암 면역치료의 이해 - IMMUNOLOGICAL TREATMENT OF CANCER > Hematology. Oncology

암은 성장함에 따라서 유전자의 변이가 지속되고, 대사작용이 정상세포와 달라져 지속적인 성장을 한다. 암세포들이 모여서 형성된 미세환경은 그 구조나 환경이 암에 유리하게 변하여 환자의 면역작용을 피해서 생존하게 된다. 이러한 변화는 환자가 섭취하는 식이와 음식물, 환자의 심적인 상태와 육체적인 운동, 그리고 공생하는 미생물 등의 영향을 받는데 암의 성장과 전이 뿐 아니라 치료의 결과와 예후에 영향을 미친다.

지난 40여 년 동안 암 환자를 진료하고 수술하며, 암에 대한 기초 및 임상연구를 하였다. 아직도 나에게 해결되지 않는 의문은 ‘왜 암세포는 자신도 죽게 되는데 자신의 숙주인 환자를 죽도록 만들까?’ 하는 것이다. 나는 그동안 시행하고 암 환자들에게 권유했던 수술, 항암화학요법, 방사선요법 등의 표준치료에 더해서 최근에 새로이 암의 표준요법으로 각광을 받는 면역요법을 알아보고자 하였다. 특히 암과 환자의 면역상태와 그것을 검사하고, 치료하는 다양한 방법들을 공부하였다. 그리고 암의 미세환경과 면역요법에 영향을 주는 약물과 물질들에 대해서 그 작용기전과 임상적인 결과들을 공부하고 종합적으로 정리하여 그 지식을 나누고자 하였다.

이 책이 암을 연구하는 연구자, 그리고 암을 치료하는 암 전문가뿐만 아니라 암에 대해 관심을 갖고 있는 많은 사람들에게 암의 면역학적인 치료방법을 이해하고, 암환자를 치료하는데 자그마한 도움과 참고가 되었으면 한다.
 

1 암 면역시스템(Cancer Immune System)·································· 1
1-1 암 면역계··········································· 1
1-2 종양항원과 면역인지······································ 3
1-3 수지상세포(Dendritic cell)의 세포독성 T세포와 교차감작· ····················· 6
1-4 암 면역세포의 종양 내로의 이동································· 10
1-5 암 면역과 염증반응······································ 12
1-6 암 면역에서 호중구의 역할· ·································· 14
1-7 암 면역에서 NK세포의 역할··································· 15
1-8 암 면역에서 B세포의 역할· ·································· 17
1-9 암 면역에서 대식세포의 역할· ································· 20
1-10 면역내성(Immune Tolerance)· ·································· 23

2 암 면역시스템 검사(Test for Cancer Immune System)···························· 27
2-1 암조직에서 면역상태(Cancer Immunogram)의 검사· ························ 27
2-1-1 선천성면역(Innate Immune)의 검사···························· 28
2-1-2 획득면역(Adaptive Immune)검사······························ 29
2-1-3 선천성과 획득면역검사· ································ 30
2-2 암 미세환경(TME)의 면역상태(Immunity)에 대한 검사· ······················ 31
2-2-1 면역점수(Immunoscore) 검사· ······························ 31
2-2-2 암 미세환경의 면역검사 방법······························· 33
2-2-3 종양의 침윤림프구와 암의 예후······························ 40
2-2-4 면역관련 유전자의 특징에 따른 암의 예후························· 41
2-2-5 면역검사에서 유전체검사· ······························· 42
2-2-6 암조직의 계통면역학적(Cancer System Immunology) 검사방법················· 42
2-2-7 종양 미세환경의 면역상태에 의한 암의 분류························ 45
2-2-8 종양 미세환경에서 면역관문(Check point)검사· ······················ 47
2-2-9 종양 미세환경에서의 면역억제검사· ··························· 51
2-2-10 종양 미세환경에서의 암 줄기세포화(Stemness) 검사· ··················· 52
2-2-11 암의 미세환경에서의 전이관련 검사· ·························· 52
2-3 말초혈액에서 면역검사····································· 53
2-3-1 호중구와 림프구· ··································· 53
2-3-2 말초혈액에서 면역검사· ································ 53
2-3-3 말초혈액소견과 면역치료 효과· ····························· 54
2-3-4 액체생검(Liquid Biopsy)의 소견과 면역치료 효과· ····················· 54
2-3-5 종양항원 특이 항체와 항원반응성 T세포·························· 55
2-3-6 기타 말초혈액소견· ·································· 55
2-4 면역세포 세포살해력 검사(Immune Cell Killing Assay)· ······················· 55
2-5 암의 면역학적인 분류와 검사 결과에 따른 암의 치료 방침····················· 56

