微卫星稳定型结直肠癌免疫检查点抑制剂疗效预测标志物研究进展

寻找微卫星稳定型结直肠癌免疫检查点抑制剂疗效预测标志物能够使更多的患者从免疫治疗中获益。肿瘤突变负荷（TMB）、POLE/POLD1突变、CMS分型、MGMT甲基化等多个指标具有对微卫星稳定型结直肠癌免疫检查点抑制剂疗效进行预测的潜能和价值。本文通过对微卫星稳定型结直肠癌免疫检查点抑制剂疗效预测标志物的相关研究进行综述,以期为寻找微卫星稳定型结直肠癌患者的最佳治疗策略提供参考。     

免疫检查点抑制剂治疗结直肠癌生物标志物的研究进展

免疫检查点抑制剂（immune checkpoint inhibitors，ICI）在多种晚期实体瘤治疗中取得了较好的临床疗效，其中包括结直肠癌。但是大多数的肿瘤患者对ICI的客观反应率（objective response rate，ORR）不理想，易发生治疗耐药性，甚至出现超进展现象。寻找预测免疫治疗疗效的生物标志物，筛选出合适的人群至关重要。目前有多种生物标志物在预测ICI治疗结直肠癌疗效显示出指导价值，但最优的标志物仍未确定，需要进一步的大规模前瞻性研究证实潜在标志物的价值。本文将对免疫检查点抑制剂治疗结直肠癌的正性和负性生物标志物的研究进展进行综述。      

结直肠癌免疫检查点治疗的研究进展

目前免疫治疗正在非小细胞肺癌、黑色素瘤、膀胱癌等各个瘤种中如火如荼地开展,其治疗方法也多种多样,包括肿瘤疫苗治疗、过继性T细胞疗法、免疫检查点抑制剂治疗等,但目前结直肠癌免疫治疗主要集中于免疫检查点抑制剂(PD-1/PD-L1及CTLA-4抑制剂等).自从PD-1/PD-L1抑制剂在dMMR/MSI-H晚期结直肠癌患者...     

免疫检查点抑制剂在结直肠癌中的研究进展CSCD

免疫治疗是当前实体肿瘤治疗研究的新方向,而在免疫系统中发挥负性调节分子的免疫检查点在限制抗肿瘤免疫反应中起着关键作用。针对PD-1及PD-L1、CTLA-4的免疫检查点抑制剂已被开发为抗肿瘤药物进行临床研究,dMMR/MSI-H型结直肠癌对免疫检查点抑制剂具有客观反应。本文基于结直肠癌免疫分型,对免疫检查点抑制剂在结直肠癌中的治疗方案进行综述。     

结直肠癌免疫检查点抑制剂治疗相关预测性标志物的研究进展

以免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）为代表的免疫疗法开辟了肿瘤治疗的新纪元。目前ICIs已经广泛应用于晚期转移性结直肠癌患者的治疗。预测性标志物是精确筛选可从ICIs治疗中受益的患者群体的重要工具。本文回顾并总结了目前ICIs治疗结直肠癌重要的预测性标志物及其研究现状,包括错配修复缺陷及微卫星不稳定性、肿瘤突变负荷、DNA聚合酶ε/DNA聚合酶δ1以及PD-L1表达等。通过了解这些标志物对于结直肠癌ICIs治疗的响应及患者预后的预测价值,有助于指导临床医生筛选潜在获益人群,提高治疗效率,实现精准化治疗。     

