Oncolytic Adenovirus With Temozolomide Induces Autophagy and Antitumor Immune Responses in Cancer Patients

• Published in: Molecular therapy 2013-06, Vol.21 (6), p.1212-1223
• Main Authors: Liikanen, Ilkka, Ahtiainen, Laura, Hirvinen, Mari LM, Bramante, Simona, Cerullo, Vincenzo, Nokisalmi, Petri, Hemminki, Otto, Diaconu, Iulia, Pesonen, Sari, Koski, Anniina, Kangasniemi, Lotta, Pesonen, Saila K, Oksanen, Minna, Laasonen, Leena, Partanen, Kaarina, Joensuu, Timo, Zhao, Fang, Kanerva, Anna, Hemminki, Akseli
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Adenosine Triphosphate - metabolism; Adenoviridae - genetics; Adenoviridae - physiology; Adenovirus; Adenoviruses; Adolescent; Adult; Aged; Animals; Antibodies, Neutralizing - blood; Antineoplastic Agents - pharmacology; Autophagy; Autophagy - drug effects; Calreticulin - metabolism; Cancer therapies; Cell death; Cell Death - drug effects; Cell Line, Tumor; Child; Combined Modality Therapy - methods; Cyclophosphamide - pharmacology; Cytokines - blood; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; DNA, Viral - blood; Dose-Response Relationship, Drug; Female; Gene therapy; HMGB1 Protein - blood; HMGB1 Protein - secretion; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Microscopy; Microscopy, Electron; Middle Aged; Neoplasms - therapy; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Original; Patients; Prostate cancer; Proteins; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumors; Virus Replication; Viruses; Xenograft Model Antitumor Assays; Young Adult
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2013.51

Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum—a possible indicator of immune response—increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.