晚期非小细胞肺癌PD-1/PD-L1单抗治疗临床转化现状

随着对肿瘤免疫逃逸机制研究的不断深入,通过阻断程序性死亡因子1（programmed cell death 1,PD-1）及其配体l （PD-1 ligand,PD-L1）构成的 PD-1/PD-L1 通路,证实了 PD-1/PD-L1 抑制剂在晚期非小细胞肺癌（non small cell lung cancer, NSCLC）患者生存的相关性,以及PD-L1作为疗效预测标志物的价值。在NSCLC的局部晚期维持治疗、二线治疗及部分一线治 疗的临床试验中,PD-1/PD-L1抑制剂治疗均获得了较好的治疗效果;PD-1/PD-L1抑制剂联合放化疗、联合细胞因子与其他免疫 抑制剂及联合细胞外调节蛋白激酶(extracel lular regulated protein kinase,ERK)通路靶向治疗也有一定获益。本文就PD-1/PD-L1 抑制剂用于NSCLC治疗现状及其影响因素作一综述。     

PD-1/PD-L1在胃癌中的研究进展

胃癌是导致癌症患者死亡的主要疾病之一,而现有的治疗手段有限。当前免疫检测点抑制剂在肿瘤的治疗中取得了突破进展,相关研究迅速覆盖到胃癌。针对免疫检查点抗程序性死亡分子1（PD-1）/PD-1配体（PD-L1）抗体的临床研究正在广泛开展。本文对胃癌发生的免疫机制,PD-1/PD-L1表达,抗PD-1/PD-L1抗体早期临床研究及抗PD-1/PD-L1抗体预测疗效的生物标志物的研究进行文献复习。     

PD-1/PD-L1抑制剂为基础的肿瘤免疫治疗疗效标志物的研究进展

目前,肿瘤的治疗手段多种多样,具体的治疗方案根据肿瘤分期、性质及患者自身状态而定。而以PD-1/PD-L1抑制剂为基础的免疫治疗疗法引领肿瘤治疗进入了新时代,在多种实体瘤中都取得了巨大成功。临床实践却发现,并非所有的患者都能从免疫治疗中获益,甚至免疫治疗会导致患者病情出现爆发性进展或假性进展。因此,为实现更精准的治疗,减少患者经济损失,提高免疫抑制剂的有效率,探寻合适的疗效预测标志物来筛选可受益的患者成为了临床重要的研究热点和迫切需求。免疫疗法拥有巨大的应用潜力,筛选其疗效预测标志物对预后分层、辅助诊断、药物选择等方面具有重要的意义。为进一步指导临床,本文就PD-1/PD-L1抑制剂的疗效标志物作出系统综述。     

PD-1/PD-L1抑制剂及其疗效预测标志物在非小细胞肺癌中的研究进展更新

程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)免疫检查点抑制剂的发展为非小细胞肺癌(NSCLC)的治疗提供了新的方向.然而,疗效预测标志物的尚未确定在很大程度上限制了其有效应用.本文对美国食品药品监督管理局(FDA)批准、尚处于试验阶段的PD-1/PD-L1抑制剂的相关临床试验进行了综述.事实上,目前仅有约20％的晚期NSCLC患者可以从PD-1/PD-L1抑制剂中获益.多数临床试验将患者的PD-L1表达水平作为疗效预测标志物,但其预测价值不尽相同,本文亦对其临床应用局限性的原因进行了讨论.随着肿瘤突变负荷、肿瘤免疫微环境等新兴标志物的出现,将其与PD-L1表达相结合,指导PD-1/PD-L1抑制剂有效的个体化应用正逐渐成为新的研究方向.     

PD-1/PD-L1抑制剂的困境与sPD-1/sPD-L1的标志物潜能

PD-1和PD-L1免疫检查点抑制剂是肿瘤治疗的又一个里程碑,但缺乏灵敏度和特异度高的标志物来筛选对免疫检查点抑制剂敏感的患者,导致在部分癌种和患者中有效率低;而且由于毒副作用和耐药性的存在,进一步限制了其临床应用。可溶性PD-1(sPD-1)和可溶性PD-L1(sPD-L1)是PD-1和PD-L1的溶解形式,已在多种肿瘤中被证实与肿瘤的临床病理特征、分期、疾病的严重程度、治疗敏感性及预后密切相关,可能成为免疫治疗的标志物。全文就PD-1/PD-L1抑制剂的作用机制和其在临床应用中的困境及sPD-1和sPD-L1的标志物潜能进行综述。     

肿瘤免疫治疗PD-1/PD-L1靶向核素分子探针的研究进展

PD-1/PD-L1免疫治疗已成为继放化疗以外治疗多种难治性、复发性肿瘤的一种重要方法,但只有部分患者从中获益。PD-1/PD-L1靶向核素分子探针核医学显像可以无创、实时、重复地进行全身(包括肿瘤及其他组织中)的PD-1/PD-L1表达水平的活体检测,便于:(1)帮助临床筛选获益患者;(2)免疫治疗的疗效评价;(3)动态监测PD-1/PD-L1在治疗过程中的变化,为治疗方案调整提供有力依据。本文将对PD-1/PD-L1靶向核素分子探针的临床前及临床转化研究进行综述,以期为肿瘤免疫治疗的临床应用及进一步研究提供参考。     

