Advanced Skin Squamous Cell Carcinoma

摘要：近年来，免疫疗法在乳腺癌（BC）治疗中显示出鼓舞人心的结果。程序性细胞死亡配体1（PD-L1）跨膜蛋白被认为是免疫反应中的共抑制因子，它与程序性细胞死亡蛋白1（PD-1）合作，刺激凋亡，抑制PD-1阳性细胞释放细胞因子，并限制PD-1阳性细胞的生长。此外，在许多恶性肿瘤中，PD-L1降低了免疫系统对肿瘤细胞的反应。这些观察结果表明，PD-1/PD-L1轴在癌症治疗和调节癌症免疫逃逸机制中发挥着重要作用。本综述旨在概述PD-1和PD-L1在BC癌症治疗中的功能。方法：本研究设计为文献综述。风格是关于PD-1/PD-L1通路相关主题或变量的传统综述。使用三个在线数据库进行了文献搜索。结果：使用关键词进行搜索，共得到248项研究。根据纳入和排除标准再次筛选每个结果，最终共有4项研究纳入文献综述。结论：PD-1/PD-L1的结合对许多恶性肿瘤至关重要。根据所提供的证据，这种结合在癌症治疗中既提供了机会也带来了挑战。由于许多实体癌症，特别是BC，表达高水平的PD-1/PD-L1，癌症治疗主要涉及靶向疗法。 1.引言 乳腺癌（BC）的治疗取决于个体情况。肿瘤学研究（基因组学、转录组学、代谢组学和蛋白质组学）、设备开发（诊断和治疗）以及药物发现在BC治疗中扮演着重要角色。手术仍然是主要的治疗方式，并且已经发展出许多创新的乳房切除技术。癌症研究传统上关注癌细胞和癌症作为一种基因疾病；然而，对这种疾病作为系统性疾病的广泛调查已经确定癌症是一种具有多种表现的复杂疾病。因此，研究已经从关注癌细胞发展到基于宿主体内的免疫系统功能及其起源环境的全面方法。与免疫系统相关的癌症两个特征是慢性炎症，它鼓励肿瘤发展，以及癌细胞逃避免疫系统破坏的能力。免疫系统可能无法抑制癌细胞的增殖并诱导这些细胞的进一步发展，这被称为免疫编辑假说。逃避免疫系统的能力是Hanahan和Weinberg概述的癌细胞十个属性中的一个重要组成部分（图1）。近年来，免疫疗法在乳腺癌（BC）治疗中显示出鼓舞人心的结果。程序性细胞死亡蛋白1（PD-1）通过防止调节性T细胞的凋亡、触发抗原特异性T细胞的凋亡和控制T细胞活性来促进自我耐受并抑制免疫反应。程序性细胞死亡配体1（PD-L1）跨膜蛋白被认为是免疫反应中的共抑制因子，它与PD-1合作，刺激凋亡，抑制PD-1阳性细胞释放细胞因子，并限制PD-1阳性细胞的生长。此外，在许多恶性肿瘤中，PD-L1降低了免疫系统对肿瘤细胞的反应。这些观察结果表明，PD-1/PD-L1轴在癌症治疗和调节癌症免疫逃逸机制中发挥着重要作用。本综述旨在概述PD-1和PD-L1在BC中的功能，以增强癌症治疗。 图1. 癌细胞的特征。使用Biorender.com创建。 2.方法 本研究设计为文献综述。风格是关于PD-1/PD-L1通路相关主题或变量的传统综述。使用三个在线数据库（PubMed、Crossref和Google Scholar）进行了文献搜索。搜索词包括主要关键词“程序性细胞死亡1受体”和“程序性细胞死亡1配体1”，以及几个辅助关键词“乳腺癌”和“免疫系统”。包括的文章是那些有全文可用且用英语发表的文章。 3.结果 使用主要关键词“程序性细胞死亡1受体”和“程序性细胞死亡1配体1”，以及之前描述的几个辅助关键词进行搜索，共得到248项研究。根据文章的标题和摘要筛选每个结果，并根据纳入和排除标准再次筛选，最终共有4项研究纳入文献综述（图2）。 图2. 本研究中使用了PRISMA流程图。 4.讨论 4.1.癌症免疫系统 为了有效地消除癌细胞，免疫反应必须包括一系列连续和重复的过程，建立癌症免疫的循环（图3）。癌细胞最初产生新抗原，随后释放并被抗原呈递细胞（APCs）捕获。为了引发抗肿瘤反应并减轻对产生的肿瘤抗原的外周抵抗，这一阶段需要一个独特的信号。这些免疫原性信号包括由凋亡肿瘤细胞释放的炎症细胞因子和化学物质。当APCs附着在主要组织相容性复合体（MHC）分子上时，处理过的抗原被呈递给T细胞。然后效应T细胞识别癌症特异性抗原作为潜在的有害入侵者，此时效应和调节性（T reg）T细胞之间的比例决定了激活的免疫反应类型。一旦激活，效应T细胞就前往肿瘤部位并与肿瘤细胞上的抗原相互作用，之后它们绑定到这些细胞并杀死它们。随着肿瘤细胞被破坏，反应循环随着更多肿瘤特异性抗原的增加而加强。这个过程并不理想，这个系统可能会出现几个问题。例如，肿瘤抗原可能未被检测到；APCs和T细胞可能将肿瘤抗原误认为是自身抗原，导致T reg反应而不是抗肿瘤反应；肿瘤微环境可能会抑制产生的效应细胞。癌症免疫循环需要多个组件的协调作用，包括激活免疫系统对抗癌细胞的免疫刺激因子和调节这种活动的抑制因子。这些因素在循环的每一步中协作。刺激因子促进免疫，而抑制因子监控正在进行的过程，减少免疫反应活动和/或防止自身免疫。像PD-L1这样的检查点蛋白，被称为免疫调节剂，表现出抑制功能以调节肿瘤组织中活跃的免疫反应。例如，当T细胞表面的PD-1受体与癌细胞表达的PD-L1结合时，T细胞功能受到抑制。PD-L1的过表达在各种类型的癌症中很常见，并因其对抗癌反应的抑制作用而与预后不良相关。 图3. 癌症免疫系统。使用Biorender.com创建。 4.2.免疫编辑 免疫编辑过程阐明了免疫系统在乳腺癌的发展和演变中的作用。免疫系统有助于预防癌症以及疾病的发生、侵袭和转移。目前，许多癌症治疗方法专注于如何更有效地利用免疫系统，例如使用适应性免疫疗法和单克隆抗体来阻止T细胞接收到的抑制信号，如抗PD-1。 免疫编辑的三个主要阶段是消除、平衡和逃逸（图4）。消除阶段涉及适应性免疫系统识别和根除癌细胞。细胞毒性免疫细胞释放穿孔素以触发癌细胞溶解。通过消除阶段的癌细胞过渡到平衡阶段，它们利用免疫系统的负向调节动态。在这个阶段，免疫反应有效地调节癌细胞的增殖、扩散和程序性细胞死亡（凋亡）。然而，癌细胞之间的异质性和遗传变异使它们能够从这种平衡中逃逸，此时激活免疫抑制机制。 图4. 免疫编辑过程的阶段。使用Biorender.com创建。 4.3.免疫反应对肿瘤发展的影响 循环肿瘤细胞（CTCs）的生长和转移涉及癌细胞的释放、逃避免疫系统以及通过粘附和渗出血管产生远距离转移。免疫系统与CTCs的相互作用对这些过程至关重要。原发肿瘤平均每天向血液中释放数千个肿瘤细胞；然而，很少测量CTCs的数量。这是因为从原始免疫抑制微环境中释放出来的肿瘤细胞变得容易受到免疫细胞的攻击。图5展示了CTCs免疫逃逸的图示。 图5. 基于免疫系统的转移级联的主要阶段。使用Biorender.com创建。 免疫反应高度依赖于免疫系统识别触发免疫反应的抗原的能力。免疫反应细胞源自多能干细胞，它们通过淋巴途径分化，产生淋巴细胞及其亚群，或通过髓系途径形成吞噬细胞和其他细胞。主要的免疫活性细胞是T淋巴细胞，而次要成分包括T辅助细胞、T细胞毒性细胞和T调节细胞，每种细胞都发挥不同的功能。 免疫编辑是肿瘤进展的重要组成部分。在平衡阶段，通过产生抑制信号等方法，消除转化细胞可以诱导产生免疫原性低且对效应T细胞更具抵抗力的肿瘤变体。此外，肿瘤衍生的可溶性因子（TDSF）可以诱导多种机制，允许在肿瘤微环境中逃避免疫细胞攻击。 免疫细胞未能消除原发肿瘤细胞导致这些细胞增殖并进行有丝分裂。细胞增殖通常与快速肿瘤生长和更具侵略性的生物学和临床行为相关，这种活动可以通过计算有丝分裂指数来识别。有丝分裂指数是确定包括BC在内的多种肿瘤的侵略性和分化程度的金标准。 由于免疫反应失败，肿瘤进展增加在观察到肿瘤增大时变得明显。肿瘤细胞的增殖和有丝分裂数量显著增加，导致体积加速增长，这可以通过临床检查和成像评估。实体癌症治疗涉及移除原发肿瘤和消除转移；因此，在临床实践中理解和控制转移很重要。转移从单个实体肿瘤开始，经历多个转移阶段，导致已经扩散且难以治愈的癌症。 在每个阶段，宿主免疫系统可以识别癌细胞。在原发肿瘤阶段，一些免疫细胞作为促转移剂，如T调节细胞，通过分泌IL 10提供免疫抑制，从而抑制细胞毒性T细胞和NK细胞的反应。其他免疫细胞，包括巨噬细胞，参与血管生成过程，其中M2肿瘤相关巨噬细胞（TAMs）产生CCL-2和IL-10以促进血管生成；通过表达精氨酸酶阻断DCs、T细胞和NK细胞来增强免疫抑制；并使用基质金属蛋白酶通过改变基质促进侵袭。一些免疫细胞作为抗转移剂，如细胞毒性NK细胞、T细胞和M1 TAMs，它们杀死癌细胞。 在M2循环阶段，TAMs和T调节细胞作为促转移剂，其中T调节细胞减少并抑制循环中的NK细胞和T细胞，这允许转移细胞存活。虽然细胞毒性T细胞和NK细胞识别并杀死癌细胞，M1 TAM细胞产生CXCL9、IL-6和IL-12来表达iNOS并通过产生一氧化氮直接破坏肿瘤细胞。在转移生态位阶段，成熟的NK细胞促进转移生态位生长，当这些细胞具有低免疫能力时。 相反，未成熟的NK细胞抑制转移生态位形成。在这个阶段，巨噬细胞（M2）通过诱导局部免疫抑制环境参与准备转移生态位，而M1刺激局部免疫。此外，当细胞毒性T细胞进入转移生态位时，它们可以识别并杀死癌细胞。 5.PD-L1  5.1.PD-L1结构  当T淋巴细胞通过识别主要组织相容性复合体（MHC）在特定细胞上的抗原时，炎症细胞因子被分泌到循环系统中。