Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors

被引：80

作者：

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

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

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

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

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

Kangasniemi, Lotta ^{[4
]}

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

Dotti, Gianpietro ^{[5
,6
]}

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

Laasonen, Leena ^{[7
]}

Partanen, Kaarina ^{[8
]}

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

Haavisto, Elina ^{[4
]}

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

Karioja-Kallio, Aila ^{[4
]}

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

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

Kauppinen, Satu ^{[8
]}

Joensuu, Timo ^{[8
]}

Kanerva, Anna ^{[1
,2
,9
]}

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

机构：

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

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

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

[4] Oncos Therapeut Inc, Helsinki, Finland

[5] Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA

[6] Methodist Hosp, Houston, TX 77030 USA

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

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

[9] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland

来源：

INTERNATIONAL JOURNAL OF CANCER | 2012年 / 130卷 / 08期

关键词：

oncolytic adenovirus; cancer immunotherapy; Granulocytemacrophage colony stimulating factor; tumor specific immunity; COLONY-STIMULATING FACTOR; PHASE-I TRIAL; DOSE CYCLOPHOSPHAMIDE; ENHANCED ONCOLYSIS; DENDRITIC CELLS; T-CELLS; CANCER; EXPRESSION; EFFICACY; IMMUNITY;

D O I：

10.1002/ijc.26216

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The safety of oncolytic viruses for treatment of cancer has been shown in clinical trials while antitumor efficacy has often remained modest. As expression of the coxsackie-adenovirus receptor may be variable in advanced tumors, we developed Ad5-D24-RGD, a p16/Rb pathway selective oncolytic adenovirus featuring RGD-4C modification of the fiber. This allows viral entry through alpha-v-beta integrins frequently highly expressed in advanced tumors. Advanced tumors are often immunosuppressive which results in lack of tumor eradication despite abnormal epitopes being present. Granulocyte-macrophage colony stimulating factor (GMCSF) is a potent activator of immune system with established antitumor properties. To stimulate antitumor immunity and break tumor associated immunotolerance, we constructed Ad5-RGD-D24-GMCSF, featuring GMCSF controlled by the adenoviral E3 promoter. Preliminary safety of Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of human cancer was established. Treatments with Ad5-D24-RGD (N = 9) and Ad5-RGD-D24-GMCSF (N 5 7) were well tolerated. Typical side effects were grade 1-2 fatigue, fever and injection site pain. 77% (10/13) of evaluable patients showed virus in circulation for at least 2 weeks. In 3 out of 6 evaluable patients, disease previously progressing stabilized after a single treatment with Ad5-RGD-D24-GMCSF. In addition, 2/3 patients had stabilization or reduction in tumor marker levels. All patients treated with Ad5-D24-RGD showed disease progression in radiological analysis, although 3/6 had temporary reduction or stabilization of marker levels. Induction of tumor and adenovirus specific immunity was demonstrated with ELISPOT in Ad5-RGD-D24-GMCSF treated patients. RGD modified oncolytic adenoviruses with or without GMCSF seem safe for further clinical development.

引用

页码：1937 / 1947

页数：11

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