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Newcastle disease virus co-expressing interleukin 7 and interleukin 15 modified tumor cells as a vaccine for cancer immunotherapy.

ABSTRACT: Interleukin 15 (IL15) and IL7 are two cytokines essential for T cell development and homeostasis. In order to improve the antitumor activity by Newcastle disease virus (NDV)-modified tumor vaccine, we generated a recombinant NDV co-expressing IL15 and IL7 (LX/IL(15+7)) through incorporation of a 2A self-processing peptide into IL15 and IL7 using reverse genetics. B16 cells infected with LX/IL(15+7) expressed both IL15 and IL7 stably. The cytotoxicity assay showed that murine melanoma cells modified with LX/IL(15+7) could significantly enhance the antitumor immune response in vitro. Then, the antitumor effects of tumor vaccine modified with recombinant virus were tested in the murine tumor models. We observed strong antitumor responses induced by LX/IL(15+7)-modified tumor cells both in prophylaxis and therapeutic models. Although the tumor-infiltrating CD4+ T cells and CD8+ T cells were both increased, the antitumor activity of the tumor vaccine modified with LX/IL(15+7) was dependent on CD8+ T cells. Taken together, our data strongly indicated that tumor vaccine modified with NDV strain LX/IL(15+7) is a promising agent for cancer immunotherapy.

SUBMITTER: Xu X

PROVIDER: S-EPMC5797827 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Newcastle disease virus co-expressing interleukin 7 and interleukin 15 modified tumor cells as a vaccine for cancer immunotherapy.

Xu Xiaojing X Sun Qing Q Mei Yu Y Liu Yonghao Y Zhao Lixiang L

Cancer science 20180109 2

Interleukin 15 (IL15) and IL7 are two cytokines essential for T cell development and homeostasis. In order to improve the antitumor activity by Newcastle disease virus (NDV)-modified tumor vaccine, we generated a recombinant NDV co-expressing IL15 and IL7 (LX/IL(15+7)) through incorporation of a 2A self-processing peptide into IL15 and IL7 using reverse genetics. B16 cells infected with LX/IL(15+7) expressed both IL15 and IL7 stably. The cytotoxicity assay showed that murine melanoma cells modif ...[more]

PMID: 29224228

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Project description:Background:The prostate cancer microenvironment is highly immunosuppressive; immune cells stimulated in the periphery by systemic immunotherapies will be rendered inactive once entering this environment. Immunotherapies for prostate cancer need to break this immune tolerance. We have previously identified interleukin-15 (IL-15) as the only cytokine tested that activates and expands immune cells in the presence of prostate cancer cells. In the current study, we aimed to identify a method of boosting the efficacy of IL-15 in prostate cancer. Methods:We engineered, by conjugation to a myristoylated peptide, a membrane-localising form of IL-15 (cyto-IL-15) and the checkpoint inhibitor antibodies cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) (cyto-abs) to enable them to bind to cell surfaces by non-specific anchoring to the phospholipid bilayer. The efficacy of these agents was investigated by intratumoral administration either alone (cyto-IL-15 or cyto-abs) or in combination (cyto-combo) in subcutaneous TRAMP-C2 prostate tumors in C57BL/6J mice and compared with their non-modified equivalents in vivo. Following the survival endpoint, histological analyses and RNA sequencing were performed on the tumors. Results:Intratumoral injection of cyto-IL-15 or cyto-combo delayed tumor growth by 50% and increased median survival to 28 and 25 days, respectively, compared with vehicle (17 days), whereas non-modified IL-15 or antibodies alone had no significant effects on tumor growth or survival. Histological analysis showed that cyto-IL-15 and cyto-combo increased necrosis and infiltration of natural killer (NK) cells and CD8 T cells in the tumors compared with vehicle and non-modified agents. Overall, the efficacy of cyto-combo was not superior to that of cyto-IL-15 alone. Conclusion:We have demonstrated that intratumoral injection of cyto-IL-15 leads to prostate cancer growth delay, induces tumor necrosis and increases survival. Hence, cytotopic modification in combination with intratumoral injection appears to be a promising novel approach for prostate cancer immunotherapy.

Project description:An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as "concomitant immunity" suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

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Newcastle disease virus co-expressing interleukin 7 and interleukin 15 modified tumor cells as a vaccine for cancer immunotherapy.

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Newcastle disease virus co-expressing interleukin 7 and interleukin 15 modified tumor cells as a vaccine for cancer immunotherapy.

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