通过特定细胞因子的作用，T细胞上的程序性死亡-1（PD-1；CD279）蛋白激活促进组织中程序性死亡配体1（PD-L1）的产生。用户包括了引用，建议包含引用或来源。 抑制性共受体PD-1存在于包括B淋巴细胞、CD8+和CD4+ T细胞、NK细胞以及其他亚型的肿瘤浸润性淋巴细胞（TILs）在内的几种细胞类型表面。用户提供的数字引用没有文本描述。鉴于长期抗原暴露可能会诱导PD-1表达的选择性增加，T细胞PD-1表达可能表明T细胞疲劳。由于缺乏信息，无法对用户的材料进行学术改写。类型1跨膜蛋白PD-1由程序性细胞死亡蛋白1（PDCD1）基因编码。 PD-1分子由三个主要结构元素组成：外部免疫球蛋白可变区（IgV）结构域、一个疏水性跨膜区域，以及几个细胞内区域。细胞内尾部组分包括免疫受体酪氨酸基开关基序（ITSM）和免疫受体酪氨酸基抑制基序（ITIM），两者都有可能发生磷酸化。免疫受体PD-1的激活被认为需要活性免疫受体酪氨酸基开关基序（ITSMs）的存在以调节T细胞反应。 PD-L2（也称为B7-DC或CD273）和PD-L1（也称为B7-H1或CD274）是作为共抑制因子并构成PD-1受体的配体。PD-L1是由CD274基因编码的蛋白质，包含290个氨基酸，分子量为40 kDa（图6）。PD-L1是适应性免疫反应的关键调节因子，可能位于染色体9 p24。 图6. PD-L1蛋白结构域、mRNA和基因的图解表示。使用Biorender.com创建。 CD274基因的启动子区域包含许多对IFN-γ有反应的成分；因此，CD274在IFN-γ诱导的PD-L1表达上调中起着关键作用。PD-L1作为一种跨膜蛋白运作，由两个细胞外域（Ig-V和Ig-C）和一个单一的跨膜区域组成。PD-L1是一个简短的细胞质域，传递细胞内信号；它由CD274基因编码，由7个外显子组成（图7），每个外显子都编码蛋白质的特定部分。 外显子1编码细胞内和跨膜域、信号序列以及IgC样和IgV样域，而外显子7编码3' UTR和细胞内域。PD-L1基因包含七个外显子（图7），PD-L1蛋白由一个跨膜域、两个类似于免疫球蛋白C和免疫球蛋白V的细胞外域，以及一个单独的细胞内域组成。 图7. PD-L1蛋白结构、mRNA和基因。使用Biorender.com创建。 5.2.PD-L1调控 包括肿瘤细胞、巨噬细胞和T细胞和B淋巴细胞在内的各种细胞表达CD40配体1（PD-L1）。然而，并非所有肿瘤或恶性细胞都表达PD-L1，尽管它存在于癌细胞的细胞质和质膜中。图8A显示了许多启动PD-L1表达的促炎分子、VEGF、GM-CSF、LPS、TNF-α、I型和II型IFN-γ、IL-4和IL-10细胞因子。其中，活化的T细胞释放最有效的触发因子，即IFN-γ，而TGF-β、PTEN和p53抑制PD-L1表达（图8B）。与PD-L1不同，PD-L2的表达仅限于APCs。研究表明，PD-L1表达受多种信号通路、转录因子和表观遗传因素的调控。 图8. PD-L1调节信号通路。使用Biorender.com创建。 5.2.1.信号通路 A.MAPK通路 丝裂原激活蛋白激酶（MAPK）信号通路的激活可能导致PD-L1表达水平的增加。MAPK通路是非小细胞肺癌（NSCLC）中的一个致癌机制，通过激活表皮生长因子受体（EGFR）上调PD-L1。化疗药物诱导的癌细胞PD-L1上调可能是由于MAPK通路的激活。例如，MEK抑制剂U0126消除了紫杉醇诱导的PD-L1表达，而顺铂浓度通过MAPK激活触发PD-L1表达。 B.PI3K/Akt通路 磷脂酰肌醇3激酶（PI3K）/Akt通路已被涉及在癌细胞中PD-L1的调控，因为已确定PI3K抑制剂降低了BRAF抑制剂耐药黑色素瘤细胞中的PD-L1表达。例如，Akt抑制消除了PTEN耗竭时发生的PD-L1增加。通过PI3K/Akt信号通路的PD-L1增加伴随着转录上调以及翻译后过程；在结肠癌细胞中，Akt的刺激导致PD-L1蛋白过表达，与PD-L1 mRNA表达水平无关。ePI3K/Akt通路的转录和翻译后机制调节各种细胞和组织以控制PD-L1表达。尽管下游效应子mTOR/S6尚未被证明介导Akt对PD-L1表达的作用，但Akt的抑制导致PD-L1表达减少。相比之下，PD-L1表达由Akt的下游靶标核因子NF-B调节，PD-L1的转录增加是由于Akt激活NF-B。 C.JAK-STAT信号通路 STAT通路被生长因子、IFNs、细胞因子和类似化学物质激活，并被认为是一个进化上保守的过程。这种策略为细胞提供了一个控制基因表达的关键工具，并代表了细胞如何响应其环境并解释信号以调节增殖和分裂的基本示例。最近的研究表明，肿瘤通过JAK/STAT系统制造PD-L1，根据Doi等人的研究，PD-L1表达可能通过使用JAK2抑制剂AG490在蛋白和mRNA水平上被阻断。这些结果支持JAK/STAT通路调节PD-L1表达的观点。此外，成纤维细胞生长因子受体（FGFR）2信号通过JAK/STAT3信号通路的有效激活与体外PD-L1表达的升高相对应。结直肠癌的异种移植模型揭示了FGFR2的过表达加速了肿瘤发展，并导致PD-L1表达激增。减轻这种影响的一种可能策略是使用JAK抑制剂来阻碍JAK/STAT3通路。 D.WNT信号通路 以前的研究表明，WNT信号的失调与肿瘤的发展、细胞从癌症到恶性的转变以及对传统癌症治疗的抵抗密切相关。异常的WNT信号破坏了癌症免疫监测的过程，导致免疫逃逸和对免疫疗法的敏感性降低，包括免疫检查点抑制剂。例如，在缺乏WNT配体的情况下，非糖基化的PD-L1在乳腺癌小鼠模型中沿GSK3B-β-TrCP轴的活跃信号时显示出加速的蛋白酶体降解。然而，GSK3阻断剂通过降低动物黑色素瘤模型中PDCD1基因表达来增加肿瘤根除。WNT活性与PD-L1表达之间的功能相互作用允许使用特定的WNT抑制剂或激活剂来治疗三阴性乳腺癌，以分别降低或提高PD-L1表达。 E.NF-κB信号通路 已经提出，Toll样受体（TLRs）或IFN-γ驱动的核因子（NF）-κB刺激PD-L1基因表达。姜黄素是一种NF-κB抑制剂，当与抗CTLA-4检查点抑制药物联合使用时，可以抑制黑色素瘤、乳腺癌和结肠癌细胞系的生长。抑制肿瘤细胞的生存和增殖，并针对肿瘤内的免疫检查点可能抑制NF-κB，这可能涉及LMP1诱导的PD-L1表达，因为咖啡酸苯乙酯（一种NF-κB抑制剂）减少了PD-L1诱导。除了INF-γ，转录因子NF-κB是PD-L1表达的关键调节因子，已被证明成功减少IFN诱导的PD-L1表达，而STAT3、PI3K和MAPK抑制剂未能实现相同的结果。Peng等人发现，化疗导致卵巢癌患者PD-L1水平更高，这是由于NF-κB介导的局部免疫抑制。 5.2.2.Hedgehog信号通路 近期的治疗进展集中在使用小分子抑制剂，如SMO和GLI，来修改Hedgehog（Hh）信号通路。该通路被认为对基质细胞的增殖至关重要，其功能的偏差可能导致肿瘤的发展。此外，Hh信号可能在调节PD-L1生产中发挥作用，Hh信号的抑制可能在淋巴细胞中引起抗肿瘤活性。根据Chakrabarti等人的研究，特定患者应该接受一种联合治疗方法，既针对Hh信号也针对免疫学检查点，因为Hh信号参与了PD-1/PD-L1的抑制，这导致Gli2诱导的耐受性和胃癌中PD-L1表达的逆转。 5.3.PD-1/PD-L1信号 许多研究报告称，通过PD-L1和PD-1之间的相互作用传递免疫病理学和免疫耐受抑制信号。PD-1/PD-L1信号可以通过磷脂酰肌醇3激酶（PI3K）、T细胞受体（TCR）和磷酸酶-1（SHP-1）信号通路阻碍免疫反应（图9）。PD-L1对效应T细胞的作用和PD-1抑制TCR信号传导，进而抑制T细胞的细胞毒性。当SHP-1被抑制时，免疫受体酪氨酸基开关基序（ITSM）和酪氨酸基抑制基序（ITIM）的活动可能增强，由钠钨酸盐控制的CD8+ T细胞活性。PD-1的ITSM基序可能被ITSM酪氨酸磷酸化，然后运送SHP-2和SHP-1到ITSM基序。在这种吸收之后，信号通路阻止树突细胞和T细胞的相互作用，并抑制停止信号。最后，阻断TCR信号传输抑制了MAPK和PI3K/Akt信号。此外，Akt的激活和PI3K的抑制减少了B细胞淋巴瘤超大（Bcl-xl）表达，进而增加了T细胞凋亡。 图9. PD-1/PD-L1信号减少CD8+ T细胞的增殖、存活和细胞因子产生 。使用Biorender.com创建。 PD-L1阻断了Ras/MEK/ERK和PI3K/Akt通路，这阻止了T细胞的激活和对T细胞存活至关重要的转录因子的运作。PD-1和PD-L1之间的相互作用可能抑制T-bet和GATA-3的表达。GATA-3转录因子参与Th2细胞的产生，而T-bet转录因子可能通过结合T盒区域增强T细胞增殖。 然而，目前尚不清楚所有类型的癌症是否都使用PD-L1信号的确切机制，因为一些癌症类型的预后不同，可能由于涉及不同的PD-L1机制。 6.PD-1/PD-L1在癌症中的功能  6.1.乳腺癌  PD表达已与人类乳腺癌干细胞（BCSCs）中的上皮-间质转化（EMT）相关联。