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Use of biological therapy to enhance both virotherapy and adoptive t-cell therapy for cancer

Kottke, T., Diaz, R. M., Kaluza, K., Pulido, J., Galivo, F., Wongthida, P., Thompson, J., Willmon, C., Barber, G. N., Chester, John D. ORCID: https://orcid.org/0000-0002-7830-3840, Selby, P., Strome, S., Harrington, K., Melcher, A. and Vile, R. G. 2008. Use of biological therapy to enhance both virotherapy and adoptive t-cell therapy for cancer. Molecular Therapy 16 (12) , pp. 1910-1918. 10.1038/mt.2008.212

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Abstract

To protect viral particles from neutralization, sequestration, nonspecific adhesion, and mislocalization following systemic delivery, we have previously exploited the natural tumor-homing properties of antigen-specific CD8+ T cells. Thus, OT-I T cells, preloaded in vitro with the oncolytic vesicular stomatitis virus (VSV), can deliver virus to established B16ova tumors to generate significantly better therapy than that achievable with OT-I T cells, or systemically delivered VSV, alone. Here, we demonstrate that preconditioning immune-competent mice with Treg depletion and interleukin-2 (IL-2), before adoptive T-cell therapy with OT-I T cells loaded with VSV, leads to further highly significant increases in antitumor therapy. Therapy was associated with antitumor immune memory, but with no detectable toxicities associated with IL-2, Treg depletion, or systemic dissemination of the oncolytic virus. Efficacy was contributed by multiple factors, including improved persistence of T cells; enhanced delivery of VSV to tumors; increased persistence of OT-I cells in vivo resulting from tumor oncolysis; and activation of NK cells, which acquire potent antitumor and proviral activities. By controlling the levels of virus loaded onto the OT-I cells, adoptive therapy was still effective in mice preimmune to the virus, indicating that therapy with virus-loaded T cells may be useful even in virus-immune patients. Taken together, our data show that it is possible to combine adoptive T-cell therapy, with biological therapy (Treg depletion+IL-2), and VSV virotherapy, to treat established tumors under conditions where none of the individual modalities alone is successful.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Publisher: Nature Publishing Group
ISSN: 1525-0016
Last Modified: 19 Oct 2022 08:42
URI: https://orca.cardiff.ac.uk/id/eprint/18798

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