Traditional Chinese medicine treatment of immune-related pneumonia caused by PD-1/PD-L1 inhibitors

With the wide application of immunotherapy drug PD-1/PD-L1 inhibitor in China and the continuous clinical research,a major problem that we have to face is the immune-related pneumonia caused by PD-1/PD-L1.At present,western medicine mainly treated it by hormone therapy,which may cause side effects,such as obesity,osteoporosis and osteonecrosis for hormone therapy by long-term,and increase the patients'pain.Under the guidance of the theory of syndrome differentiation,traditional Chinese medicine(TCM)advocates the methods of expelling wind and clearing away cold,resolving phlegm and relieving asthma,relieving heat from lung,and invigorating the spleen and tonifying the kidney,etc.Exact differentiation of symptoms and rational usage of drugs can play an important role in the early prevention and treatment of immune-related pneumonia,reflecting the important role of TCM in the prevention and treatment of side effects of new drugs.In order to provide an effective clinical reference for clinicians in the practice of using PD-1/PD-L1,this paper systematically reviewed the use of TCM in the treatment of immune-related pneumonia induced by PD-1/PD-L1 inhibitors.

Benefit-Risk Assessment for PD-1/PD-L1 Inhibitors in the Treatment of Non-Small Cell Lung Cancer

Objective To explore the benefits and risks of PD-1/PD-L1 inhibitors Atezolizumab and Nivolumab in the treatment of non-squamous non-small cell lung cancer and provide some references for clinicians.Methods Based on the data results of relevant studies published by ClinicalTrical.gov in the US clinical trial database and foreign peer-reviewed journals,the internationally recognized multi-criteria decision analysis(MCDA)model was used to assess the benefit and risk of PD-1/PD-L1 inhibitors for non-squamous non-small lung cancer comprehensively.Finally,a sensitivity analysis was performed to test the sensitivity of the weight to the evaluation.Results and Conclusion The benefit-risk evaluation result of Atezolizumab for the treatment of non-squamous non-small cell lung cancer is better than that of Nivolumab.Specifically,Atezolizumab has more benefits than Nivolumab with a lower risk.The results of MCDA model in drug benefit and risk evaluation are easy to understand.However,the selection of indicators in the model and the degree of data acquisition are limited.The evaluation results of the MCDA model should be comprehensively viewed with other evaluations to make decisions objectively.

Future of anti-PD-1/PD-L1 applications： Combinations with other therapeutic regimens

Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/PDL1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients.However, 30%–60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site,immunosuppressive factors in the tumor microenvironment（TME）, and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.

Combination of tumor-associated regulatory T cell deletion and PD-1/PD-L1 blockade: A promising immunotherapy for hepatocellular carcinoma?

During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune checkpoints programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1)blockade,brings a breakthrough for HCC[1,2].However,anti-PD-1/PD-L1 immunotherapy is not satisfactory and the response rates were between 20%and 30%[3].How to improve the efficacy of PD-1/PD-L1blockade is the main issue.

Impact of PD-1/PD-L1 inhibitors on survival in stage Ⅲ non-small-cell lung cancer:A systematic review

Background:Lung cancer is the leading cause of cancer-related death,and non-small-cell lung cancer(NSCLC)is the predominant subtype.Programmed death 1(PD-1)and programmed death-ligand 1(PD-L1)inhibitors are widely used to treat stage IV NSCLC.This study systematically reviewed the literature to clarify the impact of PD1/PD-L1 inhibitor treatment on the survival of patients with stage Ⅲ NSCLC.Methods:Randomized phase Ⅲ clinical trials of PD-1/PD-L1 inhibitors administered to patients with stage Ⅲ NSCLC that were written in English and published between November 2012 and November 2022 were eligible for review.The sources of information were the MEDLINE database(last consulted on December 26,2022),ScienceDirect website(last consulted on December 26,2022),and CENTRAL register(last consulted on December 27,2022).The outcomes of interest were overall survival(OS),progression-free survival(PFS),disease-free survival(DFS),and event-free survival(EFS).Risk of bias assessments were performed according to the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0.The findings have been assessed for certainty according to the Grading of Recommendations,Assessment,Development,and Evaluations(GRADE)guidelines.Results:Fourteen eligible studies and 2788 participants were included in the review.The key characteristics used to group the participants were disease histology,percentage of PD-L1 expression in cancer cells,and timeline of therapy.OS and PFS were improved(risk ratio[RR]:0.85;95%confidence interval[CI]:0.75–0.96 and RR:0.75;95%CI:0.70–0.86,respectively)based on the use of PD-L1 inhibitors after chemoradiation and OS was improved using first-line PD-1 inhibitors plus chemotherapy in non-squamous NSCLC(RR:0.40;95%CI:0.17–0.95),with the GRADE results indicating moderate quality of evidence.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.