与细胞系相比，MCF-7和BT-549肿瘤球中PD-L1表达的增加可能部分归因于PD-L1启动子区域内的去甲基化。此外，肿瘤中组蛋白乙酰转移酶的过表达可以加速PD-L1转录。与细胞系相比，PD-L1启动子区域内慢速组蛋白的分布不太明显。这些结果表明PD-L1在BCSCs中具有重要功能。 最近的病理学调查确定，多种亚型的雌激素受体（ER）α阴性BC含有增加的PD-L1水平。刘等人发现ERα阴性和ERα阳性乳腺癌细胞系之间PD-L1 mRNA的平均表达存在显著差异。因此，研究了ER阴性（MDA-MB-231和BT549）和ER阳性乳腺癌细胞系（MCF7和T47D）中PD-L1的表达。根据RT-qPCR和西方印迹研究，T47D和MCF7细胞中PD-L1的蛋白和mRNA水平显著低于MDA-MB-231和BT549细胞）。最近的研究表明，PD-L1抑制癌细胞的发展，当PD-L1被沉默时，BC细胞中阿霉素诱导的和自发的死亡增加。 7.癌症中PD-1/PD-L1的抑制剂 使用PD-1/PD-L1靶向疗法可能显著减缓癌症进展。图10概述了一些关键方案，以增强癌症治疗。 图10. 恶性肿瘤中的PD-1/PD-L1抑制剂 。使用Biorender.com创建。 1.Pembrolizumab Joseph等人发现，Pembrolizumab对肺转移的治疗有效性（62%）显著高于其对肝转移的治疗效果（22%）。肺和肝转移患者的一年总生存率分别为89%和53%。被诊断为转移性鳞状细胞癌（SCCHN）和/或头颈部复发的患者总体生存率有限，通常不超过六个月。在头颈部区域使用抗PD-1检查点药物进行免疫治疗已增加了生存率和肿瘤反应。在单臂II期KEYNOTE-055试验和Ib期KEYNOTE-012试验中，Pembrolizumab治疗的转移性和复发患者的反应率为18%，中位OS为6至8个月。此外，HER2阳性、曲妥珠单抗耐药和PD-L1阳性BC患者已用Pembrolizumab和曲妥珠单抗治疗。 2.Nivolumab 完全人源单克隆抗体Nivolumab可以抑制PD-L1和PD-1之间的相互作用。赵等人描述了一个案例，一名晚期肝肉瘤患者在阿帕替尼和Nivolumab治疗后部分缓解。然而，在治疗过程中，3级氨基转移酶水平显著升高。因此，在考虑联合治疗时应谨慎，并在批准实施前进行全面评估潜在风险。CheckMate 275 2期临床试验的结果表明，先前治疗中对基于铂的化疗表现出耐药性的晚期尿路上皮癌患者可能在使用Nivolumab后有良好结果。与基于铂的化疗后可用的少数化疗选择相比，免疫治疗有许多优势之一是其治疗效果的持久性增加。其他试验的长期生存率证实了这一点，包括3期CheckMate 057（n=582）和CheckMate 017（n=272）试验。这些研究比较了先前治疗过的晚期非鳞状NSCLC中多西他赛和Nivolumab的有效性。在CheckMate 057和017试验组中，多西他赛的预测3年总生存率为8%，而非鳞状NSCLC患者为17%，预测的2年OS率，多西他赛为8%，而鳞状NSCLC分别为16%和29%，分别为多西他赛和Nivolumab。 3.JQ1 刘等人研究了JQ1对多种癌细胞系和从肾细胞癌衍生的原代培养细胞中PD-L1蛋白和mRNA表达的影响。这些癌细胞系包括多种恶性肿瘤，包括前列腺、肺和肝肿瘤。这些作者报告称，JQ1对细胞生长有剂量依赖性的抑制作用。在用JQ1处理后，肺、肝、前列腺和肾癌细胞系的原代培养中观察到PD-L1表达减少。此外，在用JQ1处理的细胞中还观察到PD-L2水平的下降。因此，JQ1似乎有能力调节PD-1/PD-L1轴。 4.Cemiplimab 使用PD-1抑制剂在治疗晚期皮肤鳞状细胞癌（cSCC）方面取得了积极成果。Cemiplimab是一种单克隆抗体，能够结合程序性死亡受体-1（PD-1），抑制其与PD-L2和PD-L1的相互作用。2018年9月，食品药品监督管理局（FDA）批准Cemiplimab用于治疗局部晚期转移性结直肠癌患者，这些患者不适合放射治疗或手术。 5.Atezolizumab Atezolizumab是一种经过人源化设计的单克隆抗体，旨在选择性地抑制PD-L1与其受体B7.1和PD-1之间的相互作用。这种化合物增强了T细胞对肿瘤状况的免疫反应。Atezolizumab单药治疗已成为转移性NSCLC和UC的潜在治疗选择。最近，IMmotion 151 3期研究比较了舒尼替尼与贝伐珠单抗（抗VEGF）和Atezolizumab作为结直肠癌可能的一线治疗。根据免疫组化，贝伐珠单抗/Atezolizumab实现了其共同主要目标之一，即在与舒尼替尼相比，表达PD-L1的肿瘤浸润免疫细胞≥1%的晚期结直肠癌患者中显示出更好的研究者评估的PFS。 6.Avelumab 单克隆人IgG1抗体Avelumab抑制PD-L1受体。1b期研究（JAVELIN Solid Tumor）显示，先前接受过治疗的复发或转移性NSCLC患者的肿瘤和免疫细胞中PD-L1表达减少。包括55名晚期肾细胞癌患者的1b期、非随机试验结果显示，阿西替尼和Avelumab的联合使用是有效的。具体来说，58%的患者有成功的反应，78%的患者病情得到控制。 8.结论 PD-1/PD-L1的结合对许多恶性肿瘤至关重要；因此，需要在这一领域进行更多的研究。根据所提供的证据，这种结合在癌症治疗中既提供了机会也带来了挑战。由于许多实体癌症，特别是乳腺癌，表达高水平的PD-1/PD-L1，癌症治疗主要涉及靶向疗法。免疫疗法的有希望的发现表明，这种治疗可能会延长特定患者的生存期。PD-1/PD-L1免疫疗法阻断可能是各种癌症类型的下一个合理的进展；然而，还有许多因素尚待确定，包括剂量、持久性、有效性和安全性。 为促进抗体行业的交流与创新，2024年10月16-17日第七届金秋十月抗体产业发展大会如约而至。会议旨在为研究人员提供一个互动交流的平台，有助于推动抗体产业的进一步发展。 会议内容 时间：2024年10月16-17日 地点：上海（酒店定向通知） 规模：600-800人 主办单位：生物制品圈、抗体圈 演讲支持：Entegris、瑞孚迪、AS ONE CORPORATION 会议费用：免费FREE!（仅收取100元报名定金，含参会学习、茶歇、会议手册，定金概不退还），先到先得，报完即止！ 报名方式：扫描下方二维码或点击文章最底部“阅读原文”→ 填写表格 → 报名成功（报名志愿者，承担一定工作，请慎重考虑，免交定金）！ 组委会获得报名信息后，根据报名信息进行初筛，并进一步与报名者沟通确认，实现精准邀请。最终有机会进入大会微信群（严格审核通过）。 日程安排 更多嘉宾正在邀请中 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Biologics License Application currently under review by U.S. FDA; PDUFA goal date of December 28, 2024WALTHAM, Mass., Sept. 16, 2024 (GLOBE NEWSWIRE) -- Checkpoint Therapeutics, Inc. (“Checkpoint”) (Nasdaq: CKPT), a clinical-stage immunotherapy and targeted oncology company, today announced the presentation of longer-term data from its pivotal trial of cosibelimab, its anti-programmed death ligand-1 (“PD-L1”) antibody, in locally advanced and metastatic cutaneous squamous cell carcinoma (“cSCC”) during the European Society for Medical Oncology (“ESMO”) Congress 2024, which is taking place in Barcelona, Spain, from September 13 to 17, 2024. Poster Presentation Title: Cosibelimab in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Longer-term Efficacy and Safety Results from Pivotal Study “These longer-term results for cosibelimab presented at the ESMO Congress demonstrate a deepening of response over time, with higher objective response and complete response rates than initially observed at the primary