LEAPS Vaccine Incorporating HER-2/neu Epitope Elicits Protection That Prevents and Limits Tumor Growth and Spread of Breast Cancer in a Mouse Model (original) (raw)
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HER-2/neu Cancer Vaccines: Present Status and Future Prospects
International Journal of Peptide Research and Therapeutics, 2006
Immunotherapeutic approaches to cancer should focus on novel undertakings that modulate immune responses by synergistic enhancement of anti-tumor immunological parameters. Cancer vaccines should preferably be composed of multiple defined tumor antigen specific Band T-cell epitopes. The main focus of this article is to briefly review the present status of Her-2/neu vaccine strategies and to describe the innovative strategies developed in my laboratory for a vaccine against HER-2/neu (ErbB-2) with emphasis on the humoral arm of the immune response. Elucidating the underlining mechanisms of anti-tumor effects elicited by peptide vaccines against a self-protein is a requirement for developing an immunotherapeutic strategy that might be effective in human cancer vaccines. Our approach entails the identification of biologically relevant epitopes, establishing relevant in vitro assays for monitoring vaccine efficacy, devising strategies to engineer conformationally dependent sequences, developing highly immunogenic vaccines for an outbred population and delivering the immunogen/vaccine in a safe and efficacious vehicle, utilizing transgenic animal models for assessing tumor development, and developing challenge models using transplantable tumors to study efficacy of vaccine constructs. We have developed a multi-HER-2/neu B-cell epitope approach and shown in preclinical studies that immunization with a combination of two B-cell epitope was more effective in preventing mammary tumors than a single epitope. We have translated that work to the clinic (OSU 0105) in an FDA approved, NCI sponsored ''Phase 1 Active Immunotherapy trial with Chimeric and Multi-epitope based peptide vaccine targeting HER-2 oncoprotein and nor-MDP adjuvant in patients with metastatic and/or recurrent solid tumors'' at the James Cancer Hospital at the Ohio State University. The correlation between overexpression of HER-2/neu and up-regulation of VEGF has been demonstrated in breast cancer patients. Thus, blocking angiogenesis is an attractive strategy to inhibit tumor growth, invasion, and metastasis. The hypothesis that combination of anti-angiogenic therapy and tumor immunotherapy of cancer may be synergistic is an important future goal. In this review, I will discuss insights into our preclinical studies that might aid in the design of the next generation of cancer vaccines and become an integrated component of prophylactic/preventive and therapeutic approach.
Cancer Immunology, Immunotherapy, 2010
Our aim is to develop peptide vaccines that stimulate tumor antigen-speciWc T-lymphocyte responses against frequently detected cancers. We describe herein a novel HLA-A*0201-restricted epitope, encompassing amino acids 828-836 (residues QIAKGMSYL), which is naturally presented by various HER-2/neu + tumor cell lines. HER-2/neu(828-836), [HER-2(9 828)], possesses two anchor residues and stabilized HLA-A*0201 on T2 cells in a concentration-dependent Class I binding assay. This peptide was stable for 3.5 h in an oV-kinetic assay. HER-2(9 828) was found to be immunogenic in HLA-A*0201 transgenic (HHD) mice inducing peptide-speciWc and functionally potent CTL and long-lasting anti-tumor immunity. Most important, using HLA-A*0201 pentamer analysis we could detect increased ex vivo frequencies of CD8 + T-lymphocytes speciWcally recognizing HER-2(9 828) in 8 out of 20 HLA-A*0201 + HER-2/neu + breast cancer patients. Moreover, HER-2(9 828)-speciWc human CTL recognized the tumor cell line SKOV3.A2 as well as the primary RS.A2.1.DR1 tumor cell line both expressing HER-2/neu and HLA-A*0201. Finally, therapeutic vaccination with HER-2(9 828) in HHD mice was proven eVective against established transplantable ALC.A2.1.HER tumors, inducing complete tumor regression in 50% of mice. Our data encourage further exploitation of HER-2(9 828) as a promising candidate for peptide-based cancer vaccines.
