Cervical Squamous Cell Carcinoma

虽然早期筛查和疫苗接种计划有效减少了部分新发病例数，但宫颈癌依然是威胁女性健康的罪魁祸首之一。《每日新报》曾报道过一例51岁ⅢC1r期子宫颈鳞癌患者，在天津某医院参加TIL临床试验后，达到完全缓解（CR），患者自觉消化不良、食欲减退等不适症状明显缓解，且复查全腹部增强MRI示，宫颈未见明显异常。近期，《国际妇女健康杂志》又报道了一例患有 转移性宫颈癌 ，并经过多种常规治疗后，肿瘤依然进展的68岁患者，在接受TIL治疗后，肿瘤明显缩小，且症状缓解。TIL疗法除了治疗宫颈癌外，还在 晚期黑色素瘤、肺癌、肝癌、黑色素瘤、乳腺癌、卵巢癌 等多个实体瘤领域，具有独特的优势！ TIL疗法助力晚期宫颈癌患者重拾希望 ▲截图源自“Dovepress” 该患者于2021年11月，出现阴道流血后就诊，确诊为 宫颈鳞状细胞癌IV期 ，之后接受了 10个周期的化疗 ，但患者在每个周期化疗后，都会出现 严重的骨髓抑制 ，并伴有 白细胞减少和血小板减少 。 这也意味着一旦病情继续进展，患者很难再耐受化疗。 然而不幸的是，她的病情于2022年7月29日再次出现进展，宫颈肿瘤增大至4.5厘米，髂血管附近有更多较大的转移性淋巴细胞，被认为是非目标病变，同时血性白带症状加重。抱着最后一丝希望，患者参加了TIL临床试验。 该患者入组后，首先接受了 环磷酰胺+氟达拉滨淋巴清除方案 ；之后接受 静脉自体TIL输注 ；最后根据临床试验方案，接受了为期10天的 高剂量IL-2 （白细胞介素-2）治疗。结果显示： 增强盆腔CT ：该患者在TIL输注前、治疗后6周和12周时的增强盆腔CT扫描显示，目标病灶分别为4.9cm、3.3cm和3.0cm，显然 治疗后患者肿瘤迅速缩小 ，详见图1。 血清生物标志物 ：输注TIL后，患者的血清生物标志物 CA125和CA153水平下降 ，表明 疾病得到控制 。 症状改善 ：患者在接受TIL治疗4周后， 异常阴道分泌物的症状逐渐消失 。 这些结果表明， TIL输注可以诱导持久性和长期的系统性免疫反应 ，即便是对于有严重骨髓抑制的晚期转移性宫颈癌患者，TIL单一疗法也可能是一种有前景的治疗策略。 图1 TIL治疗前后，增强盆腔CT对比 ▲图源“Dovepress”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 何谓TILs疗法？ 肿瘤浸润淋巴细胞（tumor-infiltratinglymphocytes，TILs）疗法，属于一种过继性免疫细胞疗法，是 从患者自身的肿瘤样本中，采集浸润的淋巴细胞，在体外培养扩增后，再回输到患者体内 ，从而识别和破坏癌细胞的一种治疗方法，可谓 “以己之矛，攻己之盾” ！ TILs细胞具有特异性的肿瘤细胞靶向能力，能够特异性的杀伤肿瘤细胞，其杀伤能力为淋巴因子激活的杀伤细胞（LAK细胞）的50~100倍，与此同时还具有低脱靶毒性，为 转移性黑色素瘤、宫颈癌、乳腺癌、卵巢癌、肺癌 等多种实体瘤患者，带来了新的“曙光”！ 目前有两款TILs免疫细胞临床试验正在招募中，主要针对恶性实体肿瘤（包括宫颈癌、卵巢癌、乳腺癌、非小细胞肺癌、胆管癌、食道癌）等癌种。 有意向的患者，提交近期的治疗经历、病理报告、出院小结等，进行初步评估！ Lifileucel治疗黑色素瘤，客观缓解率达50% 大多数接受一线免疫检查点抑制剂（ICI）治疗的晚期（不可切除或转移性）黑色素瘤患者，可能会在一年内出现进展。在 2023年ESMO大会上 ，公布了 Lifileucel的Ⅱ期C-144-01临床研究结果 。 12例经抗PD-1/PD-L1治疗期间或之后进展的 粘膜黑色素瘤 患者，在接受Lifileucel治疗后，经过中位随访35.7个月，确认的 客观缓解率（ORR）为50.0% [95%置信区间（CI）21.1-78.9]。Lifileucel是一种自体肿瘤浸润淋巴细胞（TIL）制剂，在晚期肿瘤患者中具有临床意义和持久的抗肿瘤活性。 图2 接受Lifileuce治疗的黏膜黑色素瘤患者中，目标病变SOD与基线的最佳百分比变化 ▲图源“ESMOdaily”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 TIL治疗卵巢癌，6个月疾病控制率达100% 莱顿大学医学中心进行了一项关于“ 自体肿瘤浸润淋巴细胞（TIL）疗法联合铂类化疗，治疗上皮性卵巢癌的1/2期研究（NCT04072263） ”。 截至数据截止点，已有14例患者完成了完整TIL周期的治疗，并评估了临床和免疫反应。铂类化疗联合TIL输注治疗后，共有 3例患者获得完全缓解（CR），9例获得部分缓解，2例病情稳定 ， 客观缓解率达86%，6个月时疾病控制率达100%（DCR） 。治疗后中位无铂间隔（PtFI）为6.5个月（范围，2-35）。 中位无进展生存期（PFS）为10.7个月 （范围，6-39+），中位无铂生存期为6.5个月。 TIL疗法在其他实体瘤领域大放异彩 实体瘤具有高度异质性，且很难找到所有肿瘤细胞的理想靶点，这也增加了治疗难度。而TIL细胞是具有多种受体的多克隆细胞，既能检测多种靶向肿瘤相关抗原（TAA），还能克服免疫逃逸属性，从而在实体瘤的治疗方面具有独特的优势。目前针对TILs治疗开展的临床试验多达数十项，除了上文提到的领域外，还涵盖 非小细胞肺癌、乳腺癌、肝癌 等多种恶性肿瘤。 乳腺癌 美国国家癌症研究所（NCI）开展了一项“ 使用自身肿瘤浸润淋巴细胞（TIL），治疗转移性乳腺癌 ”的临床研究。 在6例可评估的转移性乳腺癌患者中，经TIL治疗后，结果显示， 一半患者经历了可测量的肿瘤缩小 。