title: Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients.
abstract: 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.
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Liikanen
authors.forename: Laura
authors.initials: L
authors.lastname: Ahtiainen
authors.forename: Mari L M
authors.initials: ML
authors.lastname: Hirvinen
authors.forename: Simona
authors.initials: S
authors.lastname: Bramante
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Petri
authors.initials: P
authors.lastname: Nokisalmi
authors.forename: Otto
authors.initials: O
authors.lastname: Hemminki
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Anniina
authors.initials: A
authors.lastname: Koski
authors.forename: Lotta
authors.initials: L
authors.lastname: Kangasniemi
authors.forename: Saila K
authors.initials: SK
authors.lastname: Pesonen
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.forename: Leena
authors.initials: L
authors.lastname: Laasonen
authors.forename: Kaarina
authors.initials: K
authors.lastname: Partanen
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D037282:Calreticulin / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D003131:Combined Modality Therapy / Q000379:methods; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004279:DNA, Viral / Q000097:blood; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000077204:Temozolomide; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D037282:Calreticulin; D016207:Cytokines; D004279:DNA, Viral; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D003606:Dacarbazine; D000255:Adenosine Triphosphate; D003520:Cyclophosphamide; D000077204:Temozolomide
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