Andra Tilgase

Latvian Biomedical Research and Study Centre

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Pēteris Alberts

Creative Commons

Agnija Rasa

Evija Olmane

Pauls Stradiņš Clinical University Hospital

Sergejs Isajevs

University of Latvia

Linda Brokāne

Guna Proboka

Riga East University Hospital

Katrīna Bandere

Riga East University Hospital

Ilze Blāķe

University of Latvia

Tatjana Zablocka

Riga East University Hospital

Mārtiņs Borodušķis

University of Latvia

Cooperative Institutions

University of Latvia

Pauls Stradiņš Clinical University Hospital

Riga East University Hospital

Latvian Biomedical Research and Study Centre

Riga Stradiņš University

Creative Commons

Uppsala University

Latvia University of Life Sciences and Technologies

Unidad de Cirugía Artroscópica

Foundation for Ichthyosis and Related Skin Types

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Melanoma Unknown Primary Brain Metastasis Treatment with ECHO-7 Oncolytic Virus Rigvir: A Case Report

Frontiers in Oncology (2018)

Guna Proboka Andra Tilgase Sergejs Isajevs Agnija Rasa Pēteris Alberts

Melanoma is considered an aggressive malignancy with a tendency for forming metastasis in the brain. Less than 10% of all melanoma cases present with unknown primary tumor location. This diagnose is yet to be fully understood, because there are only theoretical assumptions about the nature of this disease. Melanoma brain metastases have many severe side effects and unfortunately, any disease related to the brain has limited therapeutic options due to the blood brain barrier. The course of the disease after completing a treatment course, and stopping the treatment, is complicated to predict and is difficult to obtain long-lasting remission. In this report we describe a female patient with unknown primary melanoma brain metastasis being treated with the oncolytic ECHO-7 virus Rigvir® after brain surgery. The patient has been stable, as monitored by MRI, for more than 3 years with the therapy still ongoing. The median expected overall survival from the time of diagnosis is approximately five months. Additional positive effect could have been gained from use of the intranasal administration route, which is considered effective due to the direct anatomical connection between the nasal cavity and the central nervous system. However, further studies are required to fully understand this mode of drug administration.

Neuroradiology

10.3389/fonc.2018.00043

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The advent of oncolytic virotherapy in oncology: The Rigvir® story

European Journal of Pharmacology (2018)

Pēteris Alberts Andra Tilgase Agnija Rasa Katrīna Bandere Dite Venskus

Oncolytic viruses are a fast-developing cancer treatment field. Numerous viruses have been tested in clinical trials and three are approved. The first, Rigvir, is an immunomodulator with anti-tumour effect for treatment of melanoma, local treatment of skin and subcutaneous metastases of melanoma, for prevention of relapse and metastasis after radical surgery registered in Latvia, Georgia, Armenia and Uzbekistan. The aim of the present review is to summarize the development of Rigvir. Approximately 60 viruses were screened preclinically. Clinical safety and efficacy trials were with 5 oncolytic enteroviruses. Safety of the selected and melanoma-adapted ECHO-7 virus Rigvir was tested in over 180 patients with no severe adverse events observed. Pre-registration efficacy studies involved over 700 cancer patients: over 540 melanoma patients, and patients with late stage stomach (ca. 90), colorectal cancer (ca. 60), and other cancers. Patients were treated with Rigvir for 3 years after surgery and compared to immunotherapy: 3- and 5-year overall survival appeared to be increased in Rigvir treated patients. In post-marketing retrospective studies, Rigvir-treated stage II melanoma patients showed a 6.67-fold decreased risk for disease progression in comparison to those that had been observed according to guidelines, and stage IB and stage II melanoma patients that had received Rigvir therapy had 4.39-6.57-fold lower mortality. The results are confirmed and extended by case reports. Several immunological markers have been measured. In conclusion, Rigvir is an oncotropic and oncolytic virus for treatment of melanoma; the results will be confirmed and updated by modern clinical studies.

Virotherapy

10.1016/j.ejphar.2018.08.042

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A Case of Stage IV Chromophobe Renal Cell Carcinoma Treated with the Oncolytic ECHO-7 Virus, Rigvir®

American Journal of Case Reports (2019)

