neutralize the deleterious effects of TGF- may lead to more effective DC-based cancer therapies. HTS466284 and SM16 are potent small molecule TGF- receptor type I (T RI) kinase inhibitors that have been shown to block TGF- signaling by binding to the ATP-binding pocket of this receptor. The hypothesis to be tested is that T RI kinase inhibitor therapy will enhance the efficacy of DC vaccines in the treatment of established murine mammary tumors by rendering DCs resistant to TGF- -mediated immunosuppression. The specific aims of the project are to: 1) Determine the effect of T RI kinase inhibitors on spontaneous tumor metastasis, 2) Evaluate the effect of the combination T RI kinase inhibitors plus DC vaccination on the treatment of primary and metastatic breast cancer, 3) Evaluate the role of immune effector cells in the anti-tumor response following combination therapy with T RI kinase inhibitors and DC vaccines.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2007
- Accession Number
- ADA472882
Entities
People
- Matthew P. Rausch
Organizations
- University of Arizona