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An HSV-2 based oncolytic virus can function as an attractant to guide migration of adoptively transferred T cells to tumor sites.

ABSTRACT: Adoptive T-cell therapy has shown promises for cancer treatment. However, for treating solid tumors, there is a need for improving the ability of the adoptively transferred T cells to home to tumor sites. We explored the possibility of using an oncolytic virus derived from HSV-2, which can actively pull T effector cells to the site of infection, as a local attractant for migration of adoptively transferred T cells. Our data show that intratumoral administration of this virus can indeed attract active migration of the adoptively transferred T cells to the treated tumor. Moreover, once attracted to the tumor site by the virus, T cells persisted in there significantly longer than in mock-treated tumor. Chemokine profiling identified significant elevation of CXCL9 and CXCL10, as well as several other chemokines belonging to the inflammatory chemokine family in the virus-treated tumors. These chemokines initially guided the T-cell migration to and then maintained their persistence in the tumor site, leading to a significantly enhanced therapeutic effect. Our data suggests that this virotherapy may be combined with adoptive T-cell therapy to potentiate its therapeutic effect against solid tumors that are otherwise difficult to manage with the treatment alone.

SUBMITTER: Fu X

PROVIDER: S-EPMC4359264 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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An HSV-2 based oncolytic virus can function as an attractant to guide migration of adoptively transferred T cells to tumor sites.

Fu Xinping X Rivera Armando A Tao Lihua L Zhang Xiaoliu X

Oncotarget 20150101 2

Adoptive T-cell therapy has shown promises for cancer treatment. However, for treating solid tumors, there is a need for improving the ability of the adoptively transferred T cells to home to tumor sites. We explored the possibility of using an oncolytic virus derived from HSV-2, which can actively pull T effector cells to the site of infection, as a local attractant for migration of adoptively transferred T cells. Our data show that intratumoral administration of this virus can indeed attract a ...[more]

PMID: 25460506

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Project description:BackgroundAdoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity.MethodsIn this study we investigated how tumor-specific murine CD8+ T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG.ResultsHerein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell-B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+ T cells acquired a unique proteomic signature hallmarked by an IL-2RαhighICOShighCD39low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2RαhighICOShighCD39low phenotype. CpG fostered the expansion of potent CD8+ T cells with the signature phenotype and antitumor ability via empowering a direct B-T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture.ConclusionsOur results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+ T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.

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An HSV-2 based oncolytic virus can function as an attractant to guide migration of adoptively transferred T cells to tumor sites.

Publications

An HSV-2 based oncolytic virus can function as an attractant to guide migration of adoptively transferred T cells to tumor sites.

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