Many drugs that target transforming growth factor-β (TGFβ) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.

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Targeting the TGFβ signalling pathway in disease.

The transforming growth factor (TGF)-β signaling pathway is deregulated in many diseases, including cancer. In healthy cells and early-stage cancer cells, this pathway has tumor-suppressor functions, including cell-cycle arrest and apoptosis. However, its activation in late-stage cancer can promote tumorigenesis, including metastasis and chemoresistance. The dual function and pleiotropic nature of TGF-β signaling make it a challenging target and imply the need for careful therapeutic dosing of TGF-β drugs and patient selection. We review here the rationale for targeting TGF-β signaling in cancer and summarize the clinical status of pharmacological inhibitors. We discuss the direct effects of TGF-β signaling blockade on tumor and stromal cells, as well as biomarkers that can predict the efficacy of TGF-β inhibitors in cancer patients.

Targeting TGF-β Signaling in Cancer.

Transforming growth factor-beta (TGFbeta) is an immunosuppressive cytokine produced by tumour cells and immune cells that can polarize many components of the immune system. This Review covers the effects of TGFbeta on natural killer (NK) cells, dendritic cells, macrophages, neutrophils, CD8(+) and CD4(+) effector and regulatory T cells, and NKT cells in animal tumour models and in patients with cancer. Collectively, many recent studies favour the hypothesis that blocking TGFbeta-induced signalling in the tumour microenvironment enhances antitumour immunity and may be beneficial for cancer therapy. An overview of the current drugs and reagents available for inhibiting TGFbeta-induced signalling and their phase in clinical development is also provided.

The polarization of immune cells in the tumour environment by TGFβ

The influence of the microenvironment on tumour progression is becoming clearer. In this Review we address the role of an essential signalling pathway, that of transforming growth factor-β, in the regulation of components of the tumour microenvironment and how this contributes to tumour progression.

The roles of TGFβ in the tumour microenvironment

TGFβ signalling has key roles in cancer progression: most carcinoma cells have inactivated their epithelial antiproliferative response and benefit from increased TGFβ expression and autocrine TGFβ signalling through effects on gene expression, release of immunosuppressive cytokines and epithelial plasticity. As a result, TGFβ enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance. TGFβ released by cancer cells, stromal fibroblasts and other cells in the tumour microenvironment further promotes cancer progression by shaping the architecture of the tumour and by suppressing the antitumour activities of immune cells, thus generating an immunosuppressive environment that prevents or attenuates the efficacy of anticancer immunotherapies. The repression of TGFβ signalling is therefore considered a prerequisite and major avenue to enhance the efficacy of current and forthcoming immunotherapies, including in tumours comprising cancer cells that are not TGFβ responsive. Herein, we introduce the mechanisms underlying TGFβ signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms as well as the use of these approaches in cancer immunotherapies and their potential adverse effects. TGFβ released by cancer cells and other cells in the tumour microenvironment enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance as well as generating an immunosuppressive environment. The authors of this Review introduce the mechanisms underlying TGFβ signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms, in particular in the context of cancer immunotherapy.

TGFβ biology in cancer progression and immunotherapy.

