Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal ...Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.展开更多
Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive ...Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.展开更多
Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of adv...Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.展开更多
BACKGROUND The development and progression of gastric cancer(GC)are closely linked to the nutritional status of patients.Although immunotherapy has been demonstrated to be clinically effective,the relationships of sar...BACKGROUND The development and progression of gastric cancer(GC)are closely linked to the nutritional status of patients.Although immunotherapy has been demonstrated to be clinically effective,the relationships of sarcopenia and myosteatosis with the use of immune checkpoint inhibitors(ICIs)in patients with gastric cancer remain to be characterized.METHODS We performed a retrospective study of patients who were undergoing immuno-therapy for GC.For the evaluation of sarcopenia,the optimal cut-off value for the skeletal muscle index was established using receiver operating characteristic analysis of data obtained from pre-treatment computed tomography images at the L3 vertebral level.Myosteatosis was defined using the mean skeletal muscle density(SMD),with a threshold value of<41 Hounsfield units(HU)for patients with a body mass index(BMI)<25 kg/m^(2)and<33 HU for those with a BMI≥25 kg/m^(2).The log-rank test was used to compare progression-free survival(PFS)and overall survival(OS),and a Cox proportional hazard model was used to identify prognostic factors.Nomograms were developed to predict the PFS and OS of patients on the basis of the results of multivariate analyses.RESULTS We studied 115 patients who were undergoing ICI therapy for GC,of whom 27.4%had sarcopenia and 29.8%had myosteatosis.Patients with sarcopenia or myosteatosis had significantly shorter PFS and OS than those without these conditions.Furthermore,both sarcopenia and myosteatosis were found to be independent predictors of PFS and OS in patients with GC administering an ICI.The prediction models created for PFS and OS were associated with C-indexes of 0.758 and 0.781,respectively.CONCLUSION The presence of sarcopenia or myosteatosis is a reliable predictor of the clinical outcomes of patients with GC who are undergoing treatment with an ICI.展开更多
Immune checkpoint blockade(ICB)therapy for cancer has achieved great success both in clinical results and on the market.At the same time,success drives more attention from scientists to improve it.However,only a small...Immune checkpoint blockade(ICB)therapy for cancer has achieved great success both in clinical results and on the market.At the same time,success drives more attention from scientists to improve it.However,only a small portion of patients are responsive to this therapy,and it comes with a unique spectrum of side effects termed immunerelated adverse events(irAEs).The use of nanotechnology could improve ICBs’delivery to the tumor,assist them in penetrating deeper into tumor tissues and alleviate their irAEs.Liposomal nanomedicine has been investigated and used for decades,and is well-recognized as the most successful nano-drug delivery system.The successful combination of ICB with liposomal nanomedicine could help improve the efficacy of ICB therapy.In this review,we highlighted recent studies using liposomal nanomedicine(including new emerging exosomes and their inspired nanovesicles)in associating ICB therapy.展开更多
Objective:Copper death-induced tumor cell death and immune checkpoint blockade therapy are highly selective.Combining their advantages and understanding their characteristics in bladder cancer is very important for th...Objective:Copper death-induced tumor cell death and immune checkpoint blockade therapy are highly selective.Combining their advantages and understanding their characteristics in bladder cancer is very important for the development of new targeted therapy.The identification of bladder cancer by screening the characteristic genes of copper death-related immune checkpoints provide a theoretical basis for the selection of adjuvant treatment options and the application of new targets.Methods:The expression samples of normal bladder tissue and bladder cancer were obtained from TCGA and GEO databases,and 13 cop-per death genes and 79 immune checkpoint genes were extracted from previous studies.The mRNA expression of prognostic genes was verified by qPCR.The copper death-related immune checkpoint genes were screened by correlation analysis to construct a prognostic model,and the differences in the efficacy of immunotherapy and chemotherapy between the high-risk group and the low-risk group were evaluated.Results:A prognostic model consisting of BTNL9,CD160,TNFRSF14 and TNFRSF18 was constructed.Its reliable predictive ability was proved in both databases,and qPCR showed that the expression levels of the four genes were significantly different between the normal group and the cancer cell group.The effect of immunotherapy in the lowrisk group was better than that in the high-risk group.Patients in the high-risk group had better chemotherapy efficacy.Conclusion:The copper death-related immune checkpoint gene model can accurately predict the prognosis of patients.Drug and immune analysis provide a basis for clinical treatment,and the discovery of potential targets provides a new solution for clinical decision-making.