Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy

• Published in: BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy biopharmaceuticals, and gene therapy, 2022-03, Vol.36 (2), p.153-180
• Main Authors: Tschernia, Nicholas P., Gulley, James L.
• Format: Article
• Language: English
• Subjects: Activin; Antibodies; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - pharmacology; B7-H1 Antigen - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer immunotherapy; Cancer Research; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell growth; Cytokines; Enzyme inhibitors; Fusion protein; Growth factors; Humans; Immune checkpoint; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Immunoglobulin G; Immunologic Factors; Immunomodulation; Immunosuppressive agents; Immunotherapy; Kinases; Localization; Lung cancer; Lung Neoplasms - drug therapy; Melanoma; Metastases; Metastasis; Molecular Medicine; Monoclonal antibodies; Patients; PD-L1 protein; Pharmacotherapy; Protein-serine/threonine kinase; Proteins; Pyrazoles; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Review; Review Article; Smad3 protein; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta - therapeutic use; Transforming Growth Factor beta1 - antagonists & inhibitors; Transforming Growth Factor beta1 - pharmacology; Transforming Growth Factor beta1 - therapeutic use; Tumor Microenvironment; Tumors
• ISSN: 1173-8804; 1179-190X
• DOI: 10.1007/s40259-022-00521-1

Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumors as metastatic melanoma and non-small cell-lung cancer, in which immune checkpoint inhibition has become the first-line treatment of choice, only a minority of patients will benefit considerably from these treatments. This has been attributed to a number of factors, including an immune-suppressive tumor microenvironment (TME). Using different modalities to break these barriers is of utmost importance to expand the population of patients that benefit from immune checkpoint inhibition. The multifunctional cytokine transforming growth factor-β (TGF-β) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-β, yet most of these have since been discontinued. The combination of anti–TGF-β agents with immune checkpoint inhibitors now has the potential to revive this target as a viable immunomodulatory therapeutic approach. Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review.