Purpose: Transforming growth factor β (TGFβ) is a pleiotropic cytokine that affects tumor growth, metastasis, stroma, and immune response. We investigated the therapeutic efficacy of anti–TGFβ receptor II (TGFβ RII) antibody in controlling metastasis and tumor growth as well as enhancing antitumor immunity in preclinical tumor models. Experimental Design: We generated neutralizing antibodies to TGFβ RII and assessed the antibody effects on cancer, stroma, and immune cells in vitro . The efficacy and mechanism of action of the antibody as monotherapy and in combination with chemotherapy in suppression of primary tumor growth and metastasis were evaluated in several tumor models. Results: Anti–TGFβ RII antibody blocked TGFβ RII binding to TGFβ 1, 2, and 3, and attenuated the TGFβ-mediated activation of downstream Smad2 kinase, invasion of cancer cells, motility of endothelial and fibroblast cells, and induction of immunosuppressive cells. Treatment with the antibody significantly suppressed primary tumor growth and metastasis and enhanced natural killer and CTL activity in tumor-bearing mice. Immunohistochemistry analysis showed cancer cell apoptosis and massive necrosis, and increased tumor-infiltrating T effector cells and decreased tumor-infiltrating Gr-1+ myeloid cells in the antibody-treated tumors. Fluorescence-activated cell sorting analysis indicated the significant reduction of peripheral Gr-1+/CD11b+ myeloid cells in treated animals. Concomitant treatment with the cytotoxic agent cyclophosphamide resulted in a significantly increased antitumor efficacy against primary tumor growth and metastasis. Conclusions: These preclinical data provide a foundation to support using anti–TGFβ RII antibody as a therapeutic agent for TGFβ RII–dependent cancer with metastatic capacity. Clin Cancer Res; 16(4); 1191–205

https://clincancerres.aacrjournals.org/content/clincanres/16/4/1191.full.pdf

Anti-transforming growth factor beta receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells

Transforming growth factor beta (TGF \#946;) is a pleiotropic cytokine that profoundly regulates the pathogenesis of cancer and metastasis. TGF \#946; stimulates activation of TGF \#946; receptor I kinase and downstream signaling cascades that initiate broad cellular and non cellular processes i.e. survival, proliferation and differentiation, migration and motility, and deposition of the extracellular matrix and induction of cytokines contributing to tumorigenesis, metastasis, angiogenesis, and inflammation during tumor progression. Myeloid cells have been reported to be an important mediator in promoting metastasis and angiogenesis, suppressing immunity against tumor and inducing anti-VEGF resistant tumors. Therefore, targeting this multifunctional cell population will be beneficial for enhancement of antitumor therapeutic efficacy. The binding of TGF \#946; ligands to TGF \#946; receptor II (TGF \#946; RII) is one crucial step to initiate the activation of TGF \#946; signaling pathways. Here, we report that we have developed high affinity monoclonal antibodies with specific blocking activity to TGF \#946; R II binding to TGF \#946; ligands. By using the antibodies, we investigated the mechanism of actions of TGF \#946; mediated activity in promoting cancer cell invasiveness, angiogenesis and the role of Gr-1/CD11b+ myeloid cells in tumor progression and evaluated the therapeutic efficacy of anti-TGF \#946; R II antibodies in suppression of tumor growth and metastasis. Data on cell-based assays displayed the capacity of anti-TGF \#946; R II antibodies in inhibiting TGF \#946; receptor mediated signaling cascades and cellular biological functions in vitro. In vivo studies demonstrated that treatment of tumor bearing mice with the anti-TGF \#946; R II antibodies resulted in suppression of primary tumor growth and metastasis in conjunction with the blockade of cancer cell invasion and VEGF-A secretion, the inhibition of myeloid cell function and the depletion of Gr-1/CD11b/TGF \#946; R II+ myeloid cells. Most importantly, we have for first time revealed that a subset of TGF \#946; R II+ myeloid cells has a major role in promoting tumor growth and metastasis through inducing tumor cell migration and inhibiting cellular immune response. Thus, this study has provided a foundation supporting that anti-TGF \#946; R II antibody mediated abrogation of TGF \#946; R II+ myeloid cells would be an effective approach to controlling the deleterious activity of myeloid cell in cancer, and anti-TGF \#946; RII antibody-based therapeutics may represent a novel strategy for treatment of cancer, particularly for metastatic tumors. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 844.

Abstract #844: Anti-TGF beta receptor II antibody suppresses tumor growth and metastasis through inhibiting TGF beta autocrine stimulation of tumor cells and myeloid cells

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Anti-transforming growth factor beta receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells

Abstract #844: Anti-TGF beta receptor II antibody suppresses tumor growth and metastasis through inhibiting TGF beta autocrine stimulation of tumor cells and myeloid cells