扶正解毒化瘀法对免疫治疗减毒增效作用的研究进展
作者简介:
陈昱帆，女，硕士，主要从事中西医结合肿瘤防治，ORCID: 0000-0002-9301-6188
冯利: 国家癌症中心/中国医学科学院肿瘤医院中医科主任，主任医师，教授，北京协和医学院博士后及博士研究生导师，北京中医药大学及中国中医科学院博士研究生导师。全国著名中医、中西医结合肿瘤治疗专家，中央保健会诊专家，国家中医药管理局第七批全国老中医药专家学术经验继承指导老师，国家中医药管理局第三批“全国优秀中医临床人才”，北京市中西医结合肿瘤防治国际合作基地（中心）负责人，国家中医药管理局及北京市中医管理局中西医协同“旗舰科室”带头人。主要从事恶性肿瘤及并发症的临床及基础研究，发表SCI及中文核心论文100余篇，主编学术专著3部，主编及参编指南15部，获批发明专利4项，承担国家重点研发计划项目、国家自然科学基金面上项目、北京市自然科学基金面上项目等多项国家和省部级研究课题
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通信作者:
Research Progress of Fuzheng Jiedu Huayu Method in Reducing Toxicity and Enhancing Efficacy of Immunotherapy
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摘要:
近年来免疫治疗在肿瘤领域中持续取得重大突破。免疫治疗主要包括免疫检查点抑制剂、肿瘤疫苗治疗、溶瘤病毒治疗和过继细胞治疗。阻断程序性死亡受体1（PD-1）或程序性死亡配体1（PD-L1）的免疫检查点抑制剂已经纳入非小细胞肺癌、恶性黑色素瘤等晚期实体瘤的一线临床治疗。然而肿瘤原发或继发性的耐药严重限制了患者的生存获益，肺炎、甲状腺功能减退、垂体炎、心肌炎等免疫治疗相关不良反应也在很大程度上影响了患者的生活质量。“扶正解毒化瘀”抗癌理论是指导中医药防治肿瘤的重要理念，也是中医药对免疫治疗发挥减毒增效作用的重要治法治则。本文通过总结免疫治疗研究进展、从“扶正解毒化瘀”理论出发，论述中医药对免疫治疗减毒增效的机制，以期为中医协同肿瘤免疫治疗提供参考。
Abstract:Immunotherapy, including immune checkpoint inhibitors, tumor vaccine therapy, oncolytic virotherapy, and adoptive cell therapy, has made remarkably breakthroughs in the field of oncology. Immune checkpoint inhibitors, which block programmed death receptor 1 or programmed death ligand 1, have been included in the first-line clinical treatment for advanced solid tumors, such as non-small cell lung cancer and malignant melanoma. However, primary or secondary drug resistance in tumors severely limits the survival benefits for patients. Immune-related adverse reactions, such as pneumonia, hypothyroidism, hypophysitis, and myocarditis, also greatly affect the quality of life of patients. Fuzheng Jiedu Huayu is an important concept guiding the prevention and treatment of tumors with traditional Chinese medicine (TCM). It is also a curative principle and therapeutic TCM method to reduce the toxicity and enhance the efficacy of immunotherapy. This article summarizes the research progress of immunotherapy and discusses how TCM reduces the toxicity and enhances the efficacy of immunotherapy, hoping to provide a reference for the integrated treatment of tumors with TCM and immunotherapy.
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Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：陈昱帆：思路设计、论文撰写李思聪、崔译元：文献调研、文章校对冯 利：思路设计、资金支持及论文审阅修改
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表 1 免疫相关不良反应中医药研究成果汇总表
Table 1 Researches of traditional Chinese medicine on immunotherapy-related adverse reactions
Immune-related
adverse effectsTraditional Chinese medicine Treatment
durationStudy
typeStudy
sampleStudy results Skin toxicity Clearing heat and removing dampness formula[18] (Si-Miao-Yong-An decoction +coix seed) For external use, up to a maximum of one month Retrospective cohort study 30 patients with grade 2-3 immune-related rash Among the patients, 13 who previously failed corticosteroid treatment experienced relief of pain symptoms associated with rashes after using the Clearing heat and removing dampness formula, with an overall effective rate of 70%. In all the patients, including those who had not previously received corticosteroid treatment, the median time for rashes to recover to grade 1 was 8 days, with a total effective rate of 80%. Nourishing yin and eliminating rash formula[19] Oral administration for two weeks Retrospective Cohort Study 25 patients with immune-related cutaneous adverse reactions Compared with no intervention and the use of hormone therapy, the combined treatment of Yin-nourishing and rash-reducing formula significantly alleviated the severity of rashes and feverish sensation in five centers and accelerated the rate of rash resolution. Jiedu Qingzhen formula[20] Continuous medication for
21 daysRandomized controlled
clinical trial72 patients with malignant tumors complicated with wind-heat sores treated with PD-1 inhibitors Compared with the management plan for immune-related skin adverse reactions recommended by the CSCO guidelines, the Jiedu Qingzhen formula significantly improved the grading of wind-heat sores, TCM syndromes, itching grading, KPS scores, and DLQI scores. Diarrhea Modified Sheng-Yang-Yi-Wei powder[21] / Randomized controlled
clinical trial60 patients with immune-related diarrhea due to malignant tumors of spleen yang deficiency syndrome at grades 2-3 Compared with those treated solely with Western medicine (toripalimab，, sintilimab, and camrelizumab), the patients who additionally received the modified Sheng-Yang-Yi-Wei powder treatment showed significant improvements in TCM syndrome scores (P<0.05) and a notable increase in KPS scores. Modified Chaihu Guizhi decoction[22] Continuous medication for
21 daysRandomized controlled
clinical trial92 cancer patients (including various types of cancer such as gallbladder cancer, lung cancer, and liver cancer) Compared with those under treatment plans that use only immunosuppressants, such as PD-1/PD-L1 inhibitors, the patients who additionally received modified Chaihu Guizhi decoction showed reduced incidence of colitis by 28% and improved diarrhea associated with PD-1 monoclonal antibody therapy. Colitis Wumei Pills[23] / Randomized controlled experiment
in ratsForty rats were randomly divided into five groups, with eight rats in each group Compared with that in the positive control group, the serum IL-1β expression was increased in the low- and high-dose Wumei Pill groups (P<0.05). The colonic IL-1β expression was decreased in both groups (P<0.05), indicating that Wumei Pill can ameliorate the pathological damage of immune colitis. Supplemented Shaoyao Decoction[24] For acute diarrhea, take medication continuously for 5 days; for chronic diarrhea, maintain treatment after the effect is shown. Randomized controlled
clinical trial80 patients with intestinal damp-heat type who developed colitis after immunotherapy Compared with loperamide alone, its combination with Shaoyao Decoction showed superior efficacy in improving the symptoms of acute and chronic diarrhea, abdominal pain, anal burning, and bitter taste in the mouth of patients with immune-related colitis. Hepatitis Ginsenoside Rd[25] / Cell experiments+
mouse experiments32 C57BL/6 mice were randomly divided into four groups, with eight mice in each group Ginsenoside Rd exerts a protective effect against immune hepatitis in mice by inhibiting the cGAS/STING/NLRP3 inflammasome signaling pathway. Cancer-Related Fatigue Qigui Buxue Syrup[26] A treatment cycle lasts for 21 days, with two cycles of treatment Randomized controlled clinical trial Fifty patients were enrolled and randomly divided into two groups Compared with the monotherapy of sintilimab, the combined treatment with Qigui Buxue Syrup can significantly improve the multidimensional fatigue status, TCM symptoms, and physical condition in patients with qi deficiency type advanced nonsmall cell lung cancer (NSCLC) after immunotherapy. It also enhances the efficacy of immunotherapy with a high safety profile. 
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表 2 中医药增强免疫治疗疗效成果汇总
Table 2 Efficacy of traditional Chinese medicine in enhancing effect of immunotherapy
TCM Treatment duration Study type Study sample Study results Guizhi Guling pill[27] Three months Randomized controlled
clinical
studySixty patients with advanced ovarian cancer The objective response rate and disease control rate in the treatment group were 33.33% and 60.00%, respectively, both of which were significantly higher than those in the control group at 10.00% and 33.33%, respectively (P<0.05). Shenqi Fuzheng injection[28] Each 21-day period constitutes four treatment cycles Randomized controlled
clinical
study65 cases of advanced non-small cell lung cancer with negative driver genes The median progression-free survival time in the experimental group was significantly better than that in the control group (6.30 months vs. 5.54 months, P=0.043).
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