Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET

被引：15

作者：

Garcia-Moure, Marc ^{[1
,2
,3
]}

Gonzalez-Huarriz, Marisol ^{[1
,2
,3
]}

Labiano, Sara ^{[1
,2
,3
]}

Guruceaga, Elizabeth ^{[1
,4
]}

Bandres, Eva ^{[1
,5
]}

Zalacain, Marta ^{[1
,2
,3
]}

Marrodan, Lucia ^{[1
,2
,3
]}

de Andrea, Carlos ^{[1
,6
]}

Villalba, Maria ^{[1
,6
,7
]}

Martinez-Velez, Naiara ^{[1
,2
,3
]}

Laspidea, Virginia ^{[1
,2
,3
]}

Puigdelloses, Montse ^{[1
,2
,8
]}

Perez-Larraya, Jaime Gallego ^{[1
,2
,8
]}

Inigo-Marco, Ignacio ^{[1
,2
,3
]}

Stripecke, Renata ^{[9
]}

Chan, Jennifer A. ^{[10
]}

Raabe, Eric H. ^{[11
,12
]}

Kool, Marcel ^{[13
,14
,15
,16
]}

Gomez-Manzano, Candelaria ^{[17
,18
]}

Fueyo, Juan ^{[18
,19
]}

Patino-Garcia, Ana ^{[1
,2
,3
]}

Alonso, Marta M. ^{[1
,2
,3
]}

机构：

[1] Hlth Res Inst Navarra IdiSNA, Navarra, Spain

[2] Fdn Appl Med Res, Program Solid Tumors, Navarra, Spain

[3] Clin Univ Navarra, Dept Pediat, Navarra, Spain

[4] Univ Navarra, Ctr Appl Med Res CIMA, Bioinformat Platform, Navarra, Spain

[5] Complejo Hosp Navarra, Dept Hematol, Immunol Unit, Navarra, Spain

[6] Clin Univ Navarra, Dept Pathol, Navarra, Spain

[7] Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[8] Clin Univ Navarra, Dept Neurol, Navarra, Spain

[9] German Ctr Infect Res DZIF, Lab Regenerat Immune Therapies Appl Res Network R, Partner Site Hannover, Dept Hematol Hemostasis Oncol & Stem Cell Transp, Hannover, Germany

[10] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada

[11] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Baltimore, MD USA

[13] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[14] German Canc Consortium DKTK, Heidelberg, Germany

[15] Hopp Childrens Canc Ctr KITZ, Heidelberg, Germany

[16] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[17] Univ Texas MD Anderson Canc Ctr, Dept NeuroOncol, Houston, TX 77030 USA

[18] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[19] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA

来源：

CLINICAL CANCER RESEARCH | 2021年 / 27卷 / 06期

基金：

欧洲研究理事会;

关键词：

ATYPICAL TERATOID/RHABDOID TUMORS; CENTRAL-NERVOUS-SYSTEM; PRIMITIVE NEUROECTODERMAL TUMORS; BRAIN-TUMORS; MOUSE MODEL; VIRUS; MEDULLOBLASTOMA; EFFICACY; EPIDEMIOLOGY; RADIOTHERAPY;

D O I：

10.1158/1078-0432.CCR-20-3313

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. Experimental Design: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34(+)-NSG-SGM3). Results: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (10(7) or 10(8) PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8(+) T-cell infiltration. Conclusions: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.

引用

页码：1807 / 1820

页数：14

共 57 条

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