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1 대한내과학회지 : 제 88 권제 3 호 특집 (Special Review) - 혈액종양의새로운치료 최근개발된 B- 세포림프종의치료약제 한양대학교의과대학내과학교실혈액종양내과 박병배 Recently Developed Therapeutic Agents for B-cell Non-Hodgkin Lymphoma Byeong-Bae Park Division of Hematology-Oncology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea While most B-cell lymphomas are cured by chemotherapy, in recent years research interest has focused on the development of monoclonal antibodies and small molecules targeting membrane proteins, components of signaling pathways or tumor microenvironment, which are factors essential for the development and progression of lymphomas. Some of these new drugs have shown substantial clinical activity in phase I and small phase II studies in patients with relapsed and refractory disease, with response rates of up to 50-60% in some cases. These results give hope for patients who have standard treatment failure; however, their incorporation into commonly used regimens also represents a significant challenge for the future. (Korean J Med 2015;88: ) Keywords: Treatment; B-cell lymphoma; Lymphoma 서론림프종은성숙된백혈구중의하나인림프구에서생긴악성종양이며우리나라에서는연간약 4,000명정도발생한다. 림프종은호치킨과비호치킨림프종으로구분되며전체림프종의 96% 가비호치킨림프종이다 [1]. 비호치킨림프종은다시림프종의기원세포에따라 B-세포림프종과 T-세포림프종으로나누며이중 B-세포림프종이약 80% 를차지하고있어림프종이발생한경우 B-세포비호치킨림프종인경우가가장흔하다. B-세포비호치킨림프종은그종류가매우다양한데미만성거대 B-세포림프종 (diffuse large B-cell lymphoma, DLBCL) 이가장흔하며우리나라에서는 B-세포림프종의약 50% 를차지하고있다 (Table 1). 림프종은그종류에따라예후와치료전략이각기다르기때문에병리학적인정확한진단이필수요소이다. 최근분자유전학적연구의발전으로림프종발병에큰역할을하는분자유전학적이상이나단백질들이계속해서발견되고있고, 다양한면역조직염색과분자유전학적검사및바이러스검사등과같은발달된진단방법을통해이전보다비교적정확한병리학적진단을할수있게되었다. 림프종에서발견된분자유전학적이상이나이상단백질은림프종의병인을이해하고진단의도구로사용될뿐만아니라이를표적으로치료약제의개 Correspondence to Byeong-Bae Park, M.D., Ph.D. Division of Hematology-Oncology, Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul , Korea Tel: , Fax: , bbpark@hanyang.ac.kr Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 88, No. 3, Table 1. Major B-cell non-hodgkin lymphomas (WHO classification 2008) Chronic lymphocytic leukemia/small lymphocytic lymphoma Splenic marginal zone lymphoma Lymphoplasmacytic lymphoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone B-cell lymphoma (MZL) Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma (DLBCL) Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Burkitt lymphoma WHO, World Health Organization. Figure 1. Molecular targets of new agents for lymphoma treatment. 발에도이용되고있으며그에따라치료성적의향상을기대할수있게되었다. 최근개발되었거나개발되고있는림프종치료약제들은대부분발병과정에서만들어지는세포표면이나세포내에존재하는특정단백질을표적으로공격하여세포사멸을이끌어내는약제들이다. 