新型免疫肿瘤治疗临床研究现状及应用前景

Novel Immuno-oncology Therapy: Current Status of Clinical Research and Prospect of Application

张世佳 ^{and

任胜祥

^{^*}}

张世佳

200433 上海，同济大学附属上海市肺科医院肿瘤科, Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

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任胜祥

200433 上海，同济大学附属上海市肺科医院肿瘤科, Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 200433 上海，同济大学附属上海市肺科医院肿瘤科, Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China etc MEDI4736–AstraZenecaPD-L1–Non-small cell lung cancer, advanced solid tumorsAvelumab–Pfizer/MerckPD-L1Advanced or metastatic urothelial carcinoma (2017); metastatic Merkel cell carcinoma (2017)Advanced solid tumors, renal cell carcinomarHIgM12B7–Mayo Clinic/NCIPD-L2–Metastatic melanoma

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PD-1：PD-1是表达于细胞毒T细胞表面的免疫检查点受体，其配体包括PD-L1和PD-L2。临床前研究显示，阻断PD-1可使被耗竭的T细胞复苏，并恢复其细胞毒功能 ^{[

12

]} 。此外，与单纯抑制PD-L1相比，同时抑制PD-L1和PD-L2以完全抑制PD-1信号转导可能更有效地逆转T细胞耗竭。在美国FDA获批的PD-1抑制剂包括nivolumab（黑色素瘤、NSCLC、霍奇金淋巴瘤、头颈部鳞癌、肾细胞癌、尿路上皮癌）、pembrolizumab[黑色素瘤、NSCLC、头颈部鳞癌、霍奇金淋巴瘤、尿路上皮癌和高微卫星不稳定性（microsatellite instability-high, MSI-H）/错配修复缺陷（mismatch repair deficient, dMMR）实体瘤]，PD-L1抑制剂包括atezolizumab（尿路上皮癌和NSCLC）和avelumab（Merkel细胞癌和尿路上皮癌） ^{[

2

]} 。一些研究显示，肿瘤组织中的PD-L1表达水平与PD-1/PD-L1抑制剂的治疗效果相关 ^{[

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-

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]} ，但还有一些研究得出不同的结论 ^{[

6

]} 。互相矛盾的结果可能与PD-L1检测方法的缺陷有关（缺乏检测金标准、PD-L1在肿瘤中呈群集性表达导致活检易出现假阴性等） ^{[

16

]} 。其他生物标志物还包括dMMR和肿瘤突变负荷等。Ⅱ期临床试验显示，dMMR结直肠癌、错配修复功能完好（proficient mismatch repair, pMMR）结直肠癌和dMMR非结直肠癌患者接受pembrolizumab治疗后，免疫相关客观缓解率分别为40%、0和71%，免疫相关PFS率分别为78%、11%和57% ^{[

17

]} 。其他正在进行临床试验的PD-1/PD-L1抑制剂包括AMP-224、AMP-514、pidilizumab、BGB-A317、SHR-1210；PD-L1和PD-L2抑制剂包括BMS-936559、MEDI4736和rHIgM12B7等（表 1 ）。

LAG-3：淋巴细胞活化基因3（lymphocyte activation gene 3, LAG-3）是表达于活化的细胞毒T细胞和调节T细胞表面的免疫检查点受体。在活化的细胞毒T细胞与肿瘤抗原接触后，LAG-3的数量和活性可稳定升高，导致T细胞耗竭。表达LAG-3的调节T细胞也聚集在肿瘤病灶，且对细胞毒T细胞具有强抑制性。临床前研究表明LAG-3的失活可提高细胞毒T细胞对抗肿瘤的活性 ^{[

18

]} 。早期开发的LAG-3通路药物主要是LAG-3免疫球蛋白IMP321，已在晚期肾细胞癌、胰腺癌、黑色素瘤和乳腺癌中完成Ⅰ期临床试验，显示了一定的抗肿瘤和增强免疫的效果 ^{[