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)have shown promising efficacy in treatment and clinical management of advanced gastric and gastroesophageal junction cancer.However,the inhibitors also cause immune-related...BACKGROUND Immune checkpoint inhibitors(ICIs)have shown promising efficacy in treatment and clinical management of advanced gastric and gastroesophageal junction cancer.However,the inhibitors also cause immune-related adverse events(irAEs).The current systematic review and meta-analysis study aimed to investigate the incidence and nature of irAEs caused by ICIs.AIM To investigate the incidence and nature of irAEs in advanced gastric and gastroesophageal junction cancer.METHODS This systematic review was registered with PROSPERO(Reg.number:CRD42020152291).Data included in this study were collected from patients diagnosed with advanced gastric cancer or gastroesophageal junction cancer and treated with ICIs.A systematic literature search was conducted using the PubMed,EMBASE,and Cochrane Library databases.Meta-analysis was carried out using the single sample rate method.Synthesis and analysis of the data was conducted using Stata/SE and Review Manager Software.RESULTS The patients enrolled in the present study included 14 patients from 14 case reports,326 patients from 6 case series,and 1249 patients from 8 clinical trials.It was found that the overall incidence of irAEs was 16%[95%confidence interval(CI):11-20]for all grades and 3%(95%CI:2-4)for the severe grade.It was evident that the incidence of irAEs varied with the type of inhibitor and organs.A comparative study of the anti-programmed cell death receptor-1(PD-1)and antiprogrammed death receptor-ligand 1(PD-L1)treatments showed that the antiPD-1 group had a higher overall incidence of irAEs(20%)as compared with that of the anti-PD-L1 group(13%).Results of this study showed that the endocrine system experienced the highest incidence of organ-specific irAEs(7.4%),including hypothyroidism,hyperthyroidism,thyroiditis,diabetes,and adrenal insufficiency,followed by gastroenterology(2.2%),pulmonology(1.8%),neurology(1.4%),dermatology(1.4%),hematology(0.8%),and hepatology(0.7%).In clinical trials,it was found that the incidence of death related to irAEs was 1%(95%CI:0-2.0),whereby colitis and interstitial lung diseases were the leading causes of death.CONCLUSION It was evident that the incidence and nature of irAEs are both organ-and inhibitor-specific.The anti-PD-1 group had the highest incidence of all irAEs grades including the severe grades of irAEs.Early identification and management of irAEs allows clinical oncologists to effectively consider the pros and cons and hence enables them to strike a balance.展开更多
Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical out...Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical outcome.It is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical outcome.In this perspective,we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs,providing new insights for designing dual IC blockades(ICBs).展开更多
In recent years,immune checkpoint blockade(ICB)therapy has become an important treatment strategy for gastrointestinal tumors,however,it only benefits about 1/3 of patients.Since the microbiome has been shown to play ...In recent years,immune checkpoint blockade(ICB)therapy has become an important treatment strategy for gastrointestinal tumors,however,it only benefits about 1/3 of patients.Since the microbiome has been shown to play an important role in the human body for a long time,a growing number of studies are focusing on its relationship to ICB therapy in cancer,specifically how intestinal microbes affect the efficacy of immune checkpoint inhibitors(ICIs)therapy in patients.On this basis,probiotic interventions,fecal microbiota transplantation(FMT),dietary interventions,and other methods which improve or maintain the structure of the intestinal flora have attracted widespread attention.This article discusses the four aspects of the microbiome,ICB,combined treatment of gastrointestinal tumors,and regulation of gut microbiome.Particularly,the discussion focuses on the contribution of probiotic intervention in improving the therapeutic effect of ICIs to prolong the survival time of patients and reduce the severity of immune-related adverse effects(irAEs).展开更多
Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising t...Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued,which therefore provides limited benefits to patients with cancer.Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed.Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest.This review comprehensively analyses the efficacy of various repurposed drugs,such as transforming growth factor-beta(TGF-β)inhibitors,metformin,receptor activator of nuclear factor-κB ligand(RANKL)inhibitors,granulocyte macrophage colony-stimulating factor(GM-CSF),thymosinα1(Tα1),aspirin,and bisphosphonate,in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy.Additionally,we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.展开更多