이를크게분류하자면림프종세포표면에존재하는특정단백질을공격하는단클론항체 (monoclonal antibody, mab) 계통, 투여된약제가림프종세포내로흡수되어신호전달체계 (signal transduction pathway) 과정이있는특정분자물질을공격하는신호전달억제제, 그리고림프종세포주변에서림프종세포와상호작용하고있는미세환경 (microevironment) 의변화를일으켜세포사멸을유도하는약제들로구분할수있으며그외에일부는기존항암제와비슷한기전으로세포분열에관여하여세포독성을나타내는약제들로분류할수있다 (Fig. 1). 림프종은그종류별로치료전략, 반응정도, 그리고예후가각기다른특징을가지고있어일반적인림프종의치료방법이나예후를한마디로설명하는것은매우어려운일이다. 따라서림프종전체에대한새로운치료약제를나열하는것은그범위가광범위하며임상적인유용성이적다고판단되어림프종중에서도빈도가흔한 B-세포림프종에최근사용되거나개발되는약제에대해서만간단히언급하도록하겠다. 본론단클론항체림프종세포표면의특정단백질을공격하여세포사멸을유도하는단클론항체중에는이미 2000년도초반부터임상적으로사용되어이제는익숙해진 rituximab 이라는약제가대표적이다. 성숙된 B-세포림프구에는분화과정에상관없이 CD20이라는특정단백질이세포표면에항상존재하며이는 B-세포를다른세포와구분하는훌륭한표적이된다. 악성화가된 B-세포림프종세포에서도 CD20은 95% 정도발현되며 rituximab 이라는약제는 CD20에결합할수있도록만들어진단클론항체이다. Rituximab 이 CD20에결합하게되면여러방법을통해림프종의세포사멸이유도되어치료효과를얻을수있다. Rituximab 이기존의 cyclophosphamide, doxorubicin, vincristine, 그리고 prednisone (CHOP) 병합요법에추가되면서 DLBCL 환자의장기생존율및완치율은 20% 가향상되었고 [2] 현재는 R-CHOP 병합요법이 DLBCL의 1차표준치료로자리잡게되었다. B-세포림프종치료역사가 rituximab 이전의시대와이후의시대로나뉠만큼 rituximab 의출현은획기적인사건이되었다. 최근에 CD20에대한또다른단클론항체들이여러가지개발되었는데그중 rituximab 을기술적으로개량하여직접적인세포사멸력과항제의존세포독성력을강화시킨 obinutuzumab 이라는약제가기대되는약제로꼽히고있다. 이전에

3 - Byeong-Bae Park. New agents for B-cell lymphoma - 치료받지않았던만성림프구성백혈병 (chronic lymphocytic leukemia, CLL) 환자를대상으로 obinutuzumab 과 rituximab 을비교한 3상임상연구에서반응률이나무병생존율의측면에서 obinutuzumab 의우월함이입증되었기때문에 [3] 향후 B- 세포림프종치료에서 rituximab 을대체할만한약제로가능성이있다. CD20 이외에도 CD19, CD22, CD40, CD80 등을표적으로하는단클론항체들이개발되어임상시험중에있고 B-세포표면의단백질은아니지만 CD30에대한단클론항체도 B- 세포림프종치료에개발되어사용되고있다. CD30 은호치킨림프종과일부 T-세포림프종에서주로발현되는표면단백질이지만일부 CD30이발현되는 B-세포림프종에서는치료의표적이될수있다. Brentuximab vedotin 은 brentuximab 이라는 CD30에대한단클론항체에 vedotin이라는세포독성항암제가결합된약제로단클론항체의세포사멸기전과항암제의세포독성기전이합쳐져서단클론항체의단독적인효과보다강력한세포독성을나타낸다. 실제 CD30을발현하는 DLBCL 환자에서 brentuximab vedotin 의효과는기대할만하다는임상연구들이보고되고있어 [4,5] 향후이약제또한 B-세포림프종치료발전에기여할것으로보인다. 세포내신호전달억제제정상적인 B-세포림프구의성장및생존은세포표면에존재하는 B-세포수용체 (B-cell receptor, BCR) 를통한지속적인신호전달이있어야한다. BCR이세포외부로부터자극이되면그이후세포내에서 spleen tyrosine kinase (SYK), Bruton s tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K) 등의여러단백질효소를통한신호전달체계가활성화되고이정보는핵내로전달되어 B-세포림프구의세포성장및생존에관여하게된다 (Fig. 2) [6]. B-세포림프종에서 BCR의돌연변이가발생하는경우가있는데이렇게돌연변이가생기게되면외부자극이없더라도 BCR은지속적인활성화가이루어지며그이후의세포내신호전달또한지속적인활성화로림프종의성장에중요한역할을하게되는것이다 [7]. 따라서 BCR을통한세포내신호전달체계에관여하는여러가지단백질들의기능을억제할수있으면림프종의성장을억제할수있기때문에이런단백질들이치료의표적으로될수있다는것이다. BCR을통한세포내신호전달의필수적인단백질인 BTK Figure 2. Intracellular signal pathway of B-cell receptor and signal pathway inhibitors. BCR, B-cell receptor; LYN, lyn kinase; SYK, spleen tyrosine kinase; BTK, Bruton s tyrosine kinase; PI3Kδ, phosphoinositide 3-kinase δ; PLCγ2, phospholipase C-gamma 2; AKT, protein kinase B; PKC, protein kinase C; mtor, mammalian target of rapamycin. 