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A Therapeutic Her2/Neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/Neu–Expressing Tumor I

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A Therapeutic Her2/Neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/Neu–Expressing Tumor I Published OnlineFirst March 22, 2016; DOI: 10.1158/1078-0432.CCR-16-0044 Cancer Therapy: Preclinical Clinical Cancer Research A Therapeutic Her2/neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/neu–Expressing Tumor in HLA-A2 Transgenic Mice Thi Tran1,2, Mariana O. Diniz1,2,3, Estelle Dransart4,5,6, Alain Gey7, Nathalie Merillon1, Yu Chun Lone8, Sylvie Godefroy9, Craig Sibley9, Luis CS Ferreira3, Jacques Medioni10, Stephane Oudard1,2,10, Ludger Johannes4,5,6, and Eric Tartour1,2,7 Abstract þ Purpose: E75, a peptide derived from the Her2/neu protein, is tional and high-avidity E75-specific anti-CD8 T cells resulting in the most clinically advanced vaccine approach against breast a potent tumor protection in HLA-A2 transgenic mice. High cancer. In this study, we aimed to optimize the E75 vaccine using expression of HER2/neu inhibited the expression of HLA-class I a delivery vector targeting dendritic cells, the B-subunit of molecules, leading to a poor recognition of human or murine þ Shiga toxin (STxB), and to assess the role of various parameters tumors by E75-specific cytotoxic CD8 T cells. In line with these (Her2/neu expression, combination with trastuzumab) in the results, STxB-E75 preferentially inhibited the growth of HLA-A2 efficacy of this cancer vaccine in a relevant preclinical model. tumors expressing low levels of Her2/neu. Coadministration of Experimental Design: We compared the differential ability of anti-Her2/neu mAb potentiated this effect. þ the free E75 peptide or the STxB-E75 vaccine to elicit CD8 T cells, Conclusions: STxB-E75 vaccine is a potent candidate to be and the impact of the vaccine on murine HLA-A2 tumors expres- tested in patients with low Her2/neu–expressing tumors. It could sing low or high levels of Her2/neu. also be indicated in patients expressing high levels of Her2/neu Results: STxB-E75 synergized with granulocyte macrophage and low intratumoral T-cell infiltration to boost the recruitment of colony-stimulating factors and CpG and proved to be more T cells—a key parameter in the efficacy of anti-Her2/neu mAb efficient than the free E75 peptide in the induction of multifunc- therapy. Clin Cancer Res; 1–12. Ó2016 AACR. Introduction ments and chemotherapy, the progression-free survival in patients with metastatic breast cancer is 18.7 months (1). The Her2/neu proto-oncogene, is a validated target in cancer, as Intrinsic properties of Her2/neu may explain the clinical various anti-Her2/neu antibodies (trastuzumab, pertuzumab, efficacy of these approved drugs and the interest to develop adotrastuzumab emtansine, etc.) or tyrosine kinase inhibitors other therapeutic approaches against this molecule. Indeed, its (lapatinib) demonstrated their clinical efficacy in patients with overexpression is required to maintain the malignant phenotype Her2/neu–overexpressing breast and gastric cancers. Unfortunate- of these cancers and tumor escape by downregulation of Her2/ ly, even after the best combination of Her2/neu–directed treat- neu is thus more difficult to achieve. Cancer stem cells, which contribute to tumor metastasis and treatment resistance, express increased Her2/neu levels (2). Other arguments support 1INSERM U970, Universite Paris Descartes, Sorbonne Paris-Cite, Paris, France. 2Equipe Labellisee Ligue Contre le Cancer, Paris, France. the development of active immunotherapy such as anti-Her2/ 3Institute of Biomedical Sciences, University of Sao~ Paulo, Sao~ Paulo, neu T-cell vaccines to complement and improve the clinical Brazil. 4Institut Curie, PSL Research University, Chemical Biology of 5 6 activity of commercially available anti-Her2/neu antibodies. Membranes and Therapeutic Delivery Unit. INSERM, U 1143. CNRS, – fi UMR 3666, 26 rue d’Ulm, 75248 Paris Cedex 05, France. 7Service Her2/neu is immunogenic and elicits natural Her2/neu speci c d'Immunologie biologique, Hopital Europeen Georges Pompidou- T-cell responses in patients overexpressing this antigen (3, 4). APHP, Paris, France. 8Inserm U-1014, Universite Paris XI, Groupe Hos- Intratumoral T-cell infiltration is associated with a good prog- 9 pitalier Paul-Brousse, France. Immuno Target SAS, Paris, France. nosis in these patients (5) and the presence of high levels of 10Service d'Oncologie Medicale, Hopital Europeen Georges Pompi- dou, Paris, France. tumor-infiltrating lymphocytes (TIL) were associated with fi þ Note: Supplementary data for this article are available at Clinical Cancer increased trastuzumab bene tinHer2/neu breast cancer Research Online (http://clincancerres.aacrjournals.org/). patients (6). The role of T cells in controlling Her2/neu–expressing L. Johannes and E. Tartour are the principal investigators of this article. tumors was also emphasized by the demonstration that intra- Corresponding Author: Eric Tartour, Service d'Immunologie Biologique, Hopital^ tumoral