3 암의 면역요법············································· 63
3-1 암의 면역요법(Cancer Immunotherapy)······························· 63
3-1-1 면역요법의 목표· ··································· 63
3-1-2 암 면역요법의 역사· ·································· 65
3-1-3 암의 예방과 면역· ··································· 65
3-1-4 암 면역요법의 방법(Methods of Cancer Immunotherapy)· ··················· 66
3-1-5 암 면역치료에 대한 내성과 이의 극복방법························· 77
3-1-6 GM-CSF, G-CSF, M-CSF 기반 면역요법·························· 83
3-1-7 면역치료의 효과 예측· ································· 84
3-1-8 현재까지의 면역치료의 방향· ······························ 85
3-1-9 개인 맞춤형 및 복합적인 암 면역요법의 원칙······················· 86
3-1-10 면역요법의 임상적인 효과· ······························ 89
3-1-11 암의 면역요법에 대한 내성의 기전(Mechanisms of Resistance to Immunotherapy)········· 95
3-1-12 암 면역요법의 부작용· ································ 96
3-1-13 암 면역요법의 미래· ································· 98
3-2 사이토카인을 이용한 면역보강요법······························· 101
3-2-1 사이토카인 강화요법· ································· 101
3-2-2 사이토카인 차단요법· ································· 104
3-2-3 사이토카인 치료의 미래· ································ 108
3-3 면역관문(Immune Checkpoint)억제제· ······························ 113
3-3-1 면역관문(Immune Checkpoint)······························· 113
3-3-2 면역관문억제제(Immune Check point inhibitor)· ······················· 117
3-3-3 면역관문억제 치료의 생물학적인 예측표지자(Biomarkers of Checkpoint Inhibitor therapy)····· 118
3-3-4 면역관문억제제 요법(Checkpoint Inhibitor therapy)· ····················· 121
3-4 암의 입양 T세포치료(Adoptive T Cell Therapy for Cancer)······················· 142
3-4-1 사이토카인 유도 살해세포(Cytokine Induced Killer Cell Therapy: CIK, CD3+CD50+) 치료· ··· 143
3-4-2 자연살해T(NKT: Natural Killer T)세포치료· ························ 144
3-4-3 종양침윤림프구(TIL) 치료· ······························· 148
3-4-4 T세포수용체(T cell receptor: TCR) 유전자 조작 T세포 치료·················· 152
3-4-5 T세포 탈진(exhaustion) 방지 치료· ···························· 153
3-4-6 키메라항원 수용체(Chimeric Antigen Receptor)-T(CAR-T)세포 치료··············· 153
3-4-7 바이러스특이 T세포 치료(Virus Specific T cell therapy; VST)·················· 158
3-4-8 T세포의 활성도 증가 방법· ······························· 160
3-4-9 기억T(TRM)세포를 표적으로 하는 치료··························· 160
3-5 암의 NK세포 기반 치료(NK based Immunotherapy for Cancer)····················· 162
3-5-1 NK세포의 성장과 분화································· 162
3-5-2 NK세포의 기능····································· 163
3-5-3 NK세포의 항암작용 기전································ 163
3-5-4 암의 NK세포치료···································· 165
3-5-5 Allogenic(동종) NK세포 치료······························· 168
3-5-6 면역관문의 차단 및 NK세포 항종양력 상승을 위한 물질의 사용· ·············· 170
3-5-7 CAR-NK세포 치료··································· 174
3-6 면역억제세포를 표적으로 한 암의 면역치료(Cancer Immunotherapy Targeting Immunosuppressive Cell)··· 177
3-6-1 골수유래억제세포(MDSCs)를 표적으로 한 암의 치료(MDSC targeted therapy for Cancer)······ 177
3-6-2 조절T(Treg)세포를 표적으로 하는 치료· ························· 184
3-6-3 종양연관대식세포(TAMs)를 표적으로 하는 치료· ····················· 187
3-6-4 호중구의 역할과 이를 이용한 암의 면역요법························ 191
3-7 암의 백신요법········································· 191
3-7-1 암 백신의 제조· ···································· 192
3-7-2 수지상세포백신요법(Dendritic Cell Vaccine)· ························ 200
3-7-3 펩타이드/단백 백신(Peptide/Protein Vaccine)························ 204
3-7-4 핵산(DNA)/mRNA 기반 백신······························· 205
3-7-5 바이러스 백터를 이용한 백신······························· 209
3-7-6 종양용해 바이러스(Oncolytic Virus)· ··························· 209
3-7-7 암의 나노백신요법(Nanovaccine for Cancer Immunotherapy)· ················· 210
3-7-8 개인 맞춤형백신(Personalized vaccine)· ·························· 212
3-7-9 암백신의 미래 전망· ·································· 214