Objective The combination of stereotactic body radiation therapy(SBRT)and immune checkpoint inhibitors(ICIs)is actively being explored in advanced non-small-cell lung cancer(NSCLC)patients.However,little is known abou...Objective The combination of stereotactic body radiation therapy(SBRT)and immune checkpoint inhibitors(ICIs)is actively being explored in advanced non-small-cell lung cancer(NSCLC)patients.However,little is known about the optimal fractionation and radiotherapy target lesions in this scenario.This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs.Methods The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec.2015 to Sep.2021.Patients were grouped according to radiation sites.Progression-free survival(PFS)and overall survival(OS)were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank(Mantel-Cox)test.Results A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study.Radiation sites included lung lesions(lung group,n=43),bone metastases(bone group,n=24),and brain metastases(brain group,n=57).Compared with the brain group,the mean PFS(mPFS)in the lung group was significantly prolonged by 13.3 months(8.5 months vs.21.8 months,HR=0.51,95%CI:0.28–0.92,P=0.0195),and that in the bone group prolonged by 9.5 months with a 43%reduction in the risk of disease progression(8.5 months vs.18.0 months,HR=0.57,95%CI:0.29–1.13,P=0.1095).The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group.The mean OS(mOS)in the lung and bone groups was longer than that of the brain group,and the risk of death decreased by up to 60%in the lung and bone groups as compared with that of the brain group.When SBRT was concurrently given with ICIs,the mPFS in the lung and brain groups were significantly longer than that of the bone group(29.6 months vs.16.5 months vs.12.1 months).When SBRT with 8–12 Gy per fraction was combined with ICIs,the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups(25.4 months vs.15.2 months vs.12.0 months).Among patients receiving SBRT on lung lesions and brain metastases,the mPFS in the concurrent group was longer than that of the SBRT→ICIs group(29.6 months vs.11.4 months,P=0.0003 and 12.1 months vs.8.9 months,P=0.2559).Among patients receiving SBRT with<8 Gy and 8–12 Gy per fraction,the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group(20.1 months vs.5.3 months,P=0.0033 and 24.0 months vs.13.4 months,P=0.1311).The disease control rates of the lung,bone,and brain groups were 90.7%,83.3%,and 70.1%,respectively.Conclusion The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients.This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens.Dose fractionation regimens of 8–12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.展开更多
BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are incr...BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are increasingly implicated in the development of autoimmune diseases.CASE SUMMARY We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab,docetaxel,and cisplatin therapy who developed autoimmune polyendocrine syndrome typeⅡ(APS-2)including thyroiditis and type 1 diabetes mellitus and Crohn’s disease(CD).He developed thirst,abdominal pain,and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab.Biochemistry confirmed APS-2 and thyrotoxicosis.He was commenced on an insulin infusion.However,his abdominal pain persisted.Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine.He was continued on insulin and mesalazine therapy.CONCLUSION Immunotherapy can affect all kinds of organs.When clinical symptoms cannot be explained by a single disease,clinicians should consider the possibility of multisystem damage.展开更多
Immunotherapy targets the dysfunctional immune system to induce cancer cell killing by CD8-positive T cells.Immune checkpoint inhibitors(ICIs),specifically anti-PD-1 antibodies,anti-PD-L1 antibodies,and anti-CTLA4 ant...Immunotherapy targets the dysfunctional immune system to induce cancer cell killing by CD8-positive T cells.Immune checkpoint inhibitors(ICIs),specifically anti-PD-1 antibodies,anti-PD-L1 antibodies,and anti-CTLA4 antibodies,have revolutionized the management of many malignancies due to their significant role in generating a durable clinical response.However,clinical data suggest that response rates to ICI monotherapy are low due to the immunologically silent characteristics of breast cancer(BC).Chemotherapy,surgery,radiotherapy,and targeted therapy were recently reported to alter the tumor microenvironment and enhance the ICI response.Some clinical studies supported that ICIs,in combination with other treatment strategies,show superior efficacy in BC control,especially triple-negative breast cancer.Therefore,seeking a reasonable combination therapy is a promising way to improve ICI response.The present review highlights the clinical efficacy of ICIs treatment options in combination with standard-of-care therapies,such as chemotherapy and targeted therapy。展开更多
