肿瘤细胞治疗研究
英文原题：Membrane-Anchored and Tumor-Targeted IL12 (attIL12)-PBMC Therapy for Osteosarcoma.
attIL12-PBMC 疗法治疗骨肉瘤安全有效。
目的：嵌合抗原受体（CAR）T 细胞疗法治疗血液系统恶性肿瘤前景广阔，但需要较长时间扩增 T 细胞，伴随严重毒性，治疗实体瘤疗效有限。本研究设计实验以应对这些挑战。 实验设计：我们生成一种膜锚定、肿瘤靶向 IL12（attIL12），用于武装外周血单个核细胞（PBMC），而非 T 细胞，从而避免 CAR-T 所需的扩增阶段。 结果：基于 IL12 的 attIL12-PBMC 疗法在异质性骨肉瘤患者来源异种移植瘤和转移性骨肉瘤模型中均显示显著抗肿瘤疗效，且未见可观察毒性。机制上，attIL12-PBMC 治疗引起局限于肿瘤的抗肿瘤细胞因子释放，并促使 attIL12-PBMC 在肿瘤内积累；该疗法还诱导骨肉瘤细胞终末分化为类骨细胞，从而阻碍肿瘤生长。 结论：总之，attIL12-PBMC 疗法安全且对骨肉瘤有效。我们的目标是将该疗法推进至临床试验。鉴于 attIL12-PBMC 生产流程简便，我们认为其具有可行性。
PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges. EXPERIMENTAL DESIGN: We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells. RESULTS: This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. Mechanistically, attIL12-PBMC treatment resulted in tumor-restricted antitumor cytokine release and accumulation of attIL12-PBMCs in tumors. It also induced terminal differentiation of osteosarcoma cells into bone-like cells to impede tumor growth. CONCLUSIONS: In summary, attIL12-PBMC therapy is safe and effective against osteosarcoma. Our goal is to move this treatment into a clinical trial. Owing to the convenience of the attIL12-PBMC production process, we believe it will be feasible.
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