Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status.

Abstract

Bintrafusp alfa (anti-PD-L1/TGFβRII) is a first-in-class bifunctional agent designed to act both as a checkpoint inhibitor and as a "trap" for TGFβ in the tumor microenvironment (TME). This article is designed to review the preclinical studies interrogating the mode of action of bintrafusp alfa and to present a comprehensive overview of recent bintrafusp alfa clinical studies. Preclinical studies have demonstrated that bintrafusp alfa immune-mediating and antitumor activity can be enhanced by combining it with a human papillomavirus (HPV) therapeutic cancer vaccine, a tumor-targeting interleukin 12 (IL-12) immunocytokine and/or an IL-15 superagonist. The importance of TGFβ in HPV-associated malignancies is also reviewed. The clinical studies reviewed span extended phase I cohorts in patients with a spectrum of malignancies, two randomized phase II studies in lung and one in biliary tract cancers in which bintrafusp alfa did not demonstrate superiority over standard-of-care therapies, and provocative results in patients with HPV-associated malignancies, where as a monotherapy, bintrafusp alfa has shown response rates of 35%, compared to overall response rate (ORR) of 12-24% seen with other Food and Drug Administration (FDA)-approved or standard-of-care agents. This article also reviews preliminary phase II study results of patients with HPV+ malignancies employing bintrafusp alfa in combination with an HPV therapeutic vaccine and a tumor-targeting IL-12 immunocytokine in which the combination therapy outperforms standard-of-care therapies in both checkpoint naïve and checkpoint refractory patients. This review thus provides an example of the importance of conducting clinical studies in an appropriate patient population - in this case, exemplified by the role of TGFβ in HPV-associated malignancies. This review also provides preclinical and preliminary clinical study results of the combined use of multiple immune-modulating agents, each designed to engage different immune components and tumor cells in the TME.

• Authors: Sofia R Gameiro, Julius Strauss, James L Gulley, Jeffrey Schlom
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 247 Issue 13 Pg. 1124-1134 (07 2022) ISSN: 1535-3699 [Electronic] England
• PMID: 35473390 (Publication Type: Journal Article, Review, Research Support, N.I.H., Intramural)

Chemical References

• B7-H1 Antigen
• Immunologic Factors
• Transforming Growth Factor beta
• Interleukin-12
• Receptor, Transforming Growth Factor-beta Type II

Topics

• B7-H1 Antigen (metabolism)
• Clinical Trials, Phase II as Topic
• Humans
• Immunologic Factors (therapeutic use)
• Immunotherapy (methods)
• Interleukin-12
• Neoplasms
• Papillomavirus Infections
• Randomized Controlled Trials as Topic
• Receptor, Transforming Growth Factor-beta Type II (metabolism)
• Transforming Growth Factor beta
• Tumor Microenvironment