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Peptide-Based Vaccines for Breast Cancer: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
María Lilia Nicolás-Morales
,
Arianna Luisa-Sanjuan
,
Mayralina Gutiérrez-Torres
,
Amalia Vences-Velázquez
, Carlos Ortuño-Pineda , Mónica Espinoza-Rojo , Napoleón Navarro-Tito , Karen Cortés-Sarabia

Breast cancer (BC) is the main type of cancer in women and the second most frequent cancer worldwide. The conventional treatment includes surgery, chemotherapy, hormonal therapy, and immunotherapy. This immunotherapy is based on administering monoclonal therapeutic antibodies (passive) or vaccines (active) with therapeutic purposes. Tumor antigens are classified as tumor-associated antigens (TAAs) and tumor-specific antigens (TSA). New TAAs were proposed for the formulation of peptide-based vaccines, including MUC-1 (mucin-1), FRα (folate receptor alpha), members of the MAGE A family (melanoma-associated antigen), and EGFR (epidermal growth factor receptor).

  • peptide-based vaccines
  • breast cancer
  • therapeutic

1. Peptide-Based Vaccines for Breast Cancer

Vaccines based on the use of peptides are designed for the induction of humoral and cellular immune responses. Therefore, it is essential to evaluate whether the selected peptide is capable of inducing the activation of T cells (CD4+ and CD8+) and B cells [1] (Figure 1D). The technologies used for developing these types of vaccines are safe and cheap if they are compared with traditional methods for vaccine production. Also, their high purity level avoids the presence of unnecessary compounds that could promote adverse reactions in the host [2]. A pilot study using 12 patients with mixed stages of breast cancer evaluated the effect of a peptide-based vaccine formulated using 9 peptides derived from the antigens: MAGE A1, A3, and A10, CEA, NY-ESO-1, and HER2 (human epidermal growth factor receptor 2) in combination with an antagonist of TLR3 (Toll-like receptor 3) named poly-ICLC and one peptide derived from the tetanus toxoid. The treatment was well tolerated; however, the ELISPOT assays (Enzyme-Linked ImmunoSpot Assay) could not detect any type of immune response and the vaccine did not progress to the next clinical phase [3]. Rosembaun et al., in 2020, studied a group of 7 patients with metastatic breast cancer negative to the expression of HER2 that were administered with a vaccine designed with the tumor-associated carbohydrate antigen (Tn), the toxin-derived peptide of tetanus TT830–844, and the immunostimulant GSK AS15. The first results demonstrated a high production of IL-2 and antibodies IgM and IgG with the capacity to recognize and destroy positive cells to the expression of Tn by the induction of cytotoxic mechanisms associated with activating the classical pathway of the complement system [4].
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Figure 1. Types and proposed mechanisms of action in cancer vaccines. (A) Whole-cell vaccines are based on extracting dendritic cells from the patients. Afterward, they are pulsed with an antigenic load of proteins, peptides, nucleic acids, whole-cell lysates or cancer cells. After the maturation of dendritic cells, they are reinfused into the patient for the induction of an adaptive immune response associated with the destruction of the tumor. (B) DNA vaccines are based on amplifying the selected tumor-associated antigen (TAA) and its cloning into a vector for transfection of muscle cells and dendritic cells that will promote antigen presentation and the activation of T and B cells. (C) RNA vaccines are based on the internalization of an mRNA that encodes for a TAA. The mRNA will be translated and processed by the proteasome. The peptides will be coupled to MHC (major histocompatibility complex) molecules to start the adaptive immune response. (D) Peptide-based vaccines are based on the selection of one or multiple TAA and the later selection of peptides using bioinformatic tools as IEDB (http://tools.iedb.org/main/ accessed on 30 July 2022) for the selection of peptides with immunogenic and antigenic characteristics to activate the adaptive immune response. Image created in Biorender (https://biorender.com/ accessed on 2 July 2022).
