Direct incorporation of the NKT-cell activator a-galactosylceramide into a recombinant Listeria monocytogenes improves breast cancer vaccine efficacy.

British journal of cancer

PubMedID: 25314062

Singh M, Quispe-Tintaya W, Chandra D, Jahangir A, Venkataswamy MM, Ng TW, Sharma-Kharkwal S, Carreño LJ, Porcelli SA, Gravekamp C. Direct incorporation of the NKT-cell activator a-galactosylceramide into a recombinant Listeria monocytogenes improves breast cancer vaccine efficacy. Br J Cancer. 2014;.
Background:Immune suppression in the tumour microenvironment remains a major limitation to successful immunotherapy of cancer. In the current study, we analysed whether the natural killer T cell-activating glycolipid a-galactosylceramide could overcome immune suppression and improve vaccination against metastatic breast cancer.Methods:Mice with metastatic breast cancer (4T1 model) were therapeutically treated with a Listeria monocytogenes-based vaccine expressing tumour-associated antigen Mage-b followed by a-galactosylceramide as separate agents, or as a complex of a-galactosylceramide stably incorporated into Listeria-Mage-b. Effects on metastases, tumour weight, toxicity and immune responses were determined.Results:Sequential treatments of mice with established 4T1 breast carcinomas using Listeria-Mage-b followed by a-galactosylceramide as a separate agent was highly effective at reducing metastases, but was accompanied by severe liver toxicity. In contrast, combined therapy using Listeria-Mage-b modified by incorporation of a-galactosylceramide resulted in nearly complete elimination of metastases without toxicity. This was associated with a significant increase in the percentage of natural killer T cells in the spleen, and an increase in natural killer cell activity and in T cell responses to Mage-b.Conclusions:Our results suggest that direct incorporation of a-galactosylceramide into a live bacterial vaccine vector is a promising non-toxic new approach for the treatment of metastatic breast cancer.British Journal of Cancer advance online publication 14 October 2014; doi:10.1038/bjc.2014.486 www.bjcancer.com.