【两大突破进展】免疫疗法为治愈脑瘤带来新希望!
2016/03/07
高级别神经胶质瘤(glioma)是最具侵袭性的脑癌之一,尽管手术、化疗和放疗能够让病情有所改善,但是这类患者存活超过5年的不到10%。3月2日,发表在《Science Translational Medicine》上的一项研究中,科学家们提出的新一代细胞免疫疗法或将为战胜脑癌带来希望。


高级别神经胶质瘤(glioma)是最具侵袭性的脑癌之一,尽管手术、化疗和放疗能够让病情有所改善,但是这类患者存活超过5年的不到10%。3月2日,发表在《Science Translational Medicine》上的一项研究中,科学家们提出的新一代细胞免疫疗法或将为战胜脑癌带来希望。

细胞免疫疗法是通过注射治疗性抗癌疫苗刺激患者的免疫系统,使之能够攻击肿瘤。在这一研究中,鲁汶大学的科学家们将小鼠的脑癌细胞诱导成了一种特殊的死亡类型。随后,他们将这种垂死的癌细胞与树突状细胞一起培养。结果发现,垂死的癌细胞会释放危险信号,充分激活树突状细胞。

领导该研究的Patrizia Agostinis教授说:“我们将被激活的树突状细胞作为一种治疗性疫苗,重新注射到小鼠体内。观察发现,疫苗能够发出‘警报’,提醒免疫系统癌细胞的存在,并开始攻击脑瘤。”研究显示,结合化疗,这种新型的细胞免疫疗法能够显著提高脑癌小鼠的生存率,几乎50%的小鼠被完全治愈。

Agostinis表示,抗癌治疗的主要目标都是杀死所有的癌细胞,防止任何残余的恶性细胞生长或者再次扩散。然而,仅通过化疗很少能实现这样的目标,很多患者最终病情会复发。这也是为什么免疫系统的共刺激在癌症治疗中如此重要。

CAR-T治疗脑瘤获突破进展


近日,CAR-T疗法治疗实体瘤也取得了一项突破进展。发表在《Cancer Immunology Research》上的一项研究中,名古屋大学领导的研究小组发现,一种特殊的免疫细胞能够靶向肿瘤生长中的关键蛋白,帮助阻止脑癌发展。论文的通讯作者Atsushi Natsume说:“我们成功设计了能够特异性靶向podoplanin(PDPN)的CAR-T细胞疗法。”

成胶质细胞瘤(glioblastoma,GBM)是最常见、最具侵袭性的脑瘤之一,中数生存率仅14.6个月,5年生存率不到10%。PDPN是实体瘤发展过程中的一种关键蛋白。研究人员发现,注射他们设计的CAR-T细胞到79只免疫缺陷的小鼠中,成功阻止了其中60%的小鼠成胶质细胞瘤的生长。

论文的共同作者Toshihiko Wakabayashi说:“考虑到PDPN 与GBM的不良预后相关,靶向PDPN的CAR-T疗法给一线化疗后复发或耐药的患者带来了新的希望。尽管这一免疫疗法的临床应用还有很多需要克服的挑战,但这一研究是CAR-T治疗实体瘤的重要里程碑。”

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  • CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains

    Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)–transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1–based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM. Cancer Immunol Res; 4(3); 259–68. ©2016 AACR.

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  • Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell–driven rejection of high-grade glioma

    The promise of dendritic cell (DC)–based immunotherapy has been established by two decades of translational research. Of the four malignancies most targeted with clinical DC immunotherapy, high-grade glioma (HGG) has shown the highest susceptibility. HGG-induced immunosuppression is a roadblock to immunotherapy, but may be overcome by the application of T helper 1 (TH1) immunity–biased, next-generation, DC immunotherapy. To this end, we combined DC immunotherapy with immunogenic cell death (ICD; a modality shown to induce TH1 immunity) induced by hypericin-based photodynamic therapy. In an orthotopic HGG mouse model involving prophylactic/curative setups, both biologically and clinically relevant versions of ICD-based DC vaccines provided strong anti-HGG survival benefit. We found that the ability of DC vaccines to elicit HGG rejection was significantly blunted if cancer cell–associated reactive oxygen species and emanating danger signals were blocked either singly or concomitantly, showing hierarchical effect on immunogenicity, or if DCs, DC-associated MyD88 signal, or the adaptive immune system (especially CD8+ T cells) were depleted. In a curative setting, ICD-based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice by ~300%, resulting in ~50% long-term survivors. Additionally, DC vaccines also induced an immunostimulatory shift in the brain immune contexture from regulatory T cells to TH1/cytotoxic T lymphocyte/TH17 cells. Analysis of the The Cancer Genome Atlas glioblastoma cohort confirmed that increased intratumor prevalence of TH1/cytotoxic T lymphocyte/TH17 cells linked genetic signatures was associated with good patient prognosis. Therefore, pending final preclinical checks, ICD-based vaccines can be clinically translated for glioma treatment.

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