Therapeutic Adenovirus Vaccine Combined Immunization with IL-12 Induces Potent CD8+ T Cell Anti-Tumor Immunity in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the cancers with the highest morbidity and mortality in the world. However, clinical progress in the treatment of HCC has not shown a satisfactory therapeutic effect. Here, we have developed a novel strategy to treat HCC with an adenovirus (Ad)-based vaccine, which contains a specific antigen glypican-3 (GPC3) and an immunostimulatory cytokine IL-12. In the subcutaneous tumor model, Ad-IL-12/GPC3 vaccine was injected into muscles three times to evaluate its therapeutic effect. Compared with the control immunization group, the Ad-IL-12/GPC3 immunization group showed a significant tumor growth inhibition effect, which was confirmed by the reduced tumor volume and the increased tumor inhibition. Ad-IL-12/GPC3 co-immunization promoted the induction and maturation of CD11c+ or CD8+CD11c+ DCs and increased the number of tumor-infiltrating CD8+ T cells. Furthermore, in the Ad-IL-12/GPC3 group, the proliferation of CD8+ T cells, the induction of multifunctional CD8+ T cells, and CTL activity were significantly increased. Interestingly, the deletion of CD8+ T cells abolished tumor growth inhibition by Ad-IL-12/GPC3 treatment, suggesting that CD8+ T cell immune responses were required to eliminate the tumor. Likewise, Ad-IL-12/GPC3 vaccine also effectively inhibited lung tumor growth or metastasis by enhancing CD8+ DCs-mediated multifunctional CD8+ T cell immune responses in the lung metastasis model. Therefore, these results indicate that IL-12 combined with Ad-GPC3 vaccine co-immunization might provide a promising therapeutic strategy for HCC patients.

HMGB1/GPC3 dual targeting vaccine induces dendritic cells-mediated CD8+T cell immune response and elicits potential therapeutic effect in hepatocellular carcinoma

“…Both CD8 + DCs and CD103 + DCs play a vital role in activating CD8 + T cell anti-tumor immune responses in mice. 32 Remarkably, compared with the single vaccine group, mice immunized with PLGA/PEI-HMGB1/GPC3 vaccine had an increased frequency of CD8 + CD11C + DCs and CD103 + CD11C + DCs ( Figures 2 G and 2H). These results indicated that PLGA/PEI-HMGB1/GPC3 vaccine could effectively inhibit tumor growth and increase the infiltration of immune cells.…”

The next-generation DNA vaccine platforms and delivery systems: advances, challenges and prospects

“…Recombinant Ads (rAds) encompass various types, including conditionally replicating Ad (CRAd), replication-defective Ad (RDAd), and helper-dependent Ad (HDAd). These vectors have gained popularity in the fields of cancer and regenerative medicine ( 64 ), particularly in promoting anti-tumor immune responses through the introduction of tumor-associated antigens (TAA) ( 35 , 65 ). CRAd, also known as oncolytic Ad, is specifically designed to target cancer cells and release the TAAs due to its high cytotoxicity, making it a potent tool in combating tumors.…”