其中一例2018年研究中报告的患者，至今仍未患癌症；另两位女性在治疗6个月和10个月后， 肿瘤缩小率分别为52%和69% 。这些患者在TIL治疗后，大约5年和3.5年内未出现新发癌症。 肝癌 肝细胞癌（HCC）是常见的肝癌类型，TILs在肝细胞癌的预后和免疫治疗中发挥着重要作用。 一项“ TIL治疗肝细胞癌的I期临床试验 ”，共纳入了15例肝细胞癌患者，在接受肿瘤切除手术后，回输了自体TIL细胞，结果显示，中位随访14个月后， 15例患者（100%）存活，12例患者（80%）未表现出疾病证据 。 肺癌 肺癌主要分为非小细胞肺癌（约占肺癌病例的90%）、小细胞肺癌两种类型。 一项关于“ LN-145治疗非小细胞肺癌的2期IOV-LUN-202试验（NCT04614103） ”，共纳入了23例非小细胞肺癌（NSCLC）患者，这些患者存在EGFR、ROS或ALK基因突变，且抗PD-1。在给予LN-145（一种即用型TIL疗法）治疗后， 客观缓解率（ORR）达26.1% ，其中1例完全缓解，5例部分缓解， 疾病控制率为82.6% 。 小编有话说 TIL疗法自1988年尝试用于临床以来，已走过几十年的发展历程，更是在转移性黑色素瘤的治疗中取得了60%的客观缓解率（ORR），可以诱导持久性和长期的系统免疫反应。尤其是2018年，随着两款TILs产品——IovanceLN144、LN145的Ⅱ期临床试验的成功，为实体瘤治疗开辟了新的赛道。 近年来，我国也研发出多款新型TIL疗法，据悉国内的TILs疗法是在美国的肿瘤浸润淋巴细胞（TIL）疗法基础上经过改良，以提升其克服肿瘤微环境和增加自我扩增的能力，目前已获得批准正式开展人体临床试验，涉及 黑色素瘤、肺癌、宫颈癌、胆道肿瘤、头颈部肿瘤 等多款实体瘤。 参考资料 [1]Li F,et al.Autologous Tumor-Infiltrating Lymphocyte Mono-Therapy Can Rapidly Shrank Tumor in Asian Patient with Stage III/IV Cervical Cancer: Two Cases Report[J]. International Journal of Women's Health,2024, 16: 31-39. https://www.dovepress.com/autologous-tumor-infiltrating-lymphocyte-mono-therapy-can-rapidly-shra-peer-reviewed-fulltext-article-IJWH [2]https://dailyreporter.esmo.org/esmo-congress-2023/cellular-therapies/adoptive-cell-therapy-using-tils-shows-clinically-meaningful-and-durable-efficacy-in-advanced-mucosal-melanoma [3]https://www.targetedonc.com/view/novel-treatment-shows-safety-tolerability-in-ovarian-cancer [4]https://www.targetedonc.com/view/fda-says-accelerated-approval-is-probable-for-ln-145-in-nsclc 本文为全球肿瘤医生网原创，未经授权严禁转载

BRONX, N.Y., Sept. 7, 2023 /PRNewswire/ -- In findings with potentially important implications for cervical cancer screening, scientists at the National Cancer Institute (NCI)-designated Montefiore Einstein Cancer Center (MECC) have developed a test for detecting a type of cervical cancer that Pap tests often miss. The findings published online today in the Journal of the National Cancer Institute (JNCI). "Our novel test appears sensitive for detecting cervical adenocarcinoma [ADC]—which now accounts for up to 25% of cervical cancer cases—as well as its precursor lesions, adenocarcinoma in situ [AIS], that often develop into ADCs," said Howard Strickler, M.D., M.P.H., co-senior and corresponding author of the JNCI paper and a member of MECC. "Because ADCs are often missed by current screening methods, they have higher mortality rates than the more common cervical squamous cell