4 종양의 미세환경과 이를 표적으로한 암의 치료(Cancer Therapy targeting TME)· ··············· 233
4-1 종양의 미세환경(tumor microenvironment: TME)· ························· 233
4-2 종양미세환경(TME)과 암 면역계································ 235
4-3 암의 미세환경에서의 저산소증의 영향· ····························· 236
4-4 암의 기계적인 미세환경(Mechanical Microenvironment)· ······················ 237
4-5 암 면역과 염증반응······································ 239
4-6 암의 미세환경(TME)을 표적으로 하는 치료···························· 240
4-6-1 직접적인 방법(Direct Methods)· ····························· 242
4-6-2 간접적인 방법(Indirect Methods)······························ 243
4-6-3 암의 미세환경에 대한 복합적인 면역요법· ························ 253

5 암의 표준치료와 면역요법의 관계와 복합치료 전략· ···························· 259
5-1 수술과 면역요법········································ 259
5-2 항암화학요법과 면역요법···································· 265
5-3 방사선요법과 면역요법····································· 271

6 암과 대사작용(Cancer and Metabolism)································· 279
6-1 정상세포에서 암세포로 이행하는 과정· ····························· 280
6-2 암과 대사작용의 재프로그래밍(Cancer and metabolic reprogramming)·················· 282
6-2-1 암과 비만과의 관계· ·································· 284
6-2-2 암과 동물성 단백과의 관계································ 284
6-2-3 암과 면역대사(Cancer and Immunometaboloism)· ······················ 284
6-3 암의 대사작용을 표적으로 한 치료(Cancer Therapy Targeting Metabolism)················ 291
6-3-1 당대사(Glucose Metabolism)에 관계되는 대사치료· ····················· 291
6-3-1-가 메트포민(Metformin)· ······························ 294
6-3-1-나 시타글립틴(Sitagliptin; DPP4억제제)· ······················· 298
6-3-1-다 인슐린 강화요법(Insulin Potentiation Therapy)····················· 300
6-3-2 지질대사(Lipid Metabolism)에 관계되는 대사치료· ····················· 300
6-3-3 콜레스테롤 대사(Cholesterol metabolism)와 암························ 305
6-3-4 아미노산 대사와 암의 치료제······························· 310
6-3-5 핵산대사 물질을 표적으로 한 치료· ··························· 310
6-3-6 세포 증식관련 물질의 대사································ 310
6-3-7 암의 전이관련 물질의 대사를 표적으로 한 치료······················ 312
6-3-8 활성산소(ROS)와 암치료································· 313

7 암의 명상과 이완요법에 대해서······································ 329
7-1 암에 대한 스트레스의 반응과 심리요법의 효과에 대한 기전····················· 330
7-2 암 치료에 심리적인 접근· ··································· 336
7-2-1 마음신체요법(mind body technique)···························· 336
7-2-2 암 환자에 대한 심리적인 치료의 지침··························· 339
7-2-3 암종별 심리적 치료의 효과································ 340
7-2-4 정신신경면역치료의 미래· ······························· 340