免疫检查点抑制剂治疗晚期结直肠癌的疗效观察

目的:观察及评价免疫治疗在转移性结直肠癌中的疗效及不良反应。方法:对23例接受免疫联合化疗治疗的微卫星高度不稳定（MSI-H）的转移性结直肠癌患者进行临床观察。患者每3周接受一次帕博利珠单抗200 mg,持续1年,直至进展、不可接受的毒性或停药,联合化疗方案为FOLFIRI或FOLFOX4。影像学评估每9周进行一次,为期12个月。主要观察终点是客观缓解率,次要终点为无进展生存期（progression-free survival,PFS）、总生存期（overall survival,OS）、安全性和耐受性。结果:本组部分缓解5例,病情稳定13例,疾病进展5例,客观缓解率21.7%,疾病控制率78.3%。Ⅰ/Ⅱ级不良反应事件有7例疲劳,4例ALT升高,3例皮疹,2例内分泌异常,腹泻和肺炎各1例。Ⅲ级不良反应事件仅有内分泌异常1例,无Ⅳ级不良反应事件。结论:免疫检查点抑制剂治疗MSI-H转移性结直肠癌患者有一定的疗效,且安全性良好。     

MSS型结直肠癌免疫联合治疗研究进展

近年来,免疫治疗在恶性肿瘤治疗方面取得了很大的进展,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,免疫检查点抑制剂治疗对DNA错配修复缺陷（dMMR）/高微卫星不稳定性（MSI-H）转移性结直肠癌（mCRC）患者有显著临床获益,但约95%mCRC患者是错配修复完整（pMMR）/微卫星稳定（MSS）型,这类患者对单药免疫治疗的反应差,如何提高该类患者的免疫治疗疗效一直备受关注。本文就MSS型mCRC的免疫联合治疗研究进展进行综述。     

免疫检查点抑制剂联合治疗在微卫星稳定型结直肠癌治疗中的研究进展

结直肠癌是消化系统最常见的恶性肿瘤,发病率在肿瘤中排第3位,死亡率排第2位,对患者的生存期和生活质量造成了严重威胁。免疫检查点抑制剂(ICIs)已成为错配修复缺陷或微卫星高度不稳定(MSI-H/d MMR)结直肠癌的一线及后线治疗方案的重要组成,然而,MSI-H/d MMR结直肠癌仅占所有转移性结直肠癌的4%～5%,且对于微卫星稳定型(MSS)结直肠癌患者,由于肿瘤的异质性和复杂的免疫异质性肿瘤微环境,ICIs单药往往无法克服这些因子而出现应答率不高或出现继发性耐药,因此仅使用单一ICIs基本无效。目前多采用联合治疗策略如抗程序性死亡蛋白受体-1(PD-1)和细胞毒性T淋巴细胞相关蛋白4(CTLA-4)的联合治疗,ICIs联合放疗,ICIs联合细胞外信号调节激酶(MEK)抑制剂和血管内皮生长因子(VEGF)抑制剂,以及ICIs联合溶瘤病毒等提高MSS/错配修复功能完整(pMMR)结直肠癌患者对治疗的应答率。虽然上述联合治疗策略取得不错的近期疗效,在治疗转移性结直肠癌(mCRC)患者中很有前景,但多为单臂小样本探索性研究,数据指向并不完全稳定一致,安全性和有效性还需更多大样本的前瞻性临床...     

结直肠癌中的微卫生不稳定现象

微卫星不稳定DNA标记目前已被广泛用于基因作图的遗传标记、遗传疾病致病基因的连锁分析及基因位点缺失或杂合性缺失的研究。因微卫星不稳定高频型结直肠癌有其特殊的临床特征，因此微卫星不稳定现象对临床有重要的指导意义。对微卫星不稳定现象可能的原因、微卫星不稳定高频型结直肠癌的临床特征及微卫星不稳定现象与抑癌基因的关系作一简单综述。     

Homologous recombination repair gene mutations in colorectal cancer favors treatment of immune checkpoint inhibitors