In recent years,immune checkpoint molecules have made breakthroughs in the fields of inducing graft tolerance,tumor immune escape and preventing autoimmunity.These immunoregulatory factors,when combined with ligand,ca...In recent years,immune checkpoint molecules have made breakthroughs in the fields of inducing graft tolerance,tumor immune escape and preventing autoimmunity.These immunoregulatory factors,when combined with ligand,can transduce the inhibitory signal into cells to negatively regulate the immune response,which brings new enlightenment for the immune research of pregnancy and pregnancy complications.In this review,we reviewed the immunomodulatory effects of CTLA-4,PD-1 and Tim-3 in pregnancy,in order to evaluate their potential effects in pregnancy,and to provide a new direction for the immunotherapy of pregnancy complications.展开更多
This study determined the effect of orally fed polysaccharide-rich bioprocessed (fermented) black rice bran produced by culturing with shiitake (Lentinus edodes) mushroom mycelium on CT-26 colon cancer cells in vivo i...This study determined the effect of orally fed polysaccharide-rich bioprocessed (fermented) black rice bran produced by culturing with shiitake (Lentinus edodes) mushroom mycelium on CT-26 colon cancer cells in vivo in an intracutaneously transplanted mouse tumor alone and in combination with intraperitoneally administered anti-PD-1 immune checkpoint inhibitor. Analysis of the isolated tumor weights at the end of the study shows that the average tumor size in control mice is 3.78 grams, and the average tumor size in mice treated with anti-PD-1 antibody is 2.16 grams. The average tumor size in mice treated with BRB-F alone is 2.25 grams, and the average tumor size in mice treated with anti-PD-1 antibody BRB-F combination is 1.38 grams. Thus, BRB-F or anti-PD-1 antibody alone each reduce tumor size by 40.5% or 42.9%, whereas the combination of BRB-F and anti-PD-1 antibody reduces tumor size by 63.5%, with their cooperative effect being statistically significant. The observed anti-tumor effects were accompanied by a series of biomarkers associated with cancer formation and inhibition. These results indicate that the reported potentiation of cancer therapy using drug-based medical chemotherapies with added checkpoint inhibitors in human patients are mechanistically similar with the functional food evaluated in the present study. These beneficial effects in mice challenge clinicians to investigate if the black rice bran food product can also protect against human cancer.展开更多
Immune checkpoint inhibitors are today an immense hope in the management of cancers. However, since their widespread use, many cases of insulin-requiring diabetes appearing suddenly, as fulminant diabetes have been re...Immune checkpoint inhibitors are today an immense hope in the management of cancers. However, since their widespread use, many cases of insulin-requiring diabetes appearing suddenly, as fulminant diabetes have been reported. Here, we describe 4 cases that occurred at different times after the beginning of immune checkpoint inhibitor therapy with Nivolumab alone or associated with Ipilimumab. There are 3 cases of newly diagnosed diabetes and 1 case of known type 2 diabetes formerly quite well balanced with Metformin. The clinical and biological characteristics of these patients are quite similar. They were all insulin-requiring at the discovery of diabetes and remained so throughout their follow-up. This type of diabetes which looks like type 1 diabetes seems rather to be a new entity.展开更多
BACKGROUND With the wide application of immune checkpoint inhibitors(ICIs)in cancer treatment,immune-related adverse events occur frequently,involving almost all organs and systems.The incidence of ICI-associated arth...BACKGROUND With the wide application of immune checkpoint inhibitors(ICIs)in cancer treatment,immune-related adverse events occur frequently,involving almost all organs and systems.The incidence of ICI-associated arthritis(IA)is unknown.In most cases,IA is not serious and non-lethal.Higher checkpoint inhibitor arthritis disease activity may be associated with cancer progression.Here,we report a severe case of IA with high arthritis disease activity in advanced pulmonary adenocarcinoma,causing permanent withdrawal of pembrolizumab,but the patient remained in complete remission(CR)20 mo after the development of IA.CASE SUMMARY An 81-year-old smoking man was admitted to our hospital because of left chest pain for 9 mo.He was finally diagnosed with advanced pulmonary adenocarcinoma,with programmed cell death 1 ligand 1 expression of 70%.The patient responded to pembrolizumab treatment and achieved CR,but IA occurred after the 5th cycle of pembrolizumab administration.Although non-steroidal antiinflammatory drugs and disease-modifying anti-rheumatic drugs were prescribed,arthralgia and joint swelling occurred.The symptoms of arthritis were further aggravated when immunotherapy was given again after short-term withdrawal.Clinical Disease Activity Index(CDAI)score,a traditional measure of arthritis activity,was 43.Intravenous methylprednisolone was prescribed at 20 mg/d and then tapered over the subsequent 4 wk.The symptoms of arthritis steadily improved and completely resolved 4 mo after withdrawal of pembrolizumab.A recent follow-up in June 2022 revealed satisfactory clinical recovery of arthritis and the patient remained in CR.CONCLUSION This case report highlights that early recognition of IA and appropriate treatment are critical to improving the outcome of both ICI-arthritis and lung cancer.展开更多
