Anderson L D, Mori S, Mann S, Savary C A, Mullen C A
Department of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 2000 Oct 15;60(20):5797-802.
Allogeneic bone marrow transplantation (BMT) causes a beneficial graft-versus-tumor (GVT) immune response that is often associated with graft-versus-host disease (GVHD). There is substantial interest in developing therapeutic strategies that augment GVT without GVHD. We have demonstrated recently that immunization of BMT donors with cellular tumor vaccines leads to curative GVT but induces unacceptable GVHD because of the presence of recipient minor histocompatibility antigens (mHAgs) in whole-cell tumor vaccines. This study tested the hypothesis that immunization of BMT donors against a defined tumor-specific antigen with a vaccine not containing recipient mHAgs would help to separate the two responses by enhancing GVT activity without exacerbating GVHD, even when cellular vaccines were used after BMT. Recipient strain C57BL/6 fibrosarcoma cells engineered to express the well-characterized model tumor antigen, influenza nucleoprotein (NP), were used in these studies. C3H.SW donors were immunized against NP prior to BMT, and cytolytic T cells were transferred along with bone marrow into irradiated H-2-matched, mHAg-mismatched C57BL/6 recipients with established micrometastatic 205-NP tumors. Donor immunization led to a significant increase in GVT activity, as measured by reduction in tumor growth and enhanced survival. However, deaths in recipients of tumor antigen-specific immune BMT ultimately occurred because of the growth of antigen-loss variants; such tumor growth did not occur in animals receiving BMT from donors treated with whole-cell vaccines. Donor immunization did not lead to an exacerbation of GVHD, even when BMT recipients received additional immunization after BMT with a 205-NP "whole" tumor cell vaccine (which was shown to induce fatal GVHD when used for donor immunization). In conclusion, immunization of allogeneic BMT donors against a tumor-specific antigen significantly enhances GVT activity without an associated exacerbation of GVHD.
异基因骨髓移植（BMT）会引发有益的移植物抗肿瘤（GVT）免疫反应，而这一反应通常与移植物抗宿主病（GVHD）相关。人们对开发能增强GVT而不引发GVHD的治疗策略有着浓厚兴趣。我们最近证明，用细胞肿瘤疫苗对BMT供体进行免疫会导致治愈性的GVT，但由于全细胞肿瘤疫苗中存在受体次要组织相容性抗原（mHAgs），会引发难以接受的GVHD。本研究检验了这样一个假设：用不含受体mHAgs的疫苗对BMT供体进行针对特定肿瘤特异性抗原的免疫，有助于通过增强GVT活性而不加剧GVHD来区分这两种反应，即使在BMT后使用细胞疫苗时也是如此。在这些研究中，使用了经过基因工程改造以表达特征明确的模型肿瘤抗原——流感核蛋白（NP）的受体品系C57BL/6纤维肉瘤细胞。C3H.SW供体在BMT前针对NP进行免疫，然后将细胞毒性T细胞与骨髓一起转移到经照射的、H-2匹配但mHAg不匹配且已形成微转移205-NP肿瘤的C57BL/6受体体内。通过肿瘤生长的减少和存活率的提高来衡量，供体免疫导致GVT活性显著增加。然而，接受肿瘤抗原特异性免疫BMT的受体最终因抗原缺失变体的生长而死亡；在用全细胞疫苗处理的供体进行BMT的动物中未出现这种肿瘤生长情况。即使BMT受体在BMT后用205-NP“全”肿瘤细胞疫苗进行额外免疫（当用于供体免疫时会引发致命的GVHD），供体免疫也不会导致GVHD加剧。总之，对异基因BMT供体进行针对肿瘤特异性抗原的免疫能显著增强GVT活性，且不会伴随GVHD加剧。
