文章信息
- MSS型结直肠癌免疫联合治疗研究进展
- Research Progress on Combined Immunotherapy for Microsatellite Stable Colorectal Cancer
- 肿瘤防治研究, 2022, 49(9): 977-981
- Cancer Research on Prevention and Treatment, 2022, 49(9): 977-981
- http://www.zlfzyj.com/CN/10.3971/j.issn.1000-8578.2022.22.0453
- 收稿日期: 2022-04-26
- 修回日期: 2022-07-28
近年来,包括细胞毒性T淋巴细胞相关蛋白4(cytotoxic T lymphocyte-associated protein 4, CTLA-4)和程序性死亡受体1(programmed death-1, PD-1)/程序性死亡受体配体1(programmed cell death ligand 1, PD-L1)抑制剂在内的免疫治疗已经丰富了多种恶性肿瘤的治疗模式。结直肠癌是全球三大常见的恶性肿瘤之一[1],大部分患者诊断时已是转移性结直肠癌(metastatic colorectal cancer, mCRC)。目前帕博利珠单抗、纳武利尤单抗±伊匹木单抗均已获批用于DNA错配修复缺陷(mismatch repair defect, dMMR)/高微卫星不稳定性(high microsatellite instability, MSI-H)mCRC患者的治疗。然而,只有约5%的mCRC为dMMR/MSI-H型[2],剩余约95%的mCRC患者为DNA错配修复完整(mismatch repair proficient, pMMR)/微卫星稳定(microsatellite stable, MSS)型。KEYNOTE-016Ⅱ期临床试验[3]结果显示,dMMR/MSI-H mCRC患者客观缓解率(objective response rate, ORR)为40%,而pMMR/MSS mCRC患者ORR为0。临床试验中pMMR/MSS mCRC患者对单药免疫治疗均没有应答[3-4]。这种对免疫治疗抗拒的肿瘤为“冷肿瘤”[5],如何将“冷肿瘤”变成对免疫治疗有效的“热肿瘤”一直是热门研究方向。目前临床对难治性mCRC尝试多种联合治疗模式,本文就MSS型mCRC的免疫联合治疗研究进展进行综述。
1 免疫联合治疗单用免疫检查点抑制剂治疗MSS mCRC患者没有临床获益[3-4],PD-1/PD-L1抑制剂联合其他免疫疗法可能发挥协同作用从而增强抗肿瘤效应。一项Ⅱ期临床试验[6]显示,对比最佳支持治疗,PD-L1抑制剂durvalumab联合CTLA-4抑制剂tremelimumab治疗难治性mCRC患者(92%为pMMR/MSS),发现仅在肿瘤突变负荷(tumor mutation burden, TMB)≥28个突变/Mb亚组中,联合组的总生存期(overall survival, OS)显著获益。另外,PD-1抑制剂帕博利珠单抗联合抗LAG-3单抗favezelimab用于既往接受过治疗的MSS mCRC患者的Ⅰ期临床试验[7],89名患者中,4名患者表现出部分缓解、1名患者达到完全缓解。中位缓解持续时间为10.6个月,毒性可控,提示免疫联合治疗可能为MSS型肠癌患者带来生存获益。
2 免疫治疗联合靶向治疗 2.1 联合酪氨酸激酶抑制剂多靶点酪氨酸激酶抑制剂瑞戈非尼是三线治疗mCRC的主要药物之一。有研究表明瑞戈非尼可以通过抑制肿瘤相关巨噬细胞[8]、降低PD-L1和IDO1表达[9],从而增强抗肿瘤免疫作用。2019年REGONIVO研究[10]纳入24例标准治疗失败后的pMMR/MSS肠癌患者,给予瑞戈非尼80 mg联合纳武利尤单抗治疗,ORR达33.3%,可显著改善无进展生存期(progression-free survival, PFS)和OS,且耐受性较好。分析发现肺转移比肝转移患者、高TMB比低TMB患者更能获益。REGOMUNE试验评估了瑞戈非尼160 mg联合PD-L1抑制剂avelumab治疗48例MSS mCRC患者的疗效和安全性,54%患者病情稳定,中位PFS为3.6个月,中位OS为10.8个月。该研究发现与患者基线状况相比,第2周期第1天CD8+T细胞的肿瘤浸润增加的患者PFS显著延长[11]。我国一项Ⅰb/Ⅱ期临床试验[12]显示瑞戈非尼联合特瑞普利单抗治疗难治性pMMR mCRC患者,ORR为15.2%,其中不伴肝转移的ORR达30%,中位PFS为2.1个月, 中位OS达15.5个月。同时发现基线肠道微生物菌群中梭杆菌属可作为预测标志物。另外,呋喹替尼联合免疫治疗等临床试验也正在开展。有临床前研究显示,帕博利珠单抗联合仑伐替尼可通过减少肿瘤相关巨噬细胞和激活干扰素途径来激活CD8+T细胞,从而产生协同效应,增强抗肿瘤作用[13]。一项Ⅱ期临床试验[14]显示帕博利珠单抗联合仑伐替尼治疗曾接受过治疗的非dMMR/MSI-H mCRC,结果显示具有很好的抗肿瘤活性,共纳入32例患者,ORR为22%,中位PFS为2.3个月,安全性可控。这些研究显示部分pMMR/MSS mCRC患者可以从PD-1抑制剂联合酪氨酸激酶抑制剂这种模式中获益。
2.2 联合抗EGFR药物抗EGFR药物是治疗RAS野生型mCRC的靶向药物之一。有临床前研究显示抗EGFR治疗能引起肿瘤特异性免疫反应和免疫原性细胞凋亡,免疫治疗联合抗EGFR治疗可能增强抗肿瘤效应[15]。2021年ASCO-GI报道了LCCC1632Ⅱ期临床试验,结果显示了伊匹木单抗联合纳武利尤单抗联合帕尼单抗治疗pMMR/MSS mCRC的潜力[16]。另外,Ⅱ期单臂CAVE试验探讨了在三线治疗方案中用avelumab联合西妥昔单抗“再挑战”治疗RAS野生型mCRC曾一线经抗EGFR单抗治疗有效的患者[17]。在纳入的77名患者中,92%为MSS mCRC,中位OS为11.6个月。将血浆循环肿瘤DNA(circulating tumor DNA, ctDNA)进行基线分析,ctDNA RAS/BRAF野生型患者较突变型患者的中位OS和PFS更长,前景值得我们期待,但还需要Ⅲ期研究进一步探索。ctDNA RAS/BRAF野生型可能是其潜在预测性生物标志物。另外,也有avelumab联合西妥昔单抗联合化疗一线治疗MSS RAS/BRAF野生型mCRC的临床试验正在开展(NCT04513951)。
