TY - JOUR
T1 - Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors
AU - Nishio, Nobuhiro
AU - Diaconu, Iulia
AU - Liu, Hao
AU - Cerullo, Vincenzo
AU - Caruana, Ignazio
AU - Hoyos, Valentina
AU - Bouchier-Hayes, Lisa
AU - Savoldo, Barbara
AU - Dotti, Gianpietro
PY - 2014/7/24
Y1 - 2014/7/24
N2 - The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5D24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5D24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors.
AB - The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5D24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5D24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors.
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UR - http://www.scopus.com/inward/citedby.url?scp=84907546628&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-14-0697
DO - 10.1158/0008-5472.CAN-14-0697
M3 - Article
C2 - 25060519
AN - SCOPUS:84907546628
VL - 74
SP - 5195
EP - 5205
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 18
ER -