thromboplastin and Uterine-Cervical-Neoplasms

To review and compare the pharmacology, efficacy, and safety of the novel tissue factor antibody-drug conjugate, tisotumab vedotin.. Literature search was performed through PubMed MEDLINE, Google Scholar, ClinicalTrials.gov, and the Food and Drug Administration.. Tisotumab vedotin, a novel tissue factor antibody-drug conjugate, was granted accelerated approval by the US FDA on 20 September 2021 for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Tisotumab vedotin demonstrated clinical efficacy in a number of solid tumors in innovaTV 201 and more specifically in cervical cancer in the pivotal phase 2 innovaTV 204. In the single-arm innovaTV 204 study, 101 patients with recurrent or metastatic cervical cancer received intravenous tisotumab vedotin at the recommended dose of 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The independent review committee confirmed an objective response rate of 24% with 7% complete responses and 17% partial responses. Tisotumab vedotin is associated with several notable adverse events with data from innovaTV 204 including ocular toxicity, hemorrhage, and peripheral neuropathy. Ninety-two percent of patients experienced treatment-related adverse events with 28% experiencing an adverse event of grade 3 or higher.. Metastatic cervical cancer has a high risk of relapse with few effective second-line therapeutic options. Current guidelines recommend single agent tisotumab vedotin as a possible option. Ongoing trials will further define its place in therapy.

Topics: Adult; Disease Progression; Female; Humans; Immunoconjugates; Neoplasm Recurrence, Local; Thromboplastin; United States; Uterine Cervical Neoplasms

Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with primary metastatic disease. Moreover, one-third of the patients receiving chemoradiation followed by brachytherapy for locally advanced disease will have a recurrence. At the end, the vast majority of recurrent or metastatic CC not amenable to locoregional treatments are considered incurable disease with very poor prognosis. Historically, cisplatin monotherapy, then a combination of cisplatin and paclitaxel were considered the standard of care. Ten years ago, the addition of bevacizumab to chemotherapy demonstrated favorable data in terms of response rate and overall survival. Even with this improvement, novel therapies are needed for the treatment of recurrent CC in first as well as later lines. In the last decades, a better understanding of the interactions between human papillomavirus infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients. Indeed, immune checkpoint inhibitors (pembrolizumab, cemiplimab, and others) have recently emerged as novel therapeutic pillars that could provide durable responses with impact on overall survival in patients in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings. Tisotumab vedotin, an antibody-drug conjugate targeting the tissue factor, is another emerging drug. Several trials in monotherapy or in combination with immunotherapy, chemotherapy, or bevacizumab showed very promising results. There is a high need for more potent biomarkers to better accurately determine which patients would receive the greatest benefit from all these aforementioned drugs, but also to identify patients with specific molecular characteristics that could benefit from other targeted therapies. The Cancer Genome Atlas Research Network identified several genes significantly mutated, potentially targetable. These molecular data have highlighted the molecular heterogeneity of CC.

Topics: Bevacizumab; Biomarkers; Cisplatin; Female; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Neoplasm Recurrence, Local; Paclitaxel; Papillomavirus Vaccines; Thromboplastin; Uterine Cervical Neoplasms

Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population.. This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396.. 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes.. Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer.. Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

Topics: Adult; Antibodies, Monoclonal, Humanized; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oligopeptides; Thromboplastin; Uterine Cervical Neoplasms

Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like-molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology.. Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the in vitro expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT-PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated-cytotoxicity (IDCC) was evaluated in 5-hrs-51chromium-release-assays against cervical cancer cell lines in vitro.. Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real-time-PCR and flow cytometry but not in normal cervical keratinocytes (p=0.0023 qRT-PCR; p=0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing±SD, 56.2%±15.9%, range, 32.4%-76.9%, p<0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab-control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (p=0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (p=0.597).. TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of cervical cancer refractory to standard treatment modalities.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Cell Line, Tumor; Complement System Proteins; Cytotoxicity Tests, Immunologic; Drug Screening Assays, Antitumor; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunoconjugates; Immunoglobulin G; Immunotherapy; Interleukin-2; Keratinocytes; Molecular Targeted Therapy; Neoplasm Proteins; Neovascularization, Pathologic; Papillomavirus Infections; RNA, Messenger; RNA, Neoplasm; Thromboplastin; Uterine Cervical Neoplasms