Immune checkpoint inhibitor (ICI) therapy is insensitive for Colorectal cancer (CRC) patients with microsatellite stable (MSS). Genomic data of three CRC cohort, n = 35), and the Cancer Genome Atlas (TCGA CRC cohort, n = 377), were analyzed. A cohort treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC CRC cohort, n = 110) and two cases from the local hospital were characterized the impact of the HRR mutation on prognosis of CRC. Homologous recombination repair (HRR) gene mutations were more common in CN and HL cohorts (27.85%; 48.57%) than in TCGA CRC cohort (15.92%), especially in the MSS populations, the frequencies of HRR mutation were higher in CN and HL cohort (27.45%, 51.72%) than in TCGA cohort (6.85%). HRR mutations were associated with high tumor mutational burden (TMB-H). Although HRR mutation uncorrelated with an improved overall survival in the MSKCC CRC cohort (p = 0.97), HRR mutated patients had a significantly improved OS compared to the HRR wildtype population particularly in MSS subgroups (p = 0.0407) under ICI treatment. It probably contributed by a higher neoantigen and increased CD4⁺ T cell infiltration which found in the TCGA MSS HRR mutated CRC cohort. The similar phenomenon on cases was observed that MSS metastatic CRC patient with HRR mutation seemed more sensitive to ICI after multi-line chemotherapy in clinical practice than HRR wildtype. This finding suggests the feasibility of HRR mutation as an immunotherapy response predictor in MSS CRC, which highlights a potential therapeutic approach for these patients.     

Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer

Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.     

Complete pathological response after chemotherapy or immune checkpoint inhibitors in deficient MMR metastatic colorectal cancer: Results of a retrospective multicenter study

About 5% of the patients with metastatic colorectal cancers (mCRC) present microsatellite instability (MSI)/deficient mismatch repair system (dMMR). While metastasectomy is known to improve overall and progression-free survival in mCRC, specific results in selected patients with dMMR/MSI mCRC are lacking. Our study aimed to describe metastasectomy results, characterize histological response and evaluate pathological complete response (pCR) rate in patients with dMMR/MSI mCRC. We retrospectively reviewed data from all consecutive patients with dMMR/MSI mCRC who underwent surgical metastasectomy between January 2010 and June 2021 in 17 French centers. Primary outcome was to assess the pCR rate defined by tumor regression grade (TRG) 0. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), and explored TRG as predictive factor for RFS and OS. Among the 88 patients operated, 109 metastasectomies were performed in 81 patients after neoadjuvant treatment [chemotherapy ± targeted therapy (CTT): 69, 85.2%; immunotherapy (ICI): 12, 14.8%], and pCR was achieved in 13 (16.1%) patients. Among the latter, pCR rate were 10.2% in the patients having received CTT (N = 7) and 50.0% in the patients treated with ICI (N = 6). Radiological response did not predict TRG. With a median follow-up of 57.9 (IQR 34.2-81.6) months, median RFS was 20.2 (15.4-not reached) months, median OS was not reached. Major pathological responses (TRG0 + TRG1) were significantly associated with longer RFS (HR 0.12, 95% CI 0.03-0.55; P = .006). The pCR rate of 16.1% achieved with neoadjuvant treatment in patients with dMMR/MSI mCRC is consistent with previously reported rates in pMMR/MSS mCRC. Immunotherapy showed better pCR rate than chemotherapy ± targeted therapy. Further prospective trials are needed to validate immunotherapy as neoadjuvant treatment in resectable/potentially resectable dMMR/MSI mCRC and identify predictive factors for pCR.     

免疫检查点抑制剂的联合治疗在胰腺癌中的研究进展

胰腺癌的恶性程度极高,发现时通常已至晚期,中位生存时间极短,严重威胁人类生命健康.并且与其他癌种相比,近些年取得的治疗进展也十分有限.免疫检查点抑制剂(Immune checkpoint inhibitors,ICIs)作为近几年的新兴药物已在多个肿瘤中获得了令人振奋的治疗效果,但是在胰腺癌中却遭遇了滑铁卢.胰腺癌对I...     

