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Therapeutic vaccine to cure large mouse hepatocellular carcinomas.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Here we report the development of a therapeutic vaccination regimen (shortened as 'TheraVac') consisting of intratumoral delivery of high-mobility group nucleosome-binding protein 1 (HMGN1), R848/resiquimod, and one of the checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-L1, or low dose of Cytoxan). C57BL/6 mice harboring large (approximately 1 cm in diameter) established subcutaneous Hepa1-6 hepatomas were cured by intratumoral injections of TheraVac and became tumor-free long-term survivors. Importantly, the resultant tumor-free mice were resistant to re-challenge with Hepa1-6 hepatoma, not B16 melanoma, demonstrating the acquisition of hepatoma-specific immunity in the absence of any administered tumor antigen. Mechanistic studies showed that upon treatment with TheraVac, Hepa1-6-bearing mice generated increased Hepa1-6-specific CTLs in the draining lymph nodes and showed greatly upregulated expression of CXCL9, CXCL10, and IFN-? and elevated infiltration of T lymphocytes in tumor tissues. Treatment of large Hepa1-6 hepatomas on one mouse flank also eliminated smaller (approximately 0.5 cm in diameter) hepatomas implanted on the other flank. Thus, TheraVac has potential as a curative immunotherapeutic regimen for the treatment of human HCC.

SUBMITTER: Han Z

PROVIDER: S-EPMC5581012 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Therapeutic vaccine to cure large mouse hepatocellular carcinomas.

Han Zhen Z Yang De Trivett Anna A Oppenheim Joost J JJ

Oncotarget 20170718 32

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Here we report the development of a therapeutic vaccination regimen (shortened as 'TheraVac') consisting of intratumoral delivery of high-mobility group nucleosome-binding protein 1 (HMGN1), R848/resiquimod, and one of the checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-L1, or low dose of Cytoxan). C57BL/6 mice harboring large (approximately 1 cm in diameter) established subcutaneous ...[more]

PMID: 28881713

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Project description:BackgroundProprotein convertase subtilisin/kexin 9 (PCSK9) is an important regulator of low-density lipoprotein receptor (LDLR) and plasma levels of LDL cholesterol (LDL-C). PCSK9 inhibition is an efficient therapeutic approach for the treatment of dyslipidemia. We tested the therapeutic effect of a PCSK9 vaccine on dyslipidemia and atherosclerosis.MethodsLipid film hydration method was used to prepare negatively charged nanoliposomes as a vaccine delivery system. An immunogenic peptide called immunogenic fused PCSK9-tetanus (IFPT) was incorporated on the surface of nanoliposomes using DSPE-PEG-maleimide lipid (L-IFPT) and adsorbed to Alhydrogel® (L-IFPTA+). The prepared vaccine formulation (L-IFPTA+) and empty liposomes (negative control) were inoculated four times with bi-weekly intervals in C57BL/6 mice on the background of a severe atherogenic diet and poloxamer 407 (thrice weekly) injection. Antibody titers were evaluated 2 weeks after each vaccination and at the end of the study in vaccinated mice. Effects of anti-PCSK9 vaccination on plasma concentrations of PCSK9 and its interaction with LDLR were determined using ELISA. To evaluate the inflammatory response, interferon-gamma (IFN-γ)- and interleukin (IL)-10-producing splenic cells were assayed using ELISpot analysis.ResultsL-IFPTA+ vaccine induced a high IgG antibody response against PCSK9 peptide in the vaccinated hypercholesterolemic mice. L-IFPTA+-induced antibodies specifically targeted PCSK9 and decreased its plasma consecration by up to 58.5% (- 164.7 ± 9.6 ng/mL, p = 0.0001) compared with the control. PCSK9-LDLR binding assay showed that generated antibodies could inhibit PCSK9-LDLR interaction. The L-IFPTA+ vaccine reduced total cholesterol, LDL-C, and VLDL-C by up to 44.7%, 51.7%, and 19.2%, respectively, after the fourth vaccination booster, compared with the control group at week 8. Long-term studies of vaccinated hypercholesterolemic mice revealed that the L-IFPTA+ vaccine was able to induce a long-lasting humoral immune response against PCSK9 peptide, which was paralleled by a significant decrease of LDL-C by up to 42% over 16 weeks post-prime immunization compared to control. Splenocytes isolated from the vaccinated group showed increased IL-10-producing cells and decreased IFN-γ-producing cells when compared with control and naive mice, suggesting the immune safety of the vaccine.ConclusionsL-IFPTA+ vaccine could generate long-lasting, functional, and safe PCSK9-specific antibodies in C57BL/6 mice with severe atherosclerosis, which was accompanied by long-term therapeutic effect against hypercholesterolemia and atherosclerosis.

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Therapeutic vaccine to cure large mouse hepatocellular carcinomas.

Publications

Therapeutic vaccine to cure large mouse hepatocellular carcinomas.

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