编者按：在2026年妇科肿瘤学会（SGO）年会的“科学全体大会V：宫颈癌治疗的新兴策略”专场中，Min Guan医学博士/哲学博士代表美国希望之城国家医学中心T细胞治疗研究实验室，口头报告了题为“针对宫颈癌的ENG靶向CAR T细胞的开发：直接靶向肿瘤与微环境调控（Development of ENG–Targeted CAR T cells for cervical cancer:Direct tumor targeting and microenvironment modulation）”的研究。本报现场采访了Min Guan教授，就研究的核心数据、安全性及临床转化前景进行了深入对话。

 

 

宫颈癌是全球女性第四大常见癌症，预计到2026年将新增约66.7万例病例并导致约35万例死亡。晚期及复发性疾病患者的生存率极低，且现有免疫疗法的缓解率仍然有限且不稳定。这类肿瘤通常具有高度血管化特征，并富含TGF-β驱动的信号通路；同时，致密的肿瘤间质会阻挡治疗细胞进入，而免疫排斥又让进入的细胞难以存活，这两个因素构成了细胞疗法起效的主要障碍。尽管在疫苗接种和筛查方面已取得一定进展，但晚期宫颈癌仍然致命，治疗选择十分有限。

 

 

Min Guan团队开发了一种新型的第二代靶向内皮糖蛋白（endoglin）的CAR-T细胞（简称ENG-CAR）。选择ENG作为靶点的原因在于：它在宫颈癌的肿瘤起始细胞、肿瘤血管、活化间质以及新生血管内皮上均呈现高表达，同时它也是TGF-β超家族的共受体。基于内皮糖蛋白（Endoglin）的嵌合抗原受体（ENG-CAR）具有双重作用机制：①直接靶向肿瘤：识别CD105阳性的宫颈癌细胞，诱导抗原特异性的细胞杀伤作用；②重编程肿瘤微环境：靶向CD105阳性的肿瘤相关血管，破坏促血管生成的信号通路，平衡TGF-β信号传导，并增强免疫细胞的可及性。

 

该CAR采用纳米抗体构建体，对宫颈癌细胞表现出特异性激活与剂量依赖性细胞毒性，能有效抑制细胞迁移、穿透并清除三维肿瘤球体。该CAR-T细胞能够干扰肿瘤血管生成信号并重新平衡TGF-β信号通路，从而改善T细胞浸润困难的免疫抑制微环境。

 

ENG-CAR T细胞的体内抗肿瘤实验方案：采用腹腔注射HeLa细胞在小鼠体内建立宫颈癌模型，再腹腔注射CAR-T细胞，并通过眶后采血监测免疫反应。在腹腔播散型小鼠模型中，单次输注ENG-CAR-T细胞即可使100%的小鼠存活超过160天，且在治疗后的第75天进行肿瘤细胞再接种（re-challenge）时，CAR-T细胞仍能控制肿瘤生长。

 

ENG-CAR T细胞疗法的抗肿瘤活性

 

在安全性方面，ENG-CAR不会诱导“靶向非肿瘤”毒性（即不会损伤表达相同靶点的正常组织），对正常人肾细胞无明显杀伤作用，且靶向Endoglin的既往临床研究支持其可行性。

 

ENG-CAR T细胞对正常肾细胞的细胞毒性测定

 

结论与展望：该细胞疗法通过以下机制展现出强效的抗宫颈癌活性：直接靶向并杀伤肿瘤细胞、调节TGF-β信号通路、有效穿透实体肿瘤球体以及发挥抗血管生成作用。这一研究的意义在于，ENG-CAR代表了宫颈癌免疫治疗中一种创新且极具前景的策略，其通过直接细胞毒性与TGF-β通路调控的双重作用机制，有望克服肿瘤微环境所带来的治疗障碍。

 

Min Guan：这是一个很好的问题。我们选择ENG（即endoglin，也称CD105）的原因是，该标志物能通过TGF-β信号通路同时靶向肿瘤本身和肿瘤微环境。它通过肿瘤细胞表面的抗原特异性结合实现双重机制。在宫颈癌等具有高度血管生成和免疫逃逸特征的恶性肿瘤中，这种T细胞治疗已展现出积极的信号。

 

在我们的动物体内实验中，我们观察到了非常有效的抗肿瘤活性。接受这种CAR-T细胞治疗的小鼠，100%存活超过160天，并且没有观察到任何毒性反应。所有小鼠的肿瘤都消退了，即使我们在第75天进行一次再挑战（重新接种肿瘤）后，肿瘤也依然没有复发。这使得我们的构建体与传统的scFv型CAR-T平台相比具有独特和显著的优势，因为在传统平台中我们还没有观察到如此强大的疗效。

 

我们靶向ENG（CD105）的CAR结构是基于纳米抗体的构建体。纳米抗体通常比传统的scFv型CAR更小、结构更灵活，并且潜在的免疫原性更低。我们的构建体经过设计和验证，具有长期持久性。这种独特的CAR结构可能解释了为什么该疗法在小鼠模型中显示出强效且低毒性的特点。

 

Oncology Frontier:Professor Guan，it is a great honor to have you again at the SGO 2026 Annual Meeting.In your presented in vivo experiments，how effective were the ENG CAR-T cells in inhibiting tumor growth and metastasis?How did it perform compared to conventional treatments or other CAR-T cells and therapies?

 

Min Guan:This is a very good question.The reason we selected ENG，also known as endoglin or CD105，is that this marker targets both the tumor itself and the tumor microenvironment through TGF-beta signaling.It operates through a dual mechanism via antigen-specific binding on the tumor cell surface.In malignancies such as cervical cancer，which exhibit a high degree of vascular and immune evasion，this approach has shown promising signals in T cell-based therapies.

