A Therapeutic Her2-Neu Cancer Vaccine Alone Or In Combination With Anti-Her2 Mab Inhibits Tumor Growth In Hla-A2 Transgenic Mice

Her2/neu is a validated target in cancer, as various antibodies (Abs) against this antigen have demonstrated their clinical efficacy in patients presenting either breast or gastric cancers. Various preclinical and clinical studies showed that the combination of anti-Her2 Abs and vaccines aiming to induce anti-Her2-T cells synergized in promoting the regression of Her2 expressing tumors. The Her2 369-377 peptide (E75) has been shown to be immunogenic in humans and an E75 peptide vaccine is currently being tested in a phase III clinical trial. We have developed a vector based on the non-toxic B subunit of Shiga toxin (STxB) which targets antigens directly to dendritic cells and favours cross-presentation of exogenous antigens to CD8 + T cells. We coupled the E75 peptide to STxB and showed that immunization of HLA-A2 transgenic mice with STxB-E75 elicits statistically significant higher levels of anti-Her2-neu CD8 + T cells (u003e 3%) detected by tetramer analysis, than the use of the non vectorized E75 peptide ( + T cells induced by STxB-E75 were functional, cytotoxic in vivo and of higher avidity, than those elicited by the E75 peptide. We then proceeded to set up a human (h) Her2/neu-HLA-A2 expressing tumor model (B16) in HLA-A2 transgenic mice for vaccination with STxB-E75. We demonstrated than STxB-E75 was more efficient to inhibit the growth of hHer2-HLA-A2 tumor in humanized HLA-A2 TG mice, than the E75 peptide in both a prophylactic and a therapeutic setting. As control, STxB-E75 had no influence in the growth of hHer2 negative HLA-A2-B16 tumor. We then observed that the anti-Her2 CD8 + T cells elicited in HLA-A2 transgenic mice recognized human breast tumor cell lines expressing either high or low levels of hHer2/neu, as well as the HLA-A2 B16 clones expressing low levels of hHer2. To assess the relevance of this capacity of STxB-E75 to detect low levels of Her2, we grafted the HLA-A2 B16 clone expressing low levels of hHer2/neu on HLA-A2 transgenic mice. The combination of STxB-E75 and anti-Her2 mAb (4D5) was more efficient to inhibit the tumor growth, than the use of the vaccine or antibody alone. The body of experiments presented in this work clearly demonstrated that the STxB-E75 vaccine is a potent candidate to be tested in the clinics for Her2 expressing tumor. In addition, a synergy was observed for the combination of anti-Her2/neu mAb and STxB-E75 vaccine for the regression of low expressing Her2/neu tumor. Citation Format: Thi Tran, Mariana De Oliveira Diniz, Estelle Dransart, Alain Gey, Sylvie Godefroy, Craig Sibley, Ludger Johannes, Eric Tartour. A therapeutic Her2-Neu cancer vaccine alone or in combination with anti-Her2 mAb inhibits tumor growth in HLA-A2 transgenic mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2504. doi:10.1158/1538-7445.AM2015-2504