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1 대한내과학회지 : 제 87 권제 3 호 종설 (Review) 종양면역치료 : 중세암흑시대에서르네상스시대로 울산대학교의과대학서울아산병원종양내과 이대호 Cancer Immunotherapy: The Dawn of the Renaissance after the Medieval Dark Ages Dae Ho Lee Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea Cancer immunotherapy has come a long way since William Coley observed that a mixture of killed bacteria, or Coley s toxin, induced tumor regression. However, enthusiasm for cancer immunotherapy has changed to skepticism over recent decades due to its lack of efficacy, inconsistency, and significant toxicity. Of course, much of that skepticism was the result of a lack of understanding of the immune system. The recent expansion of our understanding of immunity and immune system and the success of new cancer immunotherapies has raised hope that we can treat cancer effectively via immunotherapy or combination approach using immunotherapy and other cancer therapies. Indeed, there is no doubt that cancer immunotherapy is experiencing a renaissance. Here, I will briefly review the current status of various immunotherapies, including cytokine therapy, antibody therapy, cancer vaccines, and adoptive cell therapy, and then I will summarize the results of recent clinical trials using anti-immune checkpoint monoclonal antibodies. (Korean J Med 2014;87: ) Keywords: Cancer; Immunotherapy; Anti-immune checkpoint antibody 종양면역치료는신체의면역기능을이용하여종양을치료하는전략으로, 19세기후반 William B Coley가 Coley 독소로알려진박테리아혼합물투여후종양감소를처음관찰한이후많은사람들로부터오랫동안높은관심과기대를받았었다 [1,2]. 그러나 년대를거치면서다양한종양면역치료법들이종양치료에시도되었으나실망적인결과들로인하여많은종양의사들에게종양면역치료에대한회의론내지는비관론을갖게하였다. 물론소수의환자에서 또는제한된종양에서성공적결과들이보고되었으나, 종양면역치료에대한회의적시각을극복하기에는보다일관되고재현가능한성공의결과가절실히필요하였다. 올것같지않은종양면역치료에대한희망이지난 2-3년간발표된종양면역치료제, 특히면역검문 (immune checkpoint) 에대한단클론항체들의놀라운성과들로인하여현실로다가오고있다 [3-12]. 마치르네상스시대의새로운파도가중세암흑시대를넘어뜨리고유럽의새로운역사를창조하였듯이종 Correspondence to Dae Ho Lee, M.D., Ph.D. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul , Korea Tel: , Fax: , leedaeho@amc.seoul.kr Copyright c 2014 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 - Dae Ho Lee. Cancer Immunotherapy - 양면역치료의성공또한종양치료의새로운시대를여는거대한파도가되고있다. 종양면역치료는암백신치료 (cancer vaccine therapy) 부터단클론항체치료 (monoclonal antibody therapy), 입양면역치료 (adoptive cell therapy) 또는세포치료 (cell therapy) 까지매우광범위한영역을포함한다. 종양면역치료는단클론항체, 사이토카인또는면역세포와같은체외에서만들어진면역성분을투여함으로써체내면역기능의역할을하거나또는면역기능을자극하거나유도함으로써그효과를보인다. 단클론항체는종양의특정단백질과선택적으로결합하는특이성을가진일종의표적치료제 (targeted therapeutics) 이며면역기능의도움없이도항종양효과를보이기도한다. 반면오래전부터일반적인방법으로이용되는종양면역치료는전반적인체내면역기능을증강시킴으로써종양에대한면역반응을유도하고이를통하여항종양효과를얻고자하였다. 그러나비특이적치료전략 (non-specific cancer immunotherapy) 은그효과가제한적이고상대적으로높은독성등을보이고있어이를극복할수있는새로운전략의개발이필요하다. 앞으로종양면역치료에대하여간단히살펴보고단클론항체특히가장주목받고있는항면역검문단클론항체를중심으로작용기전과성과등을살펴보고자한다. 본론사이토카인 (cytokine) 치료사이토카인은면역기능을조절하는중요한단백질의하나로사이토카인치료는사이토카인투여를통하여종양환자에서억제되어있는종양에대한면역기능을증강시켜항종양효과를얻는다. 제일처음시도된사이토카인은알파인터페론 (interferon-α, IFN-α) 으로현재일부백혈병 ( 모발세포백혈병 [hairy cell leukemia], 만성골수구성백혈병 [chronic myelogenous leukemia], 피부 T세포림프종 [cutaneous T cell lymphoma]), 악성흑색종및카포시육종환자에서사용이가능하다. 인터루킨 (interleukin-2, IL-2) 은두번째로승인받은사이토카인치료제로악성흑색종또는신장암에서사용된다. 