[摘 要] 尽管以PD-1/PD-L1抑制剂为基础的免疫治疗显著提升了肺癌患者的生存期，但耐药问题依然严峻。本文阐述了免疫治疗耐药的定义、发生机制及预测模型，介绍了针对耐药的治疗策略，包括免疫治疗继续应用、再挑战、寡转移背景下的局部治疗联合全身免疫治疗、广泛进展后的联合治疗等。此外，还探讨了新型治疗手段如过继性细胞疗法、抗体偶联药物、双特异性抗体和肿瘤疫苗等在克服耐药中的应用前景。同时，总结了肺癌免疫治疗的挑战与发展方向，强调了持续研究、创新治疗策略以及跨学科合作的重要性。为未来肺癌治疗的个体化、精准化和高效化提供新思路与研究方向。

Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

Fatty acid synthase (FASN) is an essential molecule in lipid metabolic pathways, which are crucial for cancer-related studies. Recent studies have focused on a comprehensive understanding of the novel and important regulatory effects of FASN on malignant biological behavior and immune-cell infiltration, which are closely related to tumor occurrence and development, immune escape, and immune response. FASN-targeting antitumor treatment strategies are being developed. Therefore, in this review, we focused on the effects of FASN on tumor and immune-cell infiltration and reviewed the progress of related antitumor therapy development.

In order to give full play to the important role of multi-disciplinary treatment (MDT) in oncology teaching in talent training and discipline development, an oncology teaching and research section has been established, the textbook Clinical Oncology has been compiled, excellent teaching workers in affiliated hospitals have been selected to form an MDT teaching team, and a multi-tutorial system has been established for the discipline related to specific tumor types. The multi-tutorial system of disciplines combines lecture-based learning (LBL) with case-based learning (CBL) and problem-based learning (PBL). Students are arranged to observe and participate in clinical MDT consultation during the inter-class practice, and compared with the traditional assessment form, MDT case discussion questions, review writing, classroom simulation of the MDT process and real participation in clinical MDT discussions are added. The questionnaire for students who participated in MDT teaching showed that more than 93% of the students believed that the MDT teaching model was helpful for systematically mastering the knowledge of the chapters they had learned and understanding the cutting-edge progress, improving learning initiative, thinking and problem-solving ability, clinical comprehensive analysis ability and teamwork spirit. The majority of students' expression skills [89%(169/190)] and literature review skills [79%(150/190)] were improved; 94%(178/190) of students expressed their willingness to accept this teaching method. The teaching practice experience of the Department of Oncology of Jilin University based on the MDT model helps to improve the teaching level of oncology.

Epidermal growth factor receptor ( EGFR ) mutations are common oncogenic driver mutations in patients with non-small cell lung cancer (NSCLC). The application of EGFR-tyrosine kinase inhibitors (TKIs) is beneficial for patients with advanced and early-stage NSCLC. With the development of next-generation sequencing technology, numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation; however, the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown. Thus, we review the incidence, prognosis, and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Protein Kinase Inhibitors/pharmacology* ; Mutation/genetics* ; ErbB Receptors

Immune checkpoint inhibitor (ICI) has become one of the important therapeutic strategies for the patients with advanced non-small cell lung cancer (NSCLC). The latest clinical studies have shown that immunotherapy can bring more survival benefits to patients with early lung cancer and operable patients with locally advanced lung cancer. However, the strategies of neoadjuvant immunotherapy, the timing of operation, the evaluation system of curative effect, predictive markers and other problems still need to be explored in the clinical practice of large samples. This paper reviews the progress of neoadjuvant immunotherapy in NSCLC.

近年来，通过增强机体免疫系统对肿瘤细胞的杀伤作用，免疫检查点抑制剂（immune checkpoint inhibitor，ICI）在抗 肿瘤治疗中的应用获得了显著的临床疗效。然而，多项证据表明，免疫治疗激活免疫系统的同时可导致独特的免疫相关不良反 应（immune-related adverse events，irAEs），影响免疫治疗的疗效或需要中止治疗。近几年，随着 ICI 治疗临床试验的广泛开展， irAEs 的发生情况、毒性谱及其有效管理手段的开发越来越得到临床医生的关注。常见的 irAEs 包括皮炎和甲状腺炎等，而不 同种类免疫检查点抑制剂、不同治疗剂量或组合疗法，均可导致不同的 irAEs 毒性谱，同一免疫检查点抑制剂作用于不同肿瘤 所致的毒副反应谱亦有不同。目前认为，irAEs 的发生与机体自身免疫系统功能的改变相关，包括机体免疫系统过度激活、自身 免疫耐受性的打破等，但其具体机制仍不十分清楚。本文结合近年来在 ICI 治疗中 irAEs 相关分子机制和预测标志物的关键理 论和认识方面取得的诸多新进展，对 irAEs 的发生特点和分子机制进行总结，并就其预测性标志物开发、irAEs 管理原则改进和 治疗新探索进行述评。

Precision detection techniques have promoted the development of individualized diagnosis and treatment of tumors in the era of precision medicine. At the same time, clinical demands of precision treatments have further driven the development and application of precision detection techniques. In recent years, precision medical detection techniques realized rapid transformations from low-throughput to high-throughput genomic sequencing, from tissue biopsies to liquid biopsies, and from multicell promiscuous detection to single cell precision sequencing. All these changes have promoted the emergence and development of new technologies, new targets, and new drugs in the era of precision oncology medicine. In the future, multi-dimensional combined detection could help to improve the accuracy of precision medicine; ctDNA methylation detection analysis could broaden the research field of precision medicine; and the transformation of clinical trial design could also contribute to promote the in-depth development of precision medicine.

Environmental factors are important risk factor for lung cancer. Smokers are 20 times more likely to develop lung cancer than non-smokers. However, less than 20% of smokers develop lung cancer. In recent years, many studies have shown genetic polymor‐phism plays an important role in the development of lung cancer, mainly involving single nucleotide polymorphisms and rare highexogenous mutations. The in-depth research of the gene polymorphism will be beneficial to the screen of susceptible genes in lung cancer and genetically high-risk population, providing genetic counseling and evidence for clinically precise diagnosis and treatment. This article mainly summarizes the contents regarding genetic susceptibility of lung cancer and high-risk population screening, early diagnosis of lung cancer as well as precise medication of advanced lung cancer.