analyses, and continue to expand the evidence supporting the efficacy and safety of cosibelimab as a potential new treatment for advanced cSCC,” said James Oliviero, President and Chief Executive Officer of Checkpoint. “We look forward to our upcoming December 28, 2024, Prescription Drug User Fee Act (“PDUFA”) goal date for our Biologics License Application for cosibelimab, and believe, if approved, cosibelimab’s dual mechanisms of action and safety profile may position the product, over time, as the preferred immunotherapy of U.S. oncologists.” Data highlights include: Efficacy With 16 months of additional follow-up since the primary analysis, cosibelimab demonstrated increasing objective response rates (“ORRs”) and complete response rates per independent central review in 109 patients with advanced cSCC. ORRs of 54.8% and 50.0% achieved in locally advanced and metastatic cSCC, with median follow-up durations of 24.1 and 29.3 months, respectively.Results demonstrate a deepening of response over time, with complete response rates of 25.8% and 12.8% in locally advanced and metastatic cSCC, respectively.Clinically meaningful durations of response (“DOR”) were observed, with median DORs not yet reached in either group. Safety Overall, in 192 advanced cSCC patients treated with cosibelimab, a manageable safety profile was observed, with notable low rates of treatment-emergent adverse events (“TEAEs”), severe immune-related adverse events (“irAEs”), and treatment discontinuations. 3.6% of patients experienced an irAE assessed as grade 3, with no observed grade ≥4 irAEs.No events of grade ≥3 pneumonitis, colitis, hepatitis, nephritis, or endocrinopathies.Treatment discontinuation due to TEAEs, regardless of attribution, was observed in 12 patients (6.3%); the most common reason was COVID-19/COVID-19 pneumonia (1.6%). A copy of the poster can be found on the Publications page of the Checkpoint Therapeutics website. In December 2023, the U.S. Food and Drug Administration (“FDA”) issued a complete response letter (“CRL”) for the cosibelimab Biologics License Application (“BLA”) for the treatment of patients with metastatic or locally advanced cSCC who are not candidates or curative surgery or radiation. The CRL only cited findings that arose during a multi-sponsor inspection of Checkpoint’s third-party contract manufacturing organization (“CMO”) as approvability issues to address in a resubmission. In July 2024, Checkpoint announced it had completed a resubmission of the BLA to the FDA for cosibelimab to potentially address the approvability issues cited in the CRL. The resubmission was accepted by the FDA as a complete response and the FDA has set a PDUFA goal date of December 28, 2024. About Cutaneous Squamous Cell Carcinoma (cSCC)Cutaneous Squamous Cell Carcinoma is the second most common type of skin cancer in the United States, with an estimated annual incidence of approximately 1.8 million cases according to the Skin Cancer Foundation. Important risk factors for cSCC include chronic ultraviolet exposure and immunosuppressive conditions. While most cases are localized tumors amenable to curative resection, approximately 40,000 cases will become advanced, and an estimated 15,000 people will die from this disease each year. In addition to being a life-threatening disease, cSCC causes significant functional morbidities and cosmetic deformities based on tumors commonly arising in the head and neck region and invading blood vessels, nerves and vital organs such as the eye or ear. The immune-suppressed population represents a challenging target in the treatment of advanced cSCC, as they present with a more aggressive disease and with a higher risk of developing immune-related toxicities from checkpoint inhibitor treatment. About CosibelimabCosibelimab is a potential differentiated, high affinity, fully-human monoclonal antibody