Targeting TLR-4 with a novel pharmaceutical grade plant derived agonist, Immunomax®, as a therapeutic strategy for metastatic breast cancer

Abstract

BackgroundPreviously we demonstrated that the resection of primary 4T1 tumors only slightly prolongs mouse survival, but importantly, creates a “window of opportunity” with attenuated suppressor cell and increased activated T cell populations. This suggests that additional activation of the immune system by immunostimulatory agents during this period may enhance anti-tumor immunity and potentially eradicate micro-metastatic disease in this stringent model.We hypothesized that the immunostimulator Immunomax®, which is comprised of a plant-derived polysaccharide, is non-toxic in humans and stimulates immune defense during the infectious diseases treatment, may have also anti-tumor activity and be beneficial in the adjuvant setting when endogenous anti-tumor responses are present and during the “window of opportunity” in post-resection metastatic breast cancer model. Here we provide the initial report that Immunomax® demonstrates the capacity to eliminate micro-metastatic disease in the post-resection, 4T1 mouse model of breast cancer.MethodsThe efficacy of Immunomax® was evaluated by analyzing survival rate and the number of spontaneous clonogenic tumor cells in the lung homogenates of mice. The frequencies of activated NK, CD4+ and CD8+ cells as well as myeloid-derived suppressor cells and Treg cells were evaluated using flow cytometry. Highly purified mouse and human dendritic and NK cells were sorted and the effect of Immunomax® on activation status of these cells was assessed by flow cytometry. The property of Immunomax® as TLR-4 agonist was determined by NF-κB/SEAP reporter gene assay, WB, RT-PCR.ResultsImmunomax® injections significantly prolonged overall survival and cured 31% of mice. This immunostimulator activates DCs via the TLR-4, which in turn stimulates tumoricidal NK cells and in vitro, completely inhibits growth of 4T1 cells. Incubation of PBMC from healthy donors with Immunomax® activates NK cells via activation of plasmacytoid DC leading significantly higher efficacy in killing of human NK-target cells K562 compared with non-treated cells.ConclusionThis is the first demonstration that Immunomax® is a TLR-4 agonist and the first report of a documented role for this pharmaceutical grade immunostimulator in augmenting anti-tumor activity, suggesting that incorporation of Immunomax® into developing breast cancer therapeutic strategies may be beneficial and with less potential toxicity than checkpoint inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0322-y) contains supplementary material, which is available to authorized users.

Optimization of the fermentation process of Cordyceps sobolifera Se-CEPS and its anti-tumor activity in vivo

“…Moreover, TNF-α can induce cell differentiation and promote mononuclear cells or T cells to secrete a variety of cytokines [31]. Mature T lymphocytes can be divided into two subsets: CD4 + and CD8 + [32, 33]. CD4 + cells are T helper cells that aid in secreting numerous cytokines and enhance the killing effect of CD8 + cells in tumors [34].…”

Activation of Genes Controlling the Immune Signaling Pathways: Differential Individual Sensitivity of Human Blood Cells for Interferon Preparations and Ifn Inducers

“…По-видимому, для дей-ствия Иммуномакса имеют значения дополни-тельные цитоплазматические сигнальные пути индукции синтеза IFN с участием митохон-дриального белка IPS и фактора транскрипции IRF3. Наши данные дополняют имеющуюся информацию относительно участия TLR4 в сиг-нальном механизме действия Иммуномакса, полученную на клетках с делетированными ге-нами [15]. Проведенные этими авторами иссле-дования не затрагивали гены рецепторов TLR3 и RIG1.…”

“…Специальный интерес пред-ставляет выяснение роли RIG1/IPS сигнального пути в механизме действия этого препарата в свя-зи данными об участии в нем мембранного TLR4 [15]. Результаты действия Иммуномакса на экс-прессию этих сигнальных генов представлены на рисунке 4.…”

Immune Checkpoint Inhibitors: Therapeutic Tools for Breast Cancer

“…Breast cancer is most commonly treated with surgery, which may be followed by chemotherapy or radiation therapy, or both. Although the conventional treatments for breast cancer are sometimes beneficial, a substantial proportion of breast cancer patients might have a risk for local relapse that leads to develop a recurrence of their disease and/or metastatic breast cancer (Ghochikyan et al, 2014). For this reason, investigating new and potential strategies for breast cancer treatment remains necessary.…”

“…But cancer cells are able to escape from the immune system mainly by hijacking the immune cell-intrinsic checkpoints that induce the tumor cells to evade the host immune system by inhibiting T lymphocytes activation (Criscitiello and Curigliano, 2013;Ileana et al, 2013). Blocking of these immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), PD ligand 1 (PD-L1) and lymphocyte activation gene-3 (LAG-3) with monoclonal antibodies (mAbs) or agents that are immunostimulatory can modulate the immunosuppressive environment, augment anti-tumor immunity and induce tumor regression (Stagg and Allard, 2013;Ghochikyan et al, 2014).…”