Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors

Nobuhiro Nishio, Iulia Diaconu, Hao Liu, Vincenzo Cerullo, Ignazio Caruana, Valentina Hoyos, Lisa Bouchier-Hayes, Barbara Savoldo, Gianpietro Dotti

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108 Scopus citations

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 languageEnglish (US)
Pages (from-to)5195-5205
Number of pages11
JournalCancer Research
Volume74
Issue number18
DOIs
StatePublished - Jul 24 2014

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nishio, N., Diaconu, I., Liu, H., Cerullo, V., Caruana, I., Hoyos, V., Bouchier-Hayes, L., Savoldo, B., & Dotti, G. (2014). Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Research, 74(18), 5195-5205. https://doi.org/10.1158/0008-5472.CAN-14-0697