Mage-b vaccine delivered by recombinant Listeria monocytogenes is highly effective against breast cancer metastases

Abstract

New therapies are needed that target breast cancer metastases. In previous studies, we have shown that vaccination with pcDNA3.1-Mage-b DNA vaccine is effective against breast cancer metastases. In the study presented here, we have further enhanced the efficacy of Mage-b vaccination through the improved delivery of the vaccine using recombinant Listeria monocytogenes (LM). Three overlapping fragments of Mage-b as well as the complete protein-encoding region of Mage-b have been expressed as a fusion protein with a truncated non-cytolytic form of listeriolysin O (LLO) in recombinant LM. These different Mage-b vaccine strains were preventively tested for their efficacy against breast cancer metastases in a syngeneic mouse tumour model 4T1. The LM-LLO-Mageb/2nd, expressing position 311 -660 of the cDNA of Mage-b, was the most effective vaccine strain against metastases in the 4T1 mouse breast tumour model. Vaccination with LM-LLO-Mage-b/2nd dramatically reduced the number of metastases by 96% compared with the saline group and by 88% compared with the vector control group (LM-LLO), and this correlated with strong Mage-b-specific CD8 T-cell responses in the spleen, after restimulation with Mage-b. However, no effect of LM-LLO-Mage-b/2nd was observed on 4T1 primary tumours, which may be the result of a complete absence of Mage-b-specific immune responses in the draining lymph nodes. Vaccination with LM-LLO-Mage-b/2nd could be an excellent follow-up after removal of the primary tumour, to eliminate metastases and residual tumour cells.

Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells

“…42 Kim et al found that LM based vaccines could not only remove primary tumors, but also eliminate metastases and residual tumor cells. 43 In this research, Lmdd-CD24 vaccine caused the regression of inoculated Hepa1-6-CD24 tumors, prevented tumor occurrence and growth in the prophylactic and therapeutic groups and increased tumor-free survival of the mice. This might be explained by the suppressed recruitment of Tregs in the immunized mice and the stimulation of CD8 1 T cells isolated from TILs in local tumor areas.…”

Harnessing Listeria monocytogenes to target tumors

“…We had shown earlier that Mage-b-specific immune responses are completely suppressed in the tumor microenvironment but not in normal tissues. 53,70 Also Listeria-specific immune responses are partly reduced in the tumor environment but not in normal tissues. Therefore, we concluded that Listeria bacteria in the tumor microenvironment are protected from clearance by the immune system compared to normal tissue.…”

“…Our laboratory has shown that vaccination with LM-LLO, expressing a melanoma-associated antigen (Mage), Mage-b 311-660 , completely eradicated the metastases and almost completely eradicated the primary tumors (90%) in a metastatic mouse breast tumor 4T1, expressing Mage-b. 53 However, this dramatic effect was not solely due to Mage-b-induced immune responses but also due to infection and subsequent kill of the tumor cells by LM-LLO bacteria, as we discuss in detail below. Also, vaccination with Listeria vaccines expressing fragments of Her2/neu, fused to LLO, were effective against primary tumors in a syngeneic mouse breast tumor model, NT-2, expressing Her2/neu, which correlated with strong immune responses to Her2/neu.…”

Cryoablation and Meriva have strong therapeutic effect on triple-negative breast cancer

“…34 We have also shown that high levels of IL-6 inhibits T cell responses to TAA Mage-b, and that these T cell responses could be restored using anti-IL-6 antibodies. 35 Finally, cryoablation strongly reduces tumor size, which will reduce tumor-induced immune suppression, and cryoablation also leads to the production of IFNg. In summary, it is most likely that improved T cell responses generated by Meriva have played a role in the dramatic effect on tumor and metastases and on the survival of the 4T1-treated mice but as discussed here other mechanisms were involved as well.…”

“…This IL-6 strongly reduced T cell responses to Mage-b, but elimination of IL-6 using anti-IL-6 antibodies restored T cell responses to Mage-b in vitro. 13 Agents that are able to inhibit IL-6 are of great value for immunotherapies against TNBC and other IL-6-producing cancers. One such agent could be curcumin.…”