에대한억제제로 ibrutinib은최근개발된 B-세포림프종의대표적인경구용표적치료제이다. 예후가매우안좋은것으로알려진재발성또는불응성외투세포림프종 (mantle cell lymphoma) 환자를대상으로 ibrutinib 단독요법을시행한임상연구에서보면 68% 의환자에서반응이있었고 21% 의환자에서는완전관해가나타났으며전체의 70% 의환자는장기적인무병생존을보여주었다 [8]. 부작용이심한일반적인세포독성복합항암화학요법을시행해야만하는이러한환자들에게부작용이적으면서효과적이고복용이용이한약제의출현은림프종치료의일반적인개념변화를일으키게된것이다. Iburutinib은 CLL에서도그효과가입증되었고 [9] 현재는여포성림프종 (follicular lymphoma, FL) 과 DLBCL 환자를대상으로 1차치료제로서 iburutinib 단독요법및세포독성항암제와의병용요법에대한임상연구가진행되고있으며그결과가매우기대되고있다. Idelalisib은 BCR 신호전달체계에있는 PI3K-δ 를억제하는또하나의고무적인경구용표적치료제이다. Idelalisib은최근에진행이느린재발성또는불응성 B-세포림프종에서임상연구가진행되었는데부작용이적으면서 57% 의환자에

4 - 대한내과학회지 : 제 88 권제 3 호통권제 655 호 서종양감소의반응을보여주어 FL 환자에서단독요법으로미국식품의약국 (Food and Drug Administration, FDA) 의승인을받게되었다 [10,11]. 재발성또는불응성 CLL 환자에서도 idelalisib의우월성이입증되어 [12] 확실히 B-세포림프종에효과적인약제로확인되었고현재는다른약제와의병용요법으로주로진행이느린림프종에대하여임상연구가진행되고있다. 그외에 SYK를억제하는경구용제제인 fostamatinib을비롯하여다른질환에서도사용되는 nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kb) 경로억제제인 botezomib, mammalian target of rapamycin (mtor) 억제제인 everolimus 등을포함한병용요법들이많이연구되고있으며향후대부분의림프종치료약재개발은신호전달체계의단백질표적들이이용될것으로전망된다. 미세환경 B-세포림프종이발생했을때림프종주변의현미경적인미세환경은그종류에따라매우다양한면역세포와간질세포 (stromal cell), 혈관생성세포, 세포외조직등이복잡하게서로엉켜있으며상호간의작용으로림프종이성장하 는데도움을주게된다. 따라서림프종을둘러싼미세환경을조절하는것도림프종치료의한표적이될수있다. 일반적으로골수종에서사용되는 lenalidomide라는경구용약제는종양세포를둘러싼미세환경에존재하는여러면역세포들의사이토카인균형을깨뜨리고혈관생성을억제하여세포사멸을유도하는효과가있다. 림프종환자에서도역시 lenalidomide의투여는반응이있었고 [13,14] 이러한사실은림프종에서도미세환경이림프종성장에중요한역할을하고좋은치료효과를얻을수있는표적이라는근거가될수있다. 현재는 lenalidomide를포함한병합요법에대한연구들이진행되고있다. 최근에현저하게부상하는미세환경관련림프종치료약제는 programmed cell death protein 1 (PD-1) 과 programmed death-ligand 1 (PD-L1) 과관련된것들이다. 종양에특이적으로작용하는활성화된 T-세포표면에존재하는 PD-1과항원제공세포 (antigen presenting cell) 나림프종세포표면에존재하는 PD-L1 이결합하게되면활성화된 T-세포는림프종세포에대한공격을못하게되어림프종세포가성장및생존을할수있는환경을만들어준다. 그러므로 PD-1 이나 PD-L1 에대한단클론항체를만들어투여하게되면 PD-1과 PD-L1 Figure 3. Programed cell death-1 (PD-1) pathway blockade promotes tumor-specific T cell activation and elimination of tumor cells [15]. The PD-1 pathway operates on two different levels, regulating both T cell activation by dendritic cells (DCs) and the effector function of antigen-specific T cells. PD-1 pathway blockade by monoclonal antibodies directed against PD-1 (or its ligands) promotes T cell activation by shifting the balance of signals delivered by DCs from suppressive to activating. In the tumor microenvironment, tumor-specific T cells recognize tumor cells but are subsequently inactivated by the expression of PD-L1 or PD-L2 on the tumor cell, inducing tolerance and anergy. When rescued by PD-1 pathway blockade, T cells recognize peripheral antigens and, in the absence of PD-1 engagement, they assume full effector function for tumor cell elimination. TCR, T cell receptor; MHC, major histocompatibility complex; PD-L1/2, programmed death-ligand 1/