From targeting the tumor to targeting the immune system: Transversal challenges in oncology with the inhibition of the PD-1/PD-L1 axis

After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new "immunotherapy era" with the advent of immune checkpoint inhibitors(CKI) antibodies.The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers.The new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types.The aim of this article is to review the most up to date literature about the clinical effectiveness of CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.

Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in East Asian patients with non-small cell lung cancer

Objective:The aim of this study was to investigate how the tumor immune microenvironment differs regarding tumor genomics,as well as its impact on prognoses and responses to immunotherapy in East Asian patients with non-small cell lung cancer(NSCLC).Methods:We performed an integrated analysis using publicly available data to identify associations between anti-programmed death 1(PD-1)/programmed death-ligand 1(PD-L1)immunotherapy efficacy and classic driver oncogene mutations in East Asian NSCLC patients.Four pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+tumor-infiltrating lymphocytes(TILs).Immune infiltrating patterns were also established for genomic NSCLC subgroups using the CIBERSORT algorithm.Results:Based on East Asian NSCLC patients,TIDE analyses revealed that for anti-PD-1/PD-L1 immunotherapy,epidermal growth factor receptor(EGFR)-mutant and anaplastic lymphoma kinase(ALK)-rearranged tumors yielded inferior responses;however,although Kirsten rat sarcoma viral oncogene homolog(KRAS)-mutant tumors responded better,the difference was not statistically significant(EGFR:P=0.037;ALK:P<0.001;KRAS:P=0.701).Pooled and clinical cohort analyses demonstrated tumor immune microenvironment heterogeneities correlated with oncogenic patterns.The results showed remarkably higher PD-L1-and TIL-positive KRAS-mutant tumors,suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune resistance.However,the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1-/TIL-tumors,suggesting an uninflamed phenotype with immunological ignorance.Notably,similar to triple wild-type NSCLC tumors,EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype,suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy(P<0.05).Furthermore,the CIBERSORT algorithm results revealed that EGFR-mutant and ALK-rearranged tumors were characterized by an enriched resting memory CD4+T cell population(P<0.001),as well as a lack of CD8+T cells(P<0.01),and activated memory CD4+T cells(P=0.001).Conclusions:Our study highlighted the complex relationships between immune heterogeneity and immunotherapeutic responses in East Asian NSCLC patients regarding oncogenic dependence.

PD-1/PD-L1 antagonists in gastric cancer:Current studies and perspectives

Immune checkpoints release suppressive signals for T cells,which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors.At present,programmed death receptor 1(PD-1)/programmed death ligand-1(PDL1) has become the most promising therapeutic target.PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers,such as melanoma and non-small-cell lung cancer.Moreover,PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer,and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool.Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer.Furthermore,there are many molecules involved in the regulation of PD-1/PD-L1 expression,and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer.In this review,the efficacy,safety,and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.

Current situation of programmed cell death protein 1/programmed cell death ligand 1 inhibitors in advanced triple-negative breast cancer

Triple-negative breast cancer(TNBC)has the worst prognosis among all molecular types of breast cancer.Because of the strong immunogenicity of TNBC cells,programmed death 1/programmed death ligand 1(PD-1/PD-L1)inhibitors,two kinds of immune checkpoint blockade agents,might help improve the prognosis of TNBC.However,how to better use PD-1/PD-L1 inhibitors and select patients who may benefit from treatment options remains controversial.This article summarizes published clinical studies in which PD-1/PD-L1 inhibitors were used in patients with advanced TNBC to explore how to maximize effectiveness of these medications.

