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.

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.

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。

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.

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.

PD0325901, an ERK inhibitor, enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma

ERK pathway regulated the programmed death ligand-1(PD-L1)expression which was linked to the response of programmed death-1(PD-1)/PD-L1 blockade therapy.So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy.In this study,PD0325901,an oral potent ERK inhibitor,strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma(NSCLC)cells.Mechanistically,PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3+T cells infiltration and functions in tumor tissue.There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC.And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy.Our results demonstrate that PD0325901,an ERK inhibitor,can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models.And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy.Despite the inherent advantages of small-molecule inhibitors over antibodies,the discovery of small-molecule inhibitors has fallen behind that of antibody drugs.Based on docking studies between small molecule inhibitor and PD-L1 protein,changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein,which was not reported before.A series of novel phthalimide derivatives from structure-based rational design was synthesized.P39 was identified as the best inhibitor with promising activity,which not only inhibited PD-1/PD-L1 interaction(IC_(50)=8.9 nmol/L),but also enhanced killing efficacy of immune cells on cancer cells.Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins,thereby blocking the binding of PD-1/PD-L1.Moreover,P39 exhibited a favorable safety profile with a LD_(50)>5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8^(+)T cell activation.All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

晚期胃癌一线免疫检查点抑制剂联合化疗预后因素及对二线化疗的影响

目的:探索免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)联合化疗一线治疗晚期胃癌中肝转移状态、中性粒细胞与淋巴细胞比值(neutrophil-to-lymphocyte ratio,NLR)、体质量指数(body mass index,BMI)等因素与患者预后的关系,以及一线应用ICIs对二线化疗疗效的影响。方法:收集解放军总医院2018年1月至2022年4月收治的胃癌患者临床资料,通过随访获得生存数据。采用Kaplan-Meier法进行生存分析,Log-rank检验比较胃癌一线程序性细胞死亡受体1(programmed cell death receptor-1,PD-1)/程序性细胞死亡配体1(programmed cell death-ligand 1,PD-L1)抑制剂联合化疗中不同NLR、BMI和肝转移状态对预后的影响,以及一线应用PD-1/PD-L1抑制剂对二线化疗的影响。应用Cox回归模型确定影响患者生存的预后因素。结果:共纳入晚期胃癌患者268例,在一线PD-1/PD-L1抑制剂联合化疗组中,总体客观缓解率(objective response rate,ORR)为46.5%,疾病控制率(disease control rate,DCR)为87.7%,中位无进展生存期1(median progression-free survival 1,mPFS1)为6.9(95%CI:6.0~7.8)个月。各亚组中,仅NLR<3组与NLR≥3组的中位PFS1有显著性差异(7.4 vs.6.7个月,P=0.044)。多因素分析显示,基线NLR<3的患者在PD-1/PD-L1抑制剂联合化疗中能够获得更长的无进展生存期(HR=0.57,95%CI:0.36~0.90;P=0.015),而BMI、肝转移状态与患者预后无明显相关(均P>0.05)。二线治疗中,一线PD-1/PD-L1抑制剂联合化疗进展后仅接受化疗患者的ORR(34.6%vs.14.6%,P=0.025)和mPFS2(4.4 vs.2.9个月,HR=0.54,95%CI:0.35~0.82;P=0.004)优于一、二线均仅应用化疗的患者,而DCR及中位总生存期(median overall survival,mOS)比较差异无统计学意义(均P>0.05)。结论:在一线接受PD-1/PD-L1抑制剂联合化疗的晚期胃癌中,基线NLR<3的患者更易从免疫治疗中获益,而肝转移状态、BMI与患者的预后无明显相关。另外,一线应用含免疫治疗的方案可提高胃癌患者二线化疗的疗效,使其获得更长的无进展生存期。

Immunotherapy for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is presented frequently in late stages that are not amenable for curative treatment.Even for patients who can undergo resection for curative treatment of HCC,up to 50%recur.For patients who were not exposed to systemic therapy prior to recurrence,recurrence frequently cannot be subjected to curative therapy or local treatments.Such patients have several options of immunotherapy(IO).This includes programmed cell death protein 1(PD-1)and cytotoxic T-lymphocyte associated protein 4 treatment,combination of PD-1 and vascular endothelial growth factor inhibitor or single agent PD-1 therapy when all other options are deemed inappropriate.There are also investigational therapies in this area that explore either PD-1 and tyrosine kinase inhibitors or a novel agent in addition to PD-1 with vascular endothelial growth factor inhibitors.This minireview explored IO options for patients with recurrent HCC who were not exposed to systemic therapy at the initial diagnosis.We also discussed potential IO options for patients with recurrent HCC who were exposed to first-line therapy with curative intent at diagnosis.

Engineered extracellular vesicles for concurrent Anti-PDL1 immunotherapy and chemotherapy

Immune checkpoint inhibitors(ICI)targeting PD-1/PD-L1 have been approved for the treatment of a variety of cancers.However,the efficacy of antibody-based ICIs could be further improved by mitigating anti-drug antibodies,proteolytic cleavage,and on-target off-tumor toxicity.One strategy for accomplishing this is through the use of extracellular vesicles(EVs),cell derived submicron vesicles with many unique properties.We constructed an engineered MDA-MB-231 cell line for harvesting EVs.This was accomplished by overexpressing a high-affinity variant human PD-1 protein(havPD-1),while simultaneously knocking out intrinsic PD-L1 and beta-2 microglobulin.The engineered havPD-1 EVs reduced PD-L1 overexpressing cancer cell proliferation and induced cellular apoptosis.Moreover,the EVs were shown to efficiently block PD-L1 mediated T cell suppression.Meanwhile antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not observed.The havPD-1 EVs treatment resulted in robust anti-tumor activity in both preventative co-implantation and therapeutic xenograft tumor models reconstituted with human T cells.The efficacy of the havPD-1 EVs was shown to be comparable to clinical anti-PD1 monoclonal antibodies.Additionally,loading the havPD-1 EVs with a potent PARP inhibitor was shown to further augment treatment efficacy.In brief,the engineered universal EVs harboring havPD-1 proteins can be used for cancer concurrent immunotherapy and chemotherapy.

Combination strategies for first-line treatment of patients with unresectable hepatocellular carcinoma:prospect of natural products

Liver cancer stands as a significant global health concern,contributing substantially to cancer incidence and mortality,particularly in Asian countries[1].Hepatocellular carcinoma(HCC)accounts for approximately 90%of all liver cancer cases and is characterized by a high-risk profile and a generally poor prognosis[2].To address advanced HCC,systemic therapy has been recommended,leading to the approval of a range of treatment regimens in clinical practice.Traditionally,first-line therapy involved the use of multitargeted tyrosine kinase inhibitors(TKIs)such as sorafenib or lenvatinib,while cabozantinib,ramucirumab.