2.3 联合抗VEGF药物贝伐珠单抗是一种用于mCRC的抗血管生成药物,与化疗联合使用,抑制VEGF/VEGFR途径,从而使血管正常化,增加T细胞的浸润,并通过刺激树突状细胞的成熟和减少调节性T细胞和髓源性抑制细胞的扩增来激活效应免疫细胞[18-20]。然而,有临床试验[21]评估了化疗和贝伐珠单抗联合atezolizumab与化疗和贝伐珠单抗一线治疗mCRC的比较,其中199例MSS mCRC患者,联合治疗组的PFS为12.9个月,对照组为11.4个月(P=0.07)。另外,还有一些临床试验也正在开展以评估一线化疗和贝伐珠单抗联合免疫治疗的组合,结果尚未见报道。
2.4 联合MAPK信号转导抑制剂在mCRC中常检测到RAS/BRAF/MEK/ERK通路的过表达和激活[22]。有研究报道MAPK信号转导对T细胞的发育、活化、增殖和存活至关重要,并且MAPK信号转导可能控制PD-L1和CTLA-4的表达[23-25],这为探索免疫治疗药物和RAS/BRAF/MEK/ERK途径选择性抑制剂在pMMR/MSS mCRC中的协同作用提供了依据。临床前研究[26]表明MEK抑制剂可上调主要组织相容性复合物I类分子表达,增加肿瘤内T细胞浸润,免疫检查点抑制剂联合MEK抑制剂可能提高疗效。但有研究显示atezolizumab联合MEK抑制剂考比替尼对比瑞戈非尼并未提高晚期结直肠癌患者的疗效。2020年ASCO会议报道了MEK抑制剂比美替尼联合贝伐珠单抗联合帕博利珠单抗治疗经多线治疗失败的mCRC患者的临床试验结果[27],共入组了21例pMMR/MSS mCRC患者,ORR为12%,DCR为94%,中位PFS为6.4个月,不良反应可耐受。这个方案初见疗效,但仍需Ⅲ期临床试验来确认。
抗EGFR药物和BRAF抑制剂及MEK抑制剂联用是BRAF V600E突变mCRC的治疗方案之一,但疗效仍有限。有研究发现BRAF抑制剂和MEK抑制剂及PD-1/PD-L1抑制剂联合治疗BRAF V600E突变mCRC,其反应率和耐受性均良好[28]。目前也有Ⅰ期临床试验正在进一步探索。另外,KRAS G12C抑制剂联合PD-1/PD-L1抑制剂的临床试验正在开展。
3 免疫治疗联合放疗放疗可以通过多种机制增强免疫反应。一方面,放疗通过破坏DNA诱导肿瘤细胞死亡,促进抗原呈递、T细胞募集和活化,上调炎性细胞因子,从而增强抗肿瘤免疫作用。另一方面,放疗可诱导远隔效应,为联合治疗提供了依据[29-31]。一项Ⅱ期试验[32]显示伊匹木单抗和纳武利尤单抗联合放疗治疗MSS mCRC患者,非放疗区域的远处肿瘤缩小,ORR为12.5%。该研究显示了免疫治疗联合放疗用于MSS mCRC患者的潜在可行性,但需要进一步探索免疫治疗和放疗的方案。
4 免疫治疗联合溶瘤病毒溶瘤病毒是一类可以选择性地感染和杀死癌细胞,但不伤害正常细胞的天然或重组病毒。溶瘤病毒在癌细胞内选择性复制,直接溶解肿瘤细胞;诱导系统性抗肿瘤免疫,裂解的肿瘤细胞会释放病毒颗粒,从而激活机体免疫系统。溶瘤病毒药物T-VEC联合帕博利珠单抗治疗黑色素瘤,ORR高达62%,其中33%为完全缓解[33],这一结果大大鼓舞了人们对溶瘤病毒联合免疫治疗的信心。目前正在进行一项关于溶瘤病毒药物Pexa-Vec联合durvalumab治疗MSS mCRC的Ⅰ/Ⅱ期研究,初步分析耐受性良好,但长期疗效尚未见报道[34]。另外溶瘤病毒药物Talimogene laherparepvec联合atezolizumab治疗结直肠癌肝转移患者的一项Ib期试验正在开展。
5 免疫治疗联合双特异性抗体双特异性抗体通过结合富含肿瘤的抗原(如CEA、HER2等)和免疫细胞来激发免疫反应,在不同类型的实体瘤中正在探索其疗效[35],有些双特异性抗体与免疫检查点抑制剂联合使用可增强抗肿瘤活性[36-37]。
CEA在80%的结直肠癌中过表达,其在正常组织低表达,可作为较理想的肿瘤抗原。Cibisatamab是一种T细胞双特异性抗体,可以同时靶向肿瘤细胞上的CEA和T细胞上的CD3。临床前模型中cibisatamab显示出有效的抗肿瘤活性,导致肿瘤内T细胞浸润和活化增加以及PD-1/PD-L1上调[38]。cibisatamab可上调PD-1的表达,那么其与PD-1/PD-L1抑制剂联用可能增强抗肿瘤作用。在体外试验中抗CEA双特异性抗体联合PD-1/PD-L1抑制剂可最大限度地杀灭肿瘤T细胞[39]。在两项正在进行的I期临床研究中,cibisatamab作为单药治疗或与atezolizumab联合治疗表达CEA的实体瘤患者(包括MSS mCRC患者)。在持续剂量递增的情况下,使用cibisatamab单药治疗观察到抗肿瘤活性的证据。与atezolizumab联合使用可增强抗肿瘤活性,具有可控的安全性[40]。
6 总结与展望免疫治疗在mCRC中的应用越来越受到人们的关注。免疫检查点抑制剂已获批用于dMMR/MSI-H mCRC患者的治疗,但在pMMR/MSS mCRC患者中,单药免疫治疗无效,免疫治疗联合其他疗法的多项临床试验正在积极探索中。本文介绍了联合免疫治疗以及免疫治疗联合靶向治疗、放疗、溶瘤病毒、双特异性抗体的研究进展。一些早期的临床试验已经显示了初步的疗效,但是这些数据尚不成熟,还需要进一步验证。随着更多新型的治疗技术和药物(如细胞免疫、肿瘤疫苗、细胞因子等)的成功应用,免疫联合治疗对MSS mCRC的治疗策略有望通过更多的临床试验得到验证。另外,肝转移亚组MSS mCRC可能较少从检查点免疫治疗中获益。进一步寻找更精确的免疫治疗疗效预测的生物标志物(如TMB、ctDNA RAS/BRAF野生型、肠道微生物菌群等),筛选免疫联合治疗的合适人群,寻找出优势亚组具有非常重要的临床意义。
