HDAC Inhibitors as Epigenetic Regulators

PBMCs are stimulated with CD3 in the presence of IL-2 and then transduced with the retrovirus encoding the antigen-specific TCR. therapeutics aimed at minimizing or inhibiting cancer cell proliferation and metastasis. The efficacies of traditional treatment modalities for the management of cancer, such as radiation therapy and chemotherapy, are often limited by the occurrence of severe toxicities, which account for the numerous side effects experienced by oncology patients [1]. Radiation therapy is an effective means for systemic treatment; however, localized collateral damage of healthy tissues occurs as a consequence. Chemotherapeutic agents, such BOP sodium salt as BOP sodium salt genotoxic drugs or antimetabolites, reveal short-term side effects and are often administered in combination with surgical interventions [2]. Although surgical excision of tumors is effective only in early stages of disease, it loses its effectiveness once the malignancy becomes metastatic. Cancer immunotherapy has become a staple of modern oncology since the first immunotherapy was described in 1985. Immunotherapeutic approaches utilize components of a patient’s own immune system to selectively target cancer cells thereby mitigating many of the BOP sodium salt side effects associated with traditional treatment options. The immune system can detect cancer cells in one of two ways: by recognizing molecules uniquely expressed in cancer cells (tumor-specific antigens or mutations) or by recognizing molecules that are differentially expressed in cancer cells relative to normal cells (tumor-associated antigens) [3]. Immunotherapy is an effective and promising treatment option for cancer due to its selectivity and long-lasting effects and demonstrated improved overall survival and tolerance [4]. High-dose interleukin 2 (HD IL-2) was the first reported immunotherapy capable of mediating a long-term and complete response (CR) in patients with advanced melanoma and renal cancer [5, 6]. Phase II clinical trials demonstrated that 9 patients (7%) with metastatic melanoma and 10 patients (7%) with metastatic renal cell cancer treated with biologic therapy of HD IL-2 achieved complete regression of disease with hypotension, secondary to underlying capillary leak, being the most commonly reported toxicity [7C9]. These early studies substantiated that altering host immune responses with exogenous immune effectors could safely mediate antitumor effects on a Tlr2 subset of patients with advanced malignancies [7, 8, 10]. FDA approval of HD IL-2 for the treatment of patients with renal cancer and melanoma was granted in 1992 and 1998, respectively [7, 8, 10], which established immunotherapy as the newest paradigm for the treatment of cancer. In the decades following FDA approval of HD IL-2, there have been unprecedented advancements regarding the cellular and molecular drivers of tumorigenesis and the mechanisms through which tumorigenic cells circumvent destruction by the immune system [8]. More recently, three distinct therapeutic modalities have revolutionized the field of immunooncology: checkpoint inhibitors, adoptive T cell transfer, and bivalent antibodies. 2. Checkpoint Inhibitors Cancer cells have adapted specialized cellular mechanisms to facilitate the development of the tumor microenvironment [11]. One method tumor cells employ to ensure their survival and progression is to evade immune system checkpoints [12]. Immune system checkpoints function to monitor autoimmunity and mitigate collateral tissue damage due to immune responses by modulating costimulatory and inhibitory signaling [13]. However, during tumorigenesis, the dysregulation of checkpoint protein expression can result in the aberrant activation of inhibitory checkpoint receptors thereby preventing T cells from recognizing and eliminating tumorigenic cells [12C14]. Checkpoint inhibitors are a class of immunotherapies that induce a T cell-mediated antitumor responses by selectively blocking the inhibitory checkpoint receptors subject to manipulation by cancer cells [15]. The immune checkpoint receptors that have served as the primary targets of BOP sodium salt clinical cancer immunotherapy include the following: cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), lymphocyte activation gene 3 (LAG-3), B and T lymphocyte attenuator (BTLA), and T cell immunoglobulin and mucin protein 3 (TIM-3) [13, 16]. 2.1. Anti-CTLA-4 Treatment The first immune checkpoint receptor to be clinically targeted was cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) [17]. CTLA-4 is an inhibitory immune checkpoint receptor expressed on the surface of activated T cells and regulatory T cells that binds to B7 family ligands (CD80 and CD86) on antigen-presenting cells [17, 18]. CTLA-4 functions to downregulate T cell proliferation by outcompeting CD28, a costimulatory receptor, for ligand binding and recruitment of serine/threonine phosphatase [19]. Anti-CTLA-4 relieves the natural brakes on T cells, thus allowing them to perform their effector function for an extended period of time [20]. Anti-CTLA-4 antibodies potentiate an antitumor response by blocking inhibitory CTLA-4 receptors to facilitate T cell activation [21, 22]. Ipilimumab, a monoclonal anti-CTLA-4.