Grimm E A, Jacobs S K, Lanza L A, Melin G, Roth J A, Wilson D J
Symp Fundam Cancer Res. 1986;38:209-19.
LAK are cytolytic lymphocytes with the unique capacity for killing NK-resistant fresh human tumor cells in short-term assays. LAK kill autologous as well as allogeneic tumors with complete cross-reactivity. Initial studies on the classification of LAK conclude that LAK are distinct from the classical NK and T lymphocyte systems, based on a number of criteria including surface phenotype, activation conditions, and a spectrum of susceptible target cells. LAK kill ras oncogene-transfected fibroblasts like they kill fresh tumors. As yet, the target cell determinant responsible for susceptibility to LAK lysis is unknown. Activation of LAK requires only IL 2 and is blocked by monoclonal antibodies to the IL 2 receptor. Because only IL 2 alone is sufficient for LAK activation, we have done in vitro testing to determine whether fresh PBL could be activated in the presence of tumor, as might be desirable in vivo. LAK were activated sufficiently to mediate significant destruction of fresh tumor. We also tested whether LAK could be maintained in the presence of large tumors, providing IL 2 was added. Again, results were positive, suggesting that LAK either recycle or are a self-renewing population that depend on IL 2 for continued functions. Because of these and other findings, we have initiated a clinical protocol to test whether LAK made from the PBL of patients with brain tumor could eliminate residual glioma tumor cells. Autologous LAK plus rIL 2 to maintain lytic ability are injected during surgery. Preclinical studies in a rat glioma model have shown this approach to be safe, and previous in vivo murine studies have concluded that LAK kill tumors in Winn-type lung colony formation tests (Kedar et al. 1982). Much work is needed before we can understand the LAK phenomenon and determine its usefulness in cancer therapy, as well as its inherent biologic role. We hope that this chapter will stimulate both interest and the basic research needed to realize LAK potential.
LAK是一种细胞溶解性淋巴细胞，在短期试验中具有杀死对NK有抗性的新鲜人类肿瘤细胞的独特能力。LAK能够完全交叉反应地杀死自体以及同种异体肿瘤。对LAK分类的初步研究得出结论，基于包括表面表型、激活条件和一系列敏感靶细胞等多个标准，LAK不同于经典的NK和T淋巴细胞系统。LAK杀死ras癌基因转染的成纤维细胞的方式与杀死新鲜肿瘤的方式相同。迄今为止，负责对LAK裂解敏感的靶细胞决定因素尚不清楚。LAK的激活仅需要IL-2，并且被针对IL-2受体的单克隆抗体所阻断。因为仅IL-2本身就足以激活LAK，所以我们进行了体外测试，以确定新鲜的外周血淋巴细胞（PBL）在肿瘤存在的情况下是否能够被激活，这在体内可能是理想的情况。LAK被充分激活，足以介导对新鲜肿瘤的显著破坏。我们还测试了在添加IL-2的情况下，LAK是否能够在大肿瘤存在的情况下得以维持。结果再次呈阳性，表明LAK要么循环利用，要么是一个自我更新的群体，其持续功能依赖于IL-2。由于这些以及其他发现，我们启动了一项临床方案，以测试从脑肿瘤患者的PBL制备的LAK是否能够消除残留的神经胶质瘤肿瘤细胞。在手术期间注射自体LAK加rIL-2以维持裂解能力。在大鼠神经胶质瘤模型中的临床前研究表明这种方法是安全的，并且先前的体内小鼠研究得出结论，在温氏型肺集落形成试验中LAK能够杀死肿瘤（凯达尔等人，1982年）。在我们能够理解LAK现象并确定其在癌症治疗中的效用以及其固有的生物学作用之前，还需要做大量的工作。我们希望本章将激发兴趣以及实现LAK潜力所需的基础研究。
