Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort (original) (raw)
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Journal for ImmunoTherapy of Cancer, 2020
BackgroundPatients with biliary tract cancer (BTC) have poor prognosis with few treatment options. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 antibody blocking programmed death ligand 1 (PD-L1), has shown clinical efficacy in multiple solid tumors.MethodsIn this phase I, open-label trial expansion cohort, Asian patients with BTC whose disease progressed after first-line chemotherapy received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint is safety/tolerability, while the secondary endpoints include best overall response per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsAs of August 24, 2018, 30 patients have received bintrafusp alfa for a median of 8.9 (IQR 5.7–32.1) weeks; 3 patients remained on treatment for >59.7 weeks. Nineteen (63%) pa...
Journal of Thoracic Oncology, 2020
Introduction: The safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor b (TGF-b) receptor II (a TGF-b "trap") fused to a human immunoglobulin G1 antibody blocking programmed deathligand 1 (PD-L1), was evaluated in patients with advanced NSCLC. Methods: This expansion cohort of NCT02517398, an ongoing, phase 1, open-label trial, includes 80 patients with advanced NSCLC that progressed after platinum doublet therapy or after platinum-based adjuvant or neoadjuvant treatment and those who also have not received previous immunotherapy. Patients were randomized at a one-to-one ratio to receive either bintrafusp alfa 500 mg or the recommended phase 2 dosage of 1200 mg every 2 weeks. The primary end point was the best overall response (by Response Evaluation Criteria in Solid Tumors 1.1 as adjudicated by independent review committee) and was assessed by the objective response rate (ORR). Results: A total of 80 patients were randomized to receive bintrafusp alfa 500 or 1200 mg (n ¼ 40 each). Median follow-up was 51.9 weeks (IQR, 19.6-74.0). The ORR in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 25.0% (10 of 40) for the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), respectively. At the 1200 mg dose, patients with PD-L1-positive and PD-L1-high (80% expression on tumor cells) had ORRs of 36.0% (10 of 27) and 85.7% (six of seven), respectively. Treatment-related adverse events occurred in 55 of the 80 patients (69%) and were graded as greater than or equal to 3 in 23 of the 80 patients (29%). Of the 80 patients, eight (10%) had a treatment-related adverse event that led to treatment discontinuation; no treatment-related deaths occurred. Conclusions: Bintrafusp alfa had encouraging efficacy and manageable tolerability in patients with NSCLC previously treated with platinum.
sFLT01: A Novel Fusion Protein with Antiangiogenic Activity
Molecular Cancer Therapeutics, 2011
sFLT01 is a novel fusion protein that consists of the VEGF/PlGF (placental growth factor) binding domain of human VEGFR1/Flt-1 (hVEGFR1) fused to the Fc portion of human IgG1 through a polyglycine linker. It binds to both human VEGF (hVEGF) and human PlGF (hPlGF) and to mouse VEGF (mVEGF) and mouse PlGF (mPlGF). In vitro, sFLT01 inhibited the proliferation of human umbilical vein endothelial cells and pericytes stimulated by either hVEGF or hPlGF. In vivo, sFLT01 had robust and significant antitumor activity in numerous preclinical subcutaneous tumor models including H460 non–small cell lung carcinoma, HT29 colon carcinoma, Karpas 299 lymphoma, MOLM-13 AML (acute myeloid leukemia), 786-O, and RENCA renal cell carcinoma (RCC). sFLT01 also increased median survival in the orthotopic RENCA RCC model. sFLT01 had strong antiangiogenic activity and altered intratumoral microvessel density, blood vessel lumen size and perimeter, and vascular and vessel areas in RCC models. sFLT01 treatment...
