Co-inhibitory Immune Checkpoint Research Articles

Checkpoint Blockade in Cancer Immunotherapy: Squaring the Circle

Manipulating the complex interaction between the immune system and tumour cells has been the focus of cancer research for many years, but it is only in the past decade that significant progress has been made in the field of cancer immunotherapy resulting in clinically effective treatments. The blockade of co-inhibitory immune checkpoints, essential for maintaining lymphocyte homeostasis and self-tolerance, by immunomodulatory monoclonal antibodies has resulted in the augmentation of anti-tumour responses. The greatest successes so far have been seen with the blockade of cytotoxic T lymphocyte associated antigen-4, which has resulted in the first Phase III clinical trial showing an overall survival benefit in metastatic melanoma, and in the blockade of the programmed cell death protein-1 axis. This concise review will focus on the clinical advances made by the blockade of these two pathways and their role in current cancer treatment strategies.

Immune checkpoint receptors in regulating immune reactivity in rheumatic disease.

Immune checkpoint regulators are critical modulators of the immune system, allowing the initiation of a productive immune response and preventing the onset of autoimmunity. Co-inhibitory and co-stimulatory immune checkpoint receptors are required for full T-cell activation and effector functions such as the production of cytokines. In autoimmune rheumatic diseases, impaired tolerance leads to the development of diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome. Targeting the pathways of the inhibitory immune checkpoint molecules CD152 (cytotoxic T lymphocyte antigen-4) and CD279 (programmed death-1) in cancer shows robust anti-tumor responses and tumor regression. This observation suggests that, in autoimmune diseases, the converse strategy of engaging these molecules may alleviate inflammation owing to the success of abatacept (CD152-Ig) in rheumatoid arthritis patients. We review the preclinical and clinical developments in targeting immune checkpoint regulators in rheumatic disease.

Integrating novel therapeutic monoclonal antibodies into the management of head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive malignancy. Interest in developing novel immunotherapies in HNSCC has been reawakened by the success of cetuximab, a therapeutic monoclonal antibody (mAb) against the epidermal growth factor receptor, which likely relies on immune as well as antisignaling mechanisms. This review focuses on novel therapeutic mAbs in current clinical development against established mechanisms of immune evasion in HNSCC, targeting: 1) tumor antigens, with resultant potential to induce antibody-dependent cell-mediated cytotoxicity and T cell activation; 2) immunosuppressive cytokines; 3) costimulatory tumor necrosis factor-family receptors; and 4) coinhibitory immune checkpoint receptors. Clinical trials of immunotherapeutic mAbs as monotherapy, in combination with cytolytic standard therapies exposing tumor antigens or in combination with other immunomodulatory mAbs, are urgently needed in HNSCC.