A Therapeutic Her2/neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/neu–Expressing Tumor in HLA-A2 Transgenic Mice

Abstract

Purpose: E75, a peptide derived from the Her2/neu protein, is the most clinically advanced vaccine approach against breast cancer. In this study, we aimed to optimize the E75 vaccine using a delivery vector targeting dendritic cells, the B-subunit of Shiga toxin (STxB), and to assess the role of various parameters (Her2/neu expression, combination with trastuzumab) in the efficacy of this cancer vaccine in a relevant preclinical model.Experimental Design: We compared the differential ability of the free E75 peptide or the STxB-E75 vaccine to elicit CD8 þ T cells, and the impact of the vaccine on murine HLA-A2 tumors expressing low or high levels of Her2/neu. Results: STxB-E75 synergized with granulocyte macrophage colony-stimulating factors and CpG and proved to be more efficient than the free E75 peptide in the induction of multifunctional and high-avidity E75-specific anti-CD8 þ T cells resulting in a potent tumor protection in HLA-A2 transgenic mice. High expression of HER2/neu inhibited the expression of HLA-class I molecules, leading to a poor recognition of human or murine tumors by E75-specific cytotoxic CD8 þ T cells. In line with these results, STxB-E75 preferentially inhibited the growth of HLA-A2 tumors expressing low levels of Her2/neu. Coadministration of anti-Her2/neu mAb potentiated this effect.Conclusions: STxB-E75 vaccine is a potent candidate to be tested in patients with low Her2/neu-expressing tumors. It could also be indicated in patients expressing high levels of Her2/neu and low intratumoral T-cell infiltration to boost the recruitment of T cells-a key parameter in the efficacy of anti-Her2/neu mAb therapy.

Further Insight into AE37 Peptide Vaccination in Prostate Cancer

“…In support to our results, a recent study by Tran et al. [ 16 ] reported that E75-based peptide vaccination can inhibit tumor growth only in low HER2 expressing tumors in HLA-A2 + transgenic mice. This and the fact that HER2 expression is known to increase significantly following disease progression in prostate cancer [ 17 ], could account for the inability of E75-specific cytotoxic T lymphocytes, detected in our patients, to exert an effective antitumor immune response with direct clinical impact.…”

Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy

“…17 Furthermore, it was reported that targeting of tumor antigens to DC by STxB-based delivery system was efficient to elicit efficient antitumor memory CD8 T cells. [28][29][30][31][32] Thus, our results suggest a synergistic effect of combining rapalog with STxBbased vaccines for the induction of antitumor CD8 T cells with T CM polarization.…”

“…STxB-OVA is a candidate cancer vaccine obtained by the chemical coupling of OVA to the recombinant non-toxic Shiga toxin B-subunit variant. [28][29][30][31][32] The synthetic HPV-16 E7-derived 15mer peptide (E7 [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] : GQAEPDRAHYNIVTF, G15F)the E7 49-57 peptide (RAHYNIVTF, RF9)the OVA 257-264 peptide (SIINFEKL, SL8)the AH1 6-14 peptide (SPSYVYHQF, AH1) and the Adpgk mutant peptide (ASMTNMELM, AM9) identified as immunodominant antigen recognized by CD8 + T cells from CT26 and MC38, respectively were purchased from JPT Peptide technologies. The adjuvants alpha-galactosylceramide (α-GalCer), CpG and incomplete Freund adjuvant (IFA) were purchased from Funakoshi, InvivoGen and Sigma-Aldrich, respectively.…”

Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors

“…The clinical setting in which a cancer vaccine is tested may be of utmost importance, as the same vaccine can induce a clinical response on early-stage vulvar disease, but not on late-stage cancer [4,14]. Although the Her2-Neu cancer vaccine was mainly proposed in patients expressing high levels of Her2/neu in their tumors [15], we have recently demonstrated that an Her2/neu targeting cancer vaccine is more efficient in low Her2/neu expressing tumors, as Her2 downregulates HLA-class I expression [16]. …”