종양괴사인자-알파 (tumor necrosis factor-α, TNF-α), 과립구-단핵구자극인자 (granulocyte-monocyte colony stimulating factor, GM-CSF) 등이항종양효과를보임으로써사이토카인치료법으로제시되었다. 그러나일반적으로사이토카인단 독치료는그효과가종양제한적이고그정도가크지않다. 예를들면 INF-α의경우악성흑색종에서고용량 IFN-α치료가보조요법으로효과가있는것으로알려졌으나아직전체생존기간연장은명확하게밝혀지지않았다 [13]. IL-2 역시고용량 IL-2치료법이효과가있으나일부환자에서만의미있는질병조절기능을가지고있으며해당적응증을가진모든환자에서전체생존기간의연장을증명하지는못하였다 [14]. 사이토카인은면역기능의조절에중요한역할을하지만사이토카인치료법은그효과가매우제한적이고상당수의환자에서심각한독성을보인다는점에서한편반응을예측할수있는생체표지자가아직밝혀지지않아서그사용에큰제한점을가지고있다. 이러한제한점을극복하기위하여다른종양면역치료법들과병합요법등이최근시도되고있다. 백신 (vaccination) 종양백신또는암백신으로알려진백신을이용한종양면역치료법은일종의능동적면역치료 (active immunotherapy) 로서감염치료에사용되는백신치료와마찬가지로종양특이항원에대한지속적인면역반응을유도함으로써항종양효과를유도할뿐만아니라그효과가유지되도록시도되는치료법이다. 다른감염질환에대한백신치료와마찬가지로종양을일으키는바이러스에대한백신효과를통하여이차적으로암발생에대한예방효과를기대할수있다. 예를들면, 인유두종바이러스 (human papilloma virus) 에대한백신 Cervarix R, Gardasil R 등은자궁경부암이나두경부암예방에효과가있으며 [15,16], B형간염바이러스백신역시간암예방에효과가있다. 한편, 종양자체에대한치료효과를보이는종양백신에대한많은시도또한이루어지고있다. 종양백신은종양세포자체, 종양세포의일부또는정제된종양항원을이용하여종양특이 DNA/RNA를포함하는세포를이용하여지속적으로항원이발현하도록제작하거나 (DNA vaccine), 특정항원이발현된단백질또는펩타이드자체를이용하거나이들이발현된항체를제작하거나 ( 항원백신및항체백신, antigen vaccine 또는 anti-idiotype antibody vaccine), 특정항원을보유한약화된또는죽은종양세포 ( 자가또는이종종양세포백신, autologous tumor cell vaccine 또는 allogeneic tumor cell vaccine) 를이용하거나또는특정항원에대하여반응을보이는면역세포를이용하여제작된다. 보통은

3 - 대한내과학회지 : 제 87 권제 3 호통권제 649 호 Table 1. Major clinical trials of cancer vaccine Trial Phase Design MAGEA3 vaccine with AS02 adjuvant Liposomal MUC1 peptide vaccine (L-BLP25) Vacccinia/MUC1 vaccine (TG4010) Vacccinia/MUC1 vaccine (TG4010) Allogeneic whole cell NSCLC line vaccine with anti-sense TGF-β (belagenpumatucel-l, Lucanix ) MAGEA3 NCT LBLP25 NCT L-BLP25 NCT TG4010 NCT Belagenpumatucel-L (Lucanix ) NCT Multipeptide vaccine with GMCSF adjuvant (IMA901) Tumour RNA pulsed autologous DCs (AGS003) II II II IIB II Vaccine vs. placebo after surgery for stage IB and II MAGEA3+ NSCLC LBLP25 vs. BSC for stage B or IV NSCLC with stable or responsive disease after chemo or chemoradiotherapy TG4010 ± Cisplatin/vinorelbine till PD followed by addition of Cisplatin/vinorelbine for MUC1-positive advanced NSCLC Gemcitabine/cisplatin ± TG4010 for stage 4 NSCLC Multi-dose trial for NSCLC with low volume stage II, A, B, IV disease MAGEA3 vs. placebo for resected stage IB-A NSCLC Vaccine vs. placebo for unresectable stage with stable or responding disease after chemoradiotherapy Vaccine vs. placebo for unresectable stage with stable or responding disease after chemoradiotherapy IIB/ Platinum combination ± vaccine for stage IV NSCLC II II Vaccine vs. placebo for stage A, B or IV NSCLC with stable or responding disease after initial chemotherapy vaccine ± immunomodulatory cyclophosphamide for HLAA*02+ patients Vaccine administered + sunitinib for newly diagnosed clear cell RCC undergoing resection. Sample size Comments 182 Gene expression profile: reduction of recurrence in vaccine group (HR, 0.57; p = 0.99). Primary endpoint: no difference in DFS between the two groups (HR, 0.74; p = 0.107) 171 Primary endpoint; OS LBLP25, 17.2 mon vs. BSC 13 mon (p = 0.066) Subgroup analysis: stage B patients OS 30.6 mon vs mon 65 Primary endpoint: response was met only for the concurrent TG4010 and chemotherapy arm; RR 29.5% 108 Patients