19

-

21

]} 。此外目前还有几种LAG-3单克隆抗体（BMS-986016、LAG525）正在晚期实体瘤和血液学恶性肿瘤患者中开展单药或与PD-1抑制剂联用的Ⅰ期和Ⅱ期临床试验（ {"type":"clinical-trial","attrs":{"text":"NCT01968109","term_id":"NCT01968109"}} NCT01968109 , {"type":"clinical-trial","attrs":{"text":"NCT02061761","term_id":"NCT02061761"}} NCT02061761 , {"type":"clinical-trial","attrs":{"text":"NCT02750514","term_id":"NCT02750514"}} NCT02750514 , {"type":"clinical-trial","attrs":{"text":"NCT02658981","term_id":"NCT02658981"}} NCT02658981 , {"type":"clinical-trial","attrs":{"text":"NCT02460224","term_id":"NCT02460224"}} NCT02460224 ）。

TIGIT：T细胞免疫球蛋白和ITIM结构域（T-cell immunoglobulin and ITIM domain, TIGIT）在NK细胞、效应和记忆T细胞、调节T细胞上均有表达 ^{[

18

]} 。TIGIT与其配体——抗原递呈细胞上的CD155和T细胞上的CD112结合后，竞争性抑制CD226与相同配体结合，而后者可增强细胞毒作用和抗肿瘤免疫应答。临床前研究显示，同时阻断TIGIT和PD-L1可有协同效应，使耗竭的细胞毒T细胞恢复功能，发挥持续的抗原特异性抗肿瘤效应 ^{[

22

,

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]} 。

2.1.2. 活化通路

表达于T细胞和其他免疫细胞表面的一系列活化受体被命名为共刺激因子，包括表达于静息淋巴细胞上的受体（如CD27），也包括在接触抗原后才诱导表达的受体[如CD137、糖皮质激素诱导肿瘤坏死因子受体（glucocorticoid-induced tumour necrosis factor receptor, GITR）和OX40]。这些共刺激因子在T细胞的增殖、存活和免疫功能调节方面发挥作用 ^{[

24

]} 。临床前研究显示，活化CD27、CD137、GITR、OX40等信号通路可以增强肿瘤特异性T细胞免疫应答，通过维持细胞毒T细胞的生存和减弱调节T细胞的免疫抑制作用等机制长期维持免疫效果 ^{[

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-

28

]} 。

已完成的Ⅰ期临床研究显示，使用鼠源性OX40激活剂型单克隆抗体9B12治疗晚期实体瘤的耐受性较好，可提高外周血CD4和CD8阳性T细胞的增殖水平，改善肿瘤特异性免疫应答，30%（12/30）的患者至少一处转移灶有所好转 ^{[

29

]} 。另一种激活剂型抗体PF-04518600 Ⅰ期临床试验的初步结果也显示，该抗体可有效结合目标受体并增强记忆T细胞的增殖 ^{[

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]} 。

2.2. NK细胞机制

NK细胞是免疫系统中迅速响应和机体防御癌症的第一道防线，NK细胞可通过分泌细胞因子/趋化因子进行肿瘤的免疫监视和清除。目前研究较多的活化和抑制通路包括信号淋巴细胞激活分子家族成员7（signaling lymphocytic activation molecule family member 7, SLAMF7）和杀伤细胞免疫球蛋白样受体（killer-cell immunoglobulin-like receptor, KIR）。SLAMF7与配体结合可激活NK细胞，临床前研究显示，SLAMF7的人源化单克隆抗体elotuzumab可不依赖抗体依赖的细胞毒作用（antibody dependent cell mediated cytotoxicity, ADCC）途径直接增强NK细胞的抗肿瘤细胞毒作用 ^{[

31

]} 。Ⅲ期临床试验显示，elotuzumab联合来那度胺和地塞米松用于多发性骨髓瘤患者的治疗，总缓解率高于仅来那度胺和地塞米松组（79% vs 66%, P < 0.001） ^{[