8 미생물과 암·············································· 343
8-1 인체의 미생물········································· 343
8-2 미생물의 종류와 동정(Identification of Microbiome)· ························ 347
8-3 유산균(Lactic Acid Bacteria)· ·································· 347
8-4 장내미생물에 영향을 미치는 인자· ······························· 349
8-5 운동의 장내미생물에 대한 영향과 면역······························ 352
8-6 장내미생물과 암········································ 354
8-7 장내미생물과 질병의 치료··································· 360
8-8 장내미생물과 항암요법의 효과································· 360
8-9 장내미생물과 암의 면역요법의 효과· ······························ 360
8-10 장내미생물을 이용한 암 면역요법· ······························· 363
8-11 호흡기 미생물과 암의 관계· ·································· 365

9 암의 온열요법············································· 371
9-1 온열요법의 역사········································ 371
9-2 온열치료의 기전········································ 371
9-3 온열치료의 면역학적인 효과·································· 372
9-4 온열치료의 방법········································ 378
9-5 온열요법의 임상효과······································ 381
9-6 온열요법의 통합의학적인 복합치료 상승효과· ·························· 383
9-7 온열요법의 부작용과 금기증·································· 384
9-8 온열요법의 미래········································ 385

10 운동과 암 면역(Exercise and Cancer Immunology)····························· 389
10-1 운동면역학(Exercise Immunology)································· 389
10-2 운동의 호르몬에 대한 영향· ·································· 389
10-3 노화에 의한 변화와 면역기능· ································· 392
10-4 운동과 면역기능········································ 393
10-5 운동의 암에 대한 효과의 기전·································· 396
10-5-1 암의 발생과 운동· ·································· 398
10-5-2 암의 치료와 운동의 효과· ······························· 399
10-5-3 암의 예후와 운동· ·································· 401
10-5-4 암의 증상과 치료와 연관된 부작용에 대한 운동 효과···················· 401
10-6 암 환자의 운동방법······································ 403
10-6-1 운동을 정지해야 할 경우· ······························· 404
10-6-2 암의 종류와 암 환자의 개별 맞춤형 운동요법· ······················ 405
10-6-3 암 환자에 대한 운동치료의 미래····························· 406
10-6-4 암 환자에 대한 개인 맞춤형 운동치료 처방· ······················· 406

11 암의 통합의학적인 치료에 대한 이해· ·································· 411
11-1 암의 발생과 치료의 통합의학적 개념······························· 412
11-2 암의 진행과 치료의 통합의학적 개념······························· 413
11-3 통합암의학(Integrative Oncology)· ································ 414
11-3-1 암치료에서 통합의학은 무엇인가?···························· 414
11-3-2 통합암 치료의 목표·································· 415
11-3-3 보완의학적이고 생물학적인 암 치료 방법························· 416
11-3-4 영양요법· ······································ 417
11-3-5 분자교정요법(Orthomolecular Therapy)··························· 418
11-3-6 물리적인 자극에 의한 암의 치료····························· 422
11-3-7 정화 및 해독요법··································· 422
11-3-8 면역강화요법· ···································· 423
11-3-9 메트로놈 화학요법(Metronomic Chemotherapy)· ······················ 426
11-3-10 통합의학적 암치료의 안전성에 대한 고려· ······················· 426
11-4 통합의학적 암 치료방법의 실제· ································ 427
11-4-1 미국과 유럽에서의 통합의학적인 암치료의 실제······················ 427
11-4-2 닥터 Williams의 암 면역요법 전략· ··························· 427
11-4-3 암종별 통합의학적인 치료방법과 결과· ························· 430
11-5 통합의학적인 암치료의 현재와 미래······························· 430
11-6 통합의학적인 암치료의 결론· ································· 431

