从“阳虚毒结”角度探讨免疫治疗超进展的形成及“五观辨治”干预作用  

Formation of Hyperprogression of Immunotherapy from Perspective of"Yang Deficiency and Toxin Knot"and Role of"Five Views on Differentiation and Treatment"Intervention

作　　者：韩欣璞 朱广辉 孙千惠 李杰[1] HAN Xinpu;ZHU Guanghui;SUN Qianhui;LI Jie(Guang'anmen Hospital,China Academy of Chinese Medical Sciences,Beijing 100053,China;Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]中国中医科学院广安门医院,北京100053 [2]北京中医药大学,北京100029

出　　处：《中国实验方剂学杂志》2024年第1期186-191,共6页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：国家自然科学基金项目(81774289);中国中医科学院科技创新工程项目(CI2021A01802)。

摘　　要：免疫检查点抑制剂(ICIs)在肿瘤治疗中显示出良好的疗效,改变了肿瘤的治疗格局。但部分接受ICIs治疗的患者未达到理想治疗效果,反而出现了肿瘤异常加速生长的非典型反应模式,即超进展(HPD)。目前HPD的发病机制尚不明确,诊断难度较大,为临床鉴别和确定治疗策略带来了挑战。探索HPD的可能机制是提升免疫治疗效果的重要方面,该文基于“阳虚毒结”理论,从“脾肾阳虚、毒邪鸱张”探讨免疫治疗超进展发生机制,认为p53抑癌基因失活和免疫抑制微环境是机体正气不足,脾肾阳衰的表现,为HPD发生的重要基础;ICIs所致不良反应属“药毒”范畴,鼠双微体2(MDM2)/鼠双微体4(MDM4)等癌基因激活、表皮生长因子受体(EGFR)突变及肿瘤炎性微环境的发生发展是邪气亢实,癌毒药毒相搏,乘虚鸱张的表现,可促进肿瘤细胞异常增殖,为HPD发生的核心病机要素,与疾病转归密切相关。治疗方面,在该团队结合临床实践总结提出的“五观辨治”(时空观、核心观、症状观、精准观、未病观)理论指导下,以防治HPD为切入点,复法组方,扶正温阳,实现时空全周期动态管理;解毒抗癌,实现标本全方位系统干预;在HPD宏观临床表现及微观病理改变层面富集靶点,提高药物选择靶向性和防治精准性,充分发挥中医药独特治疗优势,为临床应用中医药防治HPD提供新思路。Immune checkpoint inhibitors(ICIs)have shown good efficacy in tumor treatment and have changed the landscape of tumor treatment.However,some patients treated with ICIs have not only failed to achieve the desired therapeutic effect,but also developed an atypical response pattern of abnormally accelerated tumor growth,namely hyperprogressive disease(HPD).The pathogenesis of HPD is still unclear and it is difficult to diagnose,which poses a challenge for clinical identification and treatment decisions.Exploring the underlying mechanism of HPD is important to improve the effect of immunotherapy.Based on the theory of"Yang deficiency and toxic knot",this paper discussed the mechanism of HPD in immunotherapy from the perspective of"spleen and kidney Yang deficiency and hefty toxic pathogens".It was concluded that the inactivation of p53 oncogene and immunosuppressive microenvironment were the manifestations of the deficiency of healthy qi in the body and declined yang in the spleen and kidney,serving as an important basis for the occurrence of HPD.Adverse reactions caused by ICIs belong to the category of"drug toxicity".The occurrence and development of murine double minute 2(MDM2)/murine double minute 4(MDM4)activation,epidermal growth factor receptor(EGFR)mutation,and tumor inflammatory microenvironment are the manifestations of the hyperactivity of pathogenic Qi,conflict of cancer toxicity and drug toxicity,and being hefty by virtue of deficiency,which can promote the abnormal proliferation of tumor cells,and they are the core pathogenic elements of HPD and are closely related to disease prognosis.In terms of treatment,under the guidance of the theory of"five views on differentiation and treatment"(time-space view,core view,symptom view,precision view,and disease-before-onset view),which was summarized according to the clinical practice of this research team,this paper,taking the prevention and treatment of HPD as the entry point,formulated traditional Chinese medicine(TCM)compounds to reinforce healthy Qi and warm

关 键 词：肿瘤 阳虚毒结 免疫治疗 超进展 五观辨治 

分 类 号：R22[医药卫生—中医基础理论] R242[医药卫生—中医学] R2-031R287