BACKGROUND Immune checkpoint inhibitor-mediated colitis(IMC)is a common adverse event following immune checkpoint inhibitor(ICI)therapy for cancer.IMC has been associated with improved overall survival(OS)and progress...BACKGROUND Immune checkpoint inhibitor-mediated colitis(IMC)is a common adverse event following immune checkpoint inhibitor(ICI)therapy for cancer.IMC has been associated with improved overall survival(OS)and progression-free survival(PFS),but data are limited to a single site and predominantly for melanoma patients.AIM To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.METHODS We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age,sex,ICI class,and malignancy to a cohort of ICI users without IMC,from May 2011 to May 2020.Using univariate and multivariate logistic regression,we determined association of presence of IMC on OS,PFS,and clinical predictors of IMC.Kaplan-Meier curves were gen-erated to compare OS and PFS between ICI users with and without IMC.RESULTS IMC was significantly associated with a higher OS(mean 24.3 mo vs 17.7 mo,P=0.05)but not PFS(mean 13.7 mo vs 11.9 mo,P=0.524).IMC was significantly associated with OS greater than 12 mo[Odds ratio(OR)2.81,95%confidence interval(CI)1.17-6.77].Vitamin D supplementation was significantly associated with increased risk of IMC(OR 2.48,95%CI 1.01-6.07).CONCLUSION IMC was significantly associated with OS greater than 12 mo.In contrast to prior work,we found that vitamin D use may be a risk factor for IMC.展开更多
Immune checkpoint inhibitors(ICIs)are a new class of cancer pharmacotherapy consisting of antibodies that block inhibitory immune regulators such as cytotoxic T lymphocyte antigen 4,programmed cell death 1 and program...Immune checkpoint inhibitors(ICIs)are a new class of cancer pharmacotherapy consisting of antibodies that block inhibitory immune regulators such as cytotoxic T lymphocyte antigen 4,programmed cell death 1 and programmed death-ligand 1.Checkpoint blockade by ICIs reactivates a tumor-specific T cell response.Immune-related adverse events can occur in various organs including skin,liver,and gastrointestinal tract.Mild to severe colitis is the most common side effect with some experiencing rapid progression to more serious complications including bowel perforation and even death.Prompt diagnosis and management of ICI-induced colitis is crucial for optimal outcome.Unfortunately,its clinical,endoscopic and histopathologic presentations are non-specific and overlap with those of colitis caused by other etiologies,such as infection,medication,graftversus-host disease and inflammatory bowel disease.Thus,a definitive diagnosis can only be rendered after these other possible etiologies are excluded.Sometimes an extensive clinical,laboratory and radiologic workup is required,making it challenging to arrive at a prompt diagnosis.Most patients experience full resolution of symptoms with corticosteroids and/or infliximab.For ICI-induced colitis that is treatment-refractory,small scale studies offer alternative strategies,such as vedolizumab and fecal microbiota transplantation.In this review,we focus on the clinical features,differential diagnosis,and management of ICIinduced colitis with special attention to emerging treatment options for treatmentrefractory ICI-induced colitis.展开更多
Immune checkpoint inhibitors(ICIs)are new and promising therapeutic agents for non-small cell lung cancer(NSCLC).However,along with demonstrating remarkable efficacy,ICIs can also trigger immune-related adverse events...Immune checkpoint inhibitors(ICIs)are new and promising therapeutic agents for non-small cell lung cancer(NSCLC).However,along with demonstrating remarkable efficacy,ICIs can also trigger immune-related adverse events.Checkpoint inhibitor pneumonitis(CIP)has been reported to have a morbidity rate of 3%to 5%and a mortality rate of 10%to 17%.Moreover,the incidence of CIP in NSCLC is higher than that in other tumor types,reaching 7%to 13%.With the increased use of ICIs in NSCLC,CIP has drawn extensive attention from oncologists and cancer researchers.Identifying high risk factors for CIP and the potential mechanism of CIP are key points in preventing and monitoring serious adverse events.In this review,the results of our analysis and summary of previous studies suggested that the risk factors for CIP may include previous lung disease,prior thoracic irradiation,and combinations with other drugs.Our review also explored potential mechanisms closely related toCIP,including increasedT cell activity against associated antigens in tumor and normal tissues,preexisting autoantibodies,and inflammatory cytokines.展开更多
基金Supported by Joint Funds for the Innovation of Science and Technology,Fujian Province,China,No.2021Y9227Natural Science Foundation of Fujian Province,China,No.2023J011254+2 种基金The Science Foundation for The Excellent Youth Scholars of Fujian Provincial Health Commission,China,No.2022ZQNZD009The Special Research Funds for Local Science and Technology Development Guided by Central Government,Fujian Province,China,No.2023L3020Fujian Medical University Student Innovation and Entrepreneurship Training Project,China,No.JC2023191.
