Treatment of cancer patients with a serotype 5/3 chimeric oncolytic adenovirus expressing GMCSF.
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.
Koski
Anniina
A
Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Kangasniemi
Lotta
L
Escutenaire
Sophie
S
Pesonen
Sari
S
Cerullo
Vincenzo
V
Diaconu
Iulia
I
Nokisalmi
Petri
P
Raki
Mari
M
Rajecki
Maria
M
Guse
Kilian
K
Ranki
Tuuli
T
Oksanen
Minna
M
Holm
Sirkka-Liisa
SL
Haavisto
Elina
E
Karioja-Kallio
Aila
A
Laasonen
Leena
L
Partanen
Kaarina
K
Ugolini
Matteo
M
Helminen
Andreas
A
Karli
Eerika
E
Hannuksela
Päivi
P
Pesonen
Saila
S
Joensuu
Timo
T
Kanerva
Anna
A
Hemminki
Akseli
A
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
D007166:Immunosuppressive Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide