肿瘤细胞治疗研究
英文原题：Therapeutic Efficacy of IL7/CCL19-Expressing CAR-T Cells in Intractable Solid Tumor Models of Glioblastoma and Pancreatic Cancer.
我们的结果表明，7 19 CAR-T可能成为胶质母细胞瘤和胰腺癌的一种治疗选择。
未标注：使用免疫检查点抑制剂及其与其他抗癌疗法联合的癌症免疫治疗，由于在多种实体癌中显示出令人鼓舞的治疗效果，已成为一种新的标准治疗。然而，胶质母细胞瘤和胰腺癌仍然对免疫治疗耐药，属于预后最差、难以治疗的癌症。我们研究了产生IL7和趋化因子（C-C基序）配体19（CCL19；称为7 19 CAR-T）的下一代嵌合抗原受体（CAR）T细胞在这些难治性癌症中的治疗效果。在以下模型中，于体外和体内评估了7 19 CAR-T的细胞毒活性和治疗效果：使用EGFR变异体III（EGFRvIII）阳性胶质母细胞瘤和由健康供者外周血单个核细胞（PBMC）产生的抗EGFRvIII CAR-T的模型，或使用HER2阳性胰腺癌类器官和由同一患者PBMC产生的抗HER2 CAR-T的模型。抗EGFRvIII 7 19 CAR-T表现出对EGFRvIII阳性肿瘤特异性的细胞毒活性，诱导胶质母细胞瘤完全排斥，并伴有大量T细胞浸润和肿瘤组织中的肿瘤细胞死亡，从而延长了小鼠生存期。抗HER2 7 19 CAR-T表现出对自体HER2阳性胰腺癌类器官的强效细胞毒活性，并诱导自体肿瘤完全排斥，同时延长了小鼠生存期。我们的结果表明，7 19 CAR-T可能成为胶质母细胞瘤和胰腺癌的一种治疗选择。据我们所知，这是首个在自体模型中证明下一代 CAR-T 治疗效果的研究，该模型使用患者来源的肿瘤类器官和来自同一患者 PBMC 生成的 CAR-T，完全排除了不需要的同种异体免疫反应。意义：尽管 CAR T 细胞疗法的临床开发已取得进展，但其在实体癌中的疗效尚未确立。本研究探讨了产生 IL7/CCL19 的 CAR-T 疗法在胶质母细胞瘤和胰腺癌临床前实体癌模型中的治疗潜力和免疫机制。我们发现，由患者 PBMC 生成的产生 IL7/CCL19 的 CAR-T 细胞对通过接种来自自体肿瘤组织的类器官所建立的实体癌模型显示出强效的治疗作用。
UNLABELLED: Cancer immunotherapy using immune checkpoint inhibitors and its combination with other anticancer therapies has emerged as a new standard of care because of the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated the therapeutic effects of next-generation chimeric antigen receptor (CAR) T cells producing IL7 and chemokine (C-C motif) ligand 19 (CCL19; referred to as 7 19 CAR-T) in these intractable cancers. Cytotoxic activities and therapeutic effects of 7 19 CAR-T were evaluated in vitro and in vivo, in a model using EGFR variant III (EGFRvIII)-positive glioblastoma and anti-EGFRvIII CAR-T generated from healthy donor peripheral blood mononuclear cells (PBMC), or a model using HER2-positive pancreatic cancer organoids and anti-HER2 CAR-T generated from the same patient's PBMC. Anti-EGFRvIII 7 19 CAR-T exhibited cytotoxic activity specific to EGFRvIII-positive tumor, induced complete rejection of glioblastoma with massive T-cell infiltration and tumor cell death in the tumor tissues, and consequently prolonged mouse survival. Anti-HER2 7 19 CAR-T demonstrated a potent cytotoxic activity against autologous HER2-positive pancreatic cancer organoids and induced complete rejection of autologous tumor along with prolonged mouse survival. Our results suggest that 7 19 CAR-T could become a therapeutic option for glioblastoma and pancreatic cancer. To the best of our knowledge, this is the first study to demonstrate the therapeutic efficacy of next-generation CAR-T in an autologous model using patient-derived tumor organoids and CAR-T generated from the same patient's PBMC, in which unwanted allogeneic immune responses are fully excluded. SIGNIFICANCE: Despite the clinical development of CAR T-cell therapy, its efficacy in solid cancers has yet to be established. This study explored the therapeutic potential and immunologic mechanisms of IL7/CCL19-producing CAR-T therapy in preclinical solid cancer models of glioblastoma and pancreatic cancer. We found that IL7/CCL19-producing CAR-T cells generated from the patient's PBMC showed potent therapeutic effects against the solid cancer model established by inoculating organoids from the autologous tumor tissue.
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