32

]} 。KIR是表达于NK细胞表面的免疫检查点受体，抑制KIR可以保护正常细胞免受NK细胞杀伤，而肿瘤细胞可以通过破坏这一过程以逃脱NK细胞介导的识别和摧毁 ^{[

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]} 。抗KIR2DL单克隆抗体lirilumab目前正在晚期实体瘤和血液恶性肿瘤患者中进行Ⅰ期和Ⅱ期临床试验（ {"type":"clinical-trial","attrs":{"text":"NCT01687387","term_id":"NCT01687387"}} NCT01687387 , {"type":"clinical-trial","attrs":{"text":"NCT01714739","term_id":"NCT01714739"}} NCT01714739 , {"type":"clinical-trial","attrs":{"text":"NCT01592370","term_id":"NCT01592370"}} NCT01592370 , {"type":"clinical-trial","attrs":{"text":"NCT02252263","term_id":"NCT02252263"}} NCT02252263 , {"type":"clinical-trial","attrs":{"text":"NCT02399917","term_id":"NCT02399917"}} NCT02399917 , {"type":"clinical-trial","attrs":{"text":"NCT02481297","term_id":"NCT02481297"}} NCT02481297 , {"type":"clinical-trial","attrs":{"text":"NCT02599649","term_id":"NCT02599649"}} NCT02599649 ）。此外，各种类型或分期的皮肤T细胞淋巴瘤患者均表达KIR3DL2，另一种抗KIR3DL2单克隆抗体IPH4102正在此类患者中进行Ⅰ期临床试验（ {"type":"clinical-trial","attrs":{"text":"NCT02593045","term_id":"NCT02593045"}} NCT02593045 ）。

2.3. 其他与肿瘤免疫逃逸相关的非效应细胞机制

2.4. 肿瘤细胞靶向通路

ADCC是抗肿瘤免疫中的重要一环。通过ADCC杀伤肿瘤的抗体的Fab段特异结合肿瘤细胞表面抗原，而Fc段与巨噬细胞、NK细胞和中性粒细胞等Fc受体结合，刺激这些细胞释放多种效应分子（如TNF等）杀伤肿瘤细胞。ADCC对肿瘤细胞的杀伤仅需要较少的抗体分子，制备这类抗体进行被动免疫可阻止肿瘤生长。

目前研究较多的治疗性肿瘤靶向抗体包括抗HER2、EGFR、Fucosyl-GM1和趋化因子受体4（chemokine receptor type 4, CXCR4）单克隆抗体。HER2高表达可见于乳腺癌和部分胃癌的肿瘤细胞表面。HER2单克隆抗体曲妥珠单抗已获批准用于转移性乳腺癌、转移性胃癌和胃食管结合部腺癌的治疗。此外，Ⅲ期研究 ^{[

43

]} 显示，帕妥珠单抗和曲妥珠单抗“双重阻断”HER2并联合化疗的方案用于HER2阳性早期乳腺癌患者的新辅助治疗，可获得较高的病理学缓解率。其他抗HER2单克隆抗体还包括margetuximab，目前正在晚期乳腺癌患者中开展Ⅰ期-Ⅲ期临床试验（ {"type":"clinical-trial","attrs":{"text":"NCT01828021","term_id":"NCT01828021"}} NCT01828021 , {"type":"clinical-trial","attrs":{"text":"NCT02492711","term_id":"NCT02492711"}} NCT02492711 ）。较早获批的EGFR单克隆抗体包括西妥昔单抗和帕尼单抗，适应证包括头颈部鳞癌和转移性结直肠癌。2015年底，一种新型EGFR单克隆抗体获批与吉西他滨和顺铂联合用于转移性肺鳞癌患者的一线治疗。Fucosyl-GM1在小细胞肺癌细胞表面高表达，其单克隆抗体BMS-986012目前正在小细胞肺癌患者中开展Ⅰ期和Ⅱ期临床试验（ {"type":"clinical-trial","attrs":{"text":"NCT02247349","term_id":"NCT02247349"}} NCT02247349 , {"type":"clinical-trial","attrs":{"text":"NCT02815592","term_id":"NCT02815592"}} NCT02815592 ）。CXCR4是肿瘤最常表达的趋化因子受体之一，在肿瘤细胞增殖、迁移、转移、侵袭和存活中均发挥重要作用 ^{[

44

]} 。抗CXCR4单克隆抗体ulocuplumab目前正在晚期实体瘤患者中开展Ⅰ期和Ⅱ期临床试验（ {"type":"clinical-trial","attrs":{"text":"NCT02472977","term_id":"NCT02472977"}} NCT02472977 , {"type":"clinical-trial","attrs":{"text":"NCT02305563","term_id":"NCT02305563"}} NCT02305563 ）。

抗体-药物偶联物（antibody-drug conjugate, ADC）是I-O治疗中的另一种思路。ADC由肿瘤细胞靶点特异性结合抗体、稳定的连接体和药物制剂三个部分组成，一旦与目标靶点结合，即被肿瘤细胞内化。ADC的内化触发ADC各组分分离，在肿瘤细胞中释放出药物，从而诱导细胞死亡 ^{[

45

]} 。hRS7是一种人源化的抗Trop-2抗体，后者广泛表达于多种肿瘤和某些正常组织；而SN-38是伊立替康的活性代谢物，是比伊立替康更为强效的拓扑异构酶Ⅰ抑制剂。两者偶联而成的ADC——IMMU-132在晚期NSCLC患者的Ⅰ期-Ⅱ期临床试验中初步显示了令人肯定的疗效。在既往接受多次治疗（中位三线治疗）的晚期NSCLC患者中，经过确认的客观缓解率达13%，缓解维持时间为9个月，且耐受良好 ^{[

46

]} 。ABBV-399是靶向作用于c-Met的ADC，在体内释放能结合微管蛋白的单甲基耳抑素肽E（monomethyl auristatin E, MMAE），通过抑制有丝分裂达到阻断肿瘤细胞生长的目的。Ⅰ期临床试验显示，该药物用于c-Met表达阳性的NSCLC患者耐受性良好，19%的患者获得部分缓解 ^{[

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]} 。上述结果还有待在更多的Ⅱ期-Ⅲ期临床试验中进一步验证。此外，多个通过间皮素（间皮瘤、卵巢癌和部分鳞状细胞癌细胞表面高表达； {"type":"clinical-trial","attrs":{"text":"NCT02341625","term_id":"NCT02341625"}} NCT02341625 , {"type":"clinical-trial","attrs":{"text":"NCT02485119","term_id":"NCT02485119"}} NCT02485119 , {"type":"clinical-trial","attrs":{"text":"NCT02751918","term_id":"NCT02751918"}} NCT02751918 , {"type":"clinical-trial","attrs":{"text":"NCT01439152","term_id":"NCT01439152"}} NCT01439152 , {"type":"clinical-trial","attrs":{"text":"NCT02839681","term_id":"NCT02839681"}} NCT02839681 ）、CD30 ^{[

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]} （在霍奇金淋巴瘤和非霍奇金淋巴瘤等血液恶性肿瘤细胞表面高表达）和Glypican-3 ^{[

49

]} （在肝细胞癌、非小细胞肺鳞癌和黑色素瘤等肿瘤细胞表面高表达）等途径的ADC正在接受临床前和临床研究评估。

与ADC类似的是肿瘤靶向放射性核素治疗（targeted radionuclide therapy, TRT），即通过在肿瘤中自然聚集或与肿瘤靶向结合的载体（包括肿瘤特异性抗体），将有细胞毒作用的放射性同位素传递至肿瘤细胞。与ADC相比，TRT的优势在于α和β粒子有一定的作用范围，因此无需内化过程。临床应用的TRT包括 ⁹⁰ Y-替伊莫单抗、 ¹³¹ I-利妥昔单抗，与其他药物联合用于非霍奇金淋巴瘤患者有较好的效果，其他在研阶段的TCT包括 ²¹³ Bi-林妥珠单抗、 ²²⁵ Ac-林妥珠单抗、 ¹¹¹ In-曲妥珠单抗等 ^{[

