Oncotarget

Priority Research Papers:

Therapeutic vaccine to cure large mouse hepatocellular carcinomas

Zhen Han, De Yang _, Anna Trivett and Joost J. Oppenheim

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Oncotarget. 2017; 8:52061-52071. https://doi.org/10.18632/oncotarget.19367

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Abstract

Zhen Han1, De Yang1, Anna Trivett1 and Joost J. Oppenheim1

1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA

Correspondence to:

De Yang, email:

Joost J. Oppenheim, email:

Keywords: HMGN1, R848, anti-PD-L1, anti-CTLA4, cytoxan

Received: April 19, 2017 Accepted: May 10, 2017 Published: July 18, 2017

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-γ 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.


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