Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Strauss, Julius; Gatti‐Mays, Margaret E.; Cho, Byoung Chul; Hill, Andrew; Salas, Sébastien; McClay, Edward F.; Redman, Jason; Sater, Houssein Abdul; Donahue, Renee N.; Jochéms, Caroline; Lamping, Elizabeth; Burmeister, Andrea; Marté, Jennifer L.; Cordes, Lisa; Bilušić, Marijo; Karzai, Fatima; Ojalvo, Laureen S.; Jehl, Genevieve; Rolfe, Alex; Hinrichs, Christian S.; Madan, Ravi A.; Schlom, Jeffrey; Gulley, James L.

doi:10.1136/jitc-2020-001395

Cited by 93 publications

(65 citation statements)

References 27 publications

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“… 31 Accordingly, patients with relapsed high-risk HPV-associated malignancies experience clinical benefit from treatment with bintrafusp alpha. 26 32 Data presented here suggest that this is not the case in patients with neoplasms driven by infection with low-risk HPV, such as recurrent respiratory papillomatosis.…”

Section: Discussionmentioning

confidence: 60%

“…Dual PD-L1/TGF-b inhibition with bintrafusp alpha provides clinical benefit for patients with relapsed malignancy. 26 Genomic alterations in TGF-b superfamily genes are frequent events in cancers, 27 suggesting that genetic or epigenetic alterations in malignant cells may abrogate the antiproliferative effects of TGF-b signaling observed in non-malignant epithelial cells. We hypothesized that the rate of genomic alterations in key TGF-b superfamily genes 27 would be less frequent in normal mucosa and papillomas from subjects with recurrent respiratory papillomatosis compared with head and neck squamous cell carcinoma (HNSCC).…”

Section: Resultsmentioning

confidence: 99%

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Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis

Robbins

Friedman

Clavijo

et al. 2021

J Immunother Cancer

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BackgroundRecurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven neoplastic disorder of the upper aerodigestive tract that causes significant morbidity and can lead to fatal airway obstruction. Prior clinical study demonstrated clinical benefit with the programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Bintrafusp alpha is a bifunctional inhibitor of PD-L1 and transforming growth factor-beta (TGF-b) that has shown clinical activity in several cancer types.MethodsWe conducted a phase II clinical trial evaluating bintrafusp alpha in adults with RRP. Papilloma samples before and after treatment with bintrafusp alpha were assessed for correlates of response with multiplex immunofluorescence as well as immunological and genomic analyses. Post hoc analyses of papilloma samples before and after treatment with avelumab were assessed for comparison.ResultsDual PD-L1/TGF-b inhibition failed to abrogate papilloma growth in most subjects and increased the frequency of clinically indicated interventions after treatment in four of eight subjects based on each subject’s own historical control. TGF-b neutralization consistently decreased pSMAD3 and p21 and increased Ki67 expression within the basal layers of papillomas, indicating that TGF-b restrained proliferation. These alterations were not observed in papillomas treated with PD-L1 blockade alone. Dual PD-L1/TGF-b inhibition did not enhance anti-HPV immunity within papillomas beyond that observed with PD-L1 blockade. Genomic alterations in TGF-b superfamily genes were infrequent in papillomas and normal mucosa but present in a significant fraction of head and neck carcinomas.ConclusionsIntact TGF-b signaling restrains proliferation within papillomas, and the use of clinical agents that abrogate this pathway should be avoided in patients with RRP.Trial registration numbersNCT03707587 and NCT02859454.

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Section: Discussionmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis

Robbins

Friedman

Clavijo

et al. 2021

J Immunother Cancer

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“…An ongoing phase I/II clinical trial (NCT02517398; https://clinicaltrials.gov/ct2/show/NCT02517398 ) in patients with HPV-associated malignancies has shown promising clinical responses. Of the 36 patients who received bintrafusp alfa, there was a clinical response rate of 38.9% with an acceptable safety profile ( 40 ). Prior studies with anti–PD-1/PD-L1 agents have demonstrated 15%–25% response rates in this patient population.…”

Section: Discussionmentioning

confidence: 99%

Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009

Pellom¹,

Rumfield²,

Morillon³

et al. 2021

JCI Insight

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There are approximately 44,000 cases of human papillomavirus–associated (HPV-associated) cancer each year in the United States, most commonly caused by HPV types 16 and 18. Prophylactic vaccines successfully prevent healthy people from acquiring HPV infections via HPV-specific antibodies. In order to treat established HPV-associated malignancies, however, new therapies are necessary. Multiple recombinant gorilla adenovirus HPV vaccine constructs were evaluated in NSG-β2m –/– peripheral blood mononuclear cell–humanized mice bearing SiHa, a human HPV16 + cervical tumor, and/or in the syngeneic HPV16 + TC-1 model. PRGN-2009 is a therapeutic gorilla adenovirus HPV vaccine containing multiple cytotoxic T cell epitopes of the viral oncoproteins HPV 16/18 E6 and E7, including T cell enhancer agonist epitopes. PRGN-2009 treatment reduced tumor volume and increased CD8 + and CD4 + T cells in the tumor microenvironment of humanized mice bearing the human cervical tumor SiHa. PRGN-2009 monotherapy in the syngeneic TC-1 model also reduced tumor volumes and weights, generated high levels of HPV16 E6–specific T cells, and increased multifunctional CD8 + and CD4 + T cells in the tumor microenvironment. These studies provide the first evaluation to our knowledge of a therapeutic gorilla adenovirus HPV vaccine, PRGN-2009, showing promising preclinical antitumor efficacy and induction of HPV-specific T cells, along with the rationale for its evaluation in clinical trials.

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“…Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII) fused to the C-terminus of each heavy chain of an IgG1 antibody blocking PD-L1. This agent is currently being evaluated in multiple clinical studies, showing clinical activity with a confirmed objective response rate of 30.5% in patients with human papillomavirus-associated malignancies [ 15 , 16 ]. In a previous study, we showed that the combination of bintrafusp alfa with SX-682, a small molecule inhibitor of the chemokine receptors CXCR1 and CXCR2 that blocks signaling initiated by IL-8 and other chemokines of the CXCL family, synergizes to mediate antitumor activity in murine models of breast and lung cancer [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy

Horn

Fousek

Hamilton

et al. 2021

Cancers

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Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced Tregs and CD11b+Ly6G+ myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic.

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Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Cited by 93 publications

References 27 publications

Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis

Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis

Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009

Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy

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