Abstract 3304: Oncolytic adenovirus with low-dose temozolomide induces autophagy and antitumor immune responses preclinically and in cancer patients

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.3304-3304
• Main Authors: Liikanen, Ilkka, Ahtiainen, Laura, Hirvinen, Mari L.M, Barmante, Simona, Cerullo, Vincenzo, Nokisalmi, Petri, Hemminki, Otto, Diaconu, Iulia, Pesonen, Sari, Koski, Anniina, Kangasniemi, Lotta, Pesonen, Saila K., Oksanen, Minna, Zhao, Fang, Laasonen, Leena, Partanen, Kaarina, Joensuu, Timo, Kanerva, Anna, Hemminki, Akseli
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-3304

Tumor cell autophagy appears useful for cancer therapeutics due to immunogenic cell death and possible induction of antitumor immunity. Oncolytic adenoviruses and alkylating chemotherapeutic temozolomide have been shown to induce autophagic cell death preclinically. We studied safety, efficacy and immunological effects of oncolytic adenovirus combined with low-dose pulse of temozolomide. Metronomic low-dose cyclophosphamide was added to treatments to selectively reduce regulatory T-cells. We assessed the combination of oncolytic adenovirus with low-dose temozolomide and cyclophosphamide in breast and prostate cancer cells in vitro. Immunogenicity of cell death was studied by calreticulin exposure, adenosine triphosphate release, and nuclear protein high-mobility group box-1 (HMGB1) secretion assays. Efficacy was further tested in a prostate cancer xenograft mouse model, and tumors were assessed for autophagy by electron microscopy and LC3-immunohistochemistry. Furthermore, 41 combination treatments were given to 17 chemotherapy-refractory cancer patients in the context of an advanced therapy access program. The primary end-point was safety. In addition, autophagy assays, immunological analyses, and efficacy parameters were studied. Combination therapy resulted in increased cytotoxicity and immunogenic cell death. Autophagy induction was associated with enhanced tumor-growth inhibition in combination-treated prostate tumors (P