Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 5195-5205 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 74 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - Jul 24 2014 |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. / Nishio, Nobuhiro; Diaconu, Iulia; Liu, Hao; Cerullo, Vincenzo; Caruana, Ignazio; Hoyos, Valentina; Bouchier-Hayes, Lisa; Savoldo, Barbara; Dotti, Gianpietro.
In: Cancer Research, Vol. 74, No. 18, 24.07.2014, p. 5195-5205.Research output: Contribution to journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=84907546628&partnerID=8YFLogxK
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
VL - 74
SP - 5195
EP - 5205
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 18
ER -