with normal level of activated NK cells at baseline had an improvement in 6-month PFS and OS. Patients with high levels of active NK cells had increased toxic effects. Primary endpoint: 6 mon PFS met only for the concurrent TG4010 (43%), but not significantly different from chemotherapy alone (35%) 75 RR 15%, OS 441 days in advanced-stage disease setting 2,289 Primary endpoint: DFS 1,464 Primary endpoint: OS not met 420 Primary endpoint: OS 1,000 Primary endpoint: OS 506 Primary endpoint: OS 68 Trend toward improved OS in vaccine + low dose cyclophosphamide arm (HR, 0.57; p = 0.090) 25 Median PFS of AGS003 was 11.9 mon

4 - 이대호. 종양면역치료 : 중세암흑시대에서르네상스시대로 - Table 1. Continued Trial Phase Design IMA901 with GMCSF adjuvant NCT Sunitinib ± Vaccine/low dose cyclophosphamide in first-line setting for RCC patients with HLA-A*02+ Sample size Comments 330 Primary endpoint: OS, Secondary endpoint: OS in biomarker-defined subgroups, PFS RNA-loaded autologous DC vaccine (AGS003) NCT Sunitinib ± vaccine in advanced RCC 450 Primary endpoint: OS gp100 High dose IL2 ± gp100 peptide in montanide Allovectin-7 NCT MAGEA3 vaccine with AS02 adjuvant Allovectin-7 vs. DTIC or temozolomide for unresectable stage /IV melanoma MAGEA3 vaccine vs. placebo for surgically resected stage B/C cutaneous melanoma with macroscopic lymph-node involvement 185 Clinical RR and PFS significantly higher in combination group 390 Primary outcome: ORR at 24 wk Secondary outcome: safety/tolerability of Allovectin-7 & OS 1,349 Primary outcome: DFS Secondary outcome: Anti-MAGEA3 and anti-protein D sero-positivity status T-Vec T-Vec (attenuated herpes simplex virus) vs. GM-CSF 436 Durable RR: 16.3% (T-Vec) vs 2.1% (GM-CSF) BSC, best supportive care; DC, dendritic cell; DFS, disease-free survival; HR, hazard ratio; ORR, overall response rate; PFS, progression-free survival; RR, response rate; OS, overall survival. 면역기능을증강시키는보조제 (adjuvant) 와결합하여사용된다. 현재까지미식품의약품안전청에서최초로그리고유일하게사용승인된종양백신은호르몬저항성진행성전립선암에서 prostate acid phosphatase에대해사용되는 sipuleucel-t (Provenge R ) 가대표적이다 [17]. Sipuleucel-T 는환자로부터면역세포를분리한후종양항원인 prostate acid phosphatase 와면역기능을향상시킨 GM-CSF 로부터만들어진융합단백질인 PA2024에노출시켜이에대한면역기능을발휘할수있도록만들어진수지상세포 (dendritic cell, DC) 이다. 만들어진수지상세포는환자에게다시투여되어전립선암에대한면역기능을유도함으로써항종양효과를보인다. 어떤면에서는수지상세포를이용한세포치료로볼수있다. 현재다양한종양백신을이용한임상시험들이진행중이며, 일부좋은결과를보고하고있다 [18-23]. 앞으로많은임상시험의결과가필요하다 (Table 1). 입양세포치료 (adoptive cell therapy) 입양세포치료는이미종양에대한면역기능을가진것으로예상되는세포를투여함으로써항종양효과를기대하는 일종의수동적면역치료 (passive immunotherapy) 로서다양한면역세포들이이용되고있다 [24]. Lymphokine activated killer (LAK) 세포치료는건강인또는암환자로부터얻어진말초단핵세포 (peripheral blood mononuclear cells, PBMC) 를이용하여체외에서 IL-2과함께체외배양을통하여 LAK세포를만들거나또는암환자에게 IL-2 투여후체내에서만들어진 LAK세포를이용하여, 이를암세포를제거에이용한다. IL-2 에의해활성화된 LAK세포는전임상실험에서정상말초림프구세포와달리다양한종양세포를효과적으로제거할수있음을보여주었다. 그러나아쉽게도임상효과는적어서실제임상에적용되지않고있다 [25,26]. 이를극복하기위하여 LAK세포치료에서 IL-2만사용하는것과달리 cytokineinduced killer (CIK) 세포치료는 IL-2, IL-1, IFN-γ 및 Anti- CD3 단클론항체등을포함한다양한인자를이용하여만들어진 CIK를이용하며 LAK세포와비교하여동물모델에서상승된항종양효과를보였다. 그러나일부증례보고와제2 또는 3 상임상시험에서무진행기간등의연장등을보이는등그가능성을제시하였음에도불구하고실제로종양반응률의상승을보여주지는못하였으며결과적으로그임상효과또

