Teshima T, Mach N, Hill G R, Pan L, Gillessen S, Dranoff G, Ferrara J L
Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, Michigan 48109-0942, USA.
Cancer Res. 2001 Jan 1;61(1):162-71.
Allogeneic bone marrow transplantation (BMT) is currently restricted to hematological malignancies because of a lack of antitumor activity against solid cancers. We have tested a novel treatment strategy to stimulate specific antitumor activity against a solid tumor after BMT by vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Using the B16 melanoma model, we found that vaccination elicited potent antitumor activity in recipients of syngeneic BMT in a time-dependent fashion, and that immune reconstitution was critical for the development of antitumor activity. Vaccination did not stimulate antitumor immunity after allogeneic BMT because of the post-BMT immunodeficiency associated with graft-versus-host disease (GVHD). Remarkably, vaccination was effective in stimulating potent and long-lasting antitumor activity in recipients of T-cell-depleted (TCD) allogeneic bone marrow. Recipients of TCD bone marrow who showed significant immune reconstitution by 6 weeks after BMT developed B16-specific T-cell-cytotoxic, proliferative, and cytokine responses as a function of vaccination. T cells derived from donor stem cells were, therefore, able to recognize tumor antigens, although they remained tolerant to host histocompatibility antigens. These results demonstrate that GM-CSF-based tumor cell vaccines after allogeneic TCD BMT can stimulate potent antitumor effects without the induction of GVHD, and this strategy has important implications for the treatment of patients with solid malignancies.
由于缺乏针对实体癌的抗肿瘤活性，同种异体骨髓移植（BMT）目前仅限于血液系统恶性肿瘤。我们测试了一种新的治疗策略，即通过接种经基因工程改造以分泌粒细胞巨噬细胞集落刺激因子（GM-CSF）的辐照肿瘤细胞，在BMT后刺激针对实体瘤的特异性抗肿瘤活性。使用B16黑色素瘤模型，我们发现接种疫苗能以时间依赖性方式在同基因BMT受体中引发强大的抗肿瘤活性，并且免疫重建对于抗肿瘤活性的发展至关重要。由于与移植物抗宿主病（GVHD）相关的BMT后免疫缺陷，接种疫苗在异基因BMT后并未刺激抗肿瘤免疫。值得注意的是，接种疫苗在T细胞去除（TCD）的异基因骨髓受体中有效刺激了强大且持久的抗肿瘤活性。在BMT后6周显示出显著免疫重建的TCD骨髓受体，随着接种疫苗产生了B16特异性T细胞细胞毒性、增殖和细胞因子反应。因此，源自供体干细胞的T细胞能够识别肿瘤抗原，尽管它们对宿主组织相容性抗原仍保持耐受。这些结果表明，异基因TCD BMT后基于GM-CSF的肿瘤细胞疫苗可以刺激强大的抗肿瘤作用而不诱导GVHD，并且该策略对实体恶性肿瘤患者的治疗具有重要意义。
