Generation from tumor-bearing mice of lymphocytes with in vivo therapeutic efficacy.
Generation from tumor-bearing mice of lymphocytes with in vivo therapeutic efficacy.
复制标题
从荷瘤小鼠中产生具有体内治疗功效的淋巴细胞。
作者：
S. Shu;T. Chou;S. Rosenberg
致敏淋巴细胞的全身转移可以有效介导已形成肿瘤的消退。然而，实际上该方法的所有先前实验应用都利用来自已免疫动物的淋巴细胞来抵抗肿瘤攻击。人体中没有类似的细胞来源。通过使用弱免疫原性小鼠肿瘤 MCA 105，我们在此证明，在用活肿瘤细胞和白细胞介素 2 进行体外致敏 (IVS) 后，来自具有逐渐生长的肿瘤的小鼠的非治疗性淋巴细胞获得了抗肿瘤反应性，能够介导已形成的肺转移的消退。尽管IVS系统诱导了正常和荷瘤小鼠的淋巴细胞的非特异性淋巴因子激活的杀伤样细胞毒活性，但治疗活性细胞只能从荷瘤动物的淋巴细胞起始的培养物中产生，这表明IVS是二次体外免疫反应。在没有其他治疗的情况下，IVS 细胞可以介导抗肿瘤作用。然而，低剂量的外源白细胞介素2给药可以增强其治疗效果。通过用单克隆抗体去除体内 T 细胞亚群，初级效应细胞被鉴定为属于表达 Lyt-2 表型的细胞毒性/抑制性 T 细胞谱系。此外，在白细胞介素2存在的情况下，通过肿瘤细胞的持续刺激，这些治疗性效应细胞可以在体外进一步扩增。与开始培养的细胞数量相比，经过9天的IVS，然后再体外扩增5天，获得的细胞数量高达126倍。对肿瘤生长过程中前效应淋巴细胞出现动力学的研究表明，它们很容易从具有广泛肿瘤负荷和肿瘤生长持续时间的小鼠的引流淋巴结中获得。在体外从荷瘤宿主产生和扩增具有治疗活性的淋巴细胞的能力对于人类癌症的细胞治疗具有重要意义。
Systemic transfer of sensitized lymphocytes can effectively mediate the regression of established tumors. However, virtually all prior experimental applications of this approach have utilized lymphocytes from animals that have been immunized to reject tumor challenge. A similar source of cells is not available in the human. With the use of a weakly immunogenic murine tumor, MCA 105, we demonstrate here that following in vitro sensitization (IVS) with viable tumor cells and interleukin 2, the nontherapeutic lymphoid cells from mice bearing a progressively growing tumor acquired antitumor reactivity capable of mediating the regression of established pulmonary metastases. Although the IVS system induced nonspecific lymphokine-activated killer-like cytotoxic activity from lymphoid cells of normal as well as tumor-bearing mice, therapeutically active cells could only be generated from cultures initiated with lymphoid cells from tumor-bearing animals, indicating that the IVS was a secondary in vitro immune response. Without other treatment, the IVS cells could mediate antitumor effects. However, low doses of exogenous interleukin 2 administration could enhance their therapeutic efficacy. By in vivo T cell subset depletion with monoclonal antibodies, the primary effector cells were identified as belonging to cytotoxic/suppressor T cell lineage expressing the Lyt-2 phenotype. In addition, these therapeutic effector cells could be further expanded in numbers in vitro with continuous stimulation by tumor cells in the presence of interleukin 2. Compared to the number of cells initiating the culture, as many as 126 times the number of cells were obtained after 9 days of IVS followed by in vitro expansion for an additional 5 days. Studies on the kinetics of the occurrence of the pre-effector lymphocytes during tumor growth revealed that they were readily obtained from draining lymph nodes of mice with a broad range of tumor burdens as well as durations of tumor growth. The ability to generate and expand, in vitro, therapeutically active lymphocytes from tumor-bearing hosts has important implications for cellular therapy of human cancers.