PD-1/PD-L1抑制药联合化疗用药顺序对免疫相关不良反应的影响

目的:探讨程序性死亡蛋白-1/细胞程序性死亡蛋白配体1(PD-1/PD-L1)抑制药联合化疗的用药顺序,对免疫相关不良反应(irAEs)的影响。方法:收集某肿瘤专科医院2021年1~9月接受PD-1/PD-L1抑制药联合化疗药物治疗的200例病例,统计患者基本情况以及irAEs发生情况,并比较先使用PD-1/PD-L1抑制药再化疗的100例病例(后化疗组),与先化疗再使用PD-1/PD-L1抑制药的100例病例(先化疗组),发生irAEs的差异情况。结果:200例病例中男138例(69.0%),女62例(31.0%),年龄集中在40岁(72.5%);所患疾病主要为肺癌(28.5%)、肝癌(15.0%)和鼻咽癌(10.5%)。共发生irAEs 108例(54.0%),其中先化疗组irAEs发生率(64.0%)显著高于后化疗组的44.0%(P<0.05)。irAEs类型以肝脏毒性(14.5%)、皮肤毒性(11.0%)和内分泌毒性(9.5%)为主。毒性分级中G1G2有123例(61.5%),G3及以上7例(3.5%)。后化疗组中G1G2有51例,G3及以上4例;先化疗组中G~1G2有72例,G3及以上3例。88例患者发生1种类型的irAE,18例发生2种类型的irAE,2例发生3种类型的irAE。后化疗组与先化疗组发生≥2种类型irAEs的均为10例。结论:PD-1/PD-L1抑制药联合化疗治疗中,用药顺序与irAEs的发生密切相关,临床应加以重视。

PD-1/PD-L1抑制剂联合化疗对比免疫单药治疗晚期NSCLC疗效及安全性的Meta分析

目的系统评价PD-1/PD-L1抑制剂单药(I)或联合化疗(I+C)作为晚期非小细胞肺癌一线治疗的疗效和安全性。方法对PubMed、Embase、CNKI等数据库进行检索,纳入符合标准的随机对照试验,采用RevMan 5.3软件和R语言进行统计分析。结果共纳入13项研究,涉及7281名患者。Meta分析结果显示,PD-1/PD-L1抑制剂单药(I)或联合化疗(I+C)与化疗相比在总生存期OS和无进展生存期PFS方面均明显改善了临床疗效。间接分析(I+C vs I)中,联合治疗(I+C)较单药(I)相比可显著延长PFS,OS没有显著差异。亚组分析显示,“I+C”治疗方案在PD-L1表达阳性(≥1%)和阴性(<1%)人群中均比单药“I”和化疗具有更好的PFS。而3~5级治疗相关不良反应事件发生率在“I+C”联合治疗中更常见。结论在PD-L1表达阴性或阳性情况下,PD-1/PD-L1抑制剂联合化疗在一线治疗晚期NSCLC中均可取得较好的疗效,但不良反应发生率也较高。

Assessment of the safety and efficacy of combination chemotherapy and PD-1/PD-L1 inhibitor treatment of breast cancer:A meta-analysis

Background:As the efficacy of programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1)inhibitors combined with chemotherapy in curing breast cancer is still controversial,this meta-analysis compares the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy and chemotherapy alone in the treatment of breast cancer,which provides guidance for the clinical treatment.Methods:Relevant studies published as of April 2022 in the various databases including EMBASE,PubMed,and Cochrane Library were selected.Randomized controlled trials(RCTs)in which control patients underwent chemotherapy alone and experimental group patients underwent combination chemotherapy and PD-1/PD-L1 inhibitor treatment were included in this investigation.Investigations without complete information,researches from which information could not be extracted,duplicate articles,animal studies,review articles,and systematic reviews were excluded.STATA 15.1 was employed for all statistical analyses.Results:In total,eight eligible studies were identified,revealing that combination chemotherapy and PD-1/PD-L1 inhibitor treatment was linked to significant increases in progression-free survival(PFS)relative to chemotherapy alone(hazard ratio[HR]=0.83,95%confidence interval[CI]:0.70–0.99,P=0.032)but not overall survival(HR=0.92,95%CI:0.80–1.06,P=0.273).Pooled adverse event rates were also increased within the group of combination treatment relative to the chemotherapy group(risk ratio[RR]=1.08,95%CI:1.03–1.14,P=0.002).Specifically,nausea rates were lesser within the group of combination treatment relative to the group of chemotherapy(RR=0.48,95%CI:0.25–0.92,P=0.026).Subgroup analyses indicated that the PFS of patients who underwent combination atezolizumab or pembrolizumab and chemotherapy treatment were substantially longer than those of patients who underwent chemotherapy alone(HR=0.79,95%CI:0.69–0.89,P≤0.001;HR=0.79,95%CI:0.67–0.92,P=0.002).Conclusions:The pooled results suggest that combination chemotherapy and PD-1/PD-L1 inhibitor treatment approaches help prolong PFS in breast cancer patients,but have no statistically significant effect on overall survival(OS).Additionally,combination therapy can significantly improve complete response rate(CRR)compared with chemotherapy alone.However,combination therapy was associated with greater rates of adverse events.

