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1 日大医誌 75 (4): (2016) 156 特集免疫チェックポイント阻害薬はがんの治療の未来をどう変えるか Mechanisms of Action, Efficacy and Side Effects of Nivolumab and Its Therapeutic Use at Itabashi Hospital, Nihon University School of Medicine Satoshi Izaki, Koremasa Hayama and Tadashi Terui Division of Dermatological Science, Department of Dermatology, Nihon University School of Medicine Malignant melanomas easily metastasize and are often resistant to conventional classical therapies, i.e., surgery, chemotherapy and radiotherapy, in patients with advanced/metastatic malignant melanoma. In recent years, rapid advances have been made in the immunotherapy of malignant melanoma. New medicines, which have been approved by Federal Drug Administration (FDA), have dramatically improved the clinical outcomes for patients with advanced/metastatic melanoma. Nivolumab is an immune checkpoint inhibitor that targets programmed cell death-1 (PD-1) receptors. PD-1 is expressed on many immune cells, including T cells, B cells and natural killer cells. Engagement of PD-1 with its ligands (PD-L1 and PD-L2) induces functional exhaustion of the cytotoxic immune response. Nivolumab inhibits the PD-1 pathway, and thus activates the cytotoxic immune response. Although the immune checkpoint inhibitor tends to take a few months until it exhibits efficacy, once established, the efficacy often lasts for a long time. However, immune checkpoint inhibitors can have many adverse effects, including autoimmune-related inflammation. In particular, relevant severe adverse effects include interstitial pneumonia, colitis, liver dysfunction, thyroid disorders, and infusion reaction. Other affected organs include the skin, eyes, kidneys and nerves. Furthermore, several cases of fulminant type 1 diabetes mellitus have been reported in 2015 and Because we cannot predict what kinds of adverse effects will occur or when they will occur, we must observe patients carefully in order to detect any adverse events early on, and initiate appropriate treatments. The development of a number of new therapies will provide benefits for patients with malignant melanoma. Dermatologists must use these new drugs appropriately after determining the correct diagnostic information and providing supporting evidence. Key words: malignant melanoma, nivolumab, immune checkpoint inhibitor, PD-1, PD-L1 PD-1 PD-L1 (J. Nihon Univ. Med. Ass., 2016; 75 (4): ) はじめに American Joint Committee on Cancer 2001 TNM IV 5 13% 1) (DTIC) DTIC % 5% 2) DTIC DTIC survival benefit 3) 2011 Ⅰ. 新しい治療薬の出現 T 4 cytotoxic T lymphocyte antigen 4 CTLA BRAF Federal Drug Administration (FDA) programmed cell death-1 (PD-1)

2 75 (4) Ⅱ. ニボルマブの作用機序 PD-1 PD Ishida T I 4) PD-1 PD-1 5) 6) PD-1 PD-1 T B CD28 PD-L1 PD-L2 7) 8,9) PD-1/PD-L1 PD-1 Fig. 1 PD-L1 PD-L1 T PD-1 T 7) PD-1 PD-L1/PD-L2 T Ⅲ. ニボルマブの効果 1 3 mg/kg mg/kg mg/kg 3 3 mg/kg 2 2 mg/kg 3 10) I (ONO ) 17 11) 17 3 PR (partial response) 3 SD (stable disease) 5 (29%) 6 35 II 10) 23% Fig. 1 Suppression of tumor immunity by PD-1 and release of the suppression by anti PD-1 antibody. (Excerption from references 10)

3 158 2 II 540 PR 23% SD 65.8% 10) Response Evaluation Criteria In Solid Tumors (RECIST) (pseudo progression) 10) 11) RECIST progress disease (PD) 12) Ⅳ. ニボルマブの副作用 10) II 30 (85.7%) 16 (45.7%) FT3 FT4 ALP 13) Grade 3/4 6 (17.1%) γ-gtp (4 11.4%) AST (2 5.7%) CRP (1 2.9%) 13) 6 14) infusion reaction 1 間質性肺炎 X (KL-6 SP-A SP-D) SpO 2 X CT CT (HRCT) β-d Pneumocystis jirovecii PCR 大腸炎下痢肝機能障害肝炎 AST ALT γ-gtp ALP 甲状腺機能障害 TSH FT3 FT4 ACTH MRI Infusion reaction 2 infusion reaction Infusion reaction

4 75 (4) 劇症 1 型糖尿病その他 Stevens- Johnson 10) 15) 10) Ⅴ. 当科での使用例 mm tumor thickness 6.25 mm T4bN0M0 stage IIc 2007 DAV DTIC CT CT MRI mg/kg 3 5 MRI CT Grade 3 40 mg/ CT MRI DTIC 16) IV DTIC Fig. 2 Progression of 1 year survival rate in each drug therapy of malignant melanoma. (Excerption from references 3)

5 160 2 DTIC 3) Fig. 2 1 DTIC PD-L1 PD-1 PD-L1 17) PD-1 PD-L1 10) AST ALT TSH FT4 3 AST ALT TSH 2 FT ) おわりに BRAF Larkin 18) PD-L1 PD-1 CTLA-4 18) 1 文 1) ; ) Melanoma Skin Cancer 2009; 24: ) 2015; 57: ) Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11: ) Nishimura H, Minato N, Nakano T, et al. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol 1998; 10: ) Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11: ) Zou W, Chen L. Inhibitory B7-family molecules in the tumor microenvironment. Nat Rev Immunol 2008; 8: ) Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006; 66: ) Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 2010; 116: ) 2015; 57: ) PD ; 11: ) Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol 2012; 23 Suppl 8: viii ) Deeks ED. Nivolumab: a review of its use in patients with malignant melanoma. Drugs 2014; 74: ) Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32: ) PD-1 Derma 2015; 230: ) Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: ) Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: ) Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373: 献

2 10 The Bulletin of Meiji University of Integrative Medicine 1,2 II 1 Web PubMed elbow pain baseball elbow little leaguer s elbow acupun

2 10 The Bulletin of Meiji University of Integrative Medicine 1,2 II 1 Web PubMed elbow pain baseball elbow little leaguer s elbow acupun 10 1-14 2014 1 2 3 4 2 1 2 3 4 Web PubMed elbow pain baseball elbow little leaguer s elbow acupuncture electric acupuncture 2003 2012 10 39 32 Web PubMed Key words growth stage elbow pain baseball elbow

日大 特集追加.indd

日大特集追加.indd