西妥昔单抗联合FOLFOX 4方案一线治疗转移性结直肠癌的临床观察

目的 观察西妥昔单抗联合FOLFOX 4方案一线治疗转移性结直肠癌的临床疗效和毒副反应。方法 回顾性分析2008年4月至2011年10月经组织病理学证实的转移性结直肠癌患者36例,其中治疗组（n=18）采用西妥昔单抗（500mg／m2 静滴120min,每周1次,使用6～12次）联合FOLFOX 4方案（奥沙利铂85mg／m2静滴2h,d1;左亚叶酸钙200mg／m2静滴2h,d1、d2;氟尿嘧啶400mg／m2静滴,d1、d2;氟尿嘧啶600mg／m2持续静脉泵入22h,d1、d2。14天为1周期,化疗不超过12个周期。）治疗。对照组（n=18）仅用FOLFOX 4方案化疗,同治疗组。结果 治疗组与对照组的客观缓解率分别为66.7％和22.2％（P＜0.05）,疾病控制率分别为94.4％和67.7％（P＞0.05）。治疗组和对照组痤疮样皮疹发生率分别为389％和0,其他不良反应包括骨髓抑制、恶心呕吐、神经毒性、肝脏损害及脱发等,差异均无统计学意义（P＞0.05）。结论 西妥昔单抗联合FOLFOX 4方案治疗转移性结直肠癌的近期疗效显著,毒副反应可耐受。     

Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors

Colorectal cancer (CRC) represents the third cause of cancer-related mortalities worldwide. The progression of CRC to the metastatic phase significantly compromises the overall survival rates. Despite the advances in the therapeutic protocols, CRC treatment is still challenging. Cancer immunotherapy joined the ranks of surgery, chemotherapy, radiotherapy and targeted therapy as the fifth pillar in the foundation of cancer therapeutics. Interruption of the immunosuppressive signals within the tumor microenvironment and reactivation of antitumor immunity via targeting the molecular immune checkpoints generated promising therapeutic outcomes in several types of hard-to-treat cancers. The year 2017 witnessed the first US Food and Drug Administration (FDA) approval of immune checkpoint inhibitor (ICI) immunotherapy for the management of CRC. The approval was granted to pembrolizumab (anti-PD-1) for the treatment of patients with advanced/metastatic solid malignancies with mismatch-repair deficiency including CRCs. Such natively immunogenic tumors constitute only a minor percentage of all CRCs. Therefore, it is imperative to utilize novel combinatorial regimens to enhance the response of a wider range of CRC tumors to cancer immunotherapy and help in extending the survival rates in patients with advanced/metastatic disease. This review highlights the novel approaches under clinical development to overcome the resistance of CRCs to immunotherapy and improve the therapeutic outcomes.     

How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation

Immunotherapy, especially with immune checkpoint inhibitors (ICIs), has shown advantages in cancer treatment and is a new hope for patients who have failed multiline therapy. However, in colorectal cancer (CRC), the benefit is limited to a small subset of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic CRC (mCRC). In addition, 45% to 60% of dMMR/MSI-H mCRC patients showed primary or acquired resistance to ICIs. This means that these patients may have potential unknown pathways mediating immune escape. Almost all mismatch repair-proficient (pMMR) or microsatellite-stable (MSS) mCRC patients do not benefit from ICIs. In this review, we discuss the mechanisms of action of ICIs and their current status in CRC. We then discuss the mechanisms of primary and acquired resistance to ICIs in CRC. Finally, we discuss promising therapeutic strategies to overcome resistance to ICIs in the clinic.     

An overview of the toxicities of checkpoint inhibitors in older patients with cancer

Checkpoint inhibitors offer an exciting new option for treatment of a wide variety of cancers. By binding to surface receptors or their associated ligands on T cells, this class of drugs enhances immune activation and response to cancer cells. In available studies, the drugs are well tolerated, although toxicity involving skin, gastrointestinal tract, liver, lungs, and endocrine organs has been observed. Unfortunately, few studies to date have included patients older than 70?years of age. Since aging has been linked to changes in immune function, there are theoretical concerns that this patient population might experience a different profile of adverse events. This article reviews the tolerability of checkpoint inhibitors in older patients with cancer in clinical practice.