化疗联合PD-1抑制剂在晚期黑色素瘤患者中的疗效和安全性分析

目的探索化疗联合程序性死亡受体1(PD-1)抑制剂在中国人群晚期黑色素瘤患者中的有效性及安全性。方法收集2019年2月至2020年2月在北京大学肿瘤医院确诊为不可切除的晚期黑色素瘤患者50例,接受替莫唑胺(200 mg/m2)或白蛋白结合型紫杉醇(260 mg/m2)联合PD-1抑制剂(特瑞普利单抗240 mg,d1,每2周1次或帕博利珠单抗100 mg,d1,每3周1次)治疗。观察患者的近期疗效、总生存期(OS)、无进展生存期(PFS)及不良反应。结果50例患者中,46例可评价疗效。获CR 1例,PR 12例,SD 22例,客观有效率(ORR)为28.3%(13/46),疾病控制率(DCR)为76.1%(35/46)。替莫唑胺联合PD-1抑制剂组和白蛋白结合型紫杉醇联合PD-1抑制剂组的ORR分别为23.8%(5/21)、32.0%(8/25),但差异无统计学意义(P>0.05)。至随访截止日期,全组患者的中位OS未达,中位PFS为5.4个月(95%CI:2.6~8.2个月)。替莫唑胺联合PD-1抑制剂组的中位PFS为6.5个月(95%CI:1.1~11.9个月),长于白蛋白结合型紫杉醇联合PD-1抑制剂组的4.0个月(95%CI:1.0~7.0个月),但两者差异无统计学意义(P>0.05)。生存单因素分析结果显示,联合不同化疗药物、不同病理类型、既往是否接受过免疫治疗均未影响患者的PFS(P>0.05)。不良反应多为1~2级,3级以上不良反应发生率为40.0%(20/50),多为血细胞减少。结论化疗联合PD-1抑制剂改善了中国晚期黑色素瘤患者的ORR、PFS,且耐受性良好,可进一步开展大样本随机对照研究证实。

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors:mechanisms and strategies

Immunotherapies based on immune checkpoint blockade(ICB)have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade.To date,immune checkpoint inhibitors(ICIs)of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy.Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers,however,a large subset of refractory patients presents poor responsiveness to ICB therapy;and the underlying mechanism remains elusive.Recently,numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment(TME)with various products of metabolism,and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy.Nevertheless,a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance.Here,we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints(CTLA-4,PD-1,and PD-L1)to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

PD-L1表达指导的信迪利单抗与帕博利珠单抗联合或不联合含铂双药化疗治疗未经治晚期非小细胞肺癌患者:一项2期随机对照试验(CTONG1901)