Journal of Oral Pathology and Medicine, 2003
Background: Transforming growth factor b1 (TGFb1) is a negative growth regulator in keratinocytes, and in vitro studies lead to the concept that loss of TGFb1 responsiveness is a critical step in epithelial carcinogenesis. Objective: To investigate the prognostic relevance of TGFb1 expression in head and neck squamous cell carcinoma (HNSCC). Materials and methods: TGFb1 distribution was determined by immunohistochemistry in oral cavity/oropharynx (n ¼ 79), larynx (n ¼ 36) and hypopharynx (n ¼ 25) tumors and in matched normal adjacent mucosa. TGFb-type I and II receptors were determined in 20 cases of differentiated oral cavity/hypopharynx tumors. Cases were considered positive if displaying reactivity in >10% of the cells. Results: TGFb1-positive expression was found in 47.2% of larynx, 36.7% of oral cavity/oropharynx and in 24% of the hypopharynx tumors. Reactivity in >60% of the cells was displayed only by 11.4% of HNSCC. All normal controls were positive. TGFb1positive expression did not correlate with clinico pathological parameters. An association with differentiation was verified only in oral cavity/oropharynx tumors (P 0.001). TGFb1 was also not related to 5 years survival (Kaplan-Meier). Strong and diffuse expression of TGFb-RII was identified in 19/20 cases regardless of TGFb1 immunoreactivity. Out of 17 TGFb1-positive oral cavity/ oropharynx tumors, only nine expressed TGFb-RI suggesting a disruption of the TGFb1 pathway. We conclude that TGFb1 protein immunostaining is not a useful biomarker in assessment of prognosis in HNSCC. Squamous cell carcinomas are the most frequent head and neck neoplasms and the sixth most frequent cancer in the world (1). In Brazil, the disease represents 15.7% of all human primary cancer in men (2). Clinical and pathological parameters are still inadequate for prognostic characterization since patients with equivalent tumor site, TNM stage and pathological variables (differentiation, thickness, vascular embolization, or perineural infiltration) may differ widely in the course of the disease and survival. Thus, the identification of other factors related to the à P-value obtained from chi-square test with significance of 95%. à By Fisher's exact test.
Clinical Cancer Research, 1999
Transforming growth factor (TGF)- is a potent regulator of growth and differentiation in normal squamous epithelium. TGF- exerts its antiproliferative effect via the TGF- type II receptor (TR-II). A decrease in TR-II expression is believed to be responsible, in part, for the resistance of squamous cell carcinoma (SqCC) to the antiproliferative effects of TGF-. In the present study, we used immunohistochemistry and in situ hybridization to analyze the expression of TR-II along the successive oncogenic stages of head and neck squamous neoplasia, from normal epithelium to dysplasia to carcinoma. Quantitation of TR-II expression in 38 SqCCs was assessed on a visual scale ranging from negative (absence of staining) to 3؉ (strong staining). Normal squamous epithelium and squamous epithelium in the vicinity of the tumors showed homogenous receptor expression with moderate intensity. Dysplastic epithelium and carcinoma in situ showed a mild decrease in receptor expression intensity. Well-differentiated to moderately differentiated carcinomas showed heterogeneous expression of variable intensity, and poorly differentiated carcinomas were completely devoid of TR-II. In every tumor, the superficial component showed more intense receptor expression than the invasive component. These results indicate that TR-II expression inversely correlates with disease aggressiveness and suggest that aberrant TR-II expression is a contributing factor to the pathogenesis of SqCC.
Basic fibroblast growth factor and angiogenesis in squamous carcinoma of the tongue
Oral Oncology, 2000
The relationship between basic ®broblast growth factor (bFGF), receptors for bFGF and neoangiogenesis was investigated in 51 patients with squamous cell carcinoma of the tongue, 26 of whom had metastatic disease in cervical lymph nodes. Vessels were demonstrated by immunocytochemical labelling for CD34 and expressed as raw counts and volume-weighted counts. bFGF protein and its receptors FGFR1(¯g) and FGFR2(bek), were demonstrated using immunocytochemical labelling. In situ hybridisation for bFGF mRNA was performed using a 250-bp digoxigenin-labelled RNA probe. In normal epithelium, the expression of bFGF protein and mRNA was more intense in the basal layer, while receptors for bFGF were expressed more strongly in the super®cial parts. In carcinomas, expression of bFGF was greater in the more poorly-dierentiated cells, but showed no relation to the overall tumour dierentiation. There was strong bFGF expression in tumour-in®ltrating lymphocytes. The expression of bFGF receptors was variable, with FGFR2 being particularly high in areas of keratinisation. There were no consistent changes in bFGF or receptor expression between primary carcinomas and their lymph node metastases, and there was no correlation with measures of vascularity or tumour growth pattern. bFGF is synthesised by all squamous carcinomas and has the potential to modulate angiogenesis. However, these data suggest that changes in the expression of bFGF and its receptors are not related to the intensity of neoangiogenesis in lingual carcinomas or their nodal metastases.
Fusion genes in solid tumors: an emerging target for cancer diagnosis and treatment
Chinese Journal of Cancer, 2013
Studies over the past decades have uncovered fusion genes, a class of oncogenes that provide immense diagnostic and therapeutic advantages because of their tumor-specific expression. Originally associated with hemotologic cancers, fusion genes have recently been discovered in a wide array of solid tumors, including sarcomas, carcinomas, and tumors of the central nervous system. Fusion genes are attractive as both therapeutic targets and diagnostic tools due to their inherent expression in tumor tissue alone. Therefore, the discovery and elucidation of fusion genes in various cancer types may provide more effective therapies in the future for cancer patients.