MMR/MSI在结直肠癌抗PD-1/PD-L1免疫检查点治疗中的作用

摘 要：随着免疫检测点抑制剂类药物研究的深入,研究发现抗PD-1/PD-L1 抑制剂仅在部分患者中获得良好的疗效,寻找可靠的生物标记以区别出可获益的人群是免疫治疗能否更好应用于临床的关键。抗 PD-1/PD-L1 免疫治疗的潜在预测标志物是从肿瘤细胞、免疫细胞以及各种细胞因子的生物学特性和彼此之间相互作用中寻找,目前研究最多的有PD-L2、TILs、IFN-γ、BIM、免疫评分、体细胞基因突变的负荷和MMR基因缺失等。全文就MMR基因缺失在结直肠癌抗PD-1/PD-L1 免疫治疗疗效预测中作用作一综述。     

PD-L1和sPD-L1作为肝癌免疫治疗标志物的研究进展

肝细胞癌（HCC）是最常见的肝脏原发性肿瘤。研究显示免疫治疗可使更多的HCC患者受益,PD-1/PD-L1检查点抑制剂是癌症免疫治疗中最有前景的治疗策略。然而仍只有少数HCC患者从中受益,因此选择生物标记物来指导个性化抗PD-1的治疗使更多的患者受益尤为重要。PD-L1是PD-1的主要配体,sPD-L1是由PD-L1蛋白膜裂解释放,同样可与PD-1受体结合。PD-L1与sPD-L1已被证实在多种肿瘤中可作为预后标志物。而这两者在HCC患者中的表达及其预后价值仍有争议,本文将阐述PD-L1与sPD-L1在HCC患者中研究进展。     

PD-1/PD-L1信号通路抑制剂在宫颈癌治疗中的研究进展

程序性死亡配体1（PD-L1）是一种免疫抑制性共刺激分子,其与程序性死亡受体1（PD-1）结合可以抑制T细胞增殖分化并导致T细胞凋亡。多种肿瘤细胞通过大量表达PD-L1使肿瘤细胞逃避免疫系统的监视与攻击。PD-1/PD-L1信号通路抑制剂作为免疫疗法中的一个重要方法正在被进行广泛的研究,与现有疗法相比,以PD-1/PD-L1信号通路抑制剂为代表的免疫疗法在癌症治疗中表现出良好的疗效和较少不良反应,但也存在不检查生物标志物直接进行无差别治疗时响应率不高等问题。本文就PD-1/PD-L1信号通路抑制剂与宫颈癌治疗的研究进展加以综述。     

生物标志物在阻断PD-1/PD-L1通路治疗肿瘤中的预测性作用

确定预测PD-1/PD-L1通路阻断治疗临床反应的生物标志物有助于患者筛查和个体化治疗.研究证明治疗前肿瘤组织中肿瘤细胞和肿瘤浸润淋巴细胞PD-L1的高表达,肿瘤间CD8+T细胞的大量浸润以及肿瘤细胞基因高突变负荷的患者阻断PD-1/PD-L1通路治疗的临床疗效更明显,这些生物标志物有望成为筛查肿瘤患者的指标.     

HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression

The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies. Despite the identification of the epigenetical silencing of the NY-ESO1 gene in a large variety of tumors, the molecular mechanism involved in this phenomenon is not fully elucidated. In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes. Thus, our data illustrate the orchestration of a sequential epigenetic mechanism including the histone deacetylation and methylation, and the DNA methylation processes.     

CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility

BACKGROUND: In estrogen biosynthetic pathways, many enzymes are important for metabolism, detoxification, and bioavailability. Polymorphisms in these genes may have an effect on the enzymes' function. For example, higher expression and activation of biosynthetic enzymes and lower expression and activation of conjugation enzymes may lead to high toxicity or carcinogenesis. The authors hypothesized that single nucleotide polymorphisms (single nucleotide polymorphisms) of CYP1A1, CYP1A2, CYP1B1, CYP17, SULT1A1, SULT1E1, and SHBG genes may be risk factors for endometrial cancer. METHODS: DNA samples from 150 cases of endometrial cancer and healthy controls (n = 165) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypic frequency of 13 different polymorphic loci on the CYP1A1 (m1, m2, m3, m4), CYP1A2 1F, CYP1B1 codon432, COMT codon158, CYP17, SULT1A1 (Arg213His, 14A/G, 85C/T in the 3' flanking region), SULT1E1-64G/A promoter region, and SHBG genes. Genotyping was validated by direct DNA sequencing. The authors also investigated the relation between expression of CYP1A1 in endometrial cancer tissues and genotypes of CYP1A1 m1. RESULTS: A decreased frequency of TC + CC genotype of the CYP1A1 m1 (T/C) polymorphism was observed in endometrial cancer patients compared with controls (OR = 0.42; 95% CI, 0.27-0.69). The T-A haplotype of CYP1A1 m1 and m2 was increased in endometrial cancer patients (P = .017). The frequency of CYP1A1 m1 T/C + C/C was higher in a high CYP1A1 expression group (P = .009). The authors also found that individuals carrying the variants of SULT1A1 codon213 and 2 single nucleotide polymorphisms in the 3' flanking region (14A/G and 85C/T) had an increased risk for endometrial cancer. The frequencies of G-A-C and A-G-T haplotypes of these 3 variants were higher in endometrial cancer patients (P < .0001; P = .0002). In addition, the frequency of combined genotypes (SULT1A1 213 GA + AA and CYP1A1 m1 TT) was higher in endometrial cancer patients. (OR, 4.58; 95% CI, 2.35-8.93). CONCLUSIONS: This is the first report on the combined association of CYP1A1 and SULT gene polymorphisms in endometrial cancer that suggests a decreased single nucleotide polymorphism of CYP1A1 and an increased single nucleotide polymorphism for SULT1A1 and SULT1E1 genes may be risk factors for endometrial cancer in Caucasians.     