injection of human effector T cells genetically mod- Europeen Georges Pompidou, 20 Rue Leblanc, Paris 75015, France. Phone: 331- ified to express chimeric antigen receptor (CAR) against Her2/ 5609-3942; Fax: 331-5609-2080; E-mail: [email protected] neu completely blocked the growth and metastasis of Her2/ doi: 10.1158/1078-0432.CCR-16-0044 neu–expressing pancreatic adenocarcinoma xenografts in SCID Ó2016 American Association for Cancer Research. mice (7). www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 22, 2016; DOI: 10.1158/1078-0432.CCR-16-0044 Tran et al. doses (29), as already observed with other Her2/neu peptide– Translational Relevance based vaccines (30). The E75 peptide derived from the Her2/neu protein has We have developed and validated a nonreplicative vector that been developed as a vaccine and has generated suboptimal targets dendritic cells, the B subunit of the Shiga toxin (STxB). results in clinical trials. Using a delivery vector targeting the When coupled to various tumor antigens, STxB elicits a strong þ E75 peptide to dendritic cells, we improved its potency both in induction of specific CD8 T cells, which can be further enhanced þ terms of induction of CD8 T cells, and tumor protection in by the addition of adjuvants (31, 32). Compared with other relevant preclinical models. We also demonstrated in a series vectors, STxB targets the same glycolipid receptor, gb3 which are of human breast cancer cell lines that high Her2/neu–expres- identical in all species. In addition, we already demonstrated its sing tumor cells are not efficiently recognized by anti-E75 efficacy to favor crosspresentation in human dendritic cells (33). þ CD8 T cells compared with low Her2/neu tumors. These STxB displays intrinsic immunogenicity demonstrated by a weak results were also translated and confirmed in in vivo models. induction of anti-STxB antibodies, but which did not interfere Thus, although Her2/neu is a validated target for various mAbs with repetitive immunization (31). in breast cancer and gastric cancer expressing high levels of this The aim of this study was to improve and optimize the E75 antigen, this study demonstrates that a Her2/neu cancer vac- peptide vaccine using this delivery vector and to assess the role of cine may be preferentially indicated in low Her2/neu–expres- various parameters (Her2/neu expression, combination with sing tumors. A synergistic effect was also observed when cancer trastuzumab) in the efficacy of the cancer vaccine in a relevant vaccine was combined with anti-Her2/neu mAb treatment. preclinical model. Materials and Methods Mice Various preclinical and clinical studies showed that the com- Humanized HLA-A2 transgenic (TG) mice were obtained from bination of anti-Her2/neu antibodies and vaccines capable to Dr. Y.C. Lone (INSERM U1014, Hopital Paul Brousse, Villejuif, inducing anti-Her2/neu T cells synergized in promoting the France) and from Dr. F. Lemmonier (Institut Pasteur, Paris, France). regression of Her2/neu–expressing tumors (8–10). In mice and To set up an hHer2/neu-HLA-A2 tumor model, we transfected humans, anti-Her2/neu antibodies enhanced the induction of the B16-HLA-A2 melanoma cell line with a cDNA encoding þ Her2/neu–specific CD8 T cells and favor Th1 cell infiltration hHer2/neu. A clone coexpressing HLA-A2 and hHer2 was selected (11–14). In accordance with these results, it has been reported (Supplementary Fig. S1A). We then subcutaneously grafted this that effective Her2/neu antibody treatment also requires an adap- B16-HLA-A2-hHer2/neu clone and monitored the tumor growth þ tive immune response involving CD8 T cells (13). These data in HLA-A2 TG mice. Steady tumor growth was reproducibly argue for boosting T-cell responses against Her2/neu–positive achieved using at least 5 Â 105 cells (Supplementary Fig. S1B). breast cancer and various groups clearly demonstrated the ability All mice were kept under specific pathogen–free conditions at of Her2/neu cancer vaccines based on dendritic cells, peptides, the INSERM U970 animal facility. All experiments have been recombinant proteins, recombinant virus, or DNA to induce reviewed and approved by Paris-Descartes Ethical Committee for þ þ specific CD4 and CD8 T-cell responses in humans (15–17). Animal Experimentation (CEEA34.ET.154.12). However, up until now, no Her2/neu vaccine has been approved for the clinics. Cell lines E75, a nine amino acid peptide derived from the extracellular B16-A2 cells were obtained from Dr. Y.C. Lone (INSERM domain of Her2/neu protein (KIFGSLAFL, Her2/neu residues 369– U1014). B16-A2-Her2/neu cells were generated by stable trans- 377; ref. 18) is the best studied Her2/neu–derived peptide to date. It fection after electroporation with a plasmid encoding human bindstoHLA-A2and HLA-A3expressedin 60%–75% of the general Her2/neu provided by P. Bruhns (Institut Pasteur) and selected population and is processed and presented by tumor cells (19, 20). with 0.5 mg/mL of G418 (Invivogen) and 7 mg/mL of blasticidine Although the exact immunodominant peptide (Her2/neu 369–377 (Invivogen) supplemented medium.
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