Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Immunol Res. 2017 Dec;5(12):1152-1161. doi: 10.1158/2326-6066.CIR-17-0189. Epub 2017 Nov 6.
Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 10 or 3 × 10 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. .
嵌合抗原受体 (CAR) 是提供 T 细胞新特异性的合成分子。尽管在治疗血液恶性肿瘤方面取得了成功，但到目前为止，CAR T 细胞对实体瘤无效。我们发现，细胞表面分子 c-Met 在约 50%的乳腺癌肿瘤中表达，促使构建了一种针对 c-Met 的 CAR T 细胞，该细胞在具有肿瘤异种移植物的免疫功能低下的小鼠中阻止了肿瘤生长。然后，我们在一项 0 期临床试验 (NCT01837602) 中评估了通过瘤内注射转染 mRNA 的 c-Met-CAR T 细胞治疗转移性乳腺癌的安全性和可行性。通过限制靶向 c-Met 的非肿瘤细胞效应（靶标/脱靶），通过 mRNA 引入 CAR 构建体确保了安全性。有可触及的皮肤或淋巴结转移的转移性乳腺癌患者接受单次瘤内注射 3×10 或 3×10 个细胞。在 2 名和 4 名患者中，分别在瘤内注射后在外周血和注射肿瘤组织中检测到 CAR T mRNA。mRNA c-Met-CAR T 细胞注射耐受良好，没有患者出现大于 1 级的与研究药物相关的不良反应。通过免疫组织化学分析切除并分析用瘤内注射的 mRNA c-Met-CAR T 细胞治疗的肿瘤，在注射部位发现广泛的肿瘤坏死，细胞碎片，c-Met 免疫反应丧失，所有这些都被巨噬细胞包围在前沿和坏死区。我们得出结论，瘤内注射 mRNA c-Met-CAR T 细胞耐受良好，并在肿瘤内引发炎症反应。