 

In our in vivo animal studies，we observed highly effective anti-tumor activity.One hundred percent of the CAR-T cell-treated mice survived for over 160 days without any observed toxicity.All tumors regressed，even after we administered a single rechallenge at day 75.This makes our construct particularly distinctive and unique compared to traditional scFv-based CAR-T platforms，where we have not yet observed such potent efficacy.

 

Our CAR is derived from a nanobody-based construct.Nanobodies are generally smaller，more structurally flexible，and potentially less immunogenic than traditional scFv-based CARs.Our construct has been designed and validated for long-term persistence.This unique CAR structure may explain why the therapy demonstrates potent efficacy with low toxicity in murine models.

 

Min Guan：基于我们当前的平台，已观察到极低的“靶向非肿瘤”毒性，这是因为该CAR具有高度的肿瘤特异性。其在正常组织中的表达水平很低，仅在部分血管结构中有中度表达。我们将这些CAR-T细胞与正常的人肾细胞系共培养，未发现正常细胞增殖受到损害。此外，在临床前研究中经过160天的观察，我们未检测到任何相关不良事件或继发性恶性肿瘤，这与既往TRC105的临床经验一致。如果该平台未来进入临床应用，我们还可以引入额外的调控机制或安全开关，特别是考虑到该CAR的分子结构比传统设计更小。

 

Oncology Frontier:Regarding toxicity and safety，were any potential toxic side effects observed?And how were these risks addressed in the design?

 

Min Guan:Based on our current platform，we have observed minimal on-target，off-tumor toxicity because this CAR is highly tumor-specific.Expression is very low in normal tissues，with the exception of moderate expression in certain vascular structures.We co-cultured these CAR-T cells with normal human kidney cell lines and found no impairment of normal human cell proliferation.Furthermore，after 160 days of observation in our preclinical studies，we did not detect any associated adverse events or secondary malignancies align with prior TRC105 clinical experience.Should this platform advance into clinical settings in the future，we could potentially incorporate additional control mechanisms or safety switches，especially given that this CAR construct is smaller than traditional designs.

Min Guan：该ENG CAR-T细胞疗法专门针对复发及转移性疾病的治疗而设计，因此我们在动物模型中采用了腹腔注射的给药方式。这些CAR-T细胞能够通过血液循环迁移，并在体内持续存在至少一个月。在腹水中也能检测到它们的存在，提示即使在动物被处死的第43天，它们仍可能有效靶向腹膜转移灶。此外，ENG CAR-T细胞疗法还展现出穿透致密肿瘤结构、破坏肿瘤球体以及迁移至骨髓腔的能力。我们希望这种ENG CAR-T细胞疗法能够有效靶向远处的微小转移灶及复发灶，而目前这类患者可用的治疗手段非常有限。

 

Oncology Frontier:At which stage of cervical cancer do you believe ENG CAR-T cell therapy is most suitable for?

 

Min Guan:This ENG CAR-T cell therapy was specifically designed for treating relapsed and metastatic disease.That is why we use intraperitoneal routes for CAR-T cell administration in our models.These CAR-T cells can traffic through the bloodstream and persist in the body for at least one month.They can also be detected in ascites fluid，suggesting they may effectively target peritoneal metastases even by day 43 when animals were euthanized.ENG CAR-T cell therapy demonstrates the ability to penetrate dense tumor structure，destroyed tumor spheroids and migrate to the bone marrow compartment.We hope this CAR will effectively target distant micrometastases and relapsed disease settings where patients currently have limited therapeutic options.

 

Min Guan：尽管ENG CAR-T细胞单药治疗已展现出非常有前景的疗效，但联合治疗无疑是下一步值得探索的重要方向。已有研究表明，类似的CAR-T疗法在肝癌模型中与PD-1抑制剂联合使用，可显著增强疗效。因此，我们未来也计划采用类似的联合策略，这将是我们后续研究的重点之一。

 

Oncology Frontier:Are there plans to combine this therapy with other treatments?

 

Min Guan:That is a very important point.Although our monotherapy results are quite promising，combination therapy represents a highly feasible and logical next step.In other research，similar CAR engineering approaches have been combined with PD-1 inhibitors in liver cancer models，demonstrating enhanced efficacy.We could potentially pursue a similar strategy，and this constitutes a focus of our subsequent research.

 

Min Guan：我关注到一些探索新型TCR-T疗法在临床试验中应用的壁报和口头报告。尽管相关结果尚未完全成熟或更新，但已显示出令人鼓舞的安全性和初步疗效数据。此外，还有一些研究探索了包含PD-1抑制剂或VEGF靶向药物的联合方案，这些方案在机制上与我们的ENG CAR-T治疗策略具有某些相似之处。这些都是非常有价值的研究方向。

 

Oncology Frontier:Which other study reported at the 2026 SGO Annual Meeting are you most interested in?

 

Min Guan:I have observed several interesting posters and presentations focusing on new therapies within the TCR-T landscape in clinical trials.Although the results are not yet fully mature or updated，they demonstrate encouraging safety profiles and promising preliminary data.Additionally，there are studies exploring combination regimens involving PD-1 inhibitors or VEGF-targeted agents，which share some mechanistic similarities with our CAR approach.Those represent particularly intriguing avenues of research.

 

专家简介

Min Guan，MD，Ph.D.

希望之城国家医疗中心，T细胞治疗研究实验室