肿瘤细胞治疗研究
英文原题：Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer Using Infusional Gemcitabine: Immune Cell Infiltration Analysis and Updated Survival.
Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer Using Infusional Gemcitabine: Immune Cell Infiltration Analysis and Updated Survival.
背景：局部晚期直肠癌的标准新辅助放化疗通常采用卡培他滨或 5-氟尿嘧啶。
背景：局部晚期直肠癌标准新辅助放化疗通常采用卡培他滨或5-氟尿嘧啶。吉西他滨是另一种放射增敏剂，具有明确的免疫调节作用；但术前同步吉西他滨放疗对直肠癌微环境和长期生存的影响尚未充分阐明。方法：本研究为II期临床试验更新及二次分析。40例成人T3/T4期或淋巴结阳性、无远处转移的直肠癌患者接受新辅助放化疗：外照射45–54 Gy，联合每周24小时持续输注吉西他滨100 mg/m²（因毒性后调整为75 mg/m²），随后手术并接受辅助卡培他滨。方案修订后，采用免疫组化分析治疗前后免疫细胞浸润。主要终点为病理完全缓解（pCR）；次要终点包括R0切除率、毒性、免疫浸润、无病生存期（原文缩写为PFS）及总生存期（OS）。结果与既往卡培他滨放化疗对照数据比较。结果：40例入组患者中，83%具有高危特征；32例接受手术，31例完成切除。更新后的中位PFS为70个月（中位随访87.4个月），中位OS尚未达到。估计5年PFS和OS分别为54.4%和67.5%。与对照相比，持续输注吉西他滨使切除肿瘤中的总免疫细胞浸润显著增加（p=0.026）。手术标本中CD8⁺ T细胞密度显著增加（p=0.001），治疗后PD-L1⁺免疫细胞也显著增多（p=0.032）；CD56⁺ NK细胞浸润呈增加趋势。毒性和pCR率与既定方案相符。结论：持续输注吉西他滨的新辅助放化疗可使局部晚期直肠癌获得持久生存及显著免疫细胞浸润，结果与现代标准治疗相当。吉西他滨的免疫调节作用，尤其是CD8⁺ T细胞及PD-L1⁺免疫细胞富集，支持进一步评估包含免疫疗法的联合策略，以增强全身性疾病控制。
Background : Standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer typically employs capecitabine or 5-fluorouracil. Gemcitabine, an alternative radiosensitizer, has a well-established immunomodulatory effect. The role of preoperative concurrent gemcitabine with radiotherapy on rectal cancer microenvironment and long-term survival has not been fully elucidated. Methods : In this phase II clinical trial update and secondary analysis, 40 adult patients with stage T3/T4 or node-positive, non-metastatic rectal cancer received neoadjuvant chemoradiotherapy consisting of external beam radiation (45-54 Gy) with weekly 24-hour infusional gemcitabine (100 mg/m 2 , later 75 mg/m 2 for toxicity) followed by surgery and adjuvant capecitabine. The protocol was amended to analyse immune cell infiltration pre- and post-treatment using immunohistochemistry. The primary endpoint was pathological complete response (pCR); secondary endpoints included R0 resection rate, toxicity, immune infiltration, disease-free survival (PFS), and overall survival (OS). Results were compared to historical controls treated with capecitabine-based chemoradiation. Results : Of the 40 enrolled patients (83% high-risk features), 32 underwent surgery, and 31 were resected. The updated median PFS was 70 months (median follow-up: 87.4 months); median OS was not reached. The estimated 5-year PFS and OS were 54.4% and 67.5%, respectively. Infusional gemcitabine induced significantly higher total immune cell infiltration in resected tumors compared to controls ( p = 0.026). CD8+ T cell density increased markedly in surgical specimens ( p = 0.001), and PD-L1+ immune cells rose significantly post-therapy ( p = 0.032). There was a trend toward increased CD56+ NK cell infiltration. Toxicities and pCR rates aligned with established regimens. Conclusions : Neoadjuvant chemoradiotherapy with infusional gemcitabine yields durable survival and robust immune cell infiltration in locally advanced rectal cancer, comparable to modern standards. The immunomodulatory effects of gemcitabine-particularly the enrichment of CD8+ T cells and PD-L1+ immune cells-support further evaluation of combination strategies incorporating immunotherapy to enhance systemic disease control.
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