Shu S Y, Chou T, Rosenberg S A
J Immunol. 1987 Jul 1;139(1):295-304.
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.
致敏淋巴细胞的全身转移可有效介导已形成肿瘤的消退。然而，实际上该方法之前的所有实验应用都使用了已免疫以排斥肿瘤攻击的动物的淋巴细胞。在人类中没有类似的细胞来源。通过使用弱免疫原性的小鼠肿瘤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，来自患有进行性生长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灶的消退。尽管IVS系统诱导了正常小鼠以及荷瘤小鼠淋巴细胞产生非特异性淋巴因子激活的杀伤样细胞毒性活性，但只有从荷瘤动物的淋巴细胞起始的培养物中才能产生具有治疗活性的细胞，这表明IVS是一种继发性体外免疫反应。无需其他治疗，IVS细胞就能介导抗肿瘤作用。然而，低剂量给予外源性白细胞介素2可增强其治疗效果。通过用单克隆抗体在体内清除T细胞亚群，确定主要效应细胞属于表达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在体外数量可进一步扩增。与起始培养的细胞数量相比，IVS 9天后再进行5天体外扩增后，获得的细胞数量可达起始细胞数量的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，在肿瘤负荷范围广泛以及肿瘤生长持续时间不同的小鼠引流淋巴结中都很容易获得它们。从荷瘤宿主体外产生并扩增具有治疗活性的淋巴细胞的能力对人类癌症的细胞治疗具有重要意义。
