title: Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus.
abstract: Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T(regs)) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Lotta
authors.initials: L
authors.lastname: Kangasniemi
authors.forename: Maria
authors.initials: M
authors.lastname: Rajecki
authors.forename: Sophie
authors.initials: S
authors.lastname: Escutenaire
authors.forename: Anniina
authors.initials: A
authors.lastname: Koski
authors.forename: Valentina
authors.initials: V
authors.lastname: Romano
authors.forename: Noora
authors.initials: N
authors.lastname: Rouvinen
authors.forename: Tamara
authors.initials: T
authors.lastname: Tuuminen
authors.forename: Leena
authors.initials: L
authors.lastname: Laasonen
authors.forename: Kaarina
authors.initials: K
authors.lastname: Partanen
authors.forename: Satu
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.forename: Sirkka-Liisa
authors.initials: SL
authors.lastname: Holm
authors.forename: Elina
authors.initials: E
authors.lastname: Haavisto
authors.forename: Aila
authors.initials: A
authors.lastname: Karioja-Kallio
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Petteri T
authors.initials: PT
authors.lastname: Arstila
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002648:Child; D003131:Combined Modality Therapy; D006224:Cricetinae; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D050130:Oncolytic Virotherapy / Q000379:methods*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D003520:Cyclophosphamide