Triple-negative breast cancer (TNBC) is a molecular subtype of breast cancer that is negative for expression of estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2). Clinically, it is characterized by aggressive behavior, distinct patterns of metastasis, and high rates of recurrence and mortality. Since TNBC tumor cells lack the necessary receptors, the disease does not respond to hormonal therapy, such as Tamoxifen or aromatase inhibitors, or therapies that target HER2, such as trastuzumab (Herceptin) or lapatinib (Tykerb). Immunotherapeutic strategies, including active immunization with tumor-specific antigens that results in cytotoxic T lymphocyte (CTL)-mediated antitumor response may serve as an alternative to control the recurrence or progression of TNBC. Cancer/testis antigens (CTAs) are protein antigens whose expression in normal tissues is restricted to the germ cells of the adult testis, but which are aberrantly activated and expressed in various malignant human tumors. We have identified that the CTA sperm protein 17 (SP17) is expressed in malignant TNBC cell lines and patient tumor samples, making it a novel candidate for immunotherapeutic targeting. In this proposal, we will evaluate the efficacy of oral microparticulate vaccine based on recombinant SP17 antigen combined with specific immunomodulatory agents to prevent/retard the progression of TNBC. More specifically, vaccine components will be encapsulated into microparticles composed of a polymer matrix containing a mixture of enteric and sustained release polymers to prevent degradation of cargo molecules under acidic conditions in the stomach and enabling their controlled release at intestinal target sites, respectively. The particles are targeted to M cells present in PeyerÂ’s patches of the gut-associated lymphoid tissue, which take up the encapsulated vaccine and transport it to mucosal dendritic cells via transcytosis to generate immunogenic response. In order to overcome tumor-associated immunosuppression mediated by CD4+ regulatory T cells (T- regs) our vaccine formulation incorporates also interleukin-15 (IL-15) and p38 mitogen-activated protein kinase (MAPK) inhibitor, which act synergistically in antagonizing CD4+ T-reg induction and promoting tumor antigen- specific pro-inflammatory T helper 17 cell (Th17) responses that correlate with strong CD8+ CTL activation. The vaccine microparticles will be administered to female C57BL/6 mice bearing TNBC tumors together with the indoleamine-2,3-dioxygenase (IDO) inhibitor 1-methyl-tryptophan (1-MT) to further mitigate the risk of tumor- induced immunotolerance. Following vaccination, the systemic immune response and therapeutic efficacy will be determined by observing the change in the tumor burden and serum levels of SP17-specific IgG. In addition, the spleen and draining lymph nodes of vaccinated mice will be analyzed for the presence of T-regs to determine the effect of the vaccination on tumor-associated immunosuppression. If proven successful, our oral vaccination approach combining ease of administration, low manufacturing costs, and high patient acceptability will provide a novel therapeutic option for TNBC, a disease which at present lacks effective treatments.
Public Health Relevance Statement: NARRATIVE Of the approximately 230,000 new cases of invasive breast cancer diagnosed in the United States each year, about 15 percent are triple negative breast cancers (TNBC), where the tumors do not express three specific receptor molecules, viz. estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Patients with this breast cancer subtype have a worse chance of beating the disease as neither hormone therapy nor drug treatments that target the HER2 protein are effective. We will investigate if oral vaccination with microparticles loaded with a novel TNBC antigen in combination with specific strategies to overcome tumor-related immunosuppression is effective in inducing a therapeutic anti-tumor response by activating patientÂ’s own immune system to attack malignant cells.
Project Terms: Abate; Acetates; Active Immunization; adaptive immune response; Adult; Affect; Affinity; Aggressive behavior; Animal Cancer Model; Animal Model; Antibodies; Antibody Response; Antigens; Antitumor Response; Aromatase Inhibitors; base; beta-Cyclodextrins; Biological Assay; Biological Availability; Breast Cancer cell line; breast cancer diagnosis; C57BL/6 Mouse; cancer cell; cancer subtypes; cancer testis antigen; Cancer Vaccines; CD80 gene; CD86 gene; CD8B1 gene; Cells; Cellulose; Compliance behavior; controlled release; cost; cytokine; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Dioxygenases; Disease; effective therapy; efficacy testing; Encapsulated; Enteral; Epidermal Growth Factor Receptor; Estrogen Receptors; Female; Formulation; gastrointestinal; Germ Cells; Growth and Development function; Gut associated lymphoid tissue; hormone therapy; Human; Immune response; Immune system; Immunity; Immunization; immunogenic; immunogenicity; Immunoglobulin G; Immunologic Adjuvants; Immunotherapeutic agent; Individual; indoleamine; Inflammatory; inhibitor/antagonist; Interleukin-15; Intestines; kinase inhibitor; Kinetics; lapatinib; Lectin; Lesion; Life; Ligands; Lipids; lymph nodes; Lymphocyte Activation; M cell; Malignant - descriptor; malignant breast neoplasm; MAPK14 gene; Measures; Mediating; methyl tryptophan; Methylcellulose; MHC Class I Genes; Mitogen-Activated Protein Kinase Inhibitor; mitogen-activated protein kinase p38; molecular subtypes; Morphology; mortality; mouse model; mucosal vaccine; Mucous Membrane; Mus; Natural immunosuppression; NCAM1 gene; Neoplasm Metastasis; neoplastic cell; Normal tissue morphology; novel; novel therapeutics; Oral; Oral mucous membrane structure; oral vaccine; particle; Particulate; Patients; Pattern; Polymers; pre-clinical; prevent; Progesterone Receptors; Property; prophylactic; Proteins; receptor; Recombinants; Recurrence; Regulatory T-Lymphocyte; response; Risk; Sampling; Serum; Signal Transduction Pathway; Site; sperm protein; Spleen; Stomach; Structure of aggregated lymphoid follicle of small intestine; Succinates; System; T-Cell Proliferation; T-Lymphocyte; Tamoxifen; targeted treatment; Techniques; Technology; Testis; Therapeutic; TLR4 gene; TNFRSF5 gene; transcytosis; Trastuzumab; Treatment Efficacy; triple-negative invasive breast carcinoma; tumor; Tumor Antigens; Tumor Burden; tumor growth; Tumor Immunity; United States; uptake; Vaccinated; Vaccination; Vaccine Antigen; vaccine development; Vaccines; zeta potential