12 암 환자의 식이(Diet of Cancer Patients)·································· 435
12-1 암의 예방과 식이요법····································· 435
12-2 암의 예방식품, 암과 싸우는 음식(Food that fight cancer)· ······················ 436
12-2-1 지방산(Fatty acid)··································· 438
12-2-2 폴리페놀(Polyphenols)································· 439
12-2-3 미세영양소(Micronutrients)······························· 444
12-3 장기별 암에 따른 발암식품과 항암식품······························ 446
12-3-1 암의 발생에 관여하는 식품· ······························ 447
12-3-2 암의 치료에 해가 되는 식품······························· 449
12-4 암과 비타민요법········································ 450
12-4-1 비타민 A· ······································ 450
12-4-2 비타민 B12······································ 450
12-4-3 비타민 D· ······································ 451
12-4-4 비타민 E· ······································ 454
12-5 암 환자에서 식이 원칙· ···································· 456
12-5-1 암의 치료와 식이요법(Diet for Cancer)·························· 457
12-5-2 암의 치료에 도움이 되는 식품······························ 457
12-5-3 암의 면역반응에 영향을 주는 식이···························· 458
12-5-4 콩과류의 이소플라본(Isoflavone)과 유방암과의 관계· ··················· 459
12-5-5 지중해식 식이(Mediterranean diet)···························· 460
12-5-6 채식주의자 식이(Vegetarian diet)· ···························· 461
12-5-7 일본식 식이(Japanese diet)································ 461
12-5-8 케톤체 생성식이(Ketogenic diet),
극저탄수화물 케톤체 생성식이(very low carbohydrate ketogenic diet: VLCKD)·········· 461
12-5-9 영양결핍 없는 칼로리 제한· ······························ 464
12-6 영양요법에 대한 결론····································· 464

13 암의 치료와 식물화학물질(Phytochemicals)································ 471
13-1 암에 현재 사용되고 있는 식물화학물질(Phytochemical)· ······················ 473
13-1-1 강황(Turmeric, Curcumin)· ······························· 473
13-1-2 미슬토(Abnoba- viscum, Mistletoe extract, 겨우살이 추출물, 렉탄올, 유릭소)·········· 476
13-1-3 레스베라트롤(Resveratrol), 레스베라겐(Resveragen: 마디풀속 Polygonum cuspidatum)······ 478
13-1-4 이뮤노쎄라(Immunothera), 프로텍타겐(Protectagen)····················· 480
13-1-5 소태나무(Picrasia quass)································· 480
13-1-6 트리고넬린(Trigonellin)· ································ 481
13-1-7 베타글루칸· ····································· 481
13-1-8 녹차추출물· ····································· 482
13-1-9 Triptolide(뇌공등, 미역줄나무, Tripterygium wilfordii Hook F: TWHF)· ············ 482
13-1-10 옻나무(Rhus verniciflua stoke)· ····························· 483
13-1-11 크레스틴(PSK: protein bound polysaccharide K)······················ 483
13-1-12 식물 아로마타제 억제물질(Aromatase inhibitors)······················ 484
13-1-13 기타 식물화학물질· ································· 484
13-2 식물화학물질의 암의 치료에 대한 결론······························ 485

14 염증억제에 의한 항암효과· ······································· 489
14-1 COX-2 억제제········································· 489
14-2 파이로토시스(Pyroptosis)와 염증조절을 통한 암의 치료······················· 490
14-3 멜라토닌(Melatonin)· ····································· 494
14-4 시메티딘(양성자 교환 억제제)·································· 495
14-5 밀크씨슬(Milk thistle: 엉겅퀴)· ································· 495
14-6 디클로로아세테이트(Dichloroacetate: DCA)· ··························· 496
14-7 면역치료와 염증반응······································ 497

15 기존 개발된 약물의 항암효과와 암 치료에서의 응용 가능성· ························ 499
15-1 TGFβ 억제제: 기관지천식 약(Tranilast)· ····························· 499
15-2 발기부전 치료제: 실데나필(sildenafil, tadalafil)··························· 501
15-3 CD73억제제········································· 502
15-3-1 펜톡시필린(pentoxifylline: PTX)· ···························· 502
15-3-2 항생제 티아무린(Tiamulin)······························· 502
15-4 항기생충재제· ········································ 502
15-4-1 펜벤다졸(Fenbendazole) 및 메벤다졸(Mebendazole)· ···················· 502
15-4-2 이버맥틴(Ivermectin)· ································· 506
15-5 항곰팡이재제(Antifungal agent)·································· 507
15-5-1 이트라코나졸(Itraconazole)······························· 507
15-6 면역억제제(Immunosuppressive Agents)· ····························· 509
15-6-1 라파마이신(Raphamycin; sirolimus)···························· 509
15-7 말라리아 치료제(Antimalarial Agent)······························· 511
15-7-1 아르테수네이트(Artesunate)· ······························ 511
15-8 항정신질환 약물········································ 512
15-8-1 MALT1억제제(Mepazine, Biperiden)··························· 512
15-9 결론· ············································ 513

16 암과의 전쟁·············································· 517