5 - The Korean Journal of Medicine: Vol. 87, No. 3, 한만족스럽지못하였다 [27-30]. CIK세포치료의실패가항원특이성부족에기인한것으로예상됨에따라, 새로운전략으로서수지상세포의항원제시능력을이용한 DC-CIK세포치료이다. CIK세포를항원특이펄스 DC (antigen-specific pulsed DC) 와함께배양함으로써 DC-CIK세포치료의효능을높이고자하였다. 실제일부비소세포폐암대상임상시험에서종양무진행기간의연장을보였으며다른치료와병합하여비소세포폐암및유방암환자에서무진행기간및전체생존기간의연장을보였다. 향후 DC-CIK세포치료의효과에대한보다많은확증연구가필요하다 [31-33]. 한편, 종양침윤림프구세포 (tumor-infiltrating lymphocyte, TIL) 는종양발생및진행에중요한역할을하는것으로알려지고이를이용한 TIL 세포입양면역치료가여러종양에서효과가보고되었다. 또한 TIL세포치료는다양한종양환자로부터종양반응 (tumorreactive) TIL의채취가가능할수있으며체외에서 8,000배까지세포를배양시킬수있는장점도있다 [34,35]. 표준치료가없는악성흑색종환자를대상으로 TIL을이용한입양치료임상시험에서 50-70% 환자에서종양의감소가관찰되었으며비소세포폐암환자에서도 TIL과 IL-2를이용한입양면역치료에서 3년생존율의향상이역시관찰되었다 [36]. 그러나아쉽게도모든암환자로부터종양반응 TIL을획득하는것이가능하지않다. 악성흑색종환자 81% 에서 TIL세포가항종양효과를종양반응 TIL인반면위장관암환자 3% 정도만이 TIL세포가종양반응 TIL이었다. 효과적입양면역치료 를위해서필요한것은항종양효과가증강된 T세포이므로이를얻기위해 T세포에대한유전조작이또하나의전략으로서제시되었다 (genetically engineered T cell). 현재 T cell receptor (TCR) 유전자및 chimeric antigen receptor (CAR) 유전자를 PBMC 또는 TIL에삽입된 2종류의유전조작된 T세포가입양면역치료에사용이가능하다 [37,38]. 최근임상시험을통하여 MART-1 및 gp100에반응하는유전자조작 T세포가악성흑색종환자에서, NY-ESO-1 에대한 TCR-유전자조작 T세포가악성흑색종과활액세포육종 (synovial cell sarcoma) 에서종양진행을억제하거나종양감소를유도하였다 [39]. 입양면역치료에대한기대는다양한임상시험을통하여그효과에대한확증이필요하며, 이를통해서새로운치료전략으로자리를잡을수있을것이다 [40,41]. 항체 (antibody) 치료항체치료는단클론항체 (monoclonal antibody) 가특정세포또는특정리간드 (ligand) 에결합하는특이성을이용한일종의표적치료 (targeted therapy) 이다. 단클론항체는종양세포의특정수용체에결합하여수용체의작용을억제하거나또는세포자멸 (apoptosis) 을유도한다. 또는결합된단클론항체를통해면역기능활성화 -가령, 보체활성화 (complement activation), 항체의존세포독성 (antibody-dependent cytotoxicity) 유도, 식작용 (phagocytosis) 유도등-를통해서종양세포파괴를유도한다. 현재사용되는치료단클론항체는해당표적에따라구 Table 2. US-FDA approved monoclonal antibody Antibody Target Indication Mechanism Naked antibodies: solid malignancies Trastuzumab (Herceptin; Genentech): humanized IgG1 Bevacizumab (Avastin; Genentech/Roche): humanized IgG1 ERBB2 VEGF ERBB2-positive breast cancer as a single agent or in combination with chemotherapy for adjuvant or palliative treatment ERBB2-positive gastric or gastro-esophageal junction carcinoma as first-line treatment in combination with cisplatin and capecitabine or 5-FU For first-line and second-line treatment of metastatic colon cancer in combination with 5-FU-based chemotherapy; for first-line treatment of chemonaive advanced NSCLC in combination with carboplatin and paclitaxel; as a single agent in adult patients with glioblastoma whose tumor has progressed after initial treatment; and in combination with IFN-α for metastatic RCC Inhibition of ERBB2 signaling and ADCC Inhibition of VEGF signaling

6 - Dae Ho Lee. Cancer Immunotherapy - Table 2. Continued Antibody Target Indication Mechanism Cetuximab (Erbitux; Bristol-Myers Squibb) : chimeric human-murine IgG1 EGFR Panitumumab (Vectibix; Amgen) : EGFR human IgG2 Ipilimumab (Yervoy; Bristol-Myers CTLA4 Squibb): IgG1 Naked antibodies: hematological malignancies Rituximab (Mabthera; Roche): chimeric CD20 human-murine IgG1 Alemtuzumab (Campath; Genzyme): humanized IgG1 Ofatumumab (Arzerra; Genmab): human IgG1 CD52 CD20 Conjugated antibodies: hematological malignancies Gemtuzumab ozogamicin (Mylotarg; Wyeth): humanized IgG4 Brentuximab vedotin (Adcetris; Seattle Genetics): chimeric IgG1 CD33 CD30 90Y-labelled ibritumomab