TF is highly expressed in cancerous and atherosclerotic lesions. Monocyte recruitment is a hallmark of disease progression in these pathological states.. To examine the role of integrin signaling in TF-dependent recruitment of monocytes by endothelial cells.. The expression of flTF and asTF in cervical cancer and atherosclerotic lesions was examined. Biologic effects of the exposure of primary microvascular endothelial cells (MVEC) to truncated flTF ectodomain (LZ-TF) and recombinant asTF were assessed.. flTF and asTF exhibited nearly identical expression patterns in cancer lesions and lipid-rich plaques. Tumor lesions, as well as stromal CD68(+)  monocytes/macrophages, expressed both TF forms. Primary MVEC rapidly adhered to asTF and LZ-TF, and this was completely blocked by anti-β1 integrin antibody. asTF- and LZ-TF-treatment of MVEC promoted adhesion of peripheral blood mononuclear cells (PBMCs) under orbital shear conditions and under laminar flow; asTF-elicited adhesion was more pronounced than that elicited by LZ-TF. Expression profiling and western blotting revealed a broad activation of cell adhesion molecules (CAMs) in MVEC following asTF treatment including E-selectin, ICAM-1 and VCAM-1. In transwell assays, asTF potentiated PMBC migration through MVEC monolayers by ∼3-fold under MCP-1 gradient.. TF splice variants ligate β1 integrins on MVEC, which induces the expression of CAMs in MVEC and leads to monocyte adhesion and transendothelial migration. asTF appears more potent than flTF in eliciting these effects. Our findings underscore the pathophysiologic significance of non-proteolytic, integrin-mediated signaling by the two naturally occurring TF variants in cancer and atherosclerosis.

Topics: Alternative Splicing; Blotting, Western; Cell Adhesion Molecules; Cells, Cultured; Endothelium, Vascular; Female; Humans; Integrins; Monocytes; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thromboplastin; Uterine Cervical Neoplasms

Immunological status, levels of pro-inflammatory cytokines of non-specific resistance and tumor expression factor have been studied in patients with cervical dysplasia or cancer versus stage. Slight and moderate dysplasia involved virtually no changes in interleukin-8 (Il-8) and tumor necrotic factor TNF-alpha concentrations whereas those of Il-1 alpha and Il-1 beta were 5 times as high. Monocyte-dependent expression of tissue factor was similar to that in healthy women. In cases of advanced dysplasia and cervical carcinoma, monocyte-dependent expression of tissue factor and production of Il-1 alpha, Il-1 beta, Il-8 and TNF-alpha were significantly enhanced. Patients with cervical carcinoma stage II and III revealed signs of depression of the cellular component of immunity as well as non-specific resistance. Hence, increased concentrations of cytokines induce monocyte-dependent expression of tissue factor in advanced dysplasia and cervical carcinoma by triggering-on of hypercoaggulation.

Topics: Adult; Cytokines; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-1; Interleukin-8; Middle Aged; Neoplasm Staging; Thrombophilia; Thromboplastin; Tumor Necrosis Factor-alpha; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Topics: Abortion, Induced; Adenocarcinoma; Blood Coagulation Disorders; Carcinoma in Situ; Carcinoma, Squamous Cell; Curettage; Dilatation; Embryo, Mammalian; Female; Fetus; Gestational Age; Humans; Hypernatremia; Hypertonic Solutions; Lymphatic Metastasis; Oxytocin; Pregnancy; Prognosis; Thromboplastin; United States; Uterine Cervical Neoplasms; Uterine Neoplasms; Vaginal Smears