文摘Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.
基金supported by the National Natural Science Foundation of China (Grant Nos. 81972761 and 82202837)the National Key R&D Program of China (Grant Nos. 2016YFC1303200 and 2022YFC2505100)。
文摘Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.
基金Supported by IU Simon Comprehensive Cancer Center grant,No.5P30CA082709-24.
文摘Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
基金This study was approved by the Ethics Committee of Harbin Medical University Cancer Hospital.
文摘BACKGROUND The development and progression of gastric cancer(GC)are closely linked to the nutritional status of patients.Although immunotherapy has been demonstrated to be clinically effective,the relationships of sarcopenia and myosteatosis with the use of immune checkpoint inhibitors(ICIs)in patients with gastric cancer remain to be characterized.METHODS We performed a retrospective study of patients who were undergoing immuno-therapy for GC.For the evaluation of sarcopenia,the optimal cut-off value for the skeletal muscle index was established using receiver operating characteristic analysis of data obtained from pre-treatment computed tomography images at the L3 vertebral level.Myosteatosis was defined using the mean skeletal muscle density(SMD),with a threshold value of<41 Hounsfield units(HU)for patients with a body mass index(BMI)<25 kg/m^(2)and<33 HU for those with a BMI≥25 kg/m^(2).The log-rank test was used to compare progression-free survival(PFS)and overall survival(OS),and a Cox proportional hazard model was used to identify prognostic factors.Nomograms were developed to predict the PFS and OS of patients on the basis of the results of multivariate analyses.RESULTS We studied 115 patients who were undergoing ICI therapy for GC,of whom 27.4%had sarcopenia and 29.8%had myosteatosis.Patients with sarcopenia or myosteatosis had significantly shorter PFS and OS than those without these conditions.Furthermore,both sarcopenia and myosteatosis were found to be independent predictors of PFS and OS in patients with GC administering an ICI.The prediction models created for PFS and OS were associated with C-indexes of 0.758 and 0.781,respectively.CONCLUSION The presence of sarcopenia or myosteatosis is a reliable predictor of the clinical outcomes of patients with GC who are undergoing treatment with an ICI.
基金supported by the National Science Fund for Distinguished Young Scholars(Overseas).
文摘Immune checkpoint blockade(ICB)therapy for cancer has achieved great success both in clinical results and on the market.At the same time,success drives more attention from scientists to improve it.However,only a small portion of patients are responsive to this therapy,and it comes with a unique spectrum of side effects termed immunerelated adverse events(irAEs).The use of nanotechnology could improve ICBs’delivery to the tumor,assist them in penetrating deeper into tumor tissues and alleviate their irAEs.Liposomal nanomedicine has been investigated and used for decades,and is well-recognized as the most successful nano-drug delivery system.The successful combination of ICB with liposomal nanomedicine could help improve the efficacy of ICB therapy.In this review,we highlighted recent studies using liposomal nanomedicine(including new emerging exosomes and their inspired nanovesicles)in associating ICB therapy.
基金Key Research Project of Sichuan Provincial Department of Science and Technology(No.23ZDYF1246)。
文摘Objective:Copper death-induced tumor cell death and immune checkpoint blockade therapy are highly selective.Combining their advantages and understanding their characteristics in bladder cancer is very important for the development of new targeted therapy.The identification of bladder cancer by screening the characteristic genes of copper death-related immune checkpoints provide a theoretical basis for the selection of adjuvant treatment options and the application of new targets.Methods:The expression samples of normal bladder tissue and bladder cancer were obtained from TCGA and GEO databases,and 13 cop-per death genes and 79 immune checkpoint genes were extracted from previous studies.The mRNA expression of prognostic genes was verified by qPCR.The copper death-related immune checkpoint genes were screened by correlation analysis to construct a prognostic model,and the differences in the efficacy of immunotherapy and chemotherapy between the high-risk group and the low-risk group were evaluated.Results:A prognostic model consisting of BTNL9,CD160,TNFRSF14 and TNFRSF18 was constructed.Its reliable predictive ability was proved in both databases,and qPCR showed that the expression levels of the four genes were significantly different between the normal group and the cancer cell group.The effect of immunotherapy in the lowrisk group was better than that in the high-risk group.Patients in the high-risk group had better chemotherapy efficacy.Conclusion:The copper death-related immune checkpoint gene model can accurately predict the prognosis of patients.Drug and immune analysis provide a basis for clinical treatment,and the discovery of potential targets provides a new solution for clinical decision-making.
