Kohler P C, Sondel P M
Department of Medicine, Meriter-Madison General Hospital.
Cancer Surv. 1989;8(4):861-73.
Despite the abundance of evidence from murine models suggesting a powerful immunological approach to the treatment of cancer, the available data on clinical response have not been as dramatic. The use of interleukin-2 (IL-2) either alone or in combination with lymphokine activated killer (LAK) cells clearly is therapeutic for some patients, albeit a minority. It does not appear from the available evidence that the regimens tested show major differences in antitumour activity, although there is a sense that higher doses may be slightly more effective. Nor is it clear that the addition of LAK cells significantly or sufficiently enhances clinical responses to warrant their widespread use. It must therefore be concluded that other patient and tumour related factors must have an undefined role in the ability to attain meaningful responses. Immunological response to IL-2 and tumour burden are factors which can be examined given the available clinical data. While animal studies have shown that antitumor effects are related to the dose and number of LAK cells given, this is not as clear in patient studies. Some reports have suggested a correlation between clinical response and the in vivo induction of LAK activity or the magnitude of the rebound lymphocytosis. Clinical trials at the University of Wisconsin have shown striking increases in both the number of peripheral blood lymphocytes and LAK induction in patients who showed no clinical response. This in vivo LAK induction, as expected, is not the sole determinant in achieving a measurable response. Whether it is a necessary biological response needed to achieve antitumour effects remains uncertain. The role of tumour burden in response to IL-2 remains elusive. In many trials, including our own, patients with bulky disease have responded to therapy that was ineffective in other patients with what appeared to be a minimal tumour burden. Despite the disappointment that initial expectations have not quite been met, something extremely important has occurred in the treatment of cancer. For the first time, the controlled activation of a patient's endogenous immune system has been shown to have some promise as an antitumour treatment. Clearly, if the response rates reported to date are the best attainable its role will be limited. This remains doubtful as investigators are actively exploring combinations of IL-2 with other biologicals, cytokines, monoclonal antibodies and chemotherapeutic agents. Preclinical data suggest enhanced antitumour effects will be mediated by these combinations. While the magic bullet has not yet been found, there has been a major step forward since IL-2 was first described.
尽管来自小鼠模型的大量证据表明免疫疗法在癌症治疗中具有强大作用，但现有的临床反应数据却没有那么显著。单独使用白细胞介素-2（IL-2）或与淋巴因子激活的杀伤细胞（LAK）联合使用，对部分患者（尽管是少数）显然具有治疗作用。现有证据似乎并未表明所测试的方案在抗肿瘤活性方面存在重大差异，尽管感觉更高剂量可能会稍有效一些。同样不清楚的是，添加LAK细胞是否能显著或充分增强临床反应，从而保证其广泛应用。因此，必须得出结论，其他与患者和肿瘤相关的因素在获得有意义反应的能力方面必定起着未明确的作用。鉴于现有的临床数据，可以研究对IL-2的免疫反应和肿瘤负荷等因素。虽然动物研究表明抗肿瘤作用与给予的LAK细胞剂量和数量有关，但在患者研究中情况并非如此清晰。一些报告表明临床反应与体内LAK活性的诱导或淋巴细胞增多症的反弹程度之间存在相关性。威斯康星大学的临床试验表明，在没有临床反应的患者中，外周血淋巴细胞数量和LAK诱导均有显著增加。正如预期的那样，这种体内LAK诱导并非实现可测量反应的唯一决定因素。它是否是实现抗肿瘤作用所需的必要生物学反应仍不确定。肿瘤负荷在对IL-2反应中的作用仍然难以捉摸。在许多试验中，包括我们自己的试验，患有大块肿瘤的患者对治疗有反应，而该治疗对其他肿瘤负荷似乎最小的患者却无效。尽管最初的期望尚未完全实现令人失望，但癌症治疗中已经发生了极其重要的事情。首次证明，可控激活患者的内源性免疫系统作为一种抗肿瘤治疗方法具有一定前景。显然，如果迄今为止报道的反应率是所能达到的最佳水平，其作用将是有限的。这仍然值得怀疑，因为研究人员正在积极探索IL-2与其他生物制剂、细胞因子（细胞活素）、单克隆抗体和化疗药物的联合使用。临床前数据表明，这些联合使用将介导增强的抗肿瘤作用。虽然尚未找到万灵药，但自首次描述IL-2以来已经向前迈出了重要一步。
