Szoor Arpad, Vaidya Abishek, Velasquez Mireya Paulina, Mei Zhuyong, Galvan Daniel L, Torres David, Gee Adrian, Heczey Andras, Gottschalk Stephen
Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, TX 77030, USA.
Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Ther Oncolytics. 2017 Jul 28;6:69-79. doi: 10.1016/j.omto.2017.07.002. eCollection 2017 Sep 15.
The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3) HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL). Coculture of GPC3 cells, GPC3-ENG MSCs, and T cells resulted in T cell activation, as judged by interferon γ (IFNγ) production and killing of tumor cells by T cells. Modification of GPC3-ENG MSCs with CD80 and 41BBL was required for antigen-dependent interleukin-2 (IL-2) production by T cells and resulted in faster tumor cell killing by redirected T cells. In vivo, GPC3-ENG MSCs ± costimulatory molecules had antitumor activity in the HUH7 HCC xenograft model, resulting in a survival advantage. In conclusion, MSCs genetically modified to express GPC3-ENG ± costimulatory molecules redirect T cells to GPC3 tumor cells and have potent antitumor activity. Thus, further preclinical exploration of our modified approach to GPC3-targeted immunotherapy for HCC is warranted.
晚期肝细胞癌（HCC）的治疗效果仍然很差，这凸显了对新型疗法的需求。由于基因改造的间充质干细胞（MSCs）具有迁移至肿瘤部位的内在能力，因此正被积极探索作为癌症治疗手段。我们推断，可以对MSCs进行基因改造，使其将T细胞重定向至Glypican-3（GPC3）阳性的HCC，并用编码GPC3/CD3双特异性T细胞衔接器（GPC3-ENG）、针对无关抗原（EGFRvIII）的双特异性T细胞衔接器和/或共刺激分子（CD80和41BBL）的病毒载体对其进行基因改造。GPC3细胞、GPC3-ENG MSCs和T细胞共培养导致T细胞活化，这可通过干扰素γ（IFNγ）产生以及T细胞对肿瘤细胞的杀伤作用来判断。用CD80和41BBL对GPC3-ENG MSCs进行改造是T细胞产生抗原依赖性白细胞介素-2（IL-2）所必需的，并且可导致重定向T细胞更快地杀伤肿瘤细胞。在体内，GPC3-ENG MSCs ± 共刺激分子在HUH7 HCC异种移植模型中具有抗肿瘤活性，从而带来生存优势。总之，经基因改造以表达GPC3-ENG ± 共刺激分子的MSCs可将T细胞重定向至GPC3肿瘤细胞，并具有强大的抗肿瘤活性。因此，有必要对我们改良的GPC3靶向HCC免疫治疗方法进行进一步的临床前探索。