作者贡献:
尹竺晟:文献检索、资料整理及论文撰写
梁新军:论文修改及审校
[1] |
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI:10.3322/caac.21492 |
[2] |
Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study[J]. Lancet Oncol, 2017, 18(9): 1182-1191. DOI:10.1016/S1470-2045(17)30422-9 |
[3] |
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency[J]. N Engl J Med, 2015, 372(26): 2509-2520. DOI:10.1056/NEJMoa1500596 |
[4] |
O'Neil BH, Wallmark JM, Lorente D, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma[J]. PLoS One, 2017, 12(12): e0189848. DOI:10.1371/journal.pone.0189848 |
[5] |
Wang M, Wang S, Desai J, et al. Therapeutic strategies to remodel immunologically cold tumors[J]. Clin Transl Immunology, 2020, 9(12): e1226. |
[6] |
Chen EX, Jonker DJ, Loree J, et al. Effect of Combined Immune Checkpoint Inhibition vs. Best Supportive Care Alone in Patients with Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study[J]. JAMA Oncol, 2020, 6(6): 831-838. DOI:10.1001/jamaoncol.2020.0910 |
[7] |
Garralda E, Sukari A, Lakhani NJ, et al. A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280(favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer[J]. J Clin Oncol, 2021, 39(15 suppl): 3584. |
[8] |
Ou DL, Chen CW, Hsu CL, et al. Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages[J]. J Immunother Cancer, 2021, 9(3): e001657. DOI:10.1136/jitc-2020-001657 |
[9] |
Wu RY, Kong PF, Xia LP, et al. Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma[J]. Clin Cancer Res, 2019, 25(14): 4530-4541. DOI:10.1158/1078-0432.CCR-18-2840 |
[10] |
Fukuoka S, Hara H, Takahashi N, et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603)[J]. J Clin Oncol, 2020, 38(18): 2053-2061. DOI:10.1200/JCO.19.03296 |
[11] |
Cousin S, Cantarel C, Guegan JP, et al. Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, PhaseⅡTrial[J]. Clin Cancer Res, 2021, 27(8): 2139-2147. DOI:10.1158/1078-0432.CCR-20-3416 |
[12] |
Wang F, He MM, Yao YC, et al. Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib/Ⅱ clinical trial and gut microbiome analysis[J]. Cell Rep Med, 2021, 2(9): 100383. DOI:10.1016/j.xcrm.2021.100383 |
[13] |
Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway[J]. PLoS One, 2019, 14(2): e0212513. DOI:10.1371/journal.pone.0212513 |
[14] |
Gomez-Roca CA, Yanez E, Im SA, et al. LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors-Results from the colorectal cancer cohort[J]. J Clin Oncol, 2021, 39(15suppl): 3564. |