There are reports about peptide-based vaccines in clinical phase II. The first is the vaccine that has as a target the folate alpha receptor (FRα) based on the use of multiple epitopes (FR30, FR56, FR76, FR113, and FR238) combined with the GM-CSF (granulocyte-macrophage colony-stimulating factor). The vaccine was capable of inducing antibody production against one or more peptides with low to moderate toxicity reactions [5]. In a different study, a vaccine that used 19 peptides derived from 11 tumor-associated antigens, such as squamous cell carcinoma antigen (3SART3), leukocyte-specific protein tyrosine kinase (Lck), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and epidermal growth factor receptor (EGFR), was evaluated in triple-negative breast cancer patients. The presence of IgG against at least one peptide in 9 out of 10 patients was detected. In addition, a positive response of cytotoxic T cells in at least 5 of every 10 patients was found. Clinical phase II will be performed in a bigger group to establish the relationship between these results and the potential therapeutic utility [6].
A clinical phase I/II assay evaluated a peptide-based vaccine that contained peptides derived from the TAA: MUC1 (SAPDNRPAL), CEA (YLSGADLNL), and ErbB2 (KIFGSLAFL) in patients with ovarian and breast cancer. Results showed that some patients presented a positive CD8+ T cell response with interferon-gamma (IFN-γ) production to at least one antigen without toxicity [7]. P10s-PADRE is a phase I/II vaccine based on using peptide mimotopes and Montanide™ ISA 51 VG as an adjuvant. This vaccine could be used in combination with standard chemotherapy in patients with triple-negative breast cancer patients. High antibody response was achieved with only three immunizations without adverse reactions [8]. Using HER2 as a therapeutic target, a novel vaccine containing the peptide GP2 (IISAVVGIL654–662) combined with the granulocyte-macrophage colony-stimulating factor (GM-CSF) was developed. During clinical phase I, the GP2+GM-CSF vaccine was administered in patients with breast cancer (BC) and provided evidence about the induction of immune response and its safety [9]. Phase II concluded that patients with tumors positive for HER2 expression have a better response in combination with trastuzumab, and toxicity reactions were associated with the immunoadjuvant GM-CSF [10].
The only peptide-based vaccine in clinical phase III is NeuVax™; the efficacy of this vaccine has been tested in disease-free patients with positive and negative nodes. The formulation is based on combining the peptide E75 with GM-CSF as an immunoadjuvant [11]. Results have shown that the administration of this vaccine is safe and effective for the stimulation of in vivo immune response with the capacity to reduce the recurrence rate up to a 50% in patients with high-risk breast cancer. It has been proposed that this vaccine could be used in around 76% of the population. However, other vaccines with target peptides derived from HER2 or new targets are still under evaluation [10][12] (Table 1).
Table 1. Peptide-based vaccines derived from TAA against breast cancer.
Vaccine Description Clinical Phase Evidence
NeuVax™
Peptide derived from HER2.		 Breast cancer with low or moderate expression of HER2. GM-CSF and water. III Register: NCT01479244
[13]
GP2
Peptide derived from HER2.		 Breast cancer HLA-A2+ with positive lymph nodes in tumors with positive HER2 expression. II [10][14]
AE37
Peptide derived from HER2.		 Breast cancer with positive and negative lymph nodes, with positive expression of HER2. II [10]
KRM-19
Mixed vaccine of 19 peptides derived from multiple AATs.		 Metastatic triple-negative breast cancer with resistance to the conventional treatment. II Register: UMIN000014616
[6]
Nelipepimut-S peptide + GM-CSF + trastuzumab. Breast cancer with low expression of HER2. II [15]
HLA-matched personalized peptide vaccine. Recurrent metastatic breast cancer. II Register: UMIN000001844
[16]
P10s-PADRE Triple-negative breast cancer (TNBC) in stages I, II, or III. I/II Register: NCT02938442
Multipeptide MUC1/ErbB2/CEA high-risk disease-free ovarian and breast cancer after completion of standard therapies. I/II [7]
FRα
multi-epitope		 Vaccine + cyclophosphamide + sargramostim in treating patients with stage II-III breast cancer. II Register: NCT03012100
MAG-TN3+ AS15 Breast neoplasms. I Register: NCT02364492
[4][17]
Mimotope P10s-PADRE/MONTANIDE ISA 51 VG Peptide mimotope-based vaccine of tumor-associated carbohydrate antigens in patients with stage IV breast cancer. I Register: NCT01390064
[8]

