title: Treatment of cancer patients with a serotype 5/3 chimeric oncolytic adenovirus expressing GMCSF.
abstract: Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte-macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8(+) cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intratumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Koski
authors.forename: Lotta
authors.initials: L
authors.lastname: Kangasniemi
authors.forename: Sophie
authors.initials: S
authors.lastname: Escutenaire
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Petri
authors.initials: P
authors.lastname: Nokisalmi
authors.forename: Mari
authors.initials: M
authors.lastname: Raki
authors.forename: Maria
authors.initials: M
authors.lastname: Rajecki
authors.forename: Kilian
authors.initials: K
authors.lastname: Guse
authors.forename: Tuuli
authors.initials: T
authors.lastname: Ranki
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: Leena
authors.initials: L
authors.lastname: Laasonen
authors.forename: Kaarina
authors.initials: K
authors.lastname: Partanen
authors.forename: Matteo
authors.initials: M
authors.lastname: Ugolini
authors.forename: Andreas
authors.initials: A
authors.lastname: Helminen
authors.forename: Eerika
authors.initials: E
authors.lastname: Karli
authors.forename: Päivi
authors.initials: P
authors.lastname: Hannuksela
authors.forename: Saila
authors.initials: S
authors.lastname: Pesonen
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide