The role of intestinal flora on tumorigenesis,progression,and the efficacy of PD-1/PD-L1 antibodies in colorectal cancer

Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(CRC).Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/d MMR CRC but performed poorly in patients with MSS/p MMR CRC.In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients.Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC.Herein,we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s).We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies.In addition,we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.

Efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in treatment of advanced gastric cancer or gastroesophageal junction cancer: A meta-analysis

BACKGROUND Faced with limited and inadequate treatment options for patients with advanced gastric cancer or gastroesophageal junction cancer(GC/GEJC), researchers have turned toward, with the support of promising clinical trials, anti-PD-1/anti-PD-L1 antibody therapy. But there are also different clinical trial results. To better assess its efficacy and safety, we integrated data from 13 eligible studies for a systematic review and meta-analysis.AIM To comprehensively evaluate the efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of advanced GC/GEJC patients.METHODS PubMed, Web of Science, Cochrane Library,and EMBASE databases were searched to identify eligible articles with outcomes including objective response rate(ORR), disease control rate(DCR), overall survival(OS), progression-free survival(PFS), and adverse events(AEs) of anti-PD-1/anti-PD-L1 antibody therapy.RESULTS Our study encompassed a total of 13 trials totaling 1618 patients. The outcomes showed a pooled ORR and DCR of 15%(95% confidence interval [CI]: 14%-18%) and 40%(95%CI: 33%-46%), respectively. The pooled 6-mo OS and PFS were 54%(95%CI: 45%-64%) and 26%(95%CI: 20%-32%), respectively, and the 12-mo OS and PFS were 42%(95%CI: 21%-62%) and 11%(95%CI: 8%-13%), respectively. In addition, the incidence of any-grade AEs and grade ≥ 3 AEs was 64%(95%CI: 54%-73%) and 18%(95%CI: 16%-20%), respectively. Most importantly, PD-L1 positive patients exhibited a higher ORR rate than PD-L1 negative patients(odds ratio = 2.54, 95%CI: 1.56-4.15).CONCLUSION Anti-PD-1/anti-PD-L1 antibody therapy has shown promising anti-tumor efficacy with manageable AEs in advanced GC/GEJC patients, with PD-L1 overexpressing patients exhibiting a higher ORR. What is more, the clinical efficacy of anti-PD-1/PD-L1 combined with traditional chemotherapy drugs is even better, although the occurrence of AEs still causes considerate concerns.

Development of a radiolabeled site-specific single-domain antibody positron emission tomography probe for monitoring PD-L1 expression in cancer

Despite advances in immunotherapy for the treatment of cancers,not all patients can benefit from programmed cell death ligand 1(PD-L1)immune checkpoint blockade therapy.Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level;hence,accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects.Therefore,based on the high affinity antibody Nb109,a new site-specifically radiolabeled tracer,^(68)Ga-NODA-cysteine,aspartic acid,and valine(CDV)-Nb109,was designed and synthesized to accurately monitor PD-L1 expression.The tracer ^(68)Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95%and radiochemical purity of 97%.It showed high affinity for PD-L1 with a dissociation constant of 12.34±1.65 nM.Both the cell uptake assay and positron emission tomography(PET)imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells.Meanwhile,dynamic PET imaging of a NCI-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression,allowing timely interventional immunotherapy.In conclusion,this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.

Antitumor effect of combination treatment of Astragalus polysaccharide and PD-L1 antibody on mice with Lewis lung carcinoma

Objective:To investigate the antitumor effect of combination treatment of Astragalus polysaccharide and PD-L1 antibody on mice with Lewis lung carcinoma.Methods:Forty male C57BL/6 mice were selected and divided equally into Model group,PD-L1 group,APSgroup,and APS+PD-L1 group.Lewis lung carcinoma cells were used to establish the lung carcinoma mouse model.After successful modeling,the PD-L1 group was injected with 200μg of PD-L1 antibody intraperitoneally on day 0/4/8/12;the APS group was gavaged with 80 mg/kg of APS daily for 14 days;the APS+PD-L1 group was gavaged with 80 mg/kg of APS daily for 14 days,and in addition,200μg of PD-L1 antibody was injected intraperitoneally on day 0/4/8/12.The spleen and thymus indices of each group of mice were observed,to plot the tumor growth curve and calculate the tumor suppression rate.The ratio of T-lymphocyte subsets in peripheral blood was measured by flow cytometry;the level of T cell-related cytokines in peripheral blood was detected by ELISA;MTT assay was used to detect the tumor-killing function of spleen lymphocytes in vitro.Results:PD-L1,APS,and APS+PD-L1 groups significantly increased spleen and thymus indices and inhibited tumor growth in lung carcinoma mice;flow cytometry results showed that PD-L1,APS,and APS+PD-L1 groups increased CD4^(+)T-cell ratio and CD4^(+)/CD8^(+)T-cell ratio;ELISA results showed that PD-L1,APS,and APS+PD-L1 groups significantly increased T cell-associated cytokine levels;MTT results showed that PD-L1,APS,and APS+PD-L1 groups enhanced the tumor-killing function of splenic lymphocytes in vitro.Conclusions:Astragalus polysaccharide can inhibit tumor growth,increase spleen and thymus indices,increase CD4^(+)T-cell ratio and CD4^(+)/CD8^(+)T-cell ratio,aswell as improve T-cell-related cytokine levels and splenic lymphocyte tumor-killing function in vitro in a mouse model of lung carcinoma,essentially inhibiting tumorigenesis and progression.

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.

AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy

Background:Radiation(IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment(TME).Wee1,a cell cycle regulator,can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1(CDK1).Meanwhile,programed death-1/programed death ligand-1(PD-1/PDL-1)blockade is closely related to TME.This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody(anti-PD-1 Ab)on radiosensitization of hepatoma.Methods:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide(MTT)assay on human and mouse hepatoma cells HepG2,Hepa1-6,and H22.The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro.A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice,which were divided into control group,IR group,AZD1775 group,IR+AZD1775 group,IR+anti-PD-1 Ab group,and the IR+AZD1775+anti-PD-1 Ab group.Cytotoxic CD8^(+)T cells in TME were analyzed by flow cytometry.Results:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro.AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage.AZD1775 treatment also reduced the proportion of PD-1^(+)/CD8^(+)T cells in the spleen of hepatoma subcutaneous xenograft mice.Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferonγ(IFNγ)^(+)or Ki67^(+)CD8 T cells and decreasing the levels of CD8^(+)Tregs cells in the tumor and spleen of the hepatoma mice model,indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγexpression,enhancing CD8^(+)T cells proliferation,and weakening CD8^(+)T cells depletion.Conclusions:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8^(+)T cells in TME.

Tumor burden score and alpha-fetoprotein level predict prognosis of patients with unresectable hepatocellular carcinoma treated with tyrosine kinase inhibitor and anti-PD-1 antibody

Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patients likely benefit most from this treatment strategy has not been reported.We sought to develop a prognostic scoring system based on tumor burden score(TBS)and alpha-fetoprotein(AFP)to predict the long-term prognosis of uHCC treated with TKIs and anti-PD-1 antibodies.Methods:Data on patients with uHCC treated with TKIs and anti-PD-1 antibodies from multiple centers were collected.The prognostic accuracy of TBS,AFP,Barcelona Clinic Liver Cancer(BCLC),and CTA(Combined TBS and AFP)for 2-year progression-free survival(PFS)and overall survival(OS)was evaluated.Results:Overall,278 patients with uHCC treated with TKIs and anti-PD-1 antibodies were enrolled,including 48 BCLC-B and 230 BCLC-C HCC patients.CTA(AUC?0.721 and 0.683)outperformed TBS(AUC?0.680 and 0.621),AFP(AUC?0.606 and 0.594),and BCLC staging(AUC?0.551 and 0.555)in predicting PFS and OS.The 2-year PFS and OS for low CTA(low TBS/low AFP)were 65.7%and 94.4%,respectively,which were significantly higher than 21.6%and 44.9%(p<0.001 and p?0.002),respectively,for intermediate CTA(low TBS/high AFP or high TBS/low AFP)and 8.7%and 12.1%(both p<0.001),respectively,for high CTA(high TBS/high AFP).Multivariable Cox regression analysis indicated that CTA grading was an independent prognostic factor for PFS and OS(referent:low CTA;intermediate CTA,HR 2.87 and 7.17;high CTA,HR 5.52 and 10.31,respectively).Conclusions:CTA grading is an accurate tool for stratifying the prognosis of uHCC treated with TKIs and anti-PD-1 antibodies and may help determine which patients may benefit more from this treatment strategy.

Abrogation of Hn RNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8^(+) T cell-mediated ferroptosis in castration-resistant prostate cancer

Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that target programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for human cancers with clinical benefit.However,many patients,especially prostate cancer,fail to respond to anti-PD-1/PD-L1 treatment,so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy.In the present study,analyzing the data from our prostate cancer tissue microarray,we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L(Hn RNP L).Hence,we further investigated the potential role of Hn RNP L on the PD-L1 expression,the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC.Indeed,Hn RNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo,on the contrary,Hn RNP L overexpression led to the opposite effect in CRPC cells.In addition,consistent with the previous study,we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death,and Hn RNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells.Furthermore,Hn RNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8^(+)T cells and synergized with anti-PD-1 therapy in CRPC tumors.This study provided biological evidence that Hn RNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.

Crystal clear： visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.

A phase I study of toripalimab, an anti-PD-1 antibody, in patients with refractory malignant solid tumors

Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.

PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives

Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-l/PD-Ll-related therapeutic strategies for CC.

Elevated peripheral blood neutrophil-to-lymphocyte ratio is associated with an immunosuppressive tumour microenvironment and decreased benefit of PD-1 antibody in advanced gastric cancer

Background Due to its limited efficacy and potential toxicity,anti-PD-1 monoclonal antibody is not suitable for all advanced gastric cancer(AGC)patients and predictive biomarkers identifying patients who can benefit from it are urgently needed.This study aimed to evaluate the predictive and prognostic value of inflammatory markers in the context of the systemic inflammatory status and tumour microenvironment.Methods The study included 58 patients from a prospective study investigating the safety and efficacy of toripalimab in chemorefractory AGC patients.Patient characteristics,treatment outcomes,and haematological parameters were analysed.Immune-cell infiltration and gene expression in tumour tissue were examined using transcriptome sequencing.Results In this cohort,the median follow-up time was 4.5 months,the median progression-free survival was 1.9 months,and the median overall survival(OS)was 4.8 months.The objective response rate was 12.1%and th disease control rate(DCR)was 39.7%.Both the baseline blood neutrophil-to-lymphocyte ratio(bNLR)with a cut-point of 2.7 and the early elevated dynamic change of the bNLR(dNLR)with a cut-point of 1.5 were prognostic factors of survival.Patients in the high bNLR or dNLR group had remarkably poor DCR(25.8%vs 59.1%,P=0.023;15.8%vs 54.6%,P=0.008).In multivariate analysis,bNLR and tumour mutational burden were independent prognostic factors of OS.Tumour RNA-seq analysis revealed enriched neutrophil infiltration and a higher tumour NLR in the bNLR-high group.Corresponding tumour gene-expression profiles were associated with neutrophil recruitment and inflammatory cytokine aggregation.Conclusions Our study demonstrated the potential clinical utility of NLR as a biomarker for patient selection and clinical management in predicting the prognosis of AGC patients as well as response to anti-PD-1 therapy.In addition,high bNLR reflected the imbalance of tumour-tissue-infiltrating neutrophils and lymphocytes,and was associated with an immunosuppressive and pro-tumour microenvironment.

Assays for predicting and monitoring responses to lung cancer immunotherapy

Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 （PD-1） and its ligand （PD-L1）, have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer （NSCLC）. Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry （IHC） with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-I/PD-L1 pathway.

Relaxin-encapsulated polymeric metformin nanoparticles remodel tumor immune microenvironment by reducing CAFs for efficient triple-negative breast cancer immunotherapy

Cancer-associated fibroblasts(CAFs)are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment,leading to the failure of triple-negative breast cancer(TNBC)immunotherapy.Therefore,depleting CAFs may enhance the effect of immunotherapy(such as PD-L1 antibody).Relaxin(RLN)has been demonstrated to significantly improve transforming growth factor-β(TGF-β)induced CAFs activation and tumor immunosuppressive microenvironment.However,the short half-life and systemic vasodilation of RLN limit its in vivo efficacy.Here,plasmid encoding relaxin(pRLN)to locally express RLN was delivered with a new positively charged polymer named polymeric metformin(PolyMet),which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before.In order to improve the stability of pRLN in vivo,this complex was further formed lipid poly-γ-glutamic acid(PGA)/PolyMetpRLN nanoparticle(LPPR).The particle size of LPPR was 205.5±2.9 nm,and the zeta potential was+55.4±1.6 mV.LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1luc/CAFs tumor spheres in vitro.In vivo,it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment,which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration.Thus,LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse,and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody(aPD-L1).Altogether,this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.

