Cancer immunotherapies targeting the PD-1 signaling pathway

Journal of Biomedical Science, Nov 2017

Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. However, the failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research on combination therapies and predictive biomarkers. Here we summarize the development of PD-1-blockade immunotherapy and current issues in its clinical use.

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Cancer immunotherapies targeting the PD-1 signaling pathway

Iwai et al. Journal of Biomedical Science Cancer immunotherapies targeting the PD-1 signaling pathway Yoshiko Iwai 0 3 Junzo Hamanishi 0 2 Kenji Chamoto 0 1 Tasuku Honjo 1 0 Equal contributors 1 Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University , Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501 , Japan 2 Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University , 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 , Japan 3 Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health Japan , Kitakyushu-shi, Fukuoka 807-8555 , Japan Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. However, the failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research on combination therapies and predictive biomarkers. Here we summarize the development of PD-1blockade immunotherapy and current issues in its clinical use. PD-1; PD-L1; Cancer immunotherapy; Immune checkpoint Background Cancer immunotherapy, although controversial for many years, reached a turning point in 2014. Antibodies that specifically block PD-1 were approved for melanoma in 2014 and for non-small-cell lung cancer (NSCLC) in 2015 in the United States, European Union, and Japan. The success of clinical trials with novel drugs targeting immune-checkpoint molecules such as PD-1 led to a paradigm shift in cancer treatment. Since a PD-1 blockade targets lymphocytes rather than cancer cells, it has a long-term therapeutic effect that persists even when cancers cause mutations. Furthermore, the PD-1 blockade is effective against many types of tumors because it enhances the anti-tumor activity of cytotoxic T lymphocytes (CTLs), which recognize various tumor-specific antigens. Several companies are currently conducting phase 3 trials for different tumor types, including renalcell cancer (RCC), bladder cancer, head and neck cancer, ovarian cancer, and brain cancer. Although PD-1 blockade has dramatically improved the response rate for several cancers, three questions remain to be answered: 1) Why do some patients not respond to PD-1 blockade? 2) What is the best combination therapy using PD-1 blockade? 3) What predictive biomarkers can be used to distinguish responsive and unresponsive patients? Here we review the development of immunotherapy targeting the PD-1/PD-L1 signaling pathway and discuss the issues that still need to be resolved in clinical studies. History of cancer immunotherapy The concept of cancer immunotherapy goes back to the late nineteenth century. In 1891, a young New York surgeon named William Coley began intra-tumoral injections of bacterial products and observed tumor shrinkage in patients with sarcoma [ 1 ]. Almost a century later, the role of dendritic cells and their receptors in sensing microorganisms in the innate immune system was discovered [ 2, 3 ]. The molecular identification of cancer antigens created new approaches for effective immunotherapies [4]. In addition, the importance of IFN-γ and adaptive immunity in cancer immunosurveillance was demonstrated in preclinical tumor models using IFN-γR−/− and RAG2−/− mice [ 5 ]. These findings stimulated research into strategies to induce anti-tumor responses and led to immunotherapies such as cytokine therapy, peptide vaccine, dendritic-cell vaccine, and adoptive T-cell therapy. Most of these therapies were unsuccessful, and one primary reason was a lack of understanding of the existence and importance of immune checkpoints [ 6 ]. Immune checkpoints T-cell activating (accelerator) and inhibitory (brake) receptors regulate the balance between immune response and immune tolerance. The activation of naïve T cells requires both antigen presentation (signal 1) and a second signal sent through costimulatory receptors such as CD28 (signal 2) (Fig. 1) [ 7 ]. When ligated by B7 molecules such as CD80 (B7-1) or CD86 (B7-2), CD28 coreceptors on T cells deliver a positive costimulatory signal, whereas CTLA-4 coreceptors deliver a negative coinhibitory signal. PD-1, like CTLA-4, belongs to the CD28 family and delivers a negative signal when it interacts with its ligands, PD-L1 (B7-H1 or CD274) and PDL2 (B7-DC or CD273), which belong to the B7 family (Fig. 1) [ 8–10 ]. T cells have immune checkpoints such as PD-1 and CTLA-4 to reduce autoimmune responses against selftissues by overly exuberant immune responses to infection. While most cancer immunotherapies accelerate Tcell activity, immune-checkpoint inhibitors release the immune system’s brakes (...truncated)


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Yoshiko Iwai, Junzo Hamanishi, Kenji Chamoto, Tasuku Honjo. Cancer immunotherapies targeting the PD-1 signaling pathway, Journal of Biomedical Science, pp. 26,