of IgG1 subtype that directly binds to PD-L1 and blocks the PD-L1 interaction with the programmed death receptor-1 (“PD-1”) and B7.1 receptors. Cosibelimab’s primary mechanism of action is based on the inhibition of the interaction between PD-L1 and its receptors PD-1 and B7.1, which removes the suppressive effects of PD-L1 on anti-tumor CD8+ T-cells to restore the cytotoxic T cell response. Cosibelimab is potentially differentiated from the currently marketed PD-1 and PD-L1 antibodies through sustained high tumor target occupancy of PD-L1 to reactivate an antitumor immune response and the additional potential benefit of a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity (“ADCC”) for potential enhanced efficacy. About Checkpoint TherapeuticsCheckpoint Therapeutics, Inc. is a clinical-stage immunotherapy and targeted oncology company focused on the acquisition, development and commercialization of novel treatments for patients with solid tumor cancers. Checkpoint is evaluating its lead antibody product candidate, cosibelimab, a potential differentiated anti-PD-L1 antibody licensed from the Dana-Farber Cancer Institute, as a potential new treatment for patients with selected recurrent or metastatic cancers, including metastatic and locally advanced cSCC. Checkpoint is also evaluating its lead small-molecule, targeted anti-cancer agent, olafertinib, a third-generation epidermal growth factor receptor (“EGFR”) inhibitor, as a potential new treatment for patients with EGFR mutation-positive non-small cell lung cancer. Checkpoint is headquartered in Waltham, MA and was founded by Fortress Biotech, Inc. (Nasdaq: FBIO). For more information, visit www.checkpointtx.com. Forward‐Looking Statements This press release contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended, that involve a number of risks and uncertainties. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements regarding our resubmission of our BLA for cosibelimab and review thereof, our belief that the BLA resubmission potentially addresses all the issues in the CRL, our belief about the comprehensive nature of our BLA resubmission and reaching alignment with the FDA on our cosibelimab BLA resubmission strategy, our ability to work with our third-party CMO and the FDA to adequately address the issues raised in the CRL and execute on a pathway forward for the potential marketing approval of cosibelimab, the adequacy of the responses to the inspection issues submitted to FDA by our third-party CMO, our projections of regulatory review timelines, the commercial potential of cosibelimab, if approved, and the potential differentiation of cosibelimab, including a potentially favorable safety profile as compared to the currently available anti-PD-1 therapies and the dual mechanism of action of cosibelimab translating into potential enhanced efficacy. Factors that could cause our actual results to differ materially include the following: the risks and uncertainties associated with the regulatory review process; uncertainties regarding the timeline of FDA review of the resubmitted BLA; any inability to successfully work with the FDA to find a satisfactory solution to address any concerns in a timely manner or at all during the review process for the BLA, including any inability to provide the FDA with data, analysis or other information sufficient to support an approval of the BLA; our, and our third party CMO’s, ability to adequately address the issues raised in the CRL; issues associated with any facility inspection or re-inspection of our third party CMO or otherwise during the review process for the BLA; the risk that our third-party CMO will not meet deadlines, and/or comply with applicable regulations; whether the FDA accepts the data and results as included in the BLA resubmission at levels consistent with the published results, or at all; our