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

Gulley, James L.; Schlom, Jeffrey; Barcellos‐Hoff, Mary Helen; Wang, Xiaojing; Seoane, Joan; Audhuy, François; Lan, Yan; Dussault, Isabelle; Moustakas, Aristidis

doi:10.1002/1878-0261.13146

Cited by 80 publications

(60 citation statements)

References 136 publications

(162 reference statements)

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“…Bintrafusp alfa has been the subject of two prior review articles. 20,21 This article will review more recent data on the mechanism of action of bintrafusp alfa not included in those articles, as well as recent clinical trial results. Both preclinical and clinical studies will describe the use of bintrafusp alfa as a monotherapy and in combination therapies.…”

Section: Experimental Biology and Medicinementioning

confidence: 99%

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

Gameiro

Strauss

Gulley

et al. 2022

Exp Biol Med (Maywood)

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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.

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Section: Experimental Biology and Medicinementioning

confidence: 99%

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

Gameiro

Strauss

Gulley

et al. 2022

Exp Biol Med (Maywood)

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“…Many people have recognized the potential of TGF-β, and there are currently many clinical trials combining TGF-β targeting with PD-1/PD-L1 treatment ( 97 ). However, most studies have stalled due to serious adverse events or the observation of minimal clinical benefit ( 98 ), which may be associated with higher global drug levels.…”

Section: Modulation Of Tams To Elevate Anti-pd-1/pd-l1 Immunotherapymentioning

confidence: 99%

Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression

2022

Front. Immunol.

118

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Anti-programmed cell death 1 (PD-1) or anti-PD-ligand (L) 1 drugs, as classic immune checkpoint inhibitors, are considered promising treatment strategies for tumors. In clinical practice, some cancer patients experience drug resistance and disease progression in the process of anti-PD-1/PD-L1 immunotherapy. Tumor-associated macrophages (TAMs) play key roles in regulating PD-1/PD-L1 immunosuppression by inhibiting the recruitment and function of T cells through cytokines, superficial immune checkpoint ligands, and exosomes. There are several therapies available to recover the anticancer efficacy of PD-1/PD-L1 inhibitors by targeting TAMs, including the inhibition of TAM differentiation and re-education of TAM activation. In this review, we will summarize the roles and mechanisms of TAMs in PD-1/PD-L1 blocker resistance. Furthermore, we will discuss the therapies that were designed to deplete TAMs, re-educate TAMs, and intervene with chemokines secreted by TAMs and exosomes from M1 macrophages, providing more potential options to improve the efficacy of PD-1/PD-L1 inhibitors.

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“…Thus, the use of approaches to avoid the delivery of EVs carrying TGF-β1 (e.g. anti-TGF-β1 antibodies or hybrid anti-PD-L1 and TGFβRII biomolecules, such as bintrafusp-α ( Gulley et al, 2021 )) is a promising tool to avoid the immune evasion promoted by EVs and TGF-β signaling. Nevertheless, it is important to mention that TGF-β signaling is not the only pathway regulated by tumor-derived EVs and acting on immune cells.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer

Rodrigues‐Junior

Tsirigoti

Lim

et al. 2022

Front. Cell Dev. Biol.

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Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, and proteins known to be associated with the TGF-β pathway have been reported as constituents in the cargo of extracellular vesicles (EVs). EVs are secreted vesicles delimited by a lipid bilayer and play critical functions in intercellular communication, including regulation of the tumor microenvironment and cancer development. Thus, this review aims at summarizing the impact of EVs on TGF-β signaling by focusing on mechanisms by which EV cargo can influence tumorigenesis, metastatic spread, immune evasion and response to anti-cancer treatment. Moreover, we emphasize the potential of TGF-β-related molecules present in circulating EVs as useful biomarkers of prognosis, diagnosis, and prediction of response to treatment in cancer patients.

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

Cited by 80 publications

References 136 publications

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

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

Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression

Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer

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