Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment

Abstract

Immune checkpoint inhibitor; Tumor microenvironment

Inhibidor del punto de control inmunitario; Microambiente tumoral

Inhibidor del punt de control immunitari; Microambient tumoral

Transforming growth factor-β (TGF-β) and programmed death ligand 1 (PD-L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF-β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-to-mesenchymal transition, and angiogenesis. Meanwhile, PD-L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti-PD-L1 therapies have been approved for the treatment of various cancers, but TGF-β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF-β and PD-L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual-targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual-targeting agent is bintrafusp alfa. This drug is a first-in-class bifunctional fusion protein that consists of the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD-L1. Given the immunosuppressive effects of the TGF-β and PD-L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

This manuscript was funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), and was previously part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany, and GlaxoSmithKline. Medical writing support was provided by Spencer Hughes of ClinicalThinking, Inc., which was also funded by the healthcare business of Merck KGaA, Darmstadt, Germany, and GlaxoSmithKline in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3). This manuscript was funded in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, and by a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono, Billerica, MA, USA (CrossRef Funder ID:10.13039/100004755).