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| 1 | 帕博利珠单抗单用或与放疗联用治疗转移性非小细胞肺癌:两个随机试验的汇总分析显示文摘背景放疗可以提高整个机体对免疫治疗的应答。在Ⅱ期PEMBRO-RT研究和Ⅰ/Ⅱ期MDACC研究中,患有转移性非小细胞肺癌(NSCLC)的患者被随机分配入组,接受免疫治疗(帕博利珠单抗)+放疗联合疗法,或免疫治疗单一疗法。当上述2个研究单独分析时,联合疗法组显示出潜在获益。由于每个研究的样本量较小,缓解率和结局并未显示出统计学意义,然而却有显著的临床获益。因此,本研究进行汇总分析,来判断放疗是否会改善转移性NSCLC患者的免疫治疗应答。方法PEMBRO-RT和MDACC研究纳入标准:患者年龄≥18岁,患有转移性NSCLC,且有≥1处未经放疗照射的病灶,以便进行射野外应答监测。PEMBRO-RT研究纳入曾接受过化疗患者,MDACC研究纳入曾接受过治疗或新诊断患者。2个研究中的患者均未接受过免疫治疗。在PEMBRO-RT研究中患者被等比例随机分配入组,并根据吸烟状态进行分层(分为<10年组和≥10年组)。MDACC研究的患者根据放疗计划可行性被等比例随机分配入2个受试组。由于联合治疗组的干预本质,每个研究中的放疗均不适用盲法。在2个研究中,不论是否进行放疗,均静脉滴入帕博利珠单抗(每3周200 mg)。在PEMBRO-RT研究中,在放疗(24 Gy 3次分割照射)结束后1周给予第1剂帕博利珠单抗。在MDACC研究中,在第1次放疗(50 Gy 4次分割照射或45 Gy 15次分割照射)同时给予帕博利珠单抗。仅检测未经照射病灶的应答。本研究的终点为最佳射野外(远隔)应答率(ARR)、最佳射野外疾病控制率(ACR)、12周时ARR、12周时ACR、无进展生存期(PFS)和总生存期(OS)。2个研究的意向治疗(ITT)人群均纳入分析。PEMBRO-RT研究(NCT02492568)和MDACC研究(NCT02444741)均在ClinicalTrials.gov上注册。发现纳入148例患者,76例接受帕博利珠单抗治疗,72例接受帕博利珠单抗+放疗治疗。所有患者随访时间中位数为33个月[四分位距(IQR):32.4~33.6]。148例患者中124例(84%)组织学特征为非鳞癌,111例(75%)患者曾经接受过化疗。组间没有基线特征差异,包括PD-L1表达状态和转移灶体积。最常见的照射部位为肺转移灶(39%,28/72)、胸腔内淋巴结(21%,15/72)和非原发灶(17%,12/72)。帕博利珠单抗组和联合治疗组的最佳ARR分别为19.7%(15/76)和41.7%(30/72),OR=2.96,95%CI:1.42~6.20,P=0.0039;最佳ACR分别为43.4%(33/76)和65.3%(47/72),OR=2.51,95%CI:1.28~4.91,P=0.0071;PFS中位数分别为4.4(IQR:2.9~5.9)和9.0个月(IQR:6.8~11.2),HR=0.67,95%CI:0.45~0.99,P=0.045;OS中位数分别为8.7(IQR:6.4~11.0)和19.2个月(IQR:14.6~23.8),OR=0.67,95%CI:0.54~0.84,P=0.0004。在汇总分析中没有发现新的安全问题。解读帕博利珠单抗免疫疗法+放疗显著提高转移性NSCLC患者的应答和改善治疗结局。这些结果需要在三期临床试验中进行验证。 | 陈大卫(翻译) 于金明(校对) Willemijn S M E Theelen Vivek Verma Brian P Hobbs Heike M U Peulen Joachim G J V Aerts Idris Bahce Anna Larissa N Niemeijer Joe Y Chang Patricia M de Groot Quynh-Nhu Nguyen Nathan I Comeaux George R Simon Ferdinandos Skoulidis Steven H Lin Kewen He Roshal Patel John Heymach Paul Baas James W Welsh | 2021 | 中华肿瘤防治杂志2021，28，24： | 49 |
| 2 | Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse显示文摘Hyaluronan(HA)production by dendritic cells(DCs)is known to promote antigen presentation and to augment T-cell activation and proliferation.We hypothesized that pericellular HA can function as intercellular‘glue’directly mediating T cell–DC binding.Using primary human cells,we observed HA-dependent binding between T cells and DCs,which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone(4-MU),an agent which blocks HA synthesis.Furthermore,T cells regulate HA production by DCs via T cell-derived cytokines in a T helper(Th)subset-specific manner,as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production.Similar effects were seen upon the addition of exogenous Th1 cytokines,IL-2,interferon c(IFN-c)and tumor necrosis factor a(TNF-a).The critical factors which determined the extent of DC–T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA,as T-cell clones which were pre-treated with monensin,added to block cytokine secretion,bound equivalently irrespective of their Th subset.These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA,which in turn affects the extent of DC–T cell binding.We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation.These data point to a pivotal role for HA in DC–T cell interactions at the IS. | Paul L Bollyky Stephen P Evanko Rebecca P Wu Susan Potter-Perigo S Alice Long Brian Kinsella Helena Reijonen Kelly Guebtner Brandon Teng Christina K Chan Kathy R Braun John A Gebe Gerald T Nepom Thomas N Wight | 2010 | Cellular & Molecular Immunology2010，7，3： | 3 |
