Clinical effect of topical application of CpG oligodeoxynucleotide combined with OX40 monoclonal antibody for mouse model of hepatocellular carcinoma

Ma ShiChao; Zhang ChaoQun; Sun DianXing

doi:10.3969/j.issn.1001-5256.2019.09.020

Volume 35 Issue 9

Sep. 2019

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Clinical effect of topical application of CpG oligodeoxynucleotide combined with OX40 monoclonal antibody for mouse model of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2019.09.020

Chengde Medical University
The Liver Disease Center of PLA, the 980th Hospital of PLA Joint Logistics Support Force

Research funding:

Received Date: 2019-05-15
Published Date: 2019-09-20

Abstract

Abstract

Objective To investigate the clinical effect of topical application of CpG oligodeoxynucleotide ( CpG-ODN) combined with OX40 monoclonal antibody in the treatment of hepatocellular carcinoma and its therapeutic effect on distant homologous tumors. Methods H22 single cell suspension was subcutaneously injected into the axilla of the four limbs of BALB/c male mice to establish a tumor-bearing model. After seven days, 30 mice with a similar tumor volume were screened out and randomly divided into model control group, CpG group, and CpG + OX40 group, with 10 mice in each group, and drugs were injected into the tumor in the left lower limb. Ten normal mice in the same batch were selected as normal control group. Tumor volume was calculated, ELISA was used to measure the serum levels of interleukin-12 ( IL-12) and interferon-γ ( IFNγ) , and flow cytometry was used to measure the percentage of CD8+T lymphocytes in the spleen. The three groups were compared in terms of survival after treatment. Repeated measures analysis of variance and one-way analysis of variance were used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. The log-rank test was used to analyze survival rate for the model control group, CpG group, and CpG+ OX40 group, and survival curves were plotted. Results After treatment, the model control group had progressive growth of tumor, with significantly lower serum levels of IL-12 and IFNγ and percentage of spleen CD8+T lymphocytes than the normal control group ( all P <0. 05) . Compared with the model control group, the CpG group and the CpG + OX40 group had a significant reduction in tumor volume after intervention ( all P < 0. 05) . The CpG + OX40 group had a significantly lower growth rate of distant tumor than the CpG group and the model control group ( all P < 0. 05) , but there was no significant difference in distant tumor volume between the CpG group and the model control group ( P > 0. 05) . Compared with the model control group, the CpG group and the CpG + OX40 group had significant increases in serum levels of IL-12 and IFN-γ and percentage of spleen CD8+T lymphocytes ( all P < 0. 05) , which were significantly higher in the CpG +OX40 group than in the CpG group ( all P < 0. 05) . The CpG + OX40 group had a significantly higher survival rate than the model control group and the CpG group ( both P < 0. 05) , while there was no significant difference between the CpG group and the model control group ( P> 0. 05) . Conclusion OX40 monoclonal antibody combined with CpG-ODN can reduce liver tumor volume, effectively slow down the growth of distant tumors, and prolong the survival time of mice.
- carcinoma, hepatocellular,
- OX40,
- CpG oligodeoxynucleotide,
- immunotherapy,
- mice, inbred BALB C,
- animal experimentation

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References(21)

References

[1] GRANDHI MS, KIM A, RONNEKLEIVKELLY SM, et al. Hepatocellular carcinoma:From diagnosis to treatment[J]. Surg Oncol, 2016, 25 (2) :74-85.

[2] LIANG S, HU J, XIE Y, et al. A polyethylenimine-modified carboxyl-poly (styrene/acrylamide) copolymer nanosphere for co-delivering of CpG and TGF-βreceptor I inhibitor with remarkable additive tumor regression effect against liver cancer in mice[J]. Int J Nanomedicine, 2016, 11:6753-6762.

[3] JIA H, ZHAO T, ZOU D, et al. Therapeutic injection of a CType CpG ODN induced an antitumor immune response in C57/BL6 mice of orthotopically transplanted hepatocellular carcinoma[J]. Oncol Res, 2016, 23 (6) :321-326.