Zaurbek Ismailov Agnija Rasa Katrīna Bandere Linda Brokāne Andra Tilgase

BACKGROUND Renal cell carcinoma is the most commonly diagnosed primary malignant tumor of the kidney in adults, and includes the variant of chromophobe renal cell carcinoma. Despite new targeted therapies that improve progression-free survival (PFS) and overall survival (OS) for early-stage renal cell carcinoma, the 5-year survival for patients with stage IV renal cell carcinoma remains below 10%, and the 50% OS is less than one year. Metastatic renal cell carcinoma can be resistant to cytotoxic chemotherapy. This report is of a case of stage IV chromophobe renal cell carcinoma that responded well to treatment with the oncolytic ECHO-7 virus, Rigvir®. CASE REPORT In December 2015, a 59-year-old man presented with a right-sided chromophobe renal cell carcinoma stage IV (pT₁N₀M₁) with adrenal gland metastasis. He underwent right nephro-adrenalectomy followed by treatments with Rigvir® (≥10⁶ TCID₅₀/ml) by intramuscular (i.m.) injection on three consecutive days. Treatment with Rigvir® continued once per week for three months, and from March 2016, once per month, with continued treatment until computed tomography (CT) scans confirmed that the tumor metastases had stabilized. CONCLUSIONS This case report has demonstrated that the oncolytic ECHO-7 virus, Rigvir® should be evaluated further as a potential treatment for advanced renal carcinoma.

Echo (communications protocol)

Chromophobe cell

10.12659/ajcr.912115

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Citations (8)

The oncolytic effect of the ECHO-7 virus Rigvir® on cell viability in vitro

Intrinsic Activity (2017)

Andra Tilgase

Echo (communications protocol)

Viability assay

10.25006/ia.5.s2-a2.50

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Adrenal Gland and Gastric Malignant Melanoma without Evidence of Skin Lesion Treated with the Oncolytic Virus Rigvir

Case Reports in Oncology (2020)

Guna Proboka Andra Tilgase Sergejs Isajevs Tatjana Zablocka Evija Olmane

Adrenal gland melanoma is an extremely rare diagnosis with less than 20 cases reported. The criteria for diagnosing adrenal gland melanoma include involvement of only one adrenal gland, presence of melanin pigment in the histological examination of the tumor tissue, no primary melanoma tumor in any other organ, and no history of resection of pigmented lesions. However, it is complicated to rule out melanoma of unknown primary origin. Here we report a female patient who at the age of 75 years was admitted to hospital due to suspicion of adrenal and gastric tumor. The largest tumor was found in the adrenal gland, thus leading to the diagnosis of primary adrenal gland melanoma presenting metastases in the stomach. The melanoma was BRAF wild type. Due to the rarity of this disease, there is no standard treatment. After two subsequent surgeries, treatment with the ECHO-7 oncolytic virus Rigvir was started. The patient has received oncolytic virotherapy for 5 years and 1 month and has been stable since then with good tolerability. The therapy is still ongoing. Adrenal gland melanoma is an extremely rare diagnosis and therefore it is important to discuss the diagnostic criteria and possible treatments.

Amelanotic melanoma

10.1159/000506978

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A progressive stage IIIB melanoma treated with oncolytic ECHO-7 virus: A case report

SAGE Open Medical Case Reports (2020)

Vladimirs Sorokins Andra Tilgase Evija Olmane Sergejs Isajevs Tatjana Zablocka

Melanoma is an aggressive skin cancer form with a grave prognosis. Current results suggest that oncolytic virus treatment of melanoma has a high therapeutic potential. ECHO-7 (Rigvir) is the first oncolytic virus registered in Latvia. A female patient was diagnosed with stage IIIB melanoma in December 2012, over 9.4 years ago. After the first excision and re-excision, the patient had several recurrences and disease progressions. After the patient had received surgical treatment in 2014, ECHO-7 virus oncolytic virotherapy was started. Since then, the patient has experienced only one more disease progression episode in May 2015 and has been stable for over 60 months. The patient has not received any other treatment than surgery and oncolytic virotherapy. No severe adverse events have been reported during virotherapy. The present case suggests that ECHO-7 virotherapy is an effective treatment of skin melanoma.

Virotherapy

10.1177/2050313x20934978

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Treatment of a stage III rima glottidis patient with the oncolytic virus Rigvir

Medicine (2019)

Guna Proboka Agnija Rasa Evija Olmane Sergejs Isajevs Andra Tilgase

Of all the parts of the larynx, the glottis has the highest frequency of cancer. With disease progression, the vocal cord movement is affected and for advanced stages its anatomical and functional preservation is rarely achievable, if at all.Here we describe a 72-year-old patient who presented with hoarseness for a year and was only able to whisper.A computed tomography (CT) scan of the vocal cords (without contrast) showed higher density tissue. Histological examination disclosed a well-differentiated verrucous squamous cell carcinoma of the glottis.The patient was treated with the oncolytic ECHO-7 virus Rigvir without any of the standard treatments.As shown by CT scans, the patient has been stabilized, and the laryngeal functions are preserved with the virotherapy still ongoing. The patient was diagnosed over 4.2 years ago.Considering the present patient being treated with Rigvir without any standard treatment, the results suggest that Rigvir therapy could be a possible treatment for glottic cancer.

