Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects. Advanced biomaterials and drug delivery systems, such as nanoparticles and the use of T cells to deliver therapies, could effectively harness immunotherapies and improve their potency while reducing toxic side effects. Here, we discuss these research advances, as well as the opportunities and challenges for integrating delivery technologies into cancer immunotherapy, and we critically analyse the outlook for these emerging areas.

Delivery technologies for cancer immunotherapy

Transforming growth factor-beta (TGFbeta) signalling regulates cancer through mechanisms that function either within the tumour cell itself or through host-tumour cell interactions. Studies of tumour-cell-autonomous TGFbeta effects show clearly that TGFbeta signalling has a mechanistic role in tumour suppression and tumour promotion. In addition, factors in the tumour microenvironment, such as fibroblasts, immune cells and the extracellular matrix, influence the ability of TGFbeta to promote or suppress carcinoma progression and metastasis. The complex nature of TGFbeta signalling and crosstalk in the tumour microenvironment presents a unique challenge, and an opportunity to develop therapeutic intervention strategies for targeting cancer.

Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer

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.

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

The cytokine transforming growth factor (TGF)-beta, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment of human malignant gliomas. Here we characterize the effects of a novel TGF-beta receptor (TGF-betaR) I kinase inhibitor, SD-208, on the growth and immunogenicity of murine SMA-560 and human LN-308 glioma cells in vitro and the growth of and immune response to intracranial SMA-560 gliomas in syngeneic VM/Dk mice in vivo. SD-208 inhibits the growth inhibition of TGF-beta-sensitive CCL64 cells mediated by recombinant TGF-beta1 or TGF-beta2 or of TGF-beta-containing glioma cell supernatant at an EC(50) of 0.1 mumol/L. SD-208 blocks autocrine and paracrine TGF-beta signaling in glioma cells as detected by the phosphorylation of Smad2 or TGF-beta reporter assays and strongly inhibits constitutive and TGF-beta-evoked migration and invasion, but not viability or proliferation. Peripheral blood lymphocytes or purified T cells, cocultured with TGF-beta-releasing LN-308 glioma cells in the presence of SD-208, exhibit enhanced lytic activity against LN-308 targets. The release of interferon gamma and tumor necrosis factor alpha by these immune effector cells is enhanced by SD-208, whereas the release of interleukin 10 is reduced. SD-208 restores the lytic activity of polyclonal natural killer cells against glioma cells in the presence of recombinant TGF-beta or of TGF-beta-containing glioma cell supernatant. The oral bioavailability of SD-208 was verified by demonstrating the inhibition of TGF-beta-induced Smad phosphorylation in spleen and brain. Systemic SD-208 treatment initiated 3 days after the implantation of SMA-560 cells into the brains of syngeneic VM/Dk mice prolongs their median survival from 18.6 to 25.1 days. Histologic analysis revealed no difference in blood vessel formation, proliferation, or apoptosis. However, animals responding to SD-208 showed an increased tumor infiltration by natural killer cells, CD8 T cells, and macrophages. These data define TGF-beta receptor I kinase inhibitors such as SD-208 as promising novel agents for the treatment of human malignant glioma and other conditions associated with pathological TGF-beta activity.

https://cancerres.aacrjournals.org/content/canres/64/21/7954.full.pdf

SD-208, a Novel Transforming Growth Factor β Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma Cells In vitro and In vivo

Ramona Almirez

Papers

SD-208, a Novel Transforming Growth Factor β Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma Cells In vitro and In vivo