Harnessing macrophages in thermal and non-thermal ablative therapies for urologic cancers-Potential for immunotherapy

Prostate and bladder cancers are one of the cancers occurring worldwide.In addition to radical surgery,the past decade has also focused on targeted therapy of overexpressed cancer proteins that are lethal and critical for cancer cell survival.However,targeted therapy cannot adapt for changing of cancer molecular characteristics and,ultimately,a clone that bypasses the targeted therapy emerges.This can be overcome by immunotherapy.New studies on ablative therapy of cancers show presence of immunomodulatory effect in these modalities.Tumor ablation prime the immune system for further destruction of persistent primary tumor in addition to destruction of concurrent metastatic disease and also reduce recurrence.Ablative therapies can achieve a state of increased antigenicity.Its combination with a novel macrophage targeted therapy may enhance immune priming,trafficking,and/or effector phases;thereby improving clinical outcomes.Tumor associated macrophages or M2 phenotype are now known to mediate this immunosuppressive pro-tumorigenic effect.Alteration of macrophage differentiation may enhance tumor destruction of ablative therapy.This breakthrough in immunotherapy opens up arenas for further robust clinical trials on combinatorial therapies.In the present review,we aim to elucidate the major aspects of immune stimulatory minimal invasive approaches by combining with macrophage directed pathways.

Current Status and Clinical Research Progress of Immunotherapy for Advanced Gastric Cancer

Advanced gastric cancer is a common digestive system tumor,and its treatment has always been a difficult problem.In recent years,with the rapid development of immunotherapy,the treatment effect of advanced gastric cancer has been significantly improved.This article introduces the current status and clinical research progress of immune checkpoint inhibitors in advanced gastric cancer.Commonly used immunotherapy methods include chemical drug therapy,biological therapy,and gene therapy,among which the immune checkpoint inhibitors are currently one of the most popular immunotherapy methods,including nivolumab,pembrolizumab,and atezolizumab,which target programmed death ligand 1(PD-L1)low expression(1%–49%)and PD-L1 high expression(≥50%).The results of clinical studies have shown that immunotherapy can significantly prolong the survival of patients with advanced gastric cancer while having lower toxic side effects and better tolerance.However,immunotherapy also has some problems,such as drug resistance and repeated infection.Future research directions include exploring new immunotherapy methods,combination therapy,and individualized therapy.

Global dynamics of a tumor-immune model with an immune checkpoint inhibitor

In this paper,a mathematical ordinary differential tumor-immune model is proposed based on an immune checkpoint inhibitor,which is an innovative method for tumor immunotherapies.Two important factors in tumor-immune response are the programmed cell death protein 1(PD-1)and its ligand PD-L1.The model consists of three populations:tumor cells,activated T cells and anti-PD-1.By analyzing the dynamics of the model,it is found that there is always a unique tumor-free equilibrium and at most two tumor interior equilibria.The nonexistence of nontrivial positive periodic orbits is established by using the new Dulac function,and then a global dynamics of the model is obtained.The conclusions of our analysis show that increasing the possibility of T cells killing tumor cells(p),early detection of tumor cells,or the use of PD-1 inhibitors to activate T cells are effective in eliminating tumor cells.

Adjuvant therapies after curative treatments for hepatocellular carcinoma: Current status and prospects

Tumor recurrence rate after surgery or ablation of hepatocellular carcinoma(HCC)is as high as 70%.However,there are no widely accepted adjuvant therapies;therefore,no treatment has been recommended by guidelines from the American Association for the Study of Liver Disease or the European Association for the Study of the Liver.All the registered trials failed to find any treatment to prolong recurrence-free survival,which is the primary outcome in most studies,including sorafenib.Some investigator-initiated studies revealed that antihepatitis B virus agents,interferon-a,transcatheter chemoembolization,chemokine-induced killer cells,and other treatments prolonged patient recurrence-free survival or overall survival after curative therapies.In this review,we summarize the current status of adjuvant treatments for HCC and explain the challenges associated with designing a clinical trial for adjuvant therapy.Promising new treatments being used as adjuvant therapy,especially anti-PD-1 antibodies,are also discussed.

The advancement of immunotherapy in hepatocellular carcinoma

Most patients diagnosed with hepatocellular carcinoma(HCC)present with advanced or metastatic disease.The lack of therapeutic options in the treatment of advanced HCC accounts for its high mortality and recurrence rate.HCC is known as an immunogenic tumor,which develops in chronically inflamed livers.Anti-PD-1/PD-L1 antibodies(immune checkpoint inhibitors,ICB)were approved by the FDA to treat advanced HCC in patients previously treated with sorafenib as a second line.This has opened up a new era of anticancer treatment,although the response rate of HCC to anti-PD-1/PD-L1 antibodies is only around 20%.Other than ICB treatment,adoptive cell transfer,dendritic cell-based vaccines and oncolytic therapy are currently under clinical trials.In this review,different immunotherapy approaches for HCC is presented.Current knowledge on the mechanisms of action for each approach is discussed and relevant,ongoing clinical trials are presented.We also discuss the future of immunotherapy and combination treatment for HCC patients.