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Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation

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Cancer is a common term for a group of diseases caused by uncontrolled cell proliferation and migration. This results in abnormal growth of a tumor mass, first within an organ, then infiltrating adjacent tissues. Eventually, cancer cells can also colonize distant organs via blood or lymphatic vessels, so called metastases, causing morbidity and death

The symptoms, course and prognosis of the disease vary depending on the tissue origin. The risk of cancer increases with age and the remarkably longer life span of the world population contributes to cancer as an increasing problem. Life style and environmental factors add to this development, with smoking as the most important factor.

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James P. Allison studied a known protein that functions as a brake on the immune system, CTLA-4. He developed an antibody to CTLA-4 to block the immune system brake. He reasoned that the T cells would be unleashed and become more active and hopefully attack the cancer cells. The key experiment was performed in 1994. The results were spectacular. The mice treated with the anti-CTLA-4 antibody were cured from cancer, while the control mice developed large tumours. This seminal study represents the birth of a new concept for immunotherapy. Today often referred to as immune checkpoint inhibition. Allison was eager to apply it for the benefit of patients. A small biotech company took on the challenge to produce the human antibody and a few years later the first clinical trial started with 40 patients suffering from metastatic melanoma, the pigmented cancer of the skin. Some of the patients showed striking responses - the tumours shrank, and could even disappear. Such results had never been seen before in this patient group. Despite side effects, the results were positive enough to start a long series of larger trials conducted by clinical colleagues.

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In 1992, 4 years before Allison's observations on CTLA-4 were published, Tasuko Honjo discovered PD-1 as a novel member of the immunoglobulin gene superfamily. His new observation published in The EMBO Journal suggested that the PD-1 protein may be involved in the classical type of programmed cell death.[Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Ishida Y, Agata Y, Shibahara K, Honjo T EMBO J. 1992 Nov; 11(11):3887-95.] In 1999, Honjo et al. published another study in Immunity, This suggested that PD-1 serves as a negative regulator of immune responses

One year later in the Journal of Experimental Medicine, Honjo et al. described that the ligand of PD-1 (PD-L1) plays a central role in the inhibition of T-cell receptor-mediated lymphocyte proliferation and cytokine secretion. PD-1 and PD-L1 engagement may subsequently determine the extent of immune responses at sites of inflammation. In 2005, Honjo's laboratory published another study in International

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Definitely, the discovery and evolution of immune checkpoint inhibitors is one of the most exciting advances in cancer immunotherapy. Non-CNS tumors, specifically, have experienced impressive responses with long-lasting survival benefits

As CNS tumors can develop multiple mechanisms for immune-resistance, combinations using multiple checkpoint inhibitors targeting both CTLA-4 and PD-1, with or without other immune-based strategies may be the most effective means in generating an antitumor immune response. Awareness and multidisciplinary management of immune-related adverse events and developing cost-effective strategies for treatment are also necessary to ensure the optimal clinical benefit from these therapeutic agents.

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Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.

Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: A review. JAMA Oncol. 2016;2:1346–53.

Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.

Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.

Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity.

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