Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances

Abstract

Immunosuppressive entities in the tumor microenvironment (TME) remain a major impediment to immunotherapeutic approaches for a majority of patients with cancer. While the immunosuppressive role of transforming growth factor-β (TGF-β) in the TME is well known, clinical studies to date with anti-TGF-β agents have led to limited success. The bifunctional agent bintrafusp alfa (previously designated M7824) has been developed in an attempt to address this issue. Bintrafusp alfa consists of an IgG1targeting programmed death ligand 1 (PD-L1) moiety fused via peptide linkers to the extracellular domain of two TGF-β receptor II molecules designed to ‘trap’ TGF-β in the TME. This agent is able to bring the TGF-β trap to the TME via its anti-PD-L1 component, thus simultaneously attacking both the immunosuppressive PD-L1 and TGF-β entities. A number of preclinical studies have shown bintrafusp alfa capable of (1) preventing or reverting TGF-β-induced epithelial-mesenchymal transition in human carcinoma cells; this alteration in tumor cell plasticity was shown to render human tumor cells more susceptible to immune-mediated attack as well as to several chemotherapeutic agents; (2) altering the phenotype of natural killer and T cells, thus enhancing their cytolytic ability against tumor cells; (3) mediating enhanced lysis of human tumor cells via the antibody-dependent cell-mediated cytotoxicity mechanism; (4) reducing the suppressive activity of Tregcells; (5) mediating antitumor activity in numerous preclinical models and (6) enhancing antitumor activity in combination with radiation, chemotherapy and several other immunotherapeutic agents. A phase I clinical trial demonstrated a safety profile similar to other programmed cell death protein 1 (PD-1)/PD-L1 checkpoint inhibitors, with objective and durable clinical responses. We summarize here preclinical and emerging clinical data in the use of this bispecific and potentially multifunctional agent.

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

“…In recent years, bispecific antibodies have been the popular focus for both preclinical and clinical studies [68][69][70]. There are many bispecific antibodies in the clinical development stages.…”

TGF‐β signaling in liver metastasis

“…Moreover, bintrafusp alfa reduced the development of (lung) metastasis in spontaneously metastasizing orthotopic breast cancer models. 120,135 Compared to anti-PD-L1 treatment alone, monotreatment with bintrafusp alfa increased the tumor density and activity of CD8 + T cells, NK cells, neutrophils, and tumor associated dendritic cell and M1 macrophages. 120,135 Interestingly, myofibroblasts also seemed to be affected by bintrafusp α, since a decrease in α-SMA was seen.…”

On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges?

“…While the use of immune checkpoint inhibitors alone may favor the cytolytic activity of immune cells that are present within the cancer mass, their combination with TGF-β pharmacological inhibitors may increase the infiltration of these cells in "cold tumors." More details about the synergism between TGF-β pharmacological inhibitors and immune checkpoint inhibitors has been reviewed and discussed by others regarding its use in pre-clinical models and clinical trials (Ganesh and Massagué, 2018;Bai et al, 2019;Groeneveldt et al, 2020;Lind et al, 2020).…”

“…In this context, experimental studies regarding the immunosuppressive activity played by TGF-β should be expanded and their results compared between “cold tumors” and “hot tumors” in order to obtain a better understanding about the use of TGF-β pharmacological inhibitors to overcome the immune exclusion that is common to different types of cancer. While the use of immune checkpoint inhibitors alone may favor the cytolytic activity of immune cells that are present within the cancer mass, their combination with TGF-β pharmacological inhibitors may increase the infiltration of these cells in “cold tumors.” More details about the synergism between TGF-β pharmacological inhibitors and immune checkpoint inhibitors has been reviewed and discussed by others regarding its use in pre-clinical models and clinical trials ( Ganesh and Massagué, 2018 ; Bai et al, 2019 ; Groeneveldt et al, 2020 ; Lind et al, 2020 ).…”