Crossland K D, Lee V K, Chen W, Riddell S R, Greenberg P D, Cheever M A
Department of Medicine, University of Washington, Seattle 98195.
J Immunol. 1991 Jun 15;146(12):4414-20.
The therapeutic efficacy of adoptive immunotherapy of cancer has been shown to positively correlate with the dose of tumor-immune T cells transferred. Therefore, the success of this therapy is critically dependent on the ability to procure large numbers of functionally active T cells. Previous studies in animal models have shown that the limited therapeutic efficacy of a small number of immune T cells can be greatly enhanced by expansion of T cells in vitro to greater numbers before transfer in vivo. Optimal regimens for T cell expansion in vitro have generally employed the use of intermittent stimulation of the TCR with specific Ag followed by exogenous IL-2. The use of IL-2 alone does not provide for requisite episodic up-regulation of IL-2R. Stimulation of the invariant CD3 portion of the TCR/CD3 complex with antibody to CD3 (anti-CD3) represents an alternative method of up-regulating IL-2R and has been used to nonspecifically induce the growth of Ag-specific T cell lines and clones long-term in vitro with maintenance of function and specificity. The current study examined whether resting T cell populations containing small numbers of memory tumor-specific T cells could be rendered more effective in tumor therapy by nonspecific expansion in vitro with anti-CD3 plus IL-2. Spleens from C57BL/6 mice previously immunized to FBL-3, a syngeneic virus-induced leukemia, were nonspecifically stimulated with anti-CD3 plus IL-2. The resultant T cells were expanded in number, were nonlytic to FBL-3 but retained the ability to become lytic upon specific stimulation by FBL-3, and were effective in specific tumor therapy. The Ag-specific anti-tumor immune function declined on a per cell basis after each cycle of anti-CD3-induced T cell expansion. However, the approach resulted in a substantial increase in total T cell number and an overall net increase in the function of the effector T cell population. Thus, stimulation of tumor-immune T cell populations with anti-CD3 plus IL-2 represents a nonspecific method for expanding the number of specific effector T cells for cancer therapy.
癌症过继性免疫疗法的治疗效果已被证明与转移的肿瘤免疫T细胞剂量呈正相关。因此，这种疗法的成功关键取决于获取大量功能活跃T细胞的能力。先前在动物模型中的研究表明，少量免疫T细胞有限的治疗效果可通过在体外将T细胞扩增至更多数量后再体内转移而得到显著增强。体外T细胞扩增的最佳方案通常采用用特异性抗原间歇性刺激TCR，随后添加外源性白细胞介素-2（IL-2）。单独使用IL-2并不能提供必要的IL-2受体间歇性上调。用抗CD3抗体刺激TCR/CD3复合物的恒定CD3部分是上调IL-2受体的另一种方法，已被用于在体外长期非特异性诱导抗原特异性T细胞系和克隆的生长，并维持其功能和特异性。当前研究考察了含有少量记忆性肿瘤特异性T细胞的静息T细胞群体是否可通过用抗CD3加IL-2进行体外非特异性扩增而在肿瘤治疗中变得更有效。先前已免疫同基因病毒诱导的白血病FBL-3的C57BL/6小鼠的脾脏用抗CD3加IL-2进行非特异性刺激。产生的T细胞数量增加，对FBL-3无细胞毒性，但在受到FBL-3特异性刺激后仍保留变为细胞毒性的能力，并且在特异性肿瘤治疗中有效。在抗CD3诱导的T细胞扩增的每个周期后，每个细胞的抗原特异性抗肿瘤免疫功能下降。然而，该方法导致T细胞总数大幅增加，效应T细胞群体的功能总体净增加。因此，用抗CD3加IL-2刺激肿瘤免疫T细胞群体是一种用于癌症治疗的扩增特异性效应T细胞数量的非特异性方法。