tiuxetan CD20 (Zevalin; IDEC Pharmaceuticals): murine IgG1 131I-labelled tositumomab (Bexxar; GlaxoSmithKline): murine IgG2 CD20 In combination with radiation therapy for the initial treatment of locally or regionally advanced SCCHN; as a single agent for patients with SCCHN for whom prior platinum-based therapy has failed; and palliative treatment of pretreated metastatic EGFR-positive colorectal cancer As a single agent for the treatment of pretreated EGFR-expressing, metastatic colorectal carcinoma For the treatment of unresectable or metastatic melanoma For the treatment of CD20-positive B cell NHL and CLL, and for maintenance therapy for untreated follicular CD20-positive NHL As a single agent for the treatment of B cell chronic lymphocytic leukemia Treatment of patients with CLL refractory to fludarabine and alemtuzumab For the treatment of CD33-positive AML patients in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy; withdrawn from use in June 2010 For the treatment of relapsed or refractory Hodgkin's lymphoma and systemic anaplastic lymphoma Treatment of relapsed or refractory, low-grade or follicular B cell NHL Previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy Treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade, follicular or transformed NHL Inhibition of EGFR signaling and ADCC Inhibition of EGFR signaling Inhibition of CTLA4 signaling ADCC, direct induction of apoptosis and CDC Direct induction of apoptosis and CDC ADCC and CDC Delivery of toxic payload, calicheamicin toxin Delivery of the radioisotope 90Y Delivery of the radioisotope 131I, ADCC and direct induction of apoptosis ADCC, antibody-dependent cell-mediated cytotoxicity; AML, acute myelogenous leukemia; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CLL, chronic lymphocytic leukemia; CTLA4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; ERBB2, avian erythroblastosis oncogene B2; 5-FU, 5-fluorouracil; NHL, non-hodgkin lymphoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of head and neck; VGFR, vascular endothelial growth factor receptor. 분되기도하지만만들어진방식에따라크게두가지로구분되기도한다. 하나는가장흔한경우로단클론항체자체가효과를발휘하는것이며 ( 이를 naked monoclonal antibody 라고한다 ) 다른하나는최근에개발된단클론항체로서 방사성핵종, 항암제또는독소를결합한복합단클론항체 (conjugated monoclonal antibody) 로단클론항체의효과를증가시킨다. 종양세포에직접작용하지않지만종양세포의성장및전이에중요한역할을하는종양내혈관형성을억제

7 - 대한내과학회지 : 제 87 권제 3 호통권제 649 호 Table 3. Reported efficacy of anti-immune checkpoint monoclonal antibodies Agent Phase Tumor Type N Efficacy Anti-CTLA4 Ipilimumab (BMS) [4] Ipilimumab (BMS) [5] (Ipilimumab + gp100 vs. ipilimumab vs. gp100) (Ipilimumamb + dacarbazine vs. dacarbazine) Melanoma 676 OS 10.1 months, RR 10.9% (ipilimumab) vs. OS 6.4 months, RR 1.5% (gp100) Melanoma 502 OS 11.2 months, RR 15.2% (ipilimumab + dacarbazine) vs. 9.2 months; RR 10.3% (dacarbazine) Anti-PD-1 Nivoluma (BMS) I Melanoma 107 RR: 31% [7] I NSCLC 127 RR: 16% I RCC 34 RR: 29% PD-1 MK-3475 (Merck) [9] I Melanoma 135 RR: 37% Anti-PD-L1 BMS [6] I Melanoma 52 RR: 17%; SD 27% NSCLC 49 RR: 10%; SD 10% RCC 17 RR: 12%; SD 41% Ovarian 17 RR: 6%; SD 18% Anti-PD-L1 MPDL-3280A (Genentech/Roche) [10] I Melanoma 45 RR: 26% CTLA4, cytotoxic T-lymphocyte-associated protein 4; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PDL-1, programmed death-ligand 1; RCC, renal cell carcinoma; RR, response rate; SD, stable disease; OS, overall survival. 