cancer," Dr. Strickler added. "Our goal is to catch the disease early, before it develops into cancer." Dr. Strickler is also professor and head of the division of epidemiology and the Harold and Muriel Block Chair in Epidemiology and Population Health at Albert Einstein College of Medicine. A Novel Approach to Testing The widespread use of the Pap test, in which a pathologist examines tissue samples for abnormal cells, has significantly reduced the incidence of cervical squamous cell cancer over the past six decades. However, the incidence of ADC has not decreased, probably because the Pap test is less effective at detecting it. In recent years, testing for human papillomaviruses (HPVs)—which cause virtually all cases of cervical cancer—joined the Pap test as a standard screening tool for cervical cancer. Although there are more than 100 types of HPV, three types—HPV 16, 18, and 45—account for more than 70% of all cervical cancer cases and more than 90% of ADC cases. The current HPV tests cover all three types and can alert infected women that they face a high risk for developing cervical cancer. While vaccines for preventing cervical cancer—including Gardasil-9, which protects against nine HPV types—are safe and effective, several generations of women are above the age for receiving the vaccine. Therefore, screening and treatment for prevention of cervical cancer will remain critical for decades to come. The MECC-developed HPV test assessed HPV 16, 18, and 45 in a novel way: by specifically looking at methylation levels. "The advent of next-generation genetic testing has opened up opportunities for us to more accurately detect oncogenic HPV strains and patterns in the genomes that correspond with the development of AIS and ADC," said Robert D. Burk, M.D., professor of pediatrics, of microbiology & immunology, of epidemiology and population health, and of obstetrics & gynecology and women's health at Einstein and MECC member, who co-led the study. Methylation—the addition of methyl (CH3) groups to a region of DNA—is a routine occurrence in DNA, both viral and human, and plays a critical role in altering gene expression. The JNCI study, a collaborative project with the NCI, part of the National Institutes of Health, investigated methylation levels in cervical tissue samples from 1,400 women who had undergone cervical cancer screening at Kaiser Permanente Northern California before 