2. Immune Response after Vaccine Administration

After peptide-based vaccine administration, released peptides are captured by antigen-presenting cells (APC) by phagocytosis or endocytosis, processed, and coupled to MHC I and II molecules. Antigen presentation is performed to CD4+ and CD8+ T cells by the interaction of the TCR with MHC class I and II and costimulatory molecules, such as CD28 and CD80. CD4+ T cells could be differentiated in the subgroup Th1 and Th2. Th1 cells release interleukin-12 (IL-12) and IFN-γ, which will increase the levels of MHC molecules and promote the release of CCL3 and CCL4 chemokines for the recruitment of natural killer (NK) monocytes and cytotoxic T cells. NK cells produce perforins and granzymes to promote the apoptosis of cancer cells. CD8+ T cells could recognize the peptide derived from the TAA coupled to the MHC I in the cancer cells to promote apoptosis by releasing perforins and granzymes or by interacting with Fas/FasL. CD4+ and CD8+ T cells are capable of differentiating into effector and memory cells [18][19].
On the other hand, the subgroup Th2 derived from CD4+ T cells will secrete IL-4, IL-5, IL-6, IL-9, and IL-10 that regulate the activation and differentiation of B-cells into memory and plasma cells that release IgM and IgG antibodies. Secreted antibodies can bind to their target TAA to inhibit the function of the target protein, thus, promoting phagocytosis through the binding to the Fc region of the antibody. Also, the activation of the classical pathway of the complement can promote the formation of the membrane attack complex (MAC). Finally, antibody-dependent cellular cytotoxicity by interacting with Fc receptors in the NK cells can promote apoptosis of cancer cells [20][21] (Figure 2).
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Figure 2. Immunological mechanism of action of the peptide-based vaccines. After its administration, the peptides will be recognized by innate immune cells that promote the activation of the adaptive immune response (cellular and humoral). Released antibodies can promote the destruction of tumoral cells by ADCC, CDC, ADCP, signaling inhibition, and complement activation (classical pathway), whereas cytotoxic T cells can promote apoptosis of cancer cells by releasing perforins and granzymes or by interacting with Fas/FasL. APC: antigen-presenting cell; MHC-I: major histocompatibility complex type I; MHC-II: major histocompatibility complex type II; Th1: T helper 1; Th2: T helper 2; ADCC: antibody-dependent cellular cytotoxicity; CDC: complement-dependent cytotoxicity; ADCP: antibody-dependent cellular phagocytosis. Image created in Biorender (https://biorender.com/ accessed on 2 July 2022).

3. New Potential Therapeutic Targets for Developing Peptide-Based Vaccines for Breast Cancer

There are several types of vaccines being developed and evaluated against breast cancer. The main differences are the type and quantity of employed antigen, adjuvant, stabilizer, or the target population. In recent years, studies about breast cancer revealed new mechanisms involved in the progression and identified multiple antigens associated with the phenotype of cancer cells. Given the potential and participation of these proteins in the development of cancer, they have been proposed as potential therapeutic targets [22][23][24].

3.1. Syntenin-1

The melanoma differentiation-associated gene-9, also known as syntenin-1 or syndecan binding protein (SDCBP) [25], is a scaffold protein with a PDZ domain involved in the regulation of several biological processes such as cell-cell adhesion, cell-matrix, and signaling transduction. In breast cancer, this protein promotes the progression, growth, and metastasis of cancer stem cells [26]. An association between the overexpression of syntenin-1 and the tumor growth and metastasis to lymph nodes has been described in Balb/c mice [27]. It could be related to the role of this protein in controlling cellular growth during the transition from G1/S during the cellular cycle [28]. In addition to this protein being associated with multiple types of tumors, its role in cancer is notable and needs further studies.

3.2. PLAC-1

The placenta-specific protein-1 (PLAC-1) is part of the denominated cancer/testis antigens. It is expressed mainly in the trophoblast membrane during the development of the placenta, and, in adults, this antigen is exclusively expressed in testis [29]. The report shows that the overexpression of PLAC-1 promotes cell migration and invasion in vitro and in vivo in cell lines derived from breast cancer and promotes cellular proliferation by activating the AKT pathway. These findings suggest that PLAC-1 is involved in the inflammatory response and immunological tolerance associated with immune response evasion in cancer cells [30][31]. Using in silico approaches, several epitope candidates derived from PLAC-1 have been identified for developing new formulations that, in conjunction with adjuvants, could be used in the treatment of BC [32].