[15] |
Wang L, Wei Y, Fang W, et al. Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer[J]. Cell Physiol Biochem, 2017, 44(3): 1038-1050. DOI:10.1159/000485404 |
[16] |
Lee MS, Loehrer PJ, Imanirad I, et al. Phase Ⅱ study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC)[J]. J Clin Oncol, 2021, 39(3 suppl): 7. |
[17] |
Martinelli E, Martini G, Famiglietti V, et al. Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With RAS Wild-type Metastatic Colorectal Cancer: The Phase 2 Single-Arm Clinical CAVE Trial[J]. JAMA Oncol, 2021, 7(10): 1529-1535. DOI:10.1001/jamaoncol.2021.2915 |
[18] |
Limagne E, Euvrard R, Thibaudin M, et al. Accumulation of MDSC and Th17 Cells in Patients with Metastatic Colorectal Cancer Predicts the Efficacy of a FOLFOX-Bevacizumab Drug Treatment Regimen[J]. Cancer Res, 2016, 76(18): 5241-5252. DOI:10.1158/0008-5472.CAN-15-3164 |
[19] |
Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity[J]. Exp Mol Med, 2020, 52(9): 1475-1485. DOI:10.1038/s12276-020-00500-y |
[20] |
Bourhis M, Palle J, Galy-Fauroux I, et al. Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment[J]. Front Immunol, 2021, 12: 616837. DOI:10.3389/fimmu.2021.616837 |
[21] |
Cremolini C, Rossini D, Antoniotti C, et al. LBA20 FOLFOXIRI plus bevacizumab (bev) plus atezolizumab (atezo) versus FOLFOXIRI plus bev as first-line treatment of unresectable metastatic colorectal cancer (mCRC) patients: Results of the phase Ⅱ randomized AtezoTRIBE study by GONO[J]. Ann Oncol, 2021, 32(5 suppl): S1294-S1295. |
[22] |
Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer[J]. Lancet Oncol, 2005, 6(5): 322-327. DOI:10.1016/S1470-2045(05)70168-6 |
[23] |
Kumar S, Principe DR, Singh SK, et al. Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer[J]. Pharmaceuticals (Basel), 2020, 13(1): 9. DOI:10.3390/ph13010009 |
[24] |
Liao W, Overman MJ, Boutin AT, et al. KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer[J]. Cancer Cell, 2019, 3(4): 559-572. e7. |
[25] |
Lal N, White BS, Goussous G, et al. KRAS Mutation and Consensus Molecular Subtypes and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer[J]. Clin Cancer Res, 2018, 24(1): 224-233. DOI:10.1158/1078-0432.CCR-17-1090 |
[26] |
Hirano H, Takashima A, Hamaguchi T, et al. Current status and perspectives of immune checkpoint inhibitors for colorectal cancer[J]. Jpn J Clin Oncol, 2020, 51(1): 10-19. |
[27] |
Lieu CH, Davis SL, Leong S, et al. Results from the safety lead-in for a phase Ⅱ study of pembrolizumab in combination with binimetinib and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC)[J]. J Clin Oncol, 2020, 38(15 suppl): 4031. |