ability to execute a partnering or other relationship to enable the commercialization of cosibelimab, if approved, on acceptable terms, if at all; the risk that topline and interim data remains subject to audit and verification procedures that may result in the final data being materially different from the topline or interim data we previously published; the risk that safety issues or trends will be observed in the clinical trial when the full safety dataset is available and analyzed; the risk that a positive primary endpoint does not translate to all, or any, secondary endpoints being met; risks that regulatory authorities will not accept an application for approval of cosibelimab based on data from the Phase 1 clinical trial; the risk that the clinical results from the Phase 1 clinical trial will not support regulatory approval of cosibelimab to treat cSCC or, if approved, that cosibelimab will not be commercially successful; risks related to our chemistry, manufacturing and controls and contract manufacturing relationships; risks related to our ability to obtain, perform under and maintain financing and strategic agreements and relationships; risks related to our need for substantial additional funds; other uncertainties inherent in research and development; our dependence on third-party suppliers; government regulation; patent and intellectual property matters; competition; unfavorable market or other economic conditions; and our ability to achieve the milestones we project, including the risk that the evolving and unpredictable Russia/Ukraine conflict and COVID-19 pandemic delay achievement of those milestones. Further discussion about these and other risks and uncertainties can be found in our Annual Report on Form 10-K, and in our other filings with the U.S. Securities and Exchange Commission. The information contained herein is intended to be reviewed in its totality, and any stipulations, conditions or provisos that apply to a given piece of information in one part of this press release should be read as applying mutatis mutandis to every other instance of such information appearing herein. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law. This press release and prior releases are available at www.checkpointtx.com. The information found on our website is not incorporated by reference into this press release and is included for reference purposes only. Company Contact:Jaclyn JaffeCheckpoint Therapeutics, Inc.(781) 652-4500ir@checkpointtx.com Investor Relations Contact:Ashley R. RobinsonManaging Director, LifeSci Advisors, LLC(617) 430-7577arr@lifesciadvisors.com Media Relations Contact:Katie KennedyGregory FCA610-731-1045checkpoint@gregoryfca.com

Late-breaking data at WCLC show Libtayo monotherapy nearly doubled median overall survival and reduced the risks of death and disease progression by 41% and 50%, respectively, compared to chemotherapy WCLC presentation also reviews data on overall survival, progression-free survival and response rate among patients who added chemotherapy to Libtayo following disease progression Sept. 09, 2024 -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced five-year results from the final pre-specified overall survival (OS) analysis of the Phase 3 EMPOWER-Lung 1 trial, which evaluated Libtayo® (cemiplimab) monotherapy versus chemotherapy as a first-line treatment for adults with advanced non-small cell lung cancer (NSCLC) with ≥50% PD-L1 expression and no EGFR, ALK or ROS1 aberrations. The late-breaking results will be presented in an oral session at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer. “The five-year results from EMPOWER-Lung 1 showcase the durable survival benefit and impressive efficacy of first-line Libtayo monotherapy compared to chemotherapy in patients with PD-L1 high, advanced NSCLC, including a direct correlation between survival