3.3. Mammaglobin-α

Mammaglobin-α (MAG) is a tumor-specific antigen of breast cancer, it is expressed in around 40–80% of all the subtypes, and it is involved in cell signaling, antitumor immune response, and chemotaxis [33][34]. It has been described that MAG possesses specificity and high immunogenicity and also regulates the tumorigenesis and aggressiveness in BC by increasing the cellular proliferation, migration, and invasion of cancer cells. MAG is responsible for activating signaling pathways such as; MAPK, FAK, MMP, and NF-κB [35], and is involved in the expression of IL-2. In vitro experiments showed that positive cells to the expression of mammaglobin could promote the activation of CD4+ and CD8+ T cells capable of recognizing and lysate cancer cells [36]. There are few studies about the potential utility of MAG as a potential therapeutic target; however, it remains a strong candidate for the diagnosis and therapy of breast cancer [37].

3.4. NY-BR-1

The NY-BR-1 protein is a tumor-associated antigen recently described and identified in more than 70% of breast cancer tumors [38]. The expression of NY-BR-1 is more frequent in phase I carcinomas compared to phase II and III; the expression levels of NY-BR-1 are higher than HER2, and it is directly correlated with the expression of the estrogen receptor [39]. Balafoutas et al., [40] identified two peptides restricted by HLA-A2 for NY-BR-1 (p158–167 and p960–968) that could be recognized by CD8+ T cells derived from patients with BC. Due to the most frequent expression of NY-BR-1 compared with HER-2/neu (the reference target for breast cancer immunotherapy) this protein could be a valuable tool as a new therapeutic approach against BC [41].

3.5. PRAME

PRAME is a cancer/testis antigen, mainly expressed in melanoma and other solid tumors, such as breast, lung, and kidney cancers and leukemias [42]. In BC, the expression levels of PRAME are correlated with the negative expression of estrogens (ER), lower overall survival rates, and higher rates of distant metastasis [43][44]. Al-Khadairi et al., in 2019 [45] evaluated the expression of PRAME and its role in cellular migration and invasion in triple-negative breast cancer cell lines. Authors reported that PRAME promotes the aforementioned biological process through changes in the expression of epithelial-mesenchymal transition markers, such as SNAI1, TCF4, TWIST1, FOXC2, IL1RN, MMP2, SOX10, WNT11, MMP3, PDGFRB, and JAG1. In silico analysis of the chimeric protein of PRAME in combination with the adjuvant FliC-D2D3 shows that this protein could be a great candidate for developing a new vaccine against breast cancer and stimulating cellular and humoral immunity. These results increased the clinical value of PRAME as a prognostic biomarker and therapeutic target in BC [46].

3.6. MAGE A3 and A11

The MAGE-A family (melanoma-associated antigen) has attracted much interest as cancer-associated antigens. This family contains more than 60 genes with conserved homology and similar transcriptional regulation [47]. Particularly, the expression of MAGE A3 has been reported in malignant tumors that include melanoma, brain, breast, lung, and ovarian cancer, and it is related to the repression of genes involved in antigen processing and presentation and plays an essential role in the inhibition of T cells [48]. The expression of MAGE A3 is commonly observed in more advanced stages of cancer, and it is associated with worst prognosis [49]. Another interesting member of the MAGE family is MAGE A11, which is expressed in prostate and breast cancer, and its overexpression correlates with the expression of HER-2 and ER-β [50]. Immunoinformatic approaches identified one epitope in MAGE-A11 named 9-mer: KIIDLVHLL that could be used as a potential candidate for the design of a novel therapeutic vaccine [51].

3.7. CEACAM6

Finally, the CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6) is also overexpressed in several types of cancers, such as colorectal, pancreas, prostate, lung, and breast. Several studies have provided evidence about its role in the migration, invasion, cellular adhesion, and metastasis of cancer cells [52]. In breast cancer, CEACAM6 is overexpressed in cell lines positive to the expression of the ER; this expression was associated with the development of a more invasive and aggressive phenotype [53]. However, more evaluations need to be performed to evaluate its role in cancer and its potential utility as a therapeutic target [54] (Figure 3).
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Figure 3. Venn diagram of novel potential targets for developing peptide-based vaccines. The selected antigens are involved in the different biological processes: proliferation, apoptosis inhibition, immune response evasion, cell migration, and metastasis. Image created in Biorender (https://biorender.com/ accessed on 2 July 2022).

This entry is adapted from the peer-reviewed paper 10.3390/vaccines10081249

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