[28] |
Corcoran R, Giannakis M, Allen J, et al. SO-26 Clinical efficacy of combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients[J]. Ann Oncol, 2020, 31(3 suppl): S226-S227. |
[29] |
Rodriguez-Ruiz ME, Rodriguez I, Barbes B, et al. Brachytherapy attains abscopal effects when combined with immunostimulatory monoclonal antibodies[J]. Brachytherapy, 2017, 16(6): 1246-1251. DOI:10.1016/j.brachy.2017.06.012 |
[30] |
Martino DM, Daviaud C, Vanpouille-Box C. Radiotherapy: An immune response modifier for immuno-oncology[J]. Semin Immunol, 2021, 52: 101474. DOI:10.1016/j.smim.2021.101474 |
[31] |
Yu J, Green MD, Li S, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination[J]. Nat Med, 2021, 27(1): 152-164. DOI:10.1038/s41591-020-1131-x |
[32] |
Parikh AR, Clark JW, Wo JYL, et al. A phase Ⅱ study of ipilimumab and nivolumab with radiation in microsatellite stable (MSS) metastatic colorectal adenocarcinoma (mCRC)[J]. J Clin Oncol, 2019, 37(15): 3514. |
[33] |
Ribas A, Dummer R, Puzanov L, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy[J]. Cell, 2017, 107(6): 1109-1119. |
[34] |
Monge C, Xie C, Brar G, et al. A phase Ⅰ/Ⅱ study of JX-594 oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer[J]. Eur J Cancer, 2020, 138(2 suppl): S57-S58. |
[35] |
Labrijn AF, Janmaat ML, Reichert JM, et al. Bispecific antibodies: a mechanistic review of the pipeline[J]. Nat Rev Drug Discov, 2019, 18(8): 585-608. DOI:10.1038/s41573-019-0028-1 |
[36] |
Chang CH, Wang Y, Li R, et al. Combination Therapy with Bispecific Antibodies and PD-1 Blockade Enhances the Antitumor Potency of T Cells[J]. Cancer Res, 2017, 77(19): 5384-5394. DOI:10.1158/0008-5472.CAN-16-3431 |
[37] |
Ma H, Wang H, Sové RJ, et al. Combination therapy with T cell engager and PD-L1 blockade enhances the antitumor potency of T cells as predicted by a QSP model[J]. J Immunother Cancer, 2020, 8(2): e001141. DOI:10.1136/jitc-2020-001141 |
[38] |
Bacac M, Fauti T, Sam J, et al. A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors[J]. Clin Cancer Res, 2016, 22(13): 3286-3297. |
[39] |
Osada T, Patel SP, Hammond SA, et al. CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1[J]. Cancer Immunol Immunother, 2015, 64(6): 677-688. |
[40] |
Tabernero J, Melero I, Ros W, et al. Phase Ia and Ib studies of the novel carcinoembryonic Antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC)[J]. J Clin Oncol, 2017, 35(15 suppl): 3002. |