基金Supported by The National Natural Science Foundation of China,No.81960503.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)have shown promising efficacy in treatment and clinical management of advanced gastric and gastroesophageal junction cancer.However,the inhibitors also cause immune-related adverse events(irAEs).The current systematic review and meta-analysis study aimed to investigate the incidence and nature of irAEs caused by ICIs.AIM To investigate the incidence and nature of irAEs in advanced gastric and gastroesophageal junction cancer.METHODS This systematic review was registered with PROSPERO(Reg.number:CRD42020152291).Data included in this study were collected from patients diagnosed with advanced gastric cancer or gastroesophageal junction cancer and treated with ICIs.A systematic literature search was conducted using the PubMed,EMBASE,and Cochrane Library databases.Meta-analysis was carried out using the single sample rate method.Synthesis and analysis of the data was conducted using Stata/SE and Review Manager Software.RESULTS The patients enrolled in the present study included 14 patients from 14 case reports,326 patients from 6 case series,and 1249 patients from 8 clinical trials.It was found that the overall incidence of irAEs was 16%[95%confidence interval(CI):11-20]for all grades and 3%(95%CI:2-4)for the severe grade.It was evident that the incidence of irAEs varied with the type of inhibitor and organs.A comparative study of the anti-programmed cell death receptor-1(PD-1)and antiprogrammed death receptor-ligand 1(PD-L1)treatments showed that the antiPD-1 group had a higher overall incidence of irAEs(20%)as compared with that of the anti-PD-L1 group(13%).Results of this study showed that the endocrine system experienced the highest incidence of organ-specific irAEs(7.4%),including hypothyroidism,hyperthyroidism,thyroiditis,diabetes,and adrenal insufficiency,followed by gastroenterology(2.2%),pulmonology(1.8%),neurology(1.4%),dermatology(1.4%),hematology(0.8%),and hepatology(0.7%).In clinical trials,it was found that the incidence of death related to irAEs was 1%(95%CI:0-2.0),whereby colitis and interstitial lung diseases were the leading causes of death.CONCLUSION It was evident that the incidence and nature of irAEs are both organ-and inhibitor-specific.The anti-PD-1 group had the highest incidence of all irAEs grades including the severe grades of irAEs.Early identification and management of irAEs allows clinical oncologists to effectively consider the pros and cons and hence enables them to strike a balance.
基金supported by grants from the National Natural Science Foundation of China(No.82293630,No.82293632 and No.82070152)the Guangdong Natural Science Foundation(No.2023A1515012968)Medical Scientific Research Foundation of Guangdong Province(No.A2023330)。
文摘Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical outcome.It is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical outcome.In this perspective,we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs,providing new insights for designing dual IC blockades(ICBs).
基金supported by grants from the National Natural Science Foundation of China(No.82002619)Shanxi Science and Technology Project(No.202204041101042 and 202204051001031)the Key Medical Research Projects of Shanxi Province(No.2020XM55)。
文摘In recent years,immune checkpoint blockade(ICB)therapy has become an important treatment strategy for gastrointestinal tumors,however,it only benefits about 1/3 of patients.Since the microbiome has been shown to play an important role in the human body for a long time,a growing number of studies are focusing on its relationship to ICB therapy in cancer,specifically how intestinal microbes affect the efficacy of immune checkpoint inhibitors(ICIs)therapy in patients.On this basis,probiotic interventions,fecal microbiota transplantation(FMT),dietary interventions,and other methods which improve or maintain the structure of the intestinal flora have attracted widespread attention.This article discusses the four aspects of the microbiome,ICB,combined treatment of gastrointestinal tumors,and regulation of gut microbiome.Particularly,the discussion focuses on the contribution of probiotic intervention in improving the therapeutic effect of ICIs to prolong the survival time of patients and reduce the severity of immune-related adverse effects(irAEs).
