Oncolytic virus preclinical toxicology studies.

With the ever-emerging concerns of patient safety during medical care, the search for treatments as safe as possible is a priority, especially when focusing on cancer treatment of which therapies often go hand in hand with severe side effects. Oncolytic virotherapy is an emerging treatment for cancer that is promising in both safety and efficacy. Many currently ongoing clinical trials demonstrate the growing interest in this field. To conduct clinical trials, preclinical studies are mandatory; however, there are not many reviews of toxicology studies on oncolytic virus therapies. This article summarizes the preclinical toxicology studies of the most well studied oncolytic viruses, including Oncorine, Talimogene laherparepvec, Cavatak, ONYX-015, teserpaturev and Rigvir, a non-pathogenic ECHO-7 virus. It is concluded that oncolytic viruses have been shown to have low toxicity and high tolerability in preclinical toxicology studies.

Stage IIA Skin Melanoma Treatment With ECHO-7 Oncolytic Virus Rigvir.

Melanoma is a global problem due to the rising numbers of skin melanoma cases. Current treatment guidelines for patients with stage IIA melanoma recommend only observation after surgery. In this report, the authors describe a patient with stage IIA skin melanoma treated with surgery and Rigvir virotherapy. Two years after the patient discovered a brown spot on the right cheek, surgery was indicated because the mass had started to ulcerate. Rigvir virotherapy was applied both before and after surgery. Observations made more than 7 years after surgery indicated no signs of disease progression. This case report illustrates an early treatment approach. Neoadjuvant treatment for early-stage melanoma is gaining more interest in both scientific and medical communities; therefore, the authors believe it is relevant to share their observations.

4-Week repeated dose rat GLP toxicity study of oncolytic ECHO-7 virus Rigvir administered intramuscularly with a 4-week recovery period.

The oncolytic ECHO-7 virus Rigvir was registered in Latvia in 2004 and later in Georgia, Armenia and Uzbekistan. No severe adverse events have been observed. During drug development good laboratory practice (GLP) pre-clinical toxicology studies are generally required by regulatory agencies. Since such studies had previously not been performed, the aim of this 4-week repeated dose GLP toxicity study was to determine the potential toxicity, and reversibility of any findings after a 4-week treatment-free period. Han-Wistar rats were randomly assigned to control, Rigvir (2×106, 1×107 and 2×107 TCID50) groups. Intramuscular administration was on days 1-3, 8-10, 15-17, and 22-24. Clinical signs, average food-intake, body weights, ophthalmology, clinical pathology parameters, bioanalysis, gross necropsy, organ weights, biodistribution and histopathology were evaluated. There were no unscheduled deaths, adverse clinical signs, no changes in body weight, body weight gain, food intake, ophthalmoscopy, clinical pathology, urine volume or composition, or organ weights. Slightly higher numbers of eosinophils in Rigvir treated animals returned to normal after recovery. Rigvir biodistributed to the spleen. Low incidence of inflammatory cell infiltration at administration sites and increased lymphoid cellularity at the regional (inguinal and popliteal) lymph nodes were observed; after recovery, only those in popliteal lymph nodes remained. Therefore, 4-week Rigvir at 2×107 TCID50 administration was well tolerated in rats. The no-observed-adverse-effect level (NOAEL) was the highest dose tested, 2×107 TCID50. OBJECTIVES: The objectives of this study were to determine the potential toxicity of Rigvir, an ECHO-7 oncolytic virus, when administered intramuscularly for 4 weeks to rats, with a 4-week recovery period, and to evaluate the reversibility of any potential findings. In addition, the biodistribution of Rigvir in selected tissues was determined.

Management of a primary malignant melanoma of uterine cervix stage IVA patient with radical surgery and adjuvant oncolytic virus Rigvir® therapy: A case report.

Primary malignant melanoma of the uterine cervix is a rare disease with poor prognosis and high recurrence rate. We used Rigvir® as adjuvant therapy for a stage IVA patient. Tolerability, overall and progression-free survival are good.

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

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.

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

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.

Effect of oncolytic ECHO-7 virus strain Rigvir on uveal melanoma cell lines.

