Novel therapies emerging in oncology to target the TGF-β pathway

Abstract

The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.

Keywords: Immunosuppression; Ligand traps; Small molecule inhibitors; TGF-β receptor antagonists; Vactosertib.

Fig. 1

Agents in Development to Target the TGF-β Pathway in Oncology. Shown are noteworthy antagonists that target the TGF-β pathway and have recently been evaluated in clinical trials or are in clinical development. As indicated, many steps within the TGF-β pathway have been targeted therapeutically. Key tumor-promoting and tumor-suppressing genes transcriptionally regulated by the TGF-β pathwat are indicated

Fig. 2

Effects of TGF-β on Antitumor Immunity. TGF-β is produced by multiple cell types within the TME. TGF-β can increase (black arrow) or decrease (red block) the proliferation and functional activity of immune effectors with tumor-promoting or tumor-suppressive outcomes. TGF-β enhances pro-inflammatory Th17 cells along with IL-6. TGF-β also blocks the IFN-γ-mediated induction of pro-inflammatory Th1 cells as well as the IL-4-dependent production of Th2 cells to decrease tumor suppression. TGF-β induces naïve T cell differentiation into Tregs and Treg expansion with IL-2. Tregs then reduce CD8⁺ T cell development and expansion to increase immune suppression. TGF-β also reduces the production of mast cells (to reduce superoxide and NO production), natural killer (NK) cells (reduced cytokine and IFN-γ production), B cells (reduced IgA secretion), polymorphonuclear cells (PMNs, reduced degranulation), M1 macrophages (reduced pro-inflammatory cytokines, e.g., IL-12) and reduced dendritic cells (DCs) leading to reduced antigen presentation and cytokine production. TGF-β promotes the differentiation and expansion of MDSCs as well as the production of M2 macrophages leading to increased anti-inflammatory cytokines IL-4 and IL-10

Fig. 3

Tumor Intrinsic and Extrinsic Effects of Vactosertib. Vactosertib exerts potent antitumor effects (indicated in red) directly on cancer cells as well as on a number of other cell types