2014 and whose cervical cancer status was known. In assessing the HPVs in the cytological samples, the researchers tallied up the methylation percentages for each of 35 different viral-genome sites, with each sample receiving a final "methylation score" equal to the average methylation percentage across all 35 sites. Those women with methylation scores in the upper 25% had very high odds for having developed either ADC or AIS. "Our findings, if confirmed by clinical trials, suggest that women with a high methylation score may benefit from colposcopy and specialized tissue evaluation, beyond just a Pap test, which could lead to early diagnosis and treatment for ADC or the removal of AIS lesions before they develop into ADC," said Dr. Burk. Improving Equity in Cervical Cancer Screening "Given that our test uses equipment that could be simplified, it has the potential to expand testing in lower-resourced countries," said Dr. Strickler, who has long studied HPV in women living with HIV, who are more likely to acquire an HPV infection. Cervical cancer remains the fourth most common type of cancer in women, with the burden significantly higher in lower- and middle-income countries, including those in Sub-Saharan Africa, where HIV-HPV coinfections are common. There are also significant disparities within the United States. In New York City, rates of cervical cancer in the Bronx, which is home to the poorest urban congressional district in the country, are 50% higher than in Manhattan. More frequent and effective screening could help address this health disparity. "Ideally, the new HPV methylation test would only need to be done once every three to five years," said Dr. Strickler. "We are hopeful that this test will be able to increase cervical cancer screening equity in the U.S. as well." The paper is titled "A Novel HPV/Host DNA Methylation-Score and Detection of Cervical Adenocarcinoma." In addition to Drs. Strickler and Burk, other Einstein authors on the study were Ana Gradissimo, Ph.D., Xiaonan Xue, Ph.D., and Philip E. Castle, Ph.D, M.P.H. (also affiliated with the NCI). Other contributors were Megan A. Clarke, Ph.D., M.H.S., Mark Schiffman, M.D., M.P.H., and Nicolas Wentzensen, M.D., Ph.D., M.PH., all at NCI, and Tina R. Raine-Bennett, M.D., M.P.H. at Kaiser Permanente. About Montefiore Einstein Cancer Center Montefiore Einstein Cancer Center (MECC) is a national leader