OBJECTIVE: Uveal melanoma is a rare intraocular malignancy. Half of the patients diagnosed will develop metastases within 10 to 30 years, most commonly in the liver. Although there has been a significant development in the treatment of melanoma, no effective treatment to prevent or treat metastases of uveal melanoma is available. Oncolytic viruses are now being studied for various types of cancers and show promising results. Preclinical results show cytolytic activity of enteric cytopathic human orphan virus type 7 (ECHO-7) strain Rigvir in human melanoma, rhabdomyosarcoma, gastric adenocarcinoma, lung carcinoma and pancreas adenocarcinoma cell lines. The aim of this study was to test the possible cytolytic activity in human uveal melanoma cell lines. RESULTS: The results suggest cytolytic activity of oncolytic ECHO-7 virus strain Rigvir in MP41, 92-1 and Mel-202 cell lines.

ECHO-7 oncolytic virus Rigvir® in an adjuvant setting for stage I uveal melanoma; A retrospective case report.

PURPOSE: To describe a case of choroidal melanoma treated with Rigvir® virotherapy in an adjuvant setting. OBSERVATIONS: A female patient born in 1956 presented with a small choroidal melanoma in October 2007. 34 months after transpupillary thermotherapy the state of her eye worsened until tumor growth was visualized. Despite photodynamic therapy and transpupillary thermotherapy the tumor continued to grow locally. In October 2016 enucleation was performed. Since gene expression profile testing disclosed a tumor (class 2) with a high risk of metastasis formation in 5 years, the patient sought options to prevent progression of the disease. In December 2016 virotherapy with Rigvir® was started with 3 administrations for 3 consecutive days. Therapy was continued once per week until March 2017, when the administrations were changed to once per month. The patient is being monitored by an ophthalmologist. She is stable with the virotherapy ongoing and magnetic resonance cholangiopancreatography (7 May 2018) and abdominal ultrasound (23 March 2019) imaging excludes metastasis formation. The quality of life is high. CONCLUSIONS: To the best of our knowledge, this is the first documented case of uveal melanoma treatment with virotherapy as an adjuvant therapy. Considering the few if any available treatments and the encouraging results of the present treatment, virotherapy should be evaluated more extensively as a potential treatment of uveal melanoma.

Treatment of a stage III rima glottidis patient with the oncolytic virus Rigvir: A retrospective case report.

RATIONALE: 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. PATIENT CONCERNS: Here we describe a 72-year-old patient who presented with hoarseness for a year and was only able to whisper. DIAGNOSIS: 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. INTERVENTIONS: The patient was treated with the oncolytic ECHO-7 virus Rigvir without any of the standard treatments. OUTCOMES: 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. LESSONS: 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.

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

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.

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

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.

Multimodality Treatment of a Colorectal Cancer Stage IV Patient with FOLFOX-4, Bevacizumab, Rigvir Oncolytic Virus, and Surgery.

Colorectal cancer is one of the most commonly diagnosed cancers worldwide. The treatment consists of surgical resection, systemic chemotherapy, and new biological agents. One more recently emerging treatment option is oncolytic virotherapy. Although the use of the new treatment methods shows improved overall and progression-free survival, in general, even with the new treatments, mortality remains high and combinations of treatments should be sought to treat patients with colorectal cancer. Here we report a stage IV colorectal cancer patient who received multimodality treatment including bevacizumab, FOLFOX-4, surgery, and the oncolytic virus Rigvir. The patient shows complete pathological remission and remains stable 7.7 years after initial diagnosis. The possible benefits of combining Rigvir oncolytic virus and bevacizumab should be investigated since in vitro research suggests that anti-angiogenesis agents improve viral distribution by altering the microenvironment of the tumor.

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

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.

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

Melanoma is considered an aggressive malignancy with a tendency of 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 the 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 a treatment course is complicated to predict, and it is difficult to obtain long-lasting remission. In this report, we describe a female patient with unknown primary melanoma brain metastasis treated with the oncolytic ECHO-7 virus Rigvir® after brain surgery. The patient has been stable, as monitored by magnetic resonance imaging, for more than 3.8 years with ongoing therapy. The median expected overall survival from the time of diagnosis is approximately 5 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.