Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as ipilimumab 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 in combination with low-dose cyclophosphamide, 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. Four out of nine melanoma patients treated in ATAP were evaluable for possible therapy benefit with modified Response Evaluation Criteria In Solid Tumors (RECIST): one patient had minor response, two had stable disease, and one had progressive disease. Treatments appeared safe and well-tolerated. Two patients were alive at 559 and 1501 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.
Citation Format: Simona Bramante, Johanna K. Kaufmann, Ville Veckman, Dirk M. Nettelbeck, Otto Hemminki, Ilkka Liikanen, Lotta Vassilev, Vincenzo Cerullo, Minna Oksanen, Raita Heiskanen, Timo Joensuu, Anna Kanerva, Sari Pesonen, Markus Vähä-Koskela, Anniina Koski, Akseli Hemminki. Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B51.