Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors.

Although T lymphocytes have long been appreciated for their role in the immunosurveillance of cancer, it has been the realization that cancer cells may ultimately escape a response from tumor-reactive T cells that has ignited efforts to enhance the efficacy of anti-tumor immune responses. Recent advances in our understanding of T cell immunobiology have been particularly instrumental in informing therapeutic strategies to overcome mechanisms of tumor immune escape, and immune checkpoint blockade has emerged as one of the most promising therapeutic options for patients in the history of cancer treatment. Designed to interfere with inhibitory pathways that naturally constrain T cell reactivity, immune checkpoint blockade releases inherent limits on the activation and maintenance of T cell effector function. In the context of cancer, where negative T cell regulatory pathways are often overactive, immune checkpoint blockade has proven to be an effective strategy for enhancing the effector activity and clinical impact of anti-tumor T cells. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have yielded unprecedented and durable responses in a significant percentage of cancer patients in recent years, leading to U.S. FDA approval of six checkpoint inhibitors for numerous cancer indications since 2011. In this review, we highlight the clinical success of these FDA-approved immune checkpoint inhibitors and discuss current challenges and future strategies that must be considered going forward to maximize the efficacy of immune checkpoint blockade therapy for cancer.

Hargadon KM ，Johnson CE ，Williams CJ 《-》

Recent advances in the clinical development of immune checkpoint blockade therapy.

Ghahremanloo A ，Soltani A ，Modaresi SMS ，Hashemy SI ... -  《-》

Immune Checkpoint Blockade in Breast Cancer Therapy.

Bu X ，Yao Y ，Li X 《-》

T cell checkpoint regulators in the heart.

T lymphocyte-mediated immune responses in the heart are potentially dangerous because they can interfere with the electromechanical function. Furthermore, the myocardium has limited regenerative capacity to repair damage caused by effector T cells. Myocardial T cell responses are normally suppressed by multiple mechanisms of central and peripheral tolerance. T cell inhibitory molecules, so called immune checkpoints, limit the activation and effector function of heart antigen-reactive T cells that escape deletion during development in the thymus. Programmed cell protein death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are checkpoint molecules homologous to the costimulatory receptor CD28, and they work to block activating signals from the T cell antigen receptor and CD28. Nonetheless, PD-1 and CTLA-4 function in different ways and at different steps in a T cell response to antigen. Studies in mice have established that genetic deficiencies of checkpoint molecules, including PD-1, PD-L1, CTLA-4, and lymphocyte activation gene-3, result in enhanced risk of autoimmune T cell-mediated myocarditis and increased pathogenicity of heart antigen-specific effector T cells. The PD-1/PD-L1 pathway appears to be particularly important in cardiac protection from T cells. PD-L1 is markedly up-regulated on myocardial cells by interferon-gamma secreted by T cells and PD-1 or PD-L1 deficiency synergizes with other defects in immune regulation in promoting myocarditis. Consistent with these studies, myocarditis has emerged as a serious adverse reaction of cancer therapies that target checkpoint molecules to enhance anti-tumour T cell responses. Histopathology and immunohistochemical analyses of myocardial tissue from immune checkpoint blockade (ICB)-treated patients echoes findings in checkpoint-deficient mice. Many questions about myocarditis in the setting of cancer immunotherapy still need to be answered, including the nature of the target antigens, genetic risk factors, and variations in the disease with combined therapies. Addressing these questions will require further immunological analyses of blood and heart tissue from patients treated with ICB.

Grabie N ，Lichtman AH ，Padera R 《-》

Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapy.

Immune checkpoint inhibitors-based immunotherapy offers a new effective modality in the treatment of advanced malignancies. Considering the remarkable efficacy of immune checkpoint inhibitors in clinical trials, the FDA has approved a variety of immune checkpoint inhibitors for the treatment of advanced tumors. However, only limited patients with certain cancers can benefit from monotherapy of immune checkpoint inhibitors. Interventional therapy for cancer can not only destroy the primary tumors, but also regulate the immune system through different mechanisms, which provides a potential possibility for the combination of immune checkpoint inhibitors and interventional modalities in cancer treatment. This article reviews the possible synergistic mechanisms of interventional therapy combined with immune checkpoint inhibitors and summarizes the research progress of the combined therapy in cancer treatment.

Chang X ，Lu X ，Guo J ，Teng GJ ... -  《-》