Immune-checkpoint pathways limit T-cell-mediated immune responses. Neoplasms often escape immunemediated cytotoxicity via the immune-checkpoint pathway. Cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and negative costimulatory receptors are expressed primarily on the surface of activated T cells and work primarily in the immune-checkpoint pathway. Recently, the immune-checkpoint inhibitors, including anti CTLA-4 and anti PD-1 antibodies, have been used in some clinical settings. The application of immune-checkpoint inhibitors will change the paradigm in cancer therapy.
Recent studies have shown that depletion or reduction of regulatory T cells can improve advanced solid tumors. It is expected this new field will lead to enhancement of immune responses against tumor mass. By contrast, B cell target therapies, such as anti CD20 monoclonal antibody treatment using rituximab or other new antibody agents, have also been developed for auto immune diseases.
Antibody-drug conjugates (ADC) are new class of anti-cancer drugs that combines monoclonal antibodies and highly potent cytotoxic molecules. While this concept has been around for a long time, recent advances in antibody engineering and linker technology have allowed the advent of safe, effective ADCs. Following the approvals of gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia, brentuximab vedotin for Hodgkin lymphoma/systemic anaplastic large cell lymphoma and trastuzumab emtansine (T-DM1) for human epidermal growth factor receptor 2-positive breast cancer, the clinical utility of these ADCs has been evaluated. Furthermore, a variety of ADCs are currently under development and are expected to play prominent roles in anti-cancer treatment.
It is well known that the immune surveillance system plays a crucial role in disease control for patients with malignant neoplasm. Although chemotherapy remains the leading approach in the treatment of hematologic malignancies, immune system-targeting antibody agents, such as immune checkpoint inhibitors, are currently under clinical investigation. While treatments with small-molecule compounds do not aim to target the immune system, some compounds potentiate treatment efficacy by enhancing the immune response to neoplasms. Immunomodulatory drugs, including thalidomide, lenalidomide, and pomalidomide, are known to be effective in reducing multiple myeloma cells by enhancing natural killer cell activity. Among the tyrosine kinase inhibitors used in the clinical practice, dasatinib is the only agent that confers cytotoxic lymphocyte expansion and the phenomenon is associated with favorable outcomes in patients with Philadelphia chromosome-positive leukemia. In this paper the underlying mechanisms that confer activation of immune system and the clinical significance of immunomodulation by small-molecule compounds are highlighted.
Immunosuppressive agents have traditionally been used when glucocorticoids are ineffective. However, immunosuppressive agents have recently been used as a first line treatment. Today, immunosuppressive agents are classified as systemic conventional immunosuppressive agents, biologic agents and molecularly targeted agents. Systemic immunosuppressive agents include cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil (MMF) and methotrexate (MTX). Biologic agents include TNF inhibitors, IL-6 inhibitors, CTLA-4-Ig and CD20 inhibitors. Molecularly targeted agents include JAK inhibitors (tofacitinib). Initially, cyclophosphamide and MMF are used, followed by tacrolimus and mizoribine, in the treatment of systemic lupus erythematosus. MTX is used first in the treatment of rheumatoid arthritis (RA). TNF inhibitors, IL-6 inhibitors and CTLA-4-Ig are also often used to treat RA. However, tofacitinib is not often used, due to the potential for adverse effects. Tacrolimus and intravenous cyclophosphamide are effective in treating dermatomyositis and polymyositis complicated with interstitial pneumonia. While additional immunosuppressive agents are used to treat other collagen diseases, the evidence in support of these remain equivocal.
Anti-complement component C5 therapy (Eculizumab) utilizes a humanized monoclonal antibody that is a terminal complement inhibitor. Eculizumab was developed and was approved by the United States Food and Drug Administration (FDA) in 2007 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and in 2011 for the treatment of atypical hemolytic uremic syndrome (aHUS). Eculizumab inhibits the cleavage of C5 to C5a and C5b by the C5 convertase, which prevents the generation of the terminal complement complex C5b-9 (and also exhibits prothrombotic and proinflammatory effects). Both C5a and C5b-9 cause the terminal complementmediated events that are characteristic of aHUS. By inhibiting the complement cascade at this point, the normal, disease-preventing functions of the proximal complement system are largely preserved, while the properties of C5 that promote inflammation and cell destruction are impeded. We present a review of the role of anti-complement component C5 therapy (Eculizumab) in aHUS patients.
Psoriasis is a chronic inflammatory skin disease that is mediated by T-cell dependent immune responses. Cyclosporine, a general suppressor of T cells, has been used to treat psoriasis. Biologics targeting various immuneassociated cytokines are also currently in use or are under development. TNF-α inhibitors are successful examples of such biologics. More recent biologics have targeted a psoriasis-specific immune pathway, IL-23/Th17. The IL-12/23p40 inhibitor, ustekinumab, as well as the IL-17 antagonists secukinumab, ixekizumab, and brodalumab, have proven to be highly effective for psoriasis and have been approved for clinical use. This review discusses the treatment of psoriasis with immunosuppressants in the context of the current understanding of psoriasis pathophysiology.
The lungs have a direct connection to the outside of the body, and are particularly susceptible to environmental stresses. Environmental stresses lead to the activation of several immune functions, which are associated with the pathogenesis and development of lung diseases. This review summarizes the current topics of immunotherapy for lung diseases, such as asthma, interstitial pneumonia, and lung cancer.