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

Robbins, Yvette; Friedman, Jay; Clavijo, Paúl E.; Sievers, Cem; Bai, Ke; Donahue, Renee N.; Schlom, Jeffrey; Sinkoe, Andrew; Hinrichs, Christian S.; Allen, Clint; Sater, Houssein Abdul; Gulley, James L.; Norberg, Scott M.

doi:10.1136/jitc-2021-003113

Cited by 13 publications

(11 citation statements)

References 37 publications

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“…TGF-β is a pleiotropic cytokine with different effects on epithelial, stromal, and immune cells ( 33 ). Our results indicate that TGF-β neutralization reduced tumor cell proliferation in most patients, a finding that is the opposite of that observed following TGF-β neutralization in normal squamous mucosa and papillomas ( 18 ). Possibly related to tumor cell responses to effector molecules from T cells ( 34 ), evidence of reduced tumor cell proliferation was similarly observed following neoadjuvant ICB in patients with glioblastoma ( 7 ).…”

Section: Discussioncontrasting

confidence: 78%

“…We performed MIF analysis to evaluate changes in TGF-β pathway signaling ( Supplemental Figure 4 , A and B). In nonmalignant epithelial cells with intact TGF-β pathway signaling, TGF-β is antiproliferative, and neutralization is expected to result in decreased tumor cell phosphorylated SMAD2 (p-SMAD2), p-SMAD3, and p21 and increased Ki67 (a marker of proliferation) ( 18 ). We observed this pattern of changes in only 2 (14%) patients ( Figure 3A , patients 9 and 10).…”

Section: Resultsmentioning

confidence: 99%

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Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer

Redman¹,

Friedman²,

Robbins³

et al. 2022

Journal of Clinical Investigation

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Background: Head and neck squamous cell carcinoma not associated with human papillomavirus (HPV-unrelated HNSCC) is associated with high rates of recurrence and poor survival.Methods: We conducted a clinical trial in 14 patients with newly diagnosed, HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death-ligand 1 (PD-L1) and neutralizes transforming growth factor-beta (TGF-).Results: Bintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses were observed and 12 of 14 patients (86%) were alive and disease free at one year. Alterations in regulatory T cell infiltration and spatial distribution relative to proliferating CD8 T cells indicated reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not viral-specific responses, correlated with development of a pathologic response. Detection of neoepitope-specific responses and pathologic responses in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pretreatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF- blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multi-mechanism neoadjuvant immunotherapy in patients with HPV-unrelated HNSCC. Conclusion: Our studies provide new insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant-specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced anti-tumor immunity following such treatment.

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Section: Discussioncontrasting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer

Redman¹,

Friedman²,

Robbins³

et al. 2022

Journal of Clinical Investigation

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“…Recent clinical studies have explored whether immunotherapy can enhance viral‐specific immunity to a magnitude sufficient to control infection and associated pathology 2 . Inconsistent clinical benefit is observed following immune checkpoint blockade in adults with aggressive HPV‐associated RRP 3–5 . Here, we report a durable, 4‐year clinical benefit following a course of treatment with the programmed death‐ligand 1 (PD‐L1) monoclonal antibody avelumab in an adult patient with RRP.…”

Section: Introductionmentioning

confidence: 90%

“…2 Inconsistent clinical benefit is observed following immune checkpoint blockade in adults with aggressive HPV-associated RRP. [3][4][5] Here, we report a durable, 4-year clinical benefit following a course of treatment with the programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab in an adult patient with RRP. We identified an immunotherapyinduced HPV-specific T cell clone that durably persisted at the site of disease for years following treatment.…”

Section: Introductionmentioning

confidence: 99%

Durable response in a patient with recurrent respiratory papillomatosis treated with immune checkpoint blockade

et al. 2022

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Background: Immune checkpoint blockade can provide clinical benefit for patients with advanced cancer. Here, we report durable disease control over many years following PD-L1 blockade through induction of a viral antigen-specific T cell response in an adult patient with recurrent respiratory papillomatosis.Methods: Antigen-specific T cell response assays, single cell RNA-sequencing, and RNA-scope was used to study clinical tissues.Results: An HPV6 E2-specific T cell clone restricted to HLA-B*55, present at low frequency in the pre-treatment papilloma, significantly expanded after six doses of PD-L1 blockade and remained present and functional at the site of initial response in the larynx as a tissue resident memory T cell for 4 years. An associated reduction in E2 target gene was observed following treatment.Conclusions: Although demonstrated in a single exceptional responder, these results highlight that immune checkpoint blockade may induce durable, viral antigen-specific immunity of sufficient magnitude to control disease in patients with nonmalignant disorders.

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“…Indeed, TGF-β appears to restrain proliferation in the basal layer of papillomas in recurrent respiratory papillomatosis, and HPV-driven neoplastic process that is non-invasive (but can be deadly due to local growth). 44 However in HPV-driven invasive cancers, bintrafusp alfa has showed promising activity compared with standard-of-care therapies (see below). Thus understanding the biology of the tumor and developing appropriate biomarkers are key to understanding how best to use agents like bintrafusp alfa.…”

Section: Clinical Applications Of Bintrafusp Alfamentioning

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

Cited by 13 publications

References 37 publications

Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer

Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer

Durable response in a patient with recurrent respiratory papillomatosis treated with immune checkpoint blockade

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

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