Virotherapy

10.1097/md.0000000000017883

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Effect of the oncolytic ECHO-7 virus Rigvir® on the viability of cell lines of human origin in vitro

Journal of Cancer (2018)

Andra Tilgase Liene Patetko Ilze Blāķe Anna Ramata‐Stunda Mārtiņs Borodušķis

Background:The role of oncolytic viruses in cancer treatment is increasingly studied.The first oncolytic virus (Rigvir®, ECHO-7) was registered in Latvia over a decade ago.In a recent retrospective study Rigvir® decreased mortality 4.39-6.57-fold in stage IB-IIC melanoma patients.The aims of the present study are to test the effect of Rigvir® on cell line viability in vitro and to visualize the cellular presence of Rigvir® by immunocytochemistry.Methods: The cytolytic effect of Rigvir® on the viability of FM-9, RD, AGS, A549, HDFa, HPAF-II, MSC, MCF7, HaCaT, and Sk-Mel-28 cell lines was measured using live cell imaging.PBMC viability was measured using flow cytometry.The presence of ECHO-7 virus was visualized using immunocytochemistry.Statistical difference between treatment groups was calculated using two-way ANOVA.Results: Rigvir® (10%, volume/volume) reduced cell viability in FM-9, RD, AGS, A549, HDFa, HPAF-II and MSC cell lines by 67-100%.HaCaT cell viability was partly affected while Rigvir® had no effect on MCF7, Sk-Mel-28 and PBMC viability.Detection of ECHO-7 by immunocytochemistry in FM-9, RD, AGS, A549, HDFa, HPAF-II and Sk-Mel-28 cell lines suggests that the presence of Rigvir® in the cells preceded or coincided with the time of reduction of cell viability.Rigvir® (10%) had no effect on live PBMC count. Conclusions:The results suggest that Rigvir® in vitro reduces the viability of cells of human melanoma, rhabdomyosarcoma, gastric adenocarcinoma, lung carcinoma, pancreas adenocarcinoma but not in PBMC.The presence of Rigvir® in the sensitive cells was confirmed using anti-ECHO-7 antibodies.The present results suggest that a mechanism of action for the clinical benefit of Rigvir® is its cytolytic properties.The present results suggest that the effect of Rigvir® could be tested in other cancers besides melanoma.Further studies of possible Rigvir® entry receptors are needed.

Viability assay

10.7150/jca.23242

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Combination treatment with nivolumab and Rigvir of a progressive stage IIC skin melanoma patient

Clinical Case Reports (2019)

Linda Brokāne Inta Jaunalksne Andra Tilgase Evija Olmane Donatas Petroška

A 35-year-old male patient was diagnosed with stage IIC skin melanoma that rapidly progressed after surgery. Treatment was continued with radiotherapy, which did not stop further spread of disease and the patient was put on a combination of nivolumab and Rigvir. Subsequently, the progression has slowed.

10.1002/ccr3.2182

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Citations (2)

Hydroxycarboxylic Acid Receptor Ligands Modulate Proinflammatory Cytokine Expression in Human Macrophages and Adipocytes without Affecting Adipose Differentiation

Biological and Pharmaceutical Bulletin (2018)

Ilona Mandrika Andra Tilgase Ramona Petrovska Jānis Kloviņš

Members of the hydroxycarboxylic acid receptor (HCA1-3) family are mainly expressed in adipocytes and immune cells. HCA2 ligand, niacin, has been used for decades as lipid-modifying drug. Recent studies suggest that HCA ligands can be involved in the modulation of inflammatory processes. In this study, we evaluated the effects of HCA1-3 ligands on adipose differentiation and cytokine expression in human adipocytes and macrophages. Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes were induced to differentiate into adipocytes for 8 d in the presence or absence of HCA ligands and evaluated for lipid accumulation and adipogenic gene expression. The inhibitory effects of the ligands on the expression and production of cytokines were measured in lipopolysaccharide (LPS)-stimulated adipocytes and THP-1 macrophage cells. Preadipocytes treated with HCA ligands showed no changes in the capacity to differentiate into adipocytes and no significant alteration in peroxisome proliferator activated receptor γ (PPARγ) or its target gene expression. HCA2-3 ligands significantly downregulated LPS-induced expression of interleukin (IL)-6 (53-64%), tumor necrosis factor-α (TNF-α) (55-69%) and IL-8 (51-59%) in adipocytes and macrophages. IL-1β inhibition (58-68%) by HCA2-3 ligands was observed only in adipocytes. Furthermore, LPS increased the expression of HCA2-3 in adipocytes and macrophages and this expression was decreased by treatment with their ligands. These results suggest that HCA ligands modulated LPS-mediated pro-inflammatory gene expression in both macrophages and adipocytes without affecting adipogenesis. Therefore, targeting HCA2 and HCA3 would be beneficial in treating inflammation conditions associated with atherosclerosis and obesity.

Proinflammatory cytokine

Cytokine receptor

10.1248/bpb.b18-00301

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Citations (13)