| 3 | The effect ofGibbs adsorption on Marangoni instability in penetration mass transfer显示文摘 | Brian P L T Ross J R | 1972 | AIChE J1972，18，： | 1 |
| 4 | Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus 显示文摘 | Baltz R H Brian P Miao V | 2006 | J Ind Microbiol Biotechnol2006，33，： | 1 |
| 5 | Simultaneous inversion of pre-stack seismic data 显示文摘 | Hampson D P Brian H R Brad P B | 2005 | Expanded Abstracts of 75th Annual Internat SEG Mtg2005，，： | 1 |
| 6 | Modelling an infrared man portable air defence system显示文摘 | Birchenall R P Richardson M A Brian B | 2010 | Infrared Physics & Technology2010，53，5： | 1 |
| 7 | Transients in sheared granular matter显示文摘 | Brian Utter R P Behringer | 2004 | Eur Phys J E2004，14，： | 1 |
| 8 | Interactive seismic facies classi- fication using textural attributes and neural networks 显示文摘 | Brian P W Steve R M John E E | 2002 | The Leading Edge2002，21，10： | 1 |
| 9 | Convenient synthesis of 4-amino-3,5-disubstituted pyrazoles in one-step from the corresponding diketo oximes显示文摘 | Tahir M Corey R H Brian P | 2004 | Tetrahedron Lett2004，45，： | 1 |
| 10 | Acyl homoserine-lactone quorum-sensing signal generation 显示文摘 | Matthew R P Dale L V Brian L H | 1999 | Prog Natl Acad Sci USA1999，96，： | 1 |
| 11 | A metal-free organic-inorganic aqueous flow battery显示文摘 | Huskinson Brian Marshak Michael P Suh Changwon Er Süleyman Gerhardt Michael R Galvin Cooper J Chen Xudong Aspuru-Guzik Alán Gordon Roy G Aziz Michael J | 2014 | Nature2014，505，7482： | 1 |
| 12 | Storm-water treatment goes underground显示文摘 | BRIAN R P E | 1996 | Civil Engineering-ASCE1996，66，7： | 1 |
| 13 | Light gap disturbance,recruitment limitation,and tree diversity in a neotropical forest显示文摘 | Hubbell S P Foster R B O'Brian S T Harms K E Condit R Wechsler B Wright S J Loo de Lao S | | 0，，： | 1 |
| 14 | Optical Properties of Tm^3+ Ions in Alkali Germanate Glass显示文摘 | Brian M W Norman P B Donald J R | 2006 | Journal of Non-Crystalline Solids2006，352，： | 1 |
| 15 | Syneresis crack:subaqueous shrinkage in argillaceous sediments caused by earthquake-induced dewatering显示文摘 | BRIAN R P | 1998 | Sedimentary Geology1998，117，： | 1 |
| 16 | Frost deposition on cold surfaces显示文摘 | Brian P L T Reid R C Shah Y T | 1970 | Industrial Engineering Chemistry Fundamentals1970，9，3： | 1 |
| 17 | Septarian concretions:internal cracking caused by synsedimentary earthquakes显示文摘 | BRIAN R P | 2001 | Sedimentology2001，48，： | 1 |
| 18 | Temperature modulation in semiconductor gas sensing显示文摘 | Andrew P L Brian J R | | 0，，： | 1 |
| 19 | Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus显示文摘 | Baltz R H Brian P Miao V | | 0，，02： | 1 |
| 20 | Evaluation of ultraviolet light-emitting diodes for detection of atmospheric NO by photolysis-chemiluminescence显示文摘 | IIana B P Brian M L Thomas B R | 2010 | Journal of Atmospheric Chemistry2010，65，2： | 1 |
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