Maas R A, Dullens H F, Den Otter W
University Hospital Utrecht, Department of Pathology, The Netherlands.
Cancer Immunol Immunother. 1993;36(3):141-8. doi: 10.1007/BF01741084.
The central question to discuss in this review is whether the results of interleukin-2 (IL-2) treatment are still disappointing or again promising. Although in the (recent) past application of high doses of systemically applied rIL-2 has led to some success, the overall results are not as one had hoped. Considering these poor results it seems clear that the application of high systemic doses rIL-2 was not a good choice. IL-2 has been used more or less as a chemotherapeutic compound in the highest tolerable dose. This has led to a great number of unwanted toxic side-effects. In addition, these doses mainly stimulated nonspecific lymphokine-activated killer activity through low-affinity IL-2 receptors, which does not lead to systemic immunity. On the other hand, several groups have shown that application of intratumoral low doses of IL-2 can be highly effective against cancer and without toxic side-effects. Significant tumor loads constituting up to 6% of the total body weight of a mouse were eradicated after treatment with low-dose rIL-2 given locally. Furthermore local treatment can lead to eradication of a tumor at a distant site. This type of therapy is effective in many systems namely against different tumor types in mice, hepatocellular carcinoma in guinea-pigs and vulval papilloma and carcinoma and ocular carcinoma in cattle. Low-dose IL-2 is very effective in experimental animals if it is given relatively late after inoculation of the tumor cells. In other words, it seems necessary that some sort of immune reaction has started or is developing before low doses of rIL-2 effectively stimulate it. In fact there is strong evidence that T lymphocytes, both CD4+ and CD8+ cells, are directly involved in the process leading to induction of specific immunity. In our opinion rIL-2 therapy should therefore aim at the stimulation of such (originally weak) specific immune reaction. Under these conditions also systemic immunity can be induced. In conclusion, application of rIL-2 as a modality for cancer treatment is still promising. High priority should be given to a further delineation of the mechanisms involved after local application. The method of giving IL-2 systemically in the highest tolerable dose should be abandoned. Specific stimulation of the immune system by low-dose rIL-2 is a much more promising option.
本综述中要讨论的核心问题是白细胞介素-2（IL-2）治疗的结果是仍然令人失望还是再次充满希望。尽管在（最近的）过去，全身应用高剂量重组人IL-2（rIL-2）取得了一些成功，但总体结果并不如人们所期望的那样。考虑到这些不佳结果，显然全身应用高剂量rIL-2不是一个好选择。IL-2或多或少被用作最高耐受剂量的化疗药物。这导致了大量不良的毒副作用。此外，这些剂量主要通过低亲和力IL-2受体刺激非特异性淋巴因子激活的杀伤活性，这不会导致全身免疫。另一方面，几个研究小组表明，肿瘤内局部应用低剂量IL-2对癌症可能非常有效且无毒性副作用。局部给予低剂量rIL-2治疗后，可根除占小鼠体重高达6%的显著肿瘤负荷。此外，局部治疗可导致远处肿瘤的根除。这种治疗方法在许多系统中都有效，即对小鼠的不同肿瘤类型、豚鼠的肝细胞癌、牛的外阴乳头瘤和癌以及眼癌有效。如果在接种肿瘤细胞后相对较晚给予低剂量IL-2，其在实验动物中非常有效。换句话说，似乎在低剂量rIL-2有效刺激之前，某种免疫反应已经开始或正在发展是必要的。事实上，有强有力的证据表明，CD4+和CD8+ T淋巴细胞都直接参与导致特异性免疫诱导的过程。因此，我们认为rIL-2治疗应以刺激这种（原本较弱的）特异性免疫反应为目标。在这些条件下也可诱导全身免疫。总之，将rIL-2用作癌症治疗手段仍然很有前景。应高度优先进一步阐明局部应用后所涉及的机制。应摒弃全身给予最高耐受剂量IL-2的方法。低剂量rIL-2对免疫系统的特异性刺激是一个更有前景的选择。