5 - 박병배. B- 세포림프종의새로운치료 - 의결합을억제하게되고활성화된 T-세포는자유롭게림프종세포를공격할수있어치료효과를얻을수있다는것이다 (Fig. 3) [15]. Pidilizumab 은림프종치료제로개발된 PD-1 에결합하여억제하는단클론항체이다. Pidilizumab 은 FL과 DLBCL 환자를대상으로하는임상연구에서좋은결과를보여주고있어 [16,17] 이를시작으로현재 PD-1과연관된미세환경에대한표적치료제들의연구개발이활발히진행되고있다. 결 최근의 B-세포림프종의치료는 bendamustine 과같은새로등장한세포독성항암제를이용한전략을유지하면서새로개발되어출시되고또한연구되고있는표적치료제들을기존치료에병합하는식으로전개되고있다. 최근개발된표적치료제는기존것을개량하거나새로운세포표면단백질에대한단클론항체, 세포내신호전달체계억제제, 미세환경을조절하는약제들이주를이루고있으며림프종치료제로서다양한경구용치료제의출현은괄목할만한부분이다. 향후림프종치료는이전의세포독성치료제에서보다부작용이적고효과적인경구용표적치료제로의전환이기대되고있으며현재에도일부림프종에서는현실화되고있다. 론 중심단어 : 치료 ; B 세포림프종 ; 림프종 REFERENCES 1. Yoon SO, Suh C, Lee DH, et al. Distribution of lymphoid neoplasms in the Republic of Korea: analysis of 5318 cases according to the World Health Organization classification. Am J Hematol 2010;85: Coiffier B, Thieblemont C, Van Den Neste E, et al. Longterm outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-chop to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d Etudes des Lymphomes de l Adulte. Blood 2010; 116: Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370: Hill BT, Tubbs Do RR, Smith MR. Complete remission of CD30 positive diffuse large B-cell lymphoma (DLBCL) in a patient with post-transplant lymphoproliferative disorder (PTLD) and end-stage renal disease treated with single agent brentuximab vedotin. Leuk Lymphoma Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science 2002;296: Roschewski M, Dunleavy K, Wilson WH. Diffuse large B cell lymphoma: molecular targeted therapy. Int J Hematol 2012;96: Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369: O Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014;15: Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014;370: Miller BW, Przepiorka D, de Claro RA, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370: Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-hodgkin s lymphoma. Ann Oncol 2011;22: Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-hodgkin s lymphoma. J Clin Oncol 2009;27: Vasaturo A, Di Blasio S, Peeters DG, et al. Clinical implications of co-inhibitory molecule expression in the tumor microenvironment for DC vaccination: a game of stop and go. Front Immunol 2013;4: Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol 2013;31: Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 2014;15:

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract