Garaci Enrico, Favalli Cartesio, Pica Francesca, Sinibaldi Vallebona Paola, Palamara Anna Teresa, Matteucci Claudia, Pierimarchi Pasquale, Serafino Annalucia, Mastino Antonio, Bistoni Francesco, Romani Luigina, Rasi Guido
University of Rome Tor Vergata, Rome, Italy.
Ann N Y Acad Sci. 2007 Sep;1112:225-34. doi: 10.1196/annals.1415.044. Epub 2007 Jun 28.
After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (Talpha1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with Talpha1 and either IFN or IL-2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using Talpha1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non-small cell lung cancer (NSCLC) and melanoma with Talpha1 and IFN-alpha low doses after cis-platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of Talpha1 and IFN-alpha was also used in patients affected by chronic B and C hepatitis including IFN-nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of Talpha1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll-like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose-response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with Talpha1 at different doses after dacarbazine and a phase III one, on IFN-resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and Talpha1).
在环磷酰胺之后，使用胸腺肽α1（Tα1）和干扰素（IFN）联合治疗，在Lewis肺癌动物模型中观察到最初的显著效果后，小鼠的一些其他临床前模型（Friend红白血病和B16黑色素瘤）以及大鼠的模型（DHD/K12结直肠癌肝转移）证实了Tα1与IFN或IL-2联合化疗的疗效。这些结果为首次使用Tα1联合生物反应调节剂（BRMs）和/或化疗的临床试验提供了科学依据。在晚期非小细胞肺癌（NSCLC）和黑色素瘤患者中，顺铂或达卡巴嗪后使用低剂量Tα1和α干扰素进行的关键试验首次证明了这种方法在治疗人类癌症方面的巨大潜力。Tα1和α干扰素的联合也用于慢性B型和C型肝炎患者，包括对干扰素无反应者以及受前核心突变体或1b基因型感染的患者。进一步的研究证明了Tα1的其他生物学活性，阐明了其作用机制，部分解释了与干扰素的协同作用。已经表明，Tα1能够通过Toll样受体信号激活受感染的树突状细胞，从而影响炎症平衡，并增加肿瘤、病毒和主要组织相容性复合体（MHC）I类抗原的表达。剂量反应研究表明，有可能通过降低总体毒性来提高该分子的疗效。基于这些信息，两项临床试验正在进行：一项针对晚期黑色素瘤患者的大型II期试验，患者在达卡巴嗪后接受不同剂量的Tα1治疗；另一项III期试验，针对对干扰素耐药的丙型肝炎病毒（HCV）患者，采用三联组合疗法（干扰素、利巴韦林和Tα1）治疗。