[4] ASPESLAGH S, POSTELVINAY S, RUSAKIEWICZ S, et al.Rationale for anti-OX40 cancer immunotherapy[J]. Eur J Cancer, 2016, 52:50-66.

[5] VIRANI N, THAVATHIRU E, MCKERNAN P, et al. Anti-CD73and anti-OX40 immunotherapy coupled with a novel biocompatible enzyme prodrug system for the treatment of recurrent, metastatic ovarian cancer[J]. Cancer Lett, 2018, 425:174-182.

[6] ITO S, SHIROTA H, KASAHARA Y, et al. IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model[J]. Cancer Immunol Immunother, 2017, 66 (11) :1485-1496.

[7] VOO KS, FOGLIETTA M, PERCIVALLE E, et al. Selective targeting of Toll-like receptors and OX40 inhibit regulatory T cell function in follicular lymphoma[J]. Int J Cancer, 2014, 135 (12) :2834-2846.

[8] TU T, BUDZINSKA MA, MACZUREK AE, et al. Novel aspects of the liver microenvironment in hepatocellular carcinoma pathogenesis and development[J]. Int J Mol Sci, 2014, 15 (6) :9422-9458.

[9] DING J, WU J. Epigenetic regulation of hepatic tumor-initiating cells[J]. Front Biosci, 2015, 20 (6) :946-963.

[10] GARRIS C, ARLAUCKAS SP, KOHLER RH, et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γand IL-12[J].Immunity, 2018, 49 (6) :1148-1161.

[11] SHEN K, CUI J, WEI Y, et al. Effectiveness and safety of PD-1/PD-L1 or CTLA4 inhibitors combined with chemotherapy as a first-line treatment for lung cancer:A meta-analysis[J]. J Thorac Dis, 2018, 10 (12) :6636-6652.

[12] SIU EH, CHAN AWH, CHONG CC, et al. Treatment of advanced hepatocellular carcinoma:Immunotherapy from checkpoint blockade to potential of cellular treatment[J].Transl Gastroenterol Hepatol, 2018, 3:89.

[13] FINKELMEIER F, WAIDMANN O, TROJAN J. Nivolumab for the treatment of hepatocellular carcinoma[J]. Expert Rev Anticancer Ther, 2018, 18 (12) :1169-1175.

[14] NADEAU BA, FECHER LA, OWENS SR, et al. Liver toxicity with cancer checkpoint inhibitor therapy[J]. Semin Liver Dis, 2018, 38 (4) :366-378.

[15] SAGIVBARFI I, CZERWINSKI DK, LEVY S, et al. Eradication of spontaneous malignancy by local immunotherapy[J]. Sci Transl Med, 2018, 10 (426) :eaan4488.

[16] NOURI N, GARBE C. Intralesional immunotherapy as a strategy to treat melanoma[J]. Expert Opin Biol Ther, 2016, 16 (5) :619-626.

[17] GUPTA V, KALIA N, YADAV M, et al. Optimization and qualification of the single molecule array digital immunoassay for IL-12p70 in plasma of cancer patients[J]. Bioanalysis, 2018, 10 (17) :1413-1425.

[18] DILLINGER B, AHMADIERBER S, LAU M, et al. IFN-γand tumor gangliosides:Implications for the tumor microenvironment[J]. Cell Immunol, 2018, 325:33-40.

[19] WALLIN RPA, SUNDQUIST VS, BRAKENHIELM E, et al. Angiostatic effects of NK cell-derived IFN-γcounteracted by tumour cell Bcl-xL expression[J]. Scand J Immunol, 2014, 79 (2) :90-97.

[20] SFONDRINI L, SOMMARIVA M, TORTORETO M, et al. Antitumor activity of CpG-ODN aerosol in mouse lung metastases[J]. Int J Cancer, 2013, 133 (2) :383-393.

[21] BUCHAN SL, ROGEL A, ALSHAMKHANI A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy[J]. Blood, 2017, 131 (1) :39-48.

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Clinical effect of topical application of CpG oligodeoxynucleotide combined with OX40 monoclonal antibody for mouse model of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2019.09.020