No direct comparison has been performed between different programmed cell death-1(PD-1)inhibitors for first-line treatment in patients with advanced non-small cell lung cancer(NSCLC).The feasibility of using PD-L1-expression-guided immunotherapy remains unknown.In this open-label,phase 2 study(NCT04252365),patients with advanced NSCLC without EGFR or ALK alterations were randomized(1:1)to receive sintilimab or pembrolizumab monotherapy(PD-L1 expression≥50%),or sintilimab or pembrolizumab plus platinum-based chemotherapy(PD-L1 expression<50%).The sample size was calculated by optimal two-stage design.The primary endpoint was the objective response rate(ORR).The study included 71 patients(sintilimab arms,n=35;pembrolizumab arms,n=36)and met its primary endpoint,with a confirmed ORR of 51.4%(18/35)in the sintilimab arms.The confirmed ORR(95%confidence interval)was 46.2%(19.2%,74.9%)and 42.9%(17.7%,71.1%)for patients treated with sintilimab and pembrolizumab monotherapy;and 54.5%(32.2%,75.6%)and 45.4%(24.4%,67.8%)for those treated with sintilimab-and pembrolizumab-based combination therapies.The median progression-free survival was6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients,respectively,in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies.The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients,respectively,in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies.Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies.However,the incidence of rash was higher with sintilimab than pembrolizumab monotherapy.This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC.Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

Anlotinib in combination with Envolizumab plus Etoposide for the treatment of EX-SCLC:a case report

Background:Small cell lung cancer(SCLC)is an aggressive malignant tumor with strong immunosuppressive effects,characterized by rapid doubling time and poor prognosis.Currently,effective therapeutic options are urgently needed for Extensive-stage small-cell lung Cancer.Case description:In the present case,a combination therapy of anlotinib,envolizumab,and etoposide was administered to treat an 80-year-old female patient with extensive-stage SCLC accompanied by mediastinal lymph node and bone metastasis.After two cycles of treatment,the tumor lesions in the right lungs decreased from 5.04*3.44 cm to 1.65*1.42 cm.As of now,no significant mass is seen there and no serious adverse reactions in this patient.Until September 2023,she has survived for 18 months with no disease progression.Conclusions:Research shows that Alectinib,in combination with evolocumab plus etoposide,could be an original,viable therapeutic option for the treatment option of patients with extensive-stage SCLC.

PD-1抑制剂联合白蛋白结合型紫杉醇、铂类治疗中晚期非小细胞肺癌临床观察

目的分析程序性死亡受体-1(PD-1)抑制剂联合白蛋白结合型紫杉醇、铂类治疗中晚期非小细胞肺癌(NSCLC)患者的临床效果。方法回顾性分析淮南东方医院集团总医院2020年6月-2021年6月进行新辅助化疗的64例中晚期NSCLC患者的病历资料,其中男57例,女7例,年龄36~69岁,平均(57.76±4.68)岁,采用随机数字表分为对照组(n=32)和观察组(n=32),对照组采用白蛋白结合紫杉醇+卡铂,观察组在对照组基础上联合PD-1抑制剂,以21 d为1个治疗周期,每2个周期评估疗效与安全性。采用SPSS26.0软件进行统计分析,正态分布的计量资料以均数±标准差(±s)表示,组间比较采用t检验,计数资料以例(百分比)[例(%)]表示,组间比较采用χ^(2)检验。结果观察组有效率为78.13%,对照组为53.13%,差异有统计学意义(P=0.035)。化疗前,两组患者远期生活质量评估KPS评分差异无统计学意义(P>0.05);化疗后两组KPS评分均改善,观察组效果要优于对照组,差异有统计学意义(P=0.029);治疗前两组血清CA125、癌胚抗原、神经元特异性烯醇化酶(NSE)水平差异无统计学意义(P>0.05);治疗后两组血清CA125、癌胚抗原、NSE水平均降低,且观察组效果优于对照组,差异有统计学意义(P<0.001);治疗前两组细胞免疫指标差异无统计学意义(P>0.05);治疗后观察组CD3^(+)、CD4^(+)水平均要高于对照组,观察组CD8^(+)低于对照组,差异有统计学意义(P<0.001);治疗前两组血清炎性因子水平差异无统计学意义(P>0.05),治疗后两组均下降,且观察组要明显低于对照组,差异有统计学意义(P<0.001);远期2年随访结果表明,观察组患者2年病死率为59.37%(19/32),低于对照组的81.25%(26/32),差异有统计学意义(P=0.015);两组不良反应发生率差异无统计学意义(P=0.768)。结论PD-1抑制剂与紫杉醇、铂类药物联用,是一种有潜力的治疗中晚期非小细胞肺癌(NSCLC)的临床方法,可明显延长患者无进展生存期。