benefits and PD-L1 expression level,” says Ana Baramidze, MD, PhD, Head of Clinical Research Department at Todua Clinic, Tbilisi, Georgia. “Furthermore, EMPOWER-Lung 1 continues to offer important new data to help doctors increase their understanding of investigational treatment strategies for patients who progress on PD-1 inhibitor monotherapy. For instance, EMPOWER-Lung 1 was one of the few trials to evaluate survival when adding chemotherapy to a PD-1 inhibitor following progression.” At the five-year follow-up, Libtayo remained superior to chemotherapy in the population of patients confirmed to have ≥50% PD-L1 expression (using an FDA approved assay), demonstrating continued and clinically meaningful benefits consistent with the prior 1-year analysis in this study population (as previously published in The Lancet and also as previously provided in the approved label for the FDA-approved assay): NOTE: The analysis was conducted in a subset of the randomized population that excluded 147 patients whose tumors could not be retested or were later found to have <50% PD-L1 expression. a Based on Kaplan-Meier method b Based on stratified proportional hazards model Continued and clinically meaningful benefits were also observed at this five-year follow-up of the overall trial population (in which not all patients were confirmed to have ≥50% PD-L1 expression), as compared to the prior 1-year analysis in this population. a Based on Kaplan-Meier method b Based on stratified proportional hazards model Importantly, EMPOWER-Lung 1 allowed patients who experienced disease progression to change their therapy, with those assigned to Libtayo having the option to add four cycles of chemotherapy. Among these patients (n=75), the addition of chemotherapy was associated with a 15-month median OS (95% CI: 11 to 18 months), 7-month median PFS (95% CI: 6 to 8 months) and 28% ORR (95% CI: 18% to 40%). The exploratory subgroup analysis of EMPOWER-Lung 1 also showed direct correlations between survival and disease progression benefits and PD-L1 expression level among Libtayo patients, supporting the direct correlation between tumor response and PD-L1 expression level previously observed. At five years, those with tumor PD-L1 expression of ≥90% (n=99) derived the greatest benefit with a median OS of 39 months (95% CI: 23 months to not evaluable) and a 15-month median PFS (95% CI: 10 to 21 months). These correlations with PD-L1 expression level were not observed with chemotherapy. No new safety signals were observed at five years among evaluable patients (Libtayo=356; chemotherapy=343), following a median duration of exposure of 36 weeks to Libtayo and 18 weeks to chemotherapy. Adverse events (AEs) of any grade occurred in 93% of Libtayo patients (46% ≥Grade 3) and 96% of chemotherapy patients (52% ≥Grade 3). The most common AEs occurring in at least 10% of Libtayo patients included anemia (20%), decreased appetite (14%), fatigue (14%), pneumonia (12%), arthralgia (12%), back pain (12%), dyspnea (11%), cough (10%) and pruritus (10%). Among Libtayo patients, AEs were serious in 36% and led to permanent discontinuation in 9% and death in 10%, compared to 29%, 5% and 10% in the chemotherapy arm, respectively. Among the 75 Libtayo patients who received additive chemotherapy after disease progression, AEs of any grade occurred in 89% (36% ≥Grade 3), following a median duration of exposure of 27 weeks to Libtayo. The most common AEs included anemia (35%), alopecia (24%), diarrhea (21%), nausea (20%), neutropenia (15%) and asthenia (11%). AEs were serious in 27% of patients and led to discontinuation of treatment in 5% of patients and death in 4% of patients. Additional presentations on data from Regeneron’s oncology portfolio and pipeline are being shared at WCLC. The potential use of adding chemotherapy to Libtayo following disease progression