함으로써항종양효과를보이기도하며면역검문기능에관여하여직접종양세포가아닌 T세포를이용하여항종양효과를보이기도한다. 실제로많은그리고다양한단클론항체들이승인되어환자에게사용되고있다 (Table 2). 항면역검문단클론항체 (anti-immune checkpoint monoclonal antibody) 항원특이 T-림프구세포의면역반응은매우복잡하고정교하게조절되는과정이다. 우선 T-림프구의활성화는 T-림프구세포표면에존재하는 T-림프구항원수용체 (T-cell antigen receptor, TCR) 가항원보유세포 (antigen presenting cell, APC) 의 major histocompatibility complex (MHC, 사람의경우 human leucocyte antigen, HLA) Class II분자에결합된항원을인지하는것으로시작된다. 이때 T-림프구가충분히활성화하기위해서는항원의인지와동시에자극 (co-stimulatory) 신호가필요한데 APC에서발현하는 CD80, CD40 등이 T-림프구세포표면의리간드에해당하는 CD28, CD40L 등과동시에결합함으로써이루어지며, 이를통하여사이토카인의분비가활성화된다. TCR-MHC/epitope 의결합을통한항원의인지가이루어지더라도동시자극신호의신호전달이없을경우 T-림 프구의활성은이루어지지않는다. 그러나활성화된 T-림프구는일정시간후비활성화가되도록동시에억제 (co-inhibitory) 신호또한활성화된다. 이를통하여과도한면역자극으로인한조직손상등을예방할수있다. 다양한동시억제 (co-inhibitory) 신호가있으며대표적으로 T-림프구의 cytotoxic T lymphocyte antigen (CTLA)-4 와 programmed death-ligand 1 (PD-L1) 와이에상응하는 APC 리간드는 CD80 및 CD86 과 PD-L1 이관여한다. 부연하면 CTLA-4 의경우리간드인 CD80 과 CD86 과결합을통하여 naïve 또는 memory T-림프구의비활성화기능을주로갖고있으며 PD-1의경우 PD-L1과 PD-L2 를통하여말초조직에서 T-림프구기능을조절한다. 우리몸의면역기능은항원인지와동시에이러한동시자극신호및동시억제신호의조절을통하여전체적인 T 림프구기능을조절한다 ( 이러한조절기전을면역검문 [immune checkpoint] 이라고한다 ). 우리몸의면역기능은종양세포에서일어나는돌연변이등의변화로인해발현되는종양특이항원 (tumor-specific neo-antigen) 을감지하고이를통하여종양세포를제거한다. 종양세포는반대로이러한면역공격을회피하기위하여종양미세환경 (tumor micro-environment) 을변화시켜면역기능을억제하거나 T세포면역관용 (immune

8 - 이대호. 종양면역치료 : 중세암흑시대에서르네상스시대로 - tolerance) 또는면역편집 (immuno-editing) 등을통하여면역회피 (immune escape) 를한다. 이러한회피전략의하나로서면역검문 (immune checkpoint) 기능의변화를통하여종양특이 T림프구세포의기능을억제한다. 즉, 종양세포에서이러한억제면역검문을활성화시킴으로써종양특이 T-림프구세포의공격을회피한다. 최근 CTLA-4나 PD-1 또는리간드 PD-L1 에대한단클론항체를이용하여그기능을억제함으로써도리어억제된종양특이 T-림프구세포활성및효과를증강시킴으로써항종양효과를얻을수있다. CTLA-4 단클론항체 ipilimumab 이진행성악성흑색종환자에서그임상효과를입증하였으며, 이에따라 2010년미식품의약품안전청에서 ipilumumb 의사용을항-면역검문항체로서처음승인하였다 [4,5]. 이후 PD-1및 PD-L1 에대한단클론항체가제1상임상시험에서부터보다강력한효과를악성흑색종뿐만아니라신장암이나비소세포폐암의다양한종양에서그효과를보여줌에따라해당약제의 2상또는 3상임상시험의진행에박차를가하게하였으며, 앞으로새로운종양치료법으로자리를잡을것으로기대된다 (Table 3) [6,7,9-11]. 약제별로구체적으로살펴보면 ipilimumab 의경우진행성악성흑색종에대한일차요법에서 dacarbazine 과병합요법시 dacarbazine 단독요법과중앙생존기간 11.2개월대 9.1개월로통계학적으로유의한생존기간의연장 ( 위험비, 0.72; 95% 신뢰구간, ; p < 0.001) 을보였으며종양반응률은 15.2% 대 10.3% 로통계학적으로유의하지않지만경향성을보였다 (p = 0.09). 이전치료력이있는악성흑색종환자를대상으로시행한이차요법에서도 gp100만투여한군의중앙생존기간 6.4개월에비하여 ipilimumab 단독투여군 10.1개월과 ipilimumab 및 gp100 병용투여군 10.0개월로모두통계학적으로유의한생존기간의연장을보였다 (gp100 단독군과비교하여위험비 0.66, p = 0.003, 0.68, p < 0.001). 종양반응률의경우각각 gp100단독군 1.5%, ipilimumab 단독군 10.9%, 병합군 5.7% 으로단독투여군에서가장높은효과를보였다. 주목할점은객관적종양반응률은높지않았지만반응을보인상당수의환자에서장기간의반응을유지된다는점이며 ipilimumab 의지속치료가필요하지않다는점이다. 최근의 5,000여명의환자의자료를모은결과사용후 3년부터생존기간의안정기를보인후 10년까지연장되는것을보였다. 이에따라약 17-25% 의환자에서장기간의질병조절의이득을얻을수있었다 [8]. Ipilimumab 이 CTLA-4에 대한면역치료인점을고려하여다른약제와의병합요법에대한시도가이루어지고있다. 악성흑색종에서 BRAF억제제인 vemurafenib과병합요법에대한제1상임상시험에서는심각한간독성의발생으로진행이중단되었다 [42]. 그러나 GM-CSF 와병합요법에대한제2상임상시험에서단독요법과비교하여병합요법에서 1년생존율이통계학적으로의미있는향상을보여주었다 (1년생존율, 68.9% vs. 52.9%, stratified log-rank p1 = 0.016, p2 = 0.033, 위험비 0.65) [43]. 