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]} 。

3. 总结和展望

肿瘤免疫是一个极为复杂的体系，包括一系列活化和抑制信号通路，随着对这些通路的研究逐渐深入，已经发现越来越多潜在有治疗作用的靶点。相关药物的有效性和安全性，包括应用靶向作用于免疫过程中不同环节的药物联合治疗的潜在获益还有待在更多临床研究中进一步明确。与当今国际上日益强调的“精准医学”原则相符的是，未来癌症患者的免疫肿瘤治疗也应强调“精准免疫学”，即确定每例患者肿瘤免疫过程中的缺陷，予以最精确的免疫治疗，将有望改善所有癌症患者的预后。但采用何种生物标志物精准选择靶向治疗人群仍是免疫治疗临床应用中有待解决的问题，需要在更大范围的临床研究中进一步探索。

References

1. Hoos A. Development of immuno-oncology drugs -from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov. 2016; 15 (4):235–247. doi: 10.1038/nrd.2015.35. [ PubMed ] [ CrossRef ] [ Google Scholar ]

2. U. S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. <a href="http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm" target="_blank">http://www.fda.gov/Drugs/InformationOnDrugs/Approved Drugs/ucm279174.htm</a>

3. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39 (1):1–10. doi: 10.1016/j.immuni.2013.07.012. [ PubMed ] [ CrossRef ] [ Google Scholar ]

4. Galluzzi L, Vacchelli E, Bravo-San P J, et al. Classification of current anticancer immunotherapies. https://www.researchgate.net/publication/270004313_Classification_of_current_anticancer_immunotherapies . Oncotarget. 2014; 5 (24):12472–12508. [ PMC free article ] [ PubMed ] [ Google Scholar ]

5. Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors. http://cancerres.aacrjournals.org/content/77/13_Supplement/CT077 Cancer Res. 2017; 77 (13 Suppl):Abstract CT077. [ Google Scholar ]

6. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373 (19):1803–1813. doi: 10.1056/NEJMoa1510665. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

7. Hodi FS, Postow MA, Chesney JA, et al. Overall survival in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity in a phase Ⅱ trial (CheckMate 069) J ClinOncol. 2016; 34 (suppl):abstr 9518. [ Google Scholar ]

8. Emens LA, Ascierto PA, Darcy PK, et al. Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017; 81 :116–129. doi: 10.1016/j.ejca.2017.01.035. [ PubMed ] [ CrossRef ] [ Google Scholar ]

9. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity insolid tumors: Immune-related response criteria. Clin Cancer Res. 2009; 15 (23):7412–7420. doi: 10.1158/1078-0432.CCR-09-1624. [ PubMed ] [ CrossRef ] [ Google Scholar ]

10. Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016; 13 (8):473–486. doi: 10.1038/nrclinonc.2016.58. [ PubMed ] [ CrossRef ] [ Google Scholar ]

11. Pedicord VA, Montalvo W, Leiner IM, et al. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci U S A. 2011; 108 (1):266–271. doi: 10.1073/pnas.1016791108. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

12. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015; 125 (9):3384–3391. doi: 10.1172/JCI80011. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

13. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373 (2):123–135. doi: 10.1056/NEJMoa1504627. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

14. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015; 373 (17):1627–1639. doi: 10.1056/NEJMoa1507643. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

15. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016; 387 (10027):1540–1550. doi: 10.1016/S0140-6736(15)01281-7. [ PubMed ] [ CrossRef ] [ Google Scholar ]