as described above is investigational, and the safety and efficacy of this regimen have not been fully evaluated by any regulatory authority. We aspire to turn revolutionary discoveries into medicines that can transform the lives of those impacted by cancer. Our team around the world is driven to solve the needs and challenges of those affected by one of the most serious diseases of our time. Backed by our legacy of scientific innovation and a deep understanding of biology, genetics and the immune system, we’re pursuing potential therapies across more than 30 types of solid tumors and blood cancers. Our cancer strategy is powered by cutting-edge technologies and therapies that can be flexibly combined to investigate potentially transformative treatments for patients. Oncology assets in clinical development comprise nearly half of Regeneron’s pipeline, and include checkpoint inhibitors, bispecific antibodies and costimulatory bispecific antibodies. Our approved PD-1 inhibitor Libtayo serves as the backbone of many of our investigational combinations. To complement our extensive in-house capabilities, we collaborate with patients, healthcare providers, governments, biopharma companies and each other to further our shared goals. Together, we are united in the mission to serve as a beacon of transformation in cancer care. Libtayo is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T cells and was invented using Regeneron's proprietary VelocImmune® technology. By binding to PD-1, Libtayo has been shown to block cancer cells from using the PD-1 pathway to suppress T-cell activation. In the U.S. and other countries Libtayo is indicated in certain patients with advanced basal cell carcinoma (BCC), advanced cutaneous squamous cell carcinoma (CSCC) and advanced NSCLC, as well as in advanced cervical cancer in the European Union, Canada and Brazil. As of July 1, 2022, Libtayo is developed and marketed globally by Regeneron. In the U.S., the generic name for Libtayo in its approved indications is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA). Outside of the U.S., the generic name of Libtayo in its approved indication is cemiplimab. The extensive clinical program for Libtayo is focused on difficult-to-treat cancers. Libtayo is currently being investigated in trials as a monotherapy, as well as in combination with either conventional or novel therapeutic approaches for other solid tumors and blood cancers. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority. Regeneron's VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's co-Founder, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved or authorized fully human monoclonal antibodies. This includes REGEN-COV® (casirivimab and imdevimab), Dupixent® (dupilumab), Libtayo®, Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab-dgnb), Inmazeb® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz® (pozelimab-bbfg). Regeneron is a leading biotechnology company that invents, develops, and commercializes life-transforming medicines for people with serious diseases. Founded and led for 35 years by physician-scientists, Regeneron's unique ability to repeatedly and consistently translate science into medicine has led to numerous FDA-approved treatments and product candidates in development, almost all of which were homegrown in Regeneron's laboratories. Regeneron's medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, hematologic conditions, infectious diseases, and rare diseases. Regeneron is accelerating and improving the traditional drug development process through its proprietary VelociSuite® technologies, such as VelocImmune®, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center®, which is conducting one of the largest genetics sequencing efforts in the world. The content above comes from the network. if any infringement, please contact us to modify.