Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors
| Autor: | Petri Nokisalmi, Satu Kauppinen, Vincenzo Cerullo, Lotta Kangasniemi, Gianpietro Dotti, Anna Kanerva, Sophie Escutenaire, Iulia Diaconu, Akseli Hemminki, Eerika Karli, Kaarina Partanen, Sari Pesonen, Elina Haavisto, Aila Karioja-Kallio, Sirkka Liisa Holm, Leena Laasonen, Timo Joensuu, Minna Oksanen, Päivi Hannuksela, Mari Raki, Kilian Guse |
|---|---|
| Přispěvatelé: | Pesonen, Sari, Diaconu, Iulia, Cerullo, Vincenzo, Escutenaire, Sophie, Raki, Mari, Kangasniemi, Lotta, Nokisalmi, Petri, Dotti, Gianpietro, Guse, Kilian, Laasonen, Leena, Partanen, Kaarina, Karli, Eerika, Haavisto, Elina, Oksanen, Minna, Karioja-Kallio, Aila, Hannuksela, Päivi, Holm, Sirkka-Liisa, Kauppinen, Satu, Joensuu, Timo, Kanerva, Anna, Hemminki, Akseli |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Integrins Cancer Research viruses medicine.medical_treatment Integrin Virus Replication 0302 clinical medicine Cancer immunotherapy Neoplasms Antineoplastic Combined Chemotherapy Protocols Fatigue Oncolytic Virotherapy 0303 health sciences ELISPOT Middle Aged Viral Load 3. Good health Oncolytic Viruses Treatment Outcome Oncology 030220 oncology & carcinogenesis Oligopeptide Female Genetic Vector Oligopeptides Human Oncolytic adenovirus Adult Fever Genetic Vectors Oncolytic Viruse Real-Time Polymerase Chain Reaction Adenoviridae 03 medical and health sciences Immune system Cell Line Tumor medicine Humans 030304 developmental biology Tumor marker Aged Chemotherapy Antineoplastic Combined Chemotherapy Protocol business.industry Cancer Granulocyte-Macrophage Colony-Stimulating Factor medicine.disease Oncolytic virus Drug Resistance Neoplasm Immunology DNA Viral Cancer research Neoplasm business |
| Popis: | The safety of oncolytic viruses for treatment of cancer has been shown in clinical trials while antitumor efficacy has often remained modest. As expression of the coxsackie-adenovirus receptor may be variable in advanced tumors, we developed Ad5-D24-RGD, a p16/Rb pathway selective oncolytic adenovirus featuring RGD-4C modification of the fiber. This allows viral entry through alpha-v-beta integrins frequently highly expressed in advanced tumors. Advanced tumors are often immunosuppressive which results in lack of tumor eradication despite abnormal epitopes being present. Granulocyte-macrophage colony stimulating factor (GMCSF) is a potent activator of immune system with established antitumor properties. To stimulate antitumor immunity and break tumor associated immunotolerance, we constructed Ad5-RGD-D24-GMCSF, featuring GMCSF controlled by the adenoviral E3 promoter. Preliminary safety of Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of human cancer was established. Treatments with Ad5-D24-RGD (N = 9) and Ad5-RGD-D24-GMCSF (N = 7) were well tolerated. Typical side effects were grade 1-2 fatigue, fever and injection site pain. 77% (10/13) of evaluable patients showed virus in circulation for at least 2 weeks. In 3 out of 6 evaluable patients, disease previously progressing stabilized after a single treatment with Ad5-RGD-D24-GMCSF. In addition, 2/3 patients had stabilization or reduction in tumor marker levels. All patients treated with Ad5-D24-RGD showed disease progression in radiological analysis, although 3/6 had temporary reduction or stabilization of marker levels. Induction of tumor and adenovirus specific immunity was demonstrated with ELISPOT in Ad5-RGD-D24-GMCSF treated patients. RGD modified oncolytic adenoviruses with or without GMCSF seem safe for further clinical development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|