CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
脾脏 SORT LNP 原位生成的 CAR-T 细胞在淋巴充足 B 细胞淋巴瘤小鼠模型中延长生存期
英文原题：Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma.
查看英文原题
Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma.
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中文摘要
嵌合抗原受体（CAR）T 细胞免疫疗法正改变 B 细胞淋巴瘤患者的治疗方式，但目前 CAR-T 细胞生产流程复杂且费用高昂，需要采集患者血液、富集 T 细胞、在体外进行工程化改造和活化，并开展质量评估后才能治疗患者。
本研究利用脾脏选择性器官靶向（SORT）脂质纳米颗粒（LNP），在体内原位制备 CAR-T 细胞，从而绕过目前冗长、繁重的流程。含 10% 18:1 PA 的优化脾脏 SORT LNP 可在野生型小鼠中转染 CD3⁺、CD8⁺ 和 CD4⁺ T 细胞。静脉注射后，脾脏 SORT LNP 可分别在报告小鼠和淋巴细胞数量正常的 B 细胞淋巴瘤模型中，将 Cre 重组酶 mRNA 和 CAR 编码 mRNA 递送至 T 细胞，无需主动靶向配体。
此外，原位生成的 CAR-T 细胞可延长患较低侵袭性 B 细胞淋巴瘤小鼠的总生存期。原位转染的 CAR-T 细胞还可通过增加TIL（肿瘤浸润淋巴细胞），减少肿瘤转移至肝脏。
总体而言，这些结果为 CAR-T 细胞生产提供了一种有前景的替代方法，具备治疗血液系统恶性肿瘤的临床前潜力。
展开英文摘要原文
Chimeric Antigen Receptor (CAR) T cell immunotherapy is revolutionizing treatment for patients suffering from B-cell lymphoma (BL).
However, the current method of CAR T cell production is complicated and expensive, requiring collection of patient blood to enrich the T cell population, ex vivo engineering/activation, and quality assessment before the patient can receive the treatment.
Herein we leverage Spleen Selective ORgan Targeted (SORT) Lipid Nanoparticles (LNPs) to produce CAR T cells in situ and bypass the extensive and laborious process currently used. Optimized Spleen SORT LNPs containing 10 % 18 : 1 PA transfected CD3+, CD8+, and CD4+ T cells in wild-type mice. Spleen SORT LNPs delivered Cre recombinase mRNA and CAR encoding mRNA to T cells in reporter mice and in a lymphoreplete B cell lymphoma model (respectively) after intravenous injection without the need for active targeting ligands.
Moreover, in situ CAR T cells increased the overall survival of mice with a less aggressive form of B cell lymphoma.
In addition, in situ transfected CAR T cells reduced tumor metastasis to the liver by increasing tumor infiltrating lymphocytes.
Overall, these results offer a promising alternative method for CAR T cell production with pre-clinical potential to treat hematological malignancies.
论文信息
- 作者
- Álvarez-Benedicto E、Tian Z、Chatterjee S、Orlando D、Kim M、Guerrero ED、Wang X、Siegwart DJ
- 单位
- Department of Biomedical Engineering, Department of Biochemistry, Simmons Comprehensive Cancer Center and Program in Genetic Drug Engineering, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.United States
- 期刊
- Angewandte Chemie (International ed. in English)2023 Oct 26
- 原文标识
- PubMed 37651468 · DOI 10.1002/anie.202310395
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