Oncolytic Adenoviral Delivery of an EGFR-Targeting T-cell Engager Improves Antitumor Efficacy.
Cancer Res
; 77(8): 2052-2063, 2017 04 15.
Article
en En
| MEDLINE
| ID: mdl-28143835
ABSTRACT
Antiviral immune responses present a major hurdle to the efficacious use of oncolytic adenoviruses as cancer treatments. Despite the existence of a highly immunosuppressive tumor environment, adenovirus-infected cells can nonetheless be efficiently cleared by infiltrating cytotoxic T lymphocytes (CTL) without compromising tumor burden. In this study, we tested the hypothesis that tumor-infiltrating T cells could be more effectively activated and redirected by oncolytic adenoviruses that were armed with bispecific T-cell-engager (BiTE) antibodies. The oncolytic adenovirus ICOVIR-15K was engineered to express an EGFR-targeting BiTE (cBiTE) antibody under the control of the major late promoter, leading to generation of ICOVIR-15K-cBiTE, which retained its oncolytic properties in vitro cBiTE expression and secretion was detected in supernatants from ICOVIR-15K-cBiTE-infected cells, and the secreted BiTEs bound specifically to both CD3+ and EGFR+ cells. In cell coculture assays, ICOVIR-15K-cBiTE-mediated oncolysis resulted in robust T-cell activation, proliferation, and bystander cell-mediated cytotoxicity. Notably, intratumoral injection of this cBiTE-expressing adenovirus increased the persistence and accumulation of tumor-infiltrating T cells in vivo, compared with the parental virus lacking such effects. Moreover, in two distinct tumor xenograft models, combined delivery of ICOVIR-15K-cBiTE with peripheral blood mononuclear cells or T cells enhanced the antitumor efficacy achieved by the parental counterpart. Overall, our results show how arming oncolytic adenoviruses with BiTE can overcome key limitations in oncolytic virotherapy. Cancer Res; 77(8); 2052-63. ©2017 AACR.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Adenoviridae
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Linfocitos Infiltrantes de Tumor
/
Anticuerpos Biespecíficos
/
Viroterapia Oncolítica
/
Receptores ErbB
/
Neoplasias
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2017
Tipo del documento:
Article
País de afiliación:
España