Development of TGF-beta antagonists for cancer therapy

Wakefield, Lalage

Abstract

Despite the dual role for TGF-beta as both tumor suppressor and tumor promoter in carcinogenesis, preclinical data from our lab and others has previously suggested that strategies to antagonize TGF-beta may selectively reduce the undesirable tumor promoting effects of this growth factor, while sparing the desirable effects on tumor suppression and normal homeostasis. Based on these promising preclinical results, an anti-TGF-beta antibody is in early phase clinical trials for the treatment of advanced cancer. However, given the complex biology of TGF-beta, the successful development of TGF-beta antagonists for cancer therapy will depend on a clear understanding of how these agents work and the related question of how to select patients who will benefit from this type of treatment. In FY08, we have made substantial progress in understanding the mechanism of action of an anti-TGF-beta antibody in suppressing tumor progression and metastasis. To do this, we have performed in depth mechanistic analyses using the 4T1 syngeneic mouse transplantation model of metastatic breast cancer, in combination with global and candidate gene expression analysis, molecular histology, immunophenotyping and immunodepletion approaches. We have found that a monoclonal antibody (1D11, Genzyme Corp) that neutralizes all three TGF-beta isoforms suppresses tumorigenesis and metastasis through the synergism of many small molecular effects on multiple cellular compartments. Target cells include the tumor cell itself, components of the immune surveillance system, and the microvasculature. Most of the overall efficacy of the antibody is due to enhanced anti-tumor immune surveillance, involving both innate and adaptive arms of the immune system. In addition to the known suppressive effects of TGF-beta on cytotoxic T-cell function, we also identified a novel mechanism whereby tumor-induced TGF-beta further subverts the CD8+ arm of the immune system into providing direct trophic support for the tumor through an IL-17-dependent mechanism. TGF-beta antibodies reverse both these effects. We propose that the locally distributed mechanism of action of anti-TGF-beta antibodies on multiple cell targets at or near the tumor site may be critical for the unexpectedly low toxicity of the agent. These data have important implications for clinical biomarker development and for understanding the biological basis of the selectivity of this class of TGF-beta antagonist in affecting the tumor and not the normal tissues.