Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM‐CSF: Results in vitro, in rodents and in humans

• Published in: International journal of cancer 2015-10, Vol.137 (7), p.1775-1783
• Main Authors: Bramante, Simona, Kaufmann, Johanna K., Veckman, Ville, Liikanen, Ilkka, Nettelbeck, Dirk M., Hemminki, Otto, Vassilev, Lotta, Cerullo, Vincenzo, Oksanen, Minna, Heiskanen, Raita, Joensuu, Timo, Kanerva, Anna, Pesonen, Sari, Matikainen, Sampsa, Vähä‐Koskela, Markus, Koski, Anniina, Hemminki, Akseli
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenovirus; Animals; Cancer; Cell Differentiation - physiology; Cell Line, Tumor; combination treatment; Cricetinae; cyclophosphamide; Cyclophosphamide - pharmacology; Female; GM‐CSF; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocytes; Humans; immunotherapy; Macrophages - pathology; Macrophages - virology; Medical research; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - therapy; Melanoma - virology; Mice; Mice, Nude; Monocytes - pathology; Monocytes - virology; oncolytic adenovirus; Oncolytic Virotherapy - methods; Random Allocation; Skin cancer; Viruses; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29536

Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as immune‐checkpoint‐inhibiting antibodies or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno‐virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial. We investigated the potency of oncolytic adenovirus Ad5/3‐D24‐GMCSF on a panel of melanoma cell lines and animal models, and summarized the melanoma‐specific human data from the Advanced Therapy Access Program (ATAP). The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK‐MEL‐28 melanoma xenografts in nude mice when combined with low‐dose cyclophosphamide. Furthermore, virally‐expressed granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. In ATAP, treatments appeared safe and well‐tolerated. Four out of nine melanoma patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, two had stable disease, and one had progressive disease. Two patients were alive at 559 and 2,149 days after treatment. Ad5/3‐D24‐GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma. What's new? Oncolytic viruses hold great potential in cancer therapy, particularly for their ability to carry genes that encode molecules capable of stimulating immunity against cancer. In this study, the authors evaluated an oncolytic adenovirus that carries the gene for granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), with positive results for the treatment of melanoma. The GM‐CSF‐expressing virus successfully produced an antitumor immune response, evidenced in cells by the differentiation of human monocytes into macrophages and in animals by the eradication of melanoma xenografts. In human melanoma patients, the treatm