Effectiveness of PD-1/PD-L1 inhibitors in the treatment of lung cancer:Brightness and challenge

Immune checkpoint inhibitors(ICIs),especially inhibitors of the PD-1/PD-L1 axis,have significantly affected the outcomes of patients with lung cancer.Nivolumab and pembrolizumab have been approved as PD-1 blocking antibodies,whereas atezolizumab,avelumab,and durvalumab are approved as PD-L1 blocking antibodies by the United States Food and Drug Administration.However,which patient may benefit the most and how to identify patients at risk of primary or acquired resistance has not been completely defined.Meanwhile,close attention has been paid to the ongoing international and domestic clinical trials in Chinese patients with lung cancer.This review aimed to provide deep insight into the effectiveness of PD-1/PD-L1 inhibitors in patients with lung cancer,including the current settings for varied disease status,the predictive biomarkers,the resistance to ICIs,and the ongoing clinical trials in Chinese patients.

卡瑞利珠联合化疗治疗非小细胞肺癌的有效性及安全性Meta分析

目的讨论免疫检查点抑制剂卡瑞利珠单独用药与联合化疗治疗非小细胞肺癌的疗效差异以及安全性,综合多个临床试验数据进行聚合分析,得到更准确的疗效及安全性评价。方法通过检索PubMed、Embase、Cochrane Library、CBM数据库、中国知网、维普中文数据库和万方数据库,收集建库至2023年11月30日发表的符合要求的随机化对照试验或非随机对照实验,提取数据后应用Revman5.4软件进行数据分析。按照治疗方案的不同,将研究对象分为卡瑞利珠联合化疗组和单独化疗组进行研究讨论。结果共纳入19篇文献,共计1545名患者。Meta分析结果显示:与单纯化疗相比,卡瑞利珠联合化疗治疗非小细胞肺癌能更有效的提高治疗总体有效率(OR=2.50,95%CI:2.02~3.08,P<0.00001),提高CD4^(+)/CD8^(+)比值(MD=0.26,95%CI:0.19~0.33,P<0.00001)以及有效降低血清肿瘤标志物CA125(MD=-10.65,95%CI:-14.34~-6.96,P<0.00001)、CEA(MD=-5.56,95%CI:-7.64~-3.47,P<0.00001)、CY211(MD=-2.17,95%CI:-3.22~-1.13,P<0.00001)。不同不良反应表现不同聚类分析结果,其中卡瑞利珠联合化疗组相较于单独化疗组会增加贫血(OR=1.95,95%CI:1.09~3.51,P=0.03)、甲减(OR=5.61,95%CI:1.82~17.25,P=0.003)、毛细血管增多症(OR=2.86,95%CI:1.19~6.88,P=0.02)等症状的发生比例,差异有统计学意义(P<0.05);但是皮疹(OR=1.34,95%CI:0.82~2.16,P=0.24)、骨髓抑制(OR=1.06,95%CI:0.56~2.02,P=0.86)、白细胞减少(OR=0.78,95%CI:0.40~1.52,P=0.47)、脱发(OR=1.29,95%CI:0.57~2.92,P=0.54)、神经异常(OR=1.17,95%CI:0.39~3.56,P=0.78)、消化道异常(OR=1.10,95%CI:0.79~1.53,P=0.57)、肝功异常(OR=1.54,95%CI:0.92~2.59,P=0.10)、恶心呕吐(OR=1.16,95%CI:0.58~2.31,P=0.67)、咳血(OR=0.87,95%CI:0.30~2.49,P=0.79)、发热(OR=1.22,95%CI:0.65~2.30,P=0.54)及其他症状(OR=1.32,95%CI:0.76~2.31,P=0.32)的发生率没有明显变化,差异无统计学意义(P>0.05)。综合上述各类不良反应发生率,从总体上看,卡瑞利珠联合化疗相较于单独化疗并不会提高不良反应发生率(OR=1.32,95%CI:1.13~1.55,P=0.23),差异无统计学意义(P>0.05)。结论卡瑞利珠联合化疗方案相较于单独化疗方案而言,能更有效的提高非小细胞肺癌患者总体缓解率和CD4^(+)/CD8^(+)比值,降低血清肿瘤标志物绝对值,不会升高不良反应发生率,安全性较好。