Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine.

Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial.

Hu B ，Wang J ，Guo Y ，Chen T ，Ni W ，Yuan H ，Zhang N ，Xie F ，Tai G ... -  《-》

MUC1 and maltose‑binding protein recombinant fusion protein combined with Bacillus Calmette‑Guerin induces MUC1‑specific and nonspecific anti‑tumor immunity in mice.

Fang F ，Ma J ，Ni W ，Wang F ，Sun X ，Li Y ，Li Q ，Xie F ，Wang J ，Zhai R ，Liu Z ，Gao S ，Tai G ... -  《-》

Anti-PD1 antibody enhances the anti-tumor efficacy of MUC1-MBP fusion protein vaccine via increasing Th1, Tc1 activity and decreasing the proportion of MDSC in the B16-MUC1 melanoma mouse model.

In previous studies, we have obtained a notable anti-tumor efficacy of the recombinant MUC1-MBP vaccine in the process of mouse B16-MUC1 melanoma treatment. However, the tumor cannot be eliminated completely. We found that the tumor inhibition rate decreased from 81.67% (five immunizations) to 43.67% (eight immunizations) after more than five immunizations, indicating persistent vaccine stimulation may activate immunosuppressive factors. In the present study, we revealed that programmed cell death 1 (PD1), an inhibitory molecule suppressing T cell function, expressed on splenic and tumor-infiltrating T cells were up-regulated by the vaccine. Therefore, to optimize the anti-tumor efficacy of the vaccine, we employed combination immunotherapy with MUC1-MBP vaccine and αPD1 (anti-PD1 antibody). Results showed that combination immunotherapy induced a more remarkable anti-tumor efficacy, the tumor clearance being increased to 80% from 20% which obtain by MUC1-MBP vaccine immunizations. To investigate the possible underlying mechanism, IFN-γ secretion and cytotoxic T lymphocyte (CTL) cytotoxicity were measured by enzyme-linked immunosorbent assay (ELISA) and xCELLigence real-time cell analyzer (RTCA) respectively. T cell subsets and immunosuppressive cells in the mouse spleen and tumor microenvironment were analyzed by FACS. Results showed that the proportion of splenic CD8+T cells and tumor infiltration was increased and the activity of CTL killing, T helper 1 (Th1), Type 1 CD8+T (Tc1) was enhanced, indicating that the anti-tumor efficacy enhanced by combination immunotherapy was mainly through boosting CD8+T cells mediated anti-tumor cellular immunity. Additionally, combination immunotherapy significantly decreased the splenic and tumor-infiltrating myeloid derived suppressor cells (MDSCs). These results demonstrated that combination immunotherapy with MUC1-MBP vaccine and αPD1 was capable to invoke a more potent anti-tumor immune response and provide a foundation for further research.

Zhang Z ，Zhou H ，Liu Y ，Ren J ，Wang J ，Sang Q ，Lan Y ，Wu Y ，Yuan H ，Ni W ，Tai G ... -  《-》

MUC1-based recombinant Bacillus Calmette-Guerin vaccines as candidates for breast cancer immunotherapy.

Yuan S ，Shi C ，Liu L ，Han W ... -  《-》

Induction of MUC1-specific cellular immunity by a recombinant BCG expressing human MUC1 and secreting IL2.

He J ，Shen D ，O'Donnell MA ，Chang HR ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》