基金supported by grants from the National Natural Science Foundation of China(Grant No.81772830)。
文摘Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued,which therefore provides limited benefits to patients with cancer.Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed.Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest.This review comprehensively analyses the efficacy of various repurposed drugs,such as transforming growth factor-beta(TGF-β)inhibitors,metformin,receptor activator of nuclear factor-κB ligand(RANKL)inhibitors,granulocyte macrophage colony-stimulating factor(GM-CSF),thymosinα1(Tα1),aspirin,and bisphosphonate,in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy.Additionally,we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.
文摘Objective The combination of stereotactic body radiation therapy(SBRT)and immune checkpoint inhibitors(ICIs)is actively being explored in advanced non-small-cell lung cancer(NSCLC)patients.However,little is known about the optimal fractionation and radiotherapy target lesions in this scenario.This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs.Methods The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec.2015 to Sep.2021.Patients were grouped according to radiation sites.Progression-free survival(PFS)and overall survival(OS)were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank(Mantel-Cox)test.Results A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study.Radiation sites included lung lesions(lung group,n=43),bone metastases(bone group,n=24),and brain metastases(brain group,n=57).Compared with the brain group,the mean PFS(mPFS)in the lung group was significantly prolonged by 13.3 months(8.5 months vs.21.8 months,HR=0.51,95%CI:0.28–0.92,P=0.0195),and that in the bone group prolonged by 9.5 months with a 43%reduction in the risk of disease progression(8.5 months vs.18.0 months,HR=0.57,95%CI:0.29–1.13,P=0.1095).The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group.The mean OS(mOS)in the lung and bone groups was longer than that of the brain group,and the risk of death decreased by up to 60%in the lung and bone groups as compared with that of the brain group.When SBRT was concurrently given with ICIs,the mPFS in the lung and brain groups were significantly longer than that of the bone group(29.6 months vs.16.5 months vs.12.1 months).When SBRT with 8–12 Gy per fraction was combined with ICIs,the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups(25.4 months vs.15.2 months vs.12.0 months).Among patients receiving SBRT on lung lesions and brain metastases,the mPFS in the concurrent group was longer than that of the SBRT→ICIs group(29.6 months vs.11.4 months,P=0.0003 and 12.1 months vs.8.9 months,P=0.2559).Among patients receiving SBRT with<8 Gy and 8–12 Gy per fraction,the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group(20.1 months vs.5.3 months,P=0.0033 and 24.0 months vs.13.4 months,P=0.1311).The disease control rates of the lung,bone,and brain groups were 90.7%,83.3%,and 70.1%,respectively.Conclusion The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients.This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens.Dose fractionation regimens of 8–12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.
文摘BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are increasingly implicated in the development of autoimmune diseases.CASE SUMMARY We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab,docetaxel,and cisplatin therapy who developed autoimmune polyendocrine syndrome typeⅡ(APS-2)including thyroiditis and type 1 diabetes mellitus and Crohn’s disease(CD).He developed thirst,abdominal pain,and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab.Biochemistry confirmed APS-2 and thyrotoxicosis.He was commenced on an insulin infusion.However,his abdominal pain persisted.Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine.He was continued on insulin and mesalazine therapy.CONCLUSION Immunotherapy can affect all kinds of organs.When clinical symptoms cannot be explained by a single disease,clinicians should consider the possibility of multisystem damage.
文摘Immunotherapy targets the dysfunctional immune system to induce cancer cell killing by CD8-positive T cells.Immune checkpoint inhibitors(ICIs),specifically anti-PD-1 antibodies,anti-PD-L1 antibodies,and anti-CTLA4 antibodies,have revolutionized the management of many malignancies due to their significant role in generating a durable clinical response.However,clinical data suggest that response rates to ICI monotherapy are low due to the immunologically silent characteristics of breast cancer(BC).Chemotherapy,surgery,radiotherapy,and targeted therapy were recently reported to alter the tumor microenvironment and enhance the ICI response.Some clinical studies supported that ICIs,in combination with other treatment strategies,show superior efficacy in BC control,especially triple-negative breast cancer.Therefore,seeking a reasonable combination therapy is a promising way to improve ICI response.The present review highlights the clinical efficacy of ICIs treatment options in combination with standard-of-care therapies,such as chemotherapy and targeted therapy。