Pharmacologic Administration of Interleukin-2 Inducing a Systemic Autophagic Syndrome?
Pharmacologic Administration of Interleukin-2 Inducing a Systemic Autophagic Syndrome?
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DOI：
10.1111/j.1749-6632.2009.05160.x
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发表时间：
2009-01-01
期刊：
影响因子：
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通讯作者：
Lotze, Michael T.
中科院分区：
文献类型：
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作者：
Chavez, Antonio Romo de Vivar;Buchser, William;Lotze, Michael T.
癌症患者生物治疗的发展在一定程度上受到了极其复杂的内在反馈机制的阻碍，这些机制促进了组织损伤、修复、炎症和免疫的动态平衡。重组白介素2(IL-2)治疗始于1984年，基于其作为原型T细胞生长因子的作用，在FDA批准后后期发现了新的作用，不仅调节效应性T细胞，还调节调节性T细胞。使它的应用变得复杂的是，即使在最复杂的中心，它的使用也伴随着可控但困难的毒性，尽管有明确证据表明，在接受治疗的黑色素瘤和肾癌患者中，有5%-10%的患者完全有效，这些患者的非凡耐受性现在已经持续了近25年，因此相当于“治愈”。虽然已经努力减少毒性或提高疗效，但联合治疗的唯一实质性进展是肿瘤浸润性淋巴细胞和CTLA4抗体的应用。对与轻微的流感样症状和更令人衰弱的细胞因子“风暴”相关的“有限”毒性的更深入的了解还没有到来。在这里，我们提出的概念是，与使用IL-2相关的全身性综合征是由于全局细胞因子诱导的自噬和暂时性有限的组织功能障碍。自噬抑制剂在提高疗效和限制毒性方面的可能作用以及这种方法可能存在的问题也被考虑在内。
The development of biologic therapies for patients with cancer has in part been impeded by the extraordinary complexity and intrinsic feedback mechanisms promoting homeostasis in tissue injury, repair, inflammation, and immunity. Recombinant interleukin 2 (IL-2) therapy was initiated in 1984 based on its role as the prototypic T-cell growth factor, with novel roles deduced late after its FDA approval in regulating not only effector T cells but also regulatory T cells. Complicating its application, even in the most sophisticated centers, has been the manageable but difficult toxicities attendant on its use in spite of clear evidence of complete responses in 5-10% of treated patients with melanoma and renal cell carcinoma with extraordinary durability lasting now for almost 25 years, thus tantamount to "cures." Although efforts have been made to diminish toxicity or enhance efficacy the only substantive advance in combination therapy has been the application of tumor-infiltrating lymphocytes and the antibody to CTLA4. A deeper understanding of the "limiting" toxicity associated with mild flu-like symptoms and more debilitating cytokine "storm" not forthcoming. Here we propose the notion that the systemic syndrome associated with IL-2 administration is due to global cytokine-induced autophagy and temporally limited tissue dysfunction. The possible role of autophagy inhibitors to enhance efficacy and limit toxicity as well as possible problems with this approach are considered.