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Combined therapy with CTL cells and oncolytic adenovirus expressing IL-15-induced enhanced antitumor activity

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Tumor Biology

Abstract

Addition of immunoregulation factor to an oncolytic adenovirus being constructed is a developmental step in tumor gene therapy; however, cytokine IL-15 has not been frequently used as a potential cancer therapy agent. Here, we constructed an E2F-1 promoter oncolytic adenovirus based on type 5 adenovirus, which induces viral replication and proliferation in targeted tumor cells. We inserted the IL-15 gene into the E3 region of the model and found that human IL-15 expressing oncolytic adenovirus (Ad-E2F/IL15) shows a more intense antitumor effect than simple oncolytic viruses (Ad-E2F) do. Precisely because IL-15 can activate natural killer (NK) cells, CD8+T cells, and other immune cells, in antitumor therapy, Ad-E2F/IL15 was used in combination with cytotoxic T lymphocytes (CTL) to create a virus that can induce IL-15 gene expression while lysing tumors and stimulating the activity and function of adoptive immune cells. The therapeutic effect of this therapy is clearly stronger than that of a single application of oncolytic viruses or CTL, and hence, it could be a potential new tumor therapy.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (61170123) and Natural Science Foundation of Hainan province (813226).

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Authors and Affiliations

  1. General Surgery Department, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, China

    Yang Yan, Songyan Li, Xiaohui Du & Rong Li

  2. Oral and Maxillofacial Surgery Department, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, China

    Tingting Jia

  3. Institute of General Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, China

    Yingxin Xu, Yunshan Zhao, Li Li, Kai Liang, Wentao Liang & Huiwei Sun

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  1. Yang Yan
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Correspondence to Xiaohui Du or Yingxin Xu.

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Figure S1

PCR identification of oncolytic adenovirus Ad-E2F1/IL15. A. All Ad-E2F/IL151-2 clones showed the same band as the PXC20-E2Fp plasmid, whereas PXC20 showed a band about 440 bp. B. E2Fp-F + R identified that Ad-E2F1/IL15 virus showed the same band with the PXC20-E2FP plasmid. C. IL15-F + R identified the IL-15 gene in the Ad-E2F1/IL15 virus. D. GT210 + GT211 identified the mCMV promoter in the virus. N: negative control; P1: PXC20 plasmid; P2: PXC20-E2Fp plasmid; P3: PPE3-hIL2SPIL15 plasmid; 1-2: 2 clones of the Ad-E2F1/IL15 virus; M: Mix DNA Ladder (GIF 146 kb) (GIF 146 kb)

High Resolution image (TIFF 220 kb)

Figure S2

The phenotype of immune cells (DCs, and CTL cells) from 3 healthy donors was stained with the various antibodies discussed above. A. CD80, CD86, and CD83 expression in DC cells. B. CD3, CD4, CD8, and CD56 expression in CTL cells. (GIF 497 kb)

(GIF 491 kb)

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High Resolution Image (TIFF 1641 kb)

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Yan, Y., Li, S., Jia, T. et al. Combined therapy with CTL cells and oncolytic adenovirus expressing IL-15-induced enhanced antitumor activity. Tumor Biol. 36, 4535–4543 (2015). https://doi.org/10.1007/s13277-015-3098-7

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