Todryk S M, Birchall L J, Erlich R, Halanek N, Orleans-Lindsay J K, Dalgleish A G
The Onyvax Collaboration Laboratory, Division of Oncology, St. George's Hospital Medical School, London, UK.
Immunology. 2001 Feb;102(2):190-8. doi: 10.1046/j.1365-2567.2001.01176.x.
Whole tumour cells are a logical basis for generating immunity against the cancers they comprise or represent. A number of human trials have been initiated using cytokine-transfected whole tumour cells of autologous (patient-derived) or allogeneic [major histocompatibility complex (MHC)-disparate] origin as vaccines. Although precedent exists for the efficacy of autologous-transfected cell vaccines in animal models, little preclinical evidence confirms that these findings will extrapolate to allogeneic-transfected cell vaccines. In order to address this issue a murine melanoma cell line (K1735) was transfected to secrete interleukin (IL)-2, IL-4, IL-7 or granulocyte-macrophage colony-stimulating factor (GM-CSF); cytokines currently in use in trials. The efficacy of these cells as irradiated vaccines was tested head-to-head in syngeneic (C3H) mice and in MHC-disparate (C57BL/6) mice, the former being subsequently challenged with K1735 cells and the latter with naturally cross-reactive B16-F10 melanoma cells. Whilst the GM-CSF-secreting vaccine was the most effective at generating protection in C3H mice, little enhancement in protection above the wild-type vaccine was seen with any of the transfections for the allogeneic vaccines, even though the wild-type vaccine was more effective than the autologous B16-F10 vaccine. Anti-tumour cytotoxic T-lymphocyte (CTL) activity was detected in both models but did not correlate well with protection, whilst in vitro anti-tumour interferon-gamma (IFN-gamma) secretion tended to be higher following the GM-CSF-secreting vaccine. Cytokine transfection of vaccines generally increased anti-tumour CTL activity and IFN-gamma secretion (T helper type 1 response). Further studies in other model systems are required to confirm this apparent lack of benefit of cytokine transduction over wild-type allogeneic vaccines, and to determine which in vitro assays will correlate best with protection in vivo.
完整肿瘤细胞是产生针对其所构成或代表的癌症的免疫反应的合理基础。已经开展了一些人体试验，使用细胞因子转染的自体（患者来源）或同种异体[主要组织相容性复合体（MHC）不同]来源的完整肿瘤细胞作为疫苗。尽管自体转染细胞疫苗在动物模型中的有效性已有先例，但很少有临床前证据证实这些发现可外推至同种异体转染细胞疫苗。为了解决这个问题，将一种小鼠黑色素瘤细胞系（K1735）进行转染，使其分泌白细胞介素（IL）-2、IL-4、IL-7或粒细胞巨噬细胞集落刺激因子（GM-CSF）；这些细胞因子目前正在试验中使用。在同基因（C3H）小鼠和MHC不同（C57BL/6）小鼠中对这些经辐照的细胞作为疫苗的有效性进行了直接比较测试，前者随后用K1735细胞攻击，后者用天然交叉反应的B16-F10黑色素瘤细胞攻击。虽然分泌GM-CSF的疫苗在C3H小鼠中产生保护作用方面最有效，但对于同种异体疫苗，任何一种转染在保护作用上都没有比野生型疫苗有明显增强，尽管野生型疫苗比自体B16-F10疫苗更有效。在两种模型中均检测到抗肿瘤细胞毒性T淋巴细胞（CTL）活性，但与保护作用相关性不佳，而在体外，分泌GM-CSF的疫苗接种后抗肿瘤干扰素-γ（IFN-γ）分泌往往更高。疫苗的细胞因子转染通常会增加抗肿瘤CTL活性和IFN-γ分泌（1型辅助性T细胞反应）。需要在其他模型系统中进行进一步研究，以证实细胞因子转导相对于野生型同种异体疫苗明显缺乏益处，并确定哪些体外试验与体内保护作用相关性最佳。