폐암에서항암화학요법단독과비교하여항암화학요법과 ipilimumab 과의병합요법을비교하는제2상임상시험이진행되었다. 그결과항암화학요법 2주기투여후항암화학요법과 ipilimumab을병용한경우단독항암요법보다 WHO 반응평가기준또는면역반응평가기준모두무진행기간의향상이관찰되었다 ( 위험비, 0.69; 95% 신뢰구간, ; p = 0.02; 위험비 0.72; 95% 신뢰구간, ; p = 0.05). 그러나처음부터병용투여한경우의미있는무진행기간의연장이관찰되지못하였다 ( 위험비, 0.88; 95% 신뢰구간, ; p = 0.25; 위험비, 0.81; 95% 신뢰구간, ; p = 0.13) [44]. 특히편평상피암의경우무진행기간 ( 위험비, 0.55; 95% 신뢰구간, ) 및전체생존기간 ( 위험비, 0.48; 95% 신뢰구간, ) 의향상을관찰할수있었다. 이를바탕으로폐편평상피암을대상으로항암투여 2주기후병합요법에대한제3상임상시험이현재진행중이다. 확장기소세포폐암에서도항암화학요법 2주기투여후 ipilimumab 을병합투여한경우, 면역반응평가기준무진행기간의의미있는연장 ( 위험비, 0.64; 95% 신뢰구간, ; p = 0.03) 을보였다. WHO 반응평가기준무진행기간의의미있는연장은관찰되지않았다 ( 위험비, 0.93; 95% 신뢰구간, ; p = 0.37). 처음부터동시투여하는병합요법은 WHO 반응평가기준및면역반응평가기준무진행기간의의미있는연장은관찰되지않았다 ( 위험비 0.93, 95% 신뢰구간, , p = 0.38; 위험비 0.75, 95% 신뢰구간, , p = 0.11) [45]. 현재확장기소세포폐암환자를대상으로역시 3상임상시험이진행중이다. (BMS936558; MDX-1106; ONO-4538) 은 fullyhumanized IgG4 PD-1 억제단클론항체로 IgG4 의특성인항체의존세포독성을가지고있지않다. 대규모 1상시험에서악성흑색종에서 28% (26/94), 비소세포페암에서 18% (14/76), 신장암에서 27% (9/33) 의종양반응률을보였다. 종양반응은

9 - The Korean Journal of Medicine: Vol. 87, No. 3, Table 4. Major ongoing clinical trials of anti PD-1/PD-L1 monoclonal antibodies Agent Phase Target Study Design n Notes NCT NCT NCT NCT Enrollment completed NCT NCT NCT Pembrolizumab NCT Pembrolizumab NCT Ipilimumab + chemotherapy NCT chemotherapy NCT TKI NCT anti-kir NCT antiil21 NCT MPDL3280A (anti-pdl1) + vemurafenib NCT NSCLC vs. Docetaxel as second-line treatment for stage IV squamous cell NSCLC vs. Docetaxel as second or third-line treatment for stage IV nonsquamous cell II NSCLC for advanced squamous cell after at least 2 prior systemic regimens II RCC Randomized, blinded, dose-ranging study for progressive or advanced RCC after antiangiogenic therapy I RCC Exploratory study evaluating the immune effects of various dose levels of anti-pd1 for metastatic RCC RCC vs. everolimus for advanced or metastatic RCC after antiangiogenic therapy MEL vs. Ipilimumab vs. Combination of both MEL 2 different doses of Pembrolizumab vs. chemotherapy of choice for advanced MEL MEL 2 schedules (Q 2 wk or Q 3 wk) Pembrolizumab vs. ipilimumab for advanced MEL NSCLC Paclitaxel/carboplatin alone or plus ipilimumab for stage IV squamous cell I NSCLC Randomized multi-arm trial of platinum combination chemotherapy, ipilimumab, bevacizumab as maintenance, and erlotinib for NSCLC as first-line treatment or maintenance treatment I RCC in combination with sunitinib, pazopanib or ipilimumab for metastatic RCC I I All solid tumors, Study of the safety, tolerability and efficacy followed by cohort of KIR antibody (BMS986015) in expansions for combination with anti-pd1 for advanced RCC and NSCLC refractory solid tumors All solid tumors, Dose-escalation study of BMS followed by cohort (recombinant interleukin21, ril21) in expansions for combination with BMS (anti-pd1) RCC and NSCLC Ib MEL Dose-escalation and cohort-expansion study in combination with vemurafenib for V600E BRAF mutation 264 Primary endpoint: RR and OS 574 Primary endpoint: OS 100 Primary endpoint: RR 150 Primary endpoint: PFS in 3 dose levels (0.3, 2.0, 10 mg/kg Q 3 wk) 80 Companion biomarker study 822 Primary endpoint: OS 