Immunogenic HER-2/neu peptides as tumor vaccines
Cancer Immunology, Immunotherapy, 2006
During the last decade, a large number of tumor-associated antigens (TAA) have been identified, which can be recognized by T cells. This has led to renewed interest in the use of active immunization as a modality for the treatment of cancer. HER-2/neu is a 185-KDa receptor-like glycoprotein that is overexpressed by a variety of tumors including breast, ovarian, lung, prostate and colorectal carcinomata. Several immunogenic HER-2/neu peptides recognized by cytotoxic T lymphocytes (CTL) or helper T lymphocytes (TH) have been identified thus far. Patients with HER-2/ neu over-expressing cancers exhibit increased frequencies of peripheral blood T cells recognizing immunogenic HER-2/neu peptides. Various protocols for generating T cell-mediated immune responses specific for HER-2/neu peptides have been examined in pre-clinical models or in clinical trials. Vaccination studies in animals utilizing HER-2/neu peptides have been successful in eliminating tumor growth. In humans, however, although immunological responses have been detected against the peptides used for vaccination, no clinical responses have been described. Because HER-2/neu is a self-antigen, functional immune responses against it may be limited through tolerance mechanisms. Therefore, it would be interesting to determine whether abrogation of tolerance to HER-2/neu using appropriate adjuvants and/or peptide analogs may lead to the development of immune responses to HER-2/neu epitopes that can be of rele-vance to cancer immunotherapy. Vaccine preparations containing mixtures of HER-2/neu peptides and peptide from other tumor-related antigens might also enhance efficacy of therapeutic vaccination.
Vaccine, 2011
a b s t r a c t HER2/neu is an oncogene amplified and over-expressed in 20-30% of breast adenocarcinomas. Treatment with the humanized monoclonal antibody trastuzumab has shown efficacy in combination with cytotoxic agents, although resistance occurs over time. Novel approaches are needed to further increase antibody efficacy. In this study, we provide evidence in a mouse breast cancer therapeutic tumor model that the combination of active immunization with a modified HER2/neu DNA vaccine and passive infusion of an anti-HER2/neu monoclonal antibody leads to significant regression of established tumors. Our data indicate that combination therapy with a HER2/neu DNA vaccine and trastuzumab may have clinical activity in breast cancer patients.
Human Gene Therapy, 2014
Several cancer vaccine efforts have been directed to simultaneously cotarget multiple tumor antigens, with the intent to achieve broader immune responses and more effective control of cancer growth. Genetic cancer vaccines based on in vivo muscle electro-gene-transfer of plasmid DNA (DNA-EGT) and adenoviral vectors represent promising modalities to elicit powerful immune responses against tumor-associated antigens (TAAs) such as carcinoembryonic antigen (CEA) and human epidermal growth factor receptor-2 (HER2)/neu. Combinations of these modalities of immunization (heterologous prime-boost) can induce superior immune reactions as compared with single-modality vaccines. We have generated a dual component-dual target genetic cancer vaccine consisting of a DNA moiety containing equal amounts of two plasmids, one encoding the extracellular and transmembrane domains of HER2 (ECD.TM) and the other encoding CEA fused to the B subunit of Escherichia coli heat-labile toxin (LTB), and of an adenoviral subtype 6 dicistronic vector carrying the same two tumor antigens gene constructs. The CEA/HER2 vaccine was tested in two different CEA/HER2 double-transgenic mouse models and in NOD/scid-DR1 mice engrafted with the human immune system. The immune response was measured by enzyme-linked immunospot assay, flow cytometry, and ELISA. The CEA/HER2 vaccine was able to break immune tolerance against both antigens. Induction of a T cell and antibody immune response was detected in immune-tolerant mice. Most importantly, the vaccine was able to slow the growth of HER2/neu + and CEA + tumors. A significant T cell response was measured in NOD/scid-DR1 mice engrafted with human cord blood cells. In conclusion, the CEA/HER2 genetic vaccine was immunogenic and able to confer significant therapeutic effects. These data warrant the evaluation of this vaccination strategy in human clinical trials.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2016
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. We compared the differential ability of the free E75 peptide or the STxB-E75 vaccine to elicit CD8+T cells, and the impact of the vaccine on murine HLA-A2-tumors expressing low or high levels of Her2/neu. STxB-E75 synergized with GM-CSF and CpG and proved to be more efficient than the free E75 peptide in the induction of multi-functional and high avidity E75-specific anti-CD8+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...
International Journal of Cancer, 2007
The Ii-Key fragment from the MHC class II-associated invariant chain (or Ii protein) has been shown to facilitate direct charging of MHC class II epitopes to the peptide binding groove. The purpose of the present study was to test the potential of a series of Ii-Key/ HER-2/neu(776-790) hybrid peptides to generate increased frequencies of peptide-specific CD4 1 T cells over the native peptide in mice transgenic (Tg) for a chimeric human mouse class II molecule (DR4-IE) (H-2 b ) as well as their antitumor potency. Following in vivo priming, such hybrid peptides induced increased proliferation and frequencies of IFN-c producing CD4 1 T cells in response to either syngeneic dendritic cells pulsed with native peptide, or HLA-DR4 1 human tumor cell lines expressing HER-2/neu. Hybrid peptides were more stable in an off-rate kinetics assay compared to the native peptide. In addition, antigen-specific CD4 1 T cells from hybrid peptide immunized DR4-IE Tg mice synergized with HER-2/neu(435-443)-specific CD8 1 T cells from HLA-A2.1 Tg HHD (H-2 b ) mice in producing antitumor immunity into SCID mice xenografted with the HER-2/neu 1 , HLA-A2.1 1 and HLA-DR4 1 FM3 human melanoma cell line. High proportions of these adoptively transferred HER-2/neu peptide-specific CD4 1 and CD8 1 T cells infiltrated FM3-induced tumors (tumor infiltrating lymphocytes; TIL) in SCID mice. CD8 1 TIL exhibited long-lasting antitumor activity when cotransferred with CD4 1 TIL, inducing regression of FM3 tumors in a group of untreated, tumor-bearing SCID mice, following adoptive transfer. Our data show that Ii-Key modified HER-2/neu(776-790) hybrid peptides are sufficiently potent to provide antigen-specific CD4 1 T H cells with therapeutic antitumor activity. ' 2007 Wiley-Liss, Inc.
Cancer Research, 2010
BALB/c mice transgenic (Tg) for the transforming rat neu oncogene (BALB-neuT) are genetically predestined to develop mammary carcinogenesis in a process similar to that in humans. We crossed HLA-A2.1/HLA-DR1 (A2.1/DR1) Tg mice with BALB-neuT mice to generate A2.1/DR1 × BALB-neuT triple Tg (A2.1/DR1 × neuT +) mice, which represent an improvement over BALB-neuT mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. A vaccine formulation strategy, consisting of synthetic peptides from the rat HER-2/neu oncogene combined with granulocyte macrophage colony-stimulating factor, was highly effective in preventing the growth of established transplantable tumors in male A2.1/DR1 × neuT + mice. Vaccination with HER-2(435-443) (p435) CTL peptide alone induced weak antitumor responses, which were characterized by increased numbers of regulatory T cells (Treg) and low numbers of vaccine-specific CD8 + CTL and helper T cells (Th). The administration of p435 plus HER-2(776-790) (p776; helper peptide) reversed this situation, inducing functionally active, peptide-specific CTL and Th. There was a striking change in the intratumoral balance of Tregs (decrease) and vaccine-specific Th (increase) that directly correlated with tumor rejection. Intratumoral administration of anti-FasL antibody promoted tumor growth. The decrease in Tregs (Fas +) was due to apoptosis induced by cell contact with Fas ligand + (L) + Th. Mice vaccinated with p435 plus p776 exhibited long-lasting antitumor immunity. Our vaccine regimen also significantly delayed the outgrowth of mammary carcinomas in female A2.1/DR1 × neuT + animals. We provide a mechanism to overcome tolerance against HER-2/neu, which proposes a combined vaccination with two (Th and CTL) HER-2 peptides against HER-2/neu-expressing tumors. Cancer Res; 70(7); 2686-96. ©2010 AACR.
Cancer Immunology, Immunotherapy, 2008
Using parental FVB mice and their neu transgenic counterparts, FVBN202, we showed for the first time that dangerous hyperplasia of mammary epithelial cells coincided with breaking immunological tolerance to the neu "self" tumor antigen, though such immune responses failed to prevent formation of spontaneous neu-overexpressing mammary carcinoma (MMC) or to reject transplanted MMC in FVBN202 mice. On the other hand, neu-specific immune responses appeared to be effective against MMC in parental FVB mice because of the fact that rat neu protein was seen as "nonself" antigen in these animals and the protein was dangerously overexpressed in MMC. Interestingly, low/ intermediate expression of the neu "nonself" protein in tumors induced immune responses but such immune responses failed to reject the tumor in FVB mice. Our results showed that self-nonself (SNS) entity of a tumor antigen or danger signal alone, while may equally induce an antigen-specific immune response, will not warrant the efficacy of immune responses against tumors. On the other hand, entity of antigen in the context of dangerous conditions, i.e. abnormal/dangerous overexpression of the neu nonself protein, will warrant effective anti-tumor immune responses in FVB mice. This unified "danger-SNS" model suggests focusing on identification of naturally processed cryptic or mutated epitopes, which are considered semi-nonself by the host immune system, along with novel dangerous adjuvants in vaccine design.