Treatment of Cancer Patients With a Serotype 5/3 Chimeric Oncolytic Adenovirus Expressing GMCSF

被引：188

作者：

Koski, Anniina ^{[1
,2
,3
]}

Kangasniemi, Lotta ^{[4
]}

Escutenaire, Sophie ^{[1
,2
,3
]}

Pesonen, Sari ^{[1
,2
,3
]}

Cerullo, Vincenzo ^{[1
,2
,3
]}

Diaconu, Iulia ^{[1
,2
,3
]}

Nokisalmi, Petri ^{[1
,2
,3
]}

Raki, Mari ^{[1
,2
,3
]}

Rajecki, Maria ^{[1
,2
,3
]}

Guse, Kilian ^{[1
,2
,3
]}

Ranki, Tuuli ^{[1
,2
,3
]}

Oksanen, Minna ^{[1
,2
,3
]}

Holm, Sirkka-Liisa ^{[1
,2
,3
]}

Haavisto, Elina ^{[4
]}

Karioja-Kallio, Aila ^{[4
]}

Laasonen, Leena ^{[5
,6
]}

Partanen, Kaarina ^{[5
]}

Ugolini, Matteo ^{[1
,2
,3
]}

Helminen, Andreas ^{[5
]}

Karli, Eerika ^{[1
,2
,3
]}

Hannuksela, Paivi ^{[1
,2
,3
]}

Pesonen, Saila ^{[1
,2
,3
]}

Joensuu, Timo ^{[5
]}

Kanerva, Anna ^{[1
,2
,7
]}

Hemminki, Akseli ^{[1
,2
,3
]}

机构：

[1] Univ Helsinki, Haartman Inst, Transplantat Lab, Canc Gene Therapy Grp, Helsinki, Finland

[2] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland

[3] Helsinki Univ Cent Hosp, HUSLAB, Helsinki, Finland

[4] Oncos Therapeut Ltd, Helsinki, Finland

[5] Int Comprehens Canc Ctr Docrates, Helsinki, Finland

[6] Univ Helsinki, Helsinki Med Imaging Ctr, Helsinki, Finland

[7] Helsinki Univ Cent Hosp, Dept Obstet & Gynecol, Helsinki, Finland

来源：

MOLECULAR THERAPY | 2010年 / 18卷 / 10期

关键词：

REPLICATION-SELECTIVE ADENOVIRUS; PHASE-I; METRONOMIC CYCLOPHOSPHAMIDE; ORTHOTOPIC MODELS; OVARIAN-CANCER; GENE-TRANSFER; T-CELLS; GM-CSF; RECEPTOR; COMBINATION;

D O I：

10.1038/mt.2010.161

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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 intra-tumorally 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.

引用

页码：1874 / 1884

页数：11

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[1] Blood clearance rates of adenovirus type 5 in mice [J].