16. Zou W, Wolchok JD, Chen L, et al. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016; 8 (328):328r. [ PMC free article ] [ PubMed ] [ Google Scholar ]

17. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372 (26):2509–2520. doi: 10.1056/NEJMoa1500596. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

18. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016; 44 (5):989–1004. doi: 10.1016/j.immuni.2016.05.001. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

19. Brignone C, Escudier B, Grygar C, et al. A phase Ⅰ pharmacokinetic and biological correlative study of IMP321, a novel MHC class Ⅱ agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009; 15 (19):6225–6231. doi: 10.1158/1078-0432.CCR-09-0068. [ PubMed ] [ CrossRef ] [ Google Scholar ]

20. Brignone C, Gutierrez M, Mefti F, et al. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med. 2010; 8 :71. doi: 10.1186/1479-5876-8-71. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

21. Wang-Gillam A, Plambeck-Suess S, Goedegebuure P, et al. A phase Ⅰ study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma. Invest New Drugs. 2013; 31 (3):707–713. doi: 10.1007/s10637-012-9866-y. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

22. Johnston RJ, Yu X, Grogan JL. The checkpoint inhibitor TIGIT limits antitumor and antiviral CD8+ T cell responses. Oncoimmunology. 2015; 4 (9):e1036214. doi: 10.1080/2162402X.2015.1036214. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

23. Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014; 26 (6):923–937. doi: 10.1016/j.ccell.2014.10.018. [ PubMed ] [ CrossRef ] [ Google Scholar ]

24. Sanmamed MF, Pastor F, Rodriguez A, et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol. 2015; 42 (4):640–655. doi: 10.1053/j.seminoncol.2015.05.014. [ PubMed ] [ CrossRef ] [ Google Scholar ]

25. van de Ven K, Borst J. Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential. Immunotherapy. 2015; 7 (6):655–667. doi: 10.2217/imt.15.32. [ PubMed ] [ CrossRef ] [ Google Scholar ]

26. Makkouk A, Chester C, Kohrt HE. Rationale for anti-CD137 cancer immunotherapy. Eur J Cancer. 2016; 54 :112–119. doi: 10.1016/j.ejca.2015.09.026. [ PubMed ] [ CrossRef ] [ Google Scholar ]

27. Cohen AD, Schaer DA, Liu C, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010; 5 (5):e10436. doi: 10.1371/journal.pone.0010436. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

28. Aspeslagh S, Postel-Vinay S, Rusakiewicz S, et al. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016; 52 :50–66. doi: 10.1016/j.ejca.2015.08.021. [ PubMed ] [ CrossRef ] [ Google Scholar ]

29. Curti BD, Kovacsovics-Bankowski M, Morris N, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013; 73 (24):7189–7198. doi: 10.1158/0008-5472.CAN-12-4174. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

30. Hamid O, Thompson J A, Diab A, et al. First in human (FIH) study of an OX40 agonist monoclonal antibody (mAb) PF-04518600 (PF-8600) in adult patients (pts) with select advanced solid tumors: Preliminary safety and pharmacokinetic (PK)/pharmacodynamic results. http://abstract.asco.org/176/CatAbstView_176_540_AT.html J Clin Oncol. 2016; 34 (suppl):abstr 3079. [ Google Scholar ]

31. Boudreault JS, Touzeau C, Moreau P. The role of SLAMF7 in multiple myeloma: impact on therapy. Expert Rev ClinImmunol. 2017; 13 (1):67–75. doi: 10.1080/1744666X.2016.1209112. [ PubMed ] [ CrossRef ] [ Google Scholar ]

32. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015; 373 (7):621–631. doi: 10.1056/NEJMoa1505654. [ PubMed ] [ CrossRef ] [ Google Scholar ]

33. Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011; 132 (3):315–325. doi: 10.1111/imm.2011.132.issue-3. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

34. Yoshie O, Matsushima K. CCR4 and its ligands: from bench to bedside. IntImmunol. 2015; 27 (1):11–20. doi: 10.1093/intimm/dxu079. [ PubMed ] [ CrossRef ] [ Google Scholar ]

