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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation
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Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation

机译：同种异体干细胞移植后早期放射，自体，分泌GM-CSF的白血病细胞疫苗的生物活性

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摘要

Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12-43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients.
机译：通过免疫介导的移植物抗白血病作用，同种异体造血干细胞移植（HSCT）为许多血液系统恶性肿瘤患者提供了持久的临床益处。尽管如此，患有高危急性髓细胞性白血病或晚期骨髓增生异常的受试者经常会复发，从而强调了在这一人群中需要增强肿瘤免疫力。在临床前模型中，同种异体HSCT随后接种经过工程改造以分泌GM-CSF的辐射肿瘤细胞进行疫苗接种可产生有效的抗肿瘤作用，而不会加剧移植物抗宿主病（GVHD）的毒性。为了测试该策略在人类中是否可能具有相似的活性，我们进行了一项I期临床试验，该试验在同种异体非清髓性HSCT早期，对高危急性髓性白血病或骨髓增生异常患者进行了放射，自体，分泌GM-CSF分泌的肿瘤细胞的免疫接种。尽管使用钙调神经磷酸酶抑制剂预防GVHD，但疫苗接种引起的局部和全身反应在质量上与以前在未移植的，免疫的实体瘤患者中观察到的相似。尽管急性和慢性GVHD的频率没有增加，但完成疫苗接种的10名受试者中有9名获得了持久的完全缓解，平均随访时间为26个月（范围12-43个月）。六名长期应答者显示可溶性NKG2D配体水平显着下降，而三名表明细胞毒性淋巴细胞NKG2D表达随治疗而正常化。总之，这些结果建立了异基因HSCT后早期放射，自体，分泌GM-CSF的自分泌白血病细胞疫苗的安全性和免疫原性，并提高了这种组合免疫疗法增强患者移植物抗白血病能力的可能性。

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  • 作者

    Vincent T. Ho; Matthew Vanneman; Haesook Kim; Tetsuro Sasada; Yoon Joong Kang; Mildred Pasek; Corey Cutler; John Koreth; Edwin Alyea; Stefanie Sarantopoulos; Joseph H. Antin; Jerome Ritz; Christine Canning; Jeffery Kutok; Martin C. Mihm; Glenn Dranoff; Robert Soiffer;

  • 作者单位

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    bone marrow transplant; GVL; MICA; NKG2D; tumor immunity;

    机译：骨髓移植;GVL;云母;NKG2D;肿瘤免疫;

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