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

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Oncolytic Viruses
T-Cell Antigen Receptor
Neoplasms
Interleukin-15
Chemokine CCL5
Cell Movement
Neoplasm Antigens
Immunosuppressive Agents
Caspases
Neuroblastoma
Chemokines
Adenoviridae
Immunotherapy
Cell Survival
Leukemia
Cytokines
T-Lymphocytes

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 journalArticle

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, vol. 74, no. 18, pp. 5195-5205. https://doi.org/10.1158/0008-5472.CAN-14-0697
Nishio, Nobuhiro ; Diaconu, Iulia ; Liu, Hao ; Cerullo, Vincenzo ; Caruana, Ignazio ; Hoyos, Valentina ; Bouchier-Hayes, Lisa ; Savoldo, Barbara ; Dotti, Gianpietro. / Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. In: Cancer Research. 2014 ; Vol. 74, No. 18. pp. 5195-5205.
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