in cancer research and care located in the ethnically diverse and economically disadvantaged borough of the Bronx, N.Y. MECC combines the exceptional science of Albert Einstein College of Medicine with the multidisciplinary and team-based approach to cancer care of Montefiore Health System. Founded in 1971 and a National Cancer Institute (NCI)-designated Cancer Center since 1972, MECC is redefining excellence in cancer research, clinical care, education and training, and community outreach and engagement. Its mission is to reduce the burden of cancer for all, especially people from historically marginalized communities. SOURCE Montefiore Einstein Cancer Center

癌症进展被认为是肿瘤微环境(TME)内不同细胞类型之间不断演变的串扰的结果。区域淋巴管(LV)的重塑与包括宫颈鳞状细胞癌(CSCC)在内的实体肿瘤恶性进展增强和预后不良有关。 癌症进展被认为是肿瘤微环境(TME)内不同细胞类型之间不断演变的串扰的结果。区域淋巴管(LV)的重塑与包括宫颈鳞状细胞癌(CSCC)在内的实体肿瘤恶性进展增强和预后不良有关。除了为转移扩散提供物理途径外，肿瘤相关的LV还在转移反应的调节中扮演着积极的角色。 因此，转移和原发肿瘤的进展可以通过操纵肿瘤相关的淋巴重塑来影响。内皮-间充质转化(EndoMT)是淋巴管重塑的标志之一。在EndoMT期间，淋巴内皮细胞(LECs)经历表型转换，产生细长的、纺锤形的间充质样细胞，这些细胞高度迁移和侵袭，但缺乏细胞连接。 这些变化促使LEC功能障碍导致EndoMT相关的血管异常，这与肿瘤新淋巴管生成有很高的相似性，并加强了EndoMT在TME中的重要适应作用，有利于肿瘤的扩散。因此，对EndoMT的更好理解可以揭示淋巴转移的新机制。然而，目前对EndoMT在CSCC中的触发机制和功能意义知之甚少。 图片来源：https://doi.org/10.1186/s13046-023-02714-0 近日，来自珠海市人民医院研究者们在J Exp Clin Cancer Res杂志上发表了题为“Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells”的文章，该研究揭示了肿瘤相关成纤维细胞来源的PAI-1通过诱导淋巴管内皮细胞内源性MT促进淋巴转移。 内皮-间充质转化(EndoMT)是一种新出现的适应性过程，它调节淋巴管内皮细胞的功能以驱动肿瘤微环境(TME)中异常淋巴管的形成；然而，调控EndoMT功能的分子决定因素仍不清楚。在本研究中，研究者发现癌相关成纤维细胞(CAF)来源的PAI-1促进宫颈鳞癌(CSCC)中淋巴管内皮细胞(LECs)的内源性MT。 本研究对57例口腔鳞癌原发灶标本进行α-SMA、LYVE-1和DAPI免疫荧光染色。使用人细胞因子抗体阵列对CAF和正常成纤维细胞(NFs)分泌的细胞因子进行评估。采用实时荧光定量RT-PCR法、ELISA法和Western blotting法检测淋巴管内皮细胞(LECs)中EndoMT的表型、基因表达水平、蛋白分泌和信号通路活性。 研究者用Transwell、管形成实验、跨内皮细胞迁移实验检测淋巴管内皮细胞单层功能。采用窝淋巴转移模型检测淋巴转移情况。采用免疫组织化学方法分析PAI-1在宫颈鳞癌组织中的表达与EndoMT的关系。肿瘤基因组图谱(TCGA)数据库用于评估PAI-1与CSCC生存率的关系。 CaF来源的PAI-1促进CSCC中LECs的内源性MT。接受EndoMT治疗的LECs可启动肿瘤新淋巴管生成，促进癌细胞内/外渗入，进而促进CSCC的淋巴转移。在机制上，PAI-1通过直接与低密度脂蛋白受体相关蛋白(LRP1)相互作用激活AKT/ERK1/2通路，从而导致LEC内源性MT活性升高。 阻断PAI-1或抑制LRP1/AKT/ERK1/2可抑制内源性MT，从而减弱CAF诱导的肿瘤新生淋巴管生成。此外，临床资料还显示，在CSCC患者中，PAI-1水平升高与EndoMT活性和预后不良呈正相关。 机制总结图 图片来源：https://doi.org/10.1186/s13046-023-02714-0 本研究的数据表明，CAF来源的PAI-1通过调节LECs的内源性MT，在CSCC进展过程中发挥重要的新淋巴管生成启动分子的作用，从而促进原发部位的转移能力。PAI-1可作为判断宫颈鳞癌转移的有效生物标志物和治疗靶点。（生物谷 Bioon.com） 参考文献 Wen‑Fei Wei et al. Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells. J Exp Clin Cancer Res. 2023 Jul 6;42(1):160. doi: 10.1186/s13046-023-02714-0.