CYP1A1.

CYP1A1 plays an important role in the metabolism of polycyclic hydrocarbons that occur in the environment and several studies suggest that the genetic polymorphism of the gene may play a role in the predisposition to cancer. In order to evaluate the function of CYP1A1 in vivo as a host factor determinant of environmentally-caused cancers in humans, additional investigations are needed involving not only molecular epidemiological approaches in different ethnic populations but also more direct approaches such as the use of gene-targeted mice as a model system.     

DNA切除修复交叉互补基因1、乳腺癌易感基因、核苷酸还原酶1与非小细胞肺癌

 阐述了近年来非小细胞肺癌（NSCLC）化疗敏感性与DNA 切除修复交叉互补基因1 （ERCC1）、乳腺癌易感基因（BRCA1）、核苷酸还原酶1（RRM1）基因表达关系的研究进展，分析3个基因对NSCLC个体化化疗潜在的指导意义     

Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1

Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) catalyze the oxidative metabolism of 17 beta-estradiol (E2) to catechol estrogens (2-OHE2 and 4-OHE2) and estrogen quinones, which may lead to DNA damage. Catechol-O-methyltransferase catalyzes the methylation of catechol estrogens to methoxyestrogens (2-MeOE2, 2-OH-3-MeOE2, and 4-MeOE2), which simultaneously lowers the potential for DNA damage and increases the concentration of 2-MeOE2, an antiproliferative metabolite. In this study, we showed that CYP1A1 and CYP1B1 recognized as substrates both the parent hormone E2 and the methoxyestrogens. Using purified recombinant enzymes, we demonstrated that CYP1A1 and CYP1B1 O-demethylated the methoxyestrogens to catechol estrogens according to Michaelis-Menten kinetics. Both CYP1A1 and CYP1B1 demethylated 2-MeOE2 and 2-OH-3-MeOE2 to 2-OHE2, whereas CYP1B1 additionally demethylated 4-MeOE2 to 4-OHE2. Because the P450-mediated oxidation of E2 and the O-demethylation of methoxyestrogens both yielded identical catechol estrogens as products, we used deuterated E2 (E2-d4), unlabeled methoxyestrogens, and gas chromatography/mass spectrometry to examine both reactions simultaneously. Kinetic analysis revealed that methoxyestrogens acted as noncompetitive inhibitors of E2 oxidation with K(i) ranging from 27 to 153 micro M. For both enzymes, the order of inhibition by methoxyestrogens was 2-OH-3-MeOE2 > or = 2-MeOE2 > 4-MeOE2. Thus, methoxyestrogens exert feedback inhibition on CYP1A1- and CYP1B1-mediated oxidative estrogen metabolism, thereby reducing the potential for estrogen-induced DNA damage.     

CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure

Certain human biotransformation enzymes have been implicated in the formation and scavenging of the ultimate reactive metabolites, the diolepoxides, from polycyclic aromatic hydrocarbons (PAHs). In the present study, performed on aluminum smelter workers, we have analyzed airborne PAH, the pyrene metabolite 1-hydroxypyrene (1-OHP) in urine, and genotypes for biotransformation enzymes involved in PAH metabolism. The aim was to evaluate the correlation between external exposure and biomarkers of exposure and to investigate to what extent genetic polymorphism in metabolic enzymes can explain interindividual variation in urinary 1-OHP levels. DNA was prepared from blood samples from 98 potroom workers and 55 controls and altogether eight polymorphisms in the CYP1A1, mEH, GSTM1, GSTP1 and GSTT1 genes were analyzed. The 1-OHP excretion was found to correlate significantly (P 100-fold) and univariate and multivariate regression analyses were used to find the variables that could determine differences in excretion. The variation could, to some degree, be explained by differences in exposure to airborne particulate-associated PAHs, the use of personal respiratory protection devices, smoking habits and genetic polymorphisms in the cytochrome P450 1A1, GSTM1 and GSTT1 enzymes. The part of the variance that could be explained by differences in biotransformation genotypes seemed to be of the same order of magnitude as the variance explained by differences in exposure. In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype. The results show that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that it may also to some extent reflect the interindividual variation in susceptibility to PAHs.     

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age < or =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.