肿瘤细胞治疗研究
英文原题：Local delivery of GPC3-CAR T cells in a thermosensitive hydrogel enhances antitumor efficacy in hepatocellular carcinoma.
我们的水凝胶平台为局部 CAR-T 细胞治疗提供了一种安全、可行且有效的策略，提高了实体瘤的治疗效果。
CAR T细胞疗法在血液系统恶性肿瘤中显示出显著抗肿瘤疗效，但用于实体瘤仍面临挑战，主要由于免疫抑制性肿瘤微环境阻碍T细胞浸润并降低其功能。与标准静脉给药相比，局部递送策略在实体瘤CAR T治疗中具有显著潜力。然而，多数已报告方法依赖复杂生物材料，且主要用于免疫豁免组织。本研究开发了一种可注射、温敏型壳聚糖/β-甘油磷酸/明胶（CS/G/GP）水凝胶，用于局部递送GPC3-CAR T细胞和细胞因子IL-15，以增强实体瘤治疗效果。该水凝胶不仅支持CAR T细胞体外存活和增殖，还限制IL-15被动扩散，从而维持GPC3-CAR T细胞活性、扩增及细胞毒性。在肝细胞癌（HCC）NCG小鼠体内模型中，水凝胶介导的局部注射显著增强肿瘤组织中的CAR T细胞浸润和抗肿瘤活性，且未见明显全身毒性。总体而言，该水凝胶平台为局部CAR T细胞疗法提供了安全、可行且有效的策略，可提高实体瘤治疗效果。
CAR T cell therapy has demonstrated remarkable antitumor efficacy in hematologic malignancies, but its application in solid tumors remains challenging. This is primarily due to the suppressive tumor microenvironment, which impedes T cell infiltration and reduces their functionality. Compared with standard intravenous administration, localized delivery strategies offer significant promise for CAR T therapy in solid tumors. Nevertheless, most reported approaches rely on complex biomaterials and are mainly applied in immune-privileged tissues. Here, we developed an injectable, thermosensitive chitosan/ -glycerophosphate/gelatin (CS/G/GP) hydrogel for local delivery of GPC3-CAR T cells and the cytokine IL-15 to enhance therapeutic efficacy against solid tumors. This hydrogel not only supported in vitro survival and proliferation of CAR T cells but also limited passive diffusion of IL-15, thereby sustaining GPC3-CAR T cell activity, expansion, and cytotoxicity. In an in vivo NCG mouse model of hepatocellular carcinoma (HCC), hydrogel-mediated local injection markedly enhanced CAR T cell infiltration and antitumor activity within tumor tissues, without apparent systemic toxicity. Overall, our hydrogel platform offers a safe, feasible, and effective strategy for localized CAR T cell therapy, improving treatment efficacy in solid tumors.
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