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

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-beta (TGF-beta) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-beta, yet most of these have since been discontinued. The combination of anti-TGF-beta 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-beta are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-beta 1; NIS 793, a monoclonal antibody targeting TGF-beta; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-beta 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 TGF beta RI; SB-431542, an inhibitor targeting several TGF-beta superfamily Type I activin receptor-like kinases as well as TGF-beta 1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGF beta RI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-beta 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.

Automated summary

Cancer immunotherapy with monoclonal antibodies targeting immune checkpoints has significantly changed the landscape of cancer treatment. However, only a minority of patients benefit considerably from these treatments, attributed to factors like the immune-suppressive tumor microenvironment and TGF-beta. Therefore, investigating and developing inhibitors targeting TGF-beta in combination with immune checkpoint inhibitors is crucial for improving patient outcomes.