35. Geoghegan JC, Diedrich G, Lu X, et al. Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action. MAbs. 2016; 8 (3):454–467. doi: 10.1080/19420862.2016.1143182. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

36. Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014; 6 (6):a021857. doi: 10.1101/cshperspect.a021857. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

37. Stagg J, Divisekera U, Mclaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010; 107 (4):1547–1552. doi: 10.1073/pnas.0908801107. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

38. Hausler SF, Del BI, Diessner J, et al. Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion. Am J Transl Res. 2014; 6 (2):129–139. [ PMC free article ] [ PubMed ] [ Google Scholar ]

39. Vacchelli E, Aranda F, Eggermont A, et al. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology. 2014; 3 (10):e957994. doi: 10.4161/21624011.2014.957994. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

40. Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther. 2015; 147 :22–31. doi: 10.1016/j.pharmthera.2014.11.001. [ PubMed ] [ CrossRef ] [ Google Scholar ]

41. Richardsen E, Uglehus RD, Johnsen SH, et al. Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer Res. 2015; 35 (2):865–874. [ PubMed ] [ Google Scholar ]

42. Ries CH, Cannarile MA, Hoves S, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014; 25 (6):846–859. doi: 10.1016/j.ccr.2014.05.016. [ PubMed ] [ CrossRef ] [ Google Scholar ]

43. Loibl S, Jackisch C, Schneeweiss A, et al. Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase Ⅲ GeparSepto trial. https://www.ncbi.nlm.nih.gov/pubmed/27831502 . Ann Oncol. 2017; 28 (3):497–504. [ PubMed ] [ Google Scholar ]

44. Scala S. Molecular pathways: targeting the CXCR4-CXCL12 axis--untapped potential in the tumor microenvironment. Clin Cancer Res. 2015; 21 (19):4278–4285. doi: 10.1158/1078-0432.CCR-14-0914. [ PubMed ] [ CrossRef ] [ Google Scholar ]

45. Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015; 35 (4):pii: e00225. doi: 10.1042/BSR20150089. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

46. Camidge DR, Heist RS, Masters GA, et al. Therapy of metastatic, non-small cell lung cancer (mNSCLC) with the anti-Trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumabgovitecan (IMMU-132) http://clincancerres.aacrjournals.org/content/clincanres/early/2015/07/16/1078-0432.CCR-14-3321.full.pdf J Clin Oncol. 2016; 34 (suppl):abstr 9011. [ Google Scholar ]

47. Strickler JH, Nemunaitis JJ, Weekes CD, et al. Phase 1, open-label, dose-escalation and expansion study of ABBV-399, an antibody drug conjugate (ADC) targeting c-Met, in patients (pts) with advanced solid tumors. https://www.sciencedirect.com/journal/european-journal-of-cancer/vol/69/suppl/S1 J Clin Oncol. 2016; 34 (suppl):abstr 2510. [ Google Scholar ]

48. Schirrmann T, Steinwand M, Wezler X, et al. CD30 as a therapeutic target for lymphoma. https://link.springer.com/content/pdf/10.1007/s40259-013-0068-8.pdf Bio Drugs. 2014; 28 (2):181–209. [ PubMed ] [ Google Scholar ]

49. Hanaoka H, Nagaya T, Sato K, et al. Glypican-3 targeted human heavy chain antibody as a drug carrier for hepatocellular carcinoma therapy. Mol Pharm. 2015; 12 (6):2151–2157. doi: 10.1021/acs.molpharmaceut.5b00132. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

50. Gill MR, Falzone N, Du Y, et al. Targeted radionuclide therapy in combined-modality regimens. Lancet Oncol. 2017; 18 (7):e414–e423. doi: 10.1016/S1470-2045(17)30379-0. [ PubMed ] [ CrossRef ] [ Google Scholar ]

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