915 Primary endpoint: OS 510 Co-primary endpoint: PFS and OS 645 Co-primary endpoint: PFS and OS 920 Primary endpoint: OS 108+ Dose de-escalation phase I study with primary endpoint of safety 72 Primary endpoint: safety and tolerability 150 Primary endpoint: safety and tolerability 165 Primary endpoint: safety 44 Another study of safety and tolerability of ipilimumab plus vemurafenib was closed to further accrual after high levels of toxicity were observed among the first 12 patients enrolled MEL, malignant melanoma; NSCLC, non-small cell lung cancer; PFS, progression-free survival; RCC, renal cell carcinoma; RR, response rate; OS, overall survival

10 - Dae Ho Lee. Cancer Immunotherapy - 빠르게나타나완전관해또는부분관해를보인환자의 45% 는이미치료시작 8주평가에서이미종양반응을확인할수있었다. 41% 의환자에서폐렴, 백반증, 장염, 간염등의면역관련이상반응을보였다. Pembrolizumab (MK-3475) 을 humanized IgG4 PD-1 단클론항체로서 135명의악성흑색종환자를대상으로시행한 1상임상시험에서 10 mg/kg 2 주간격, 2 mg/kg 3주간격및 10 mg/kg 3주간격투여등의다양한치료용량을사용한결과전체적으로 38% 의종양반응률을보였으며, 10 mg/kg 2주간격투여에서가장높은 52% 의종양반응률을보였다. BMS (MDX-1105) 는 fully humanized PD-L1 억제단클론항체로종양반응률은악성흑색종 17% (9/52), 비소세포폐암 10% (5/49), 신장암 12% (2/17) 및난소암 1/17 (6%) 을보였다 % 의환자는 24주이상의안정병변을관찰할수있었다. MPDL-3280A 역시 fully-human PD-L1 억제단클론항체로서악성흑색종에서 29% (11/38), 비소세포폐암에서 23% (12/53) 에서종양반응을확인하였다. 최근 ipilimumab 과 nivolumab의병용요법에대한 52명을대상으로시행된 1상임상시험에서전체적으로종양반응률은 40% 를보였으며임상적이득을보인환자는 65% 를보고하였다 [12]. PD-1 과 PD-L1 에대한임상시험은아직초기임상단계임에도불구하고많은약제들이단독또는임상시험들이진행중이다 (Table 4). 종양면역치료의미래르네상스를통하여중세암흑시대를넘어찬란한유럽문화가피어났듯이최근종양면역치료와관련된다양하고혁신적인성과들은종양치료법발전에크게기여하고있으며종양면역치료의부흥기를이끌고있다. 이제는종양면역치료가종양치료의중추적역할을할것으로기대된다. 그러나르네상스시대가갑자기시작되지않았듯이중세암흑시대의눈에보이지않는많은성과들이르네상스의바탕이되었듯이, 과거면역기전에대한많은연구성과들이우리의이해를증진시키고이를바탕으로새로운종양면역치료의시대를열었다. 그러나종양면역치료와관련하여아직해결되지않은많은문제들이있다. 현재종양면역치료는여명기에불과하다. 다양한종양면역치료법들이임상에널리사용되기위해서는보다많은기초연구와이행성연구성과가필요하다. 단독요법뿐만아니라병합요법에사용될적절한용량과용법에대한많은초기임상시험결과들이필요하다. 최 적의치료를위한생체표지자의발굴또한종양면역치료관련독성을고려할때반드시필요하다. 보다많은연구성과들을바탕으로면역에대한보다깊은이해를통하여종양면역치료는보다빠르게발전할것이다. 앞으로종양면역치료가종양치료의전성기를이끌고나아갈중추역할을할것이다. 중심단어 : 종양 ; 면역치료 ; 항면역검문항체 REFERENCES 1. McCarthy EF. The toxins of William B: coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J 2006;26: Hoption Cann SA, van Netten JP, van Netten C, Glover DW. Spontaneous regression: a hidden treasure buried in time. Med Hypotheses 2002;58: Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011;480: Hodi FS, O Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363: Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364: Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-pd-l1 antibody in patients with advanced cancer. N Engl J Med 2012;366: Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. N Engl J Med 2012;366: Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Eur Cancer Congr 2013 (ECCO-ESMO-ESTRO); September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-pd-1) in melanoma. N Engl J Med 2013;369: Hamid O, Sosman JA, Lawrence DP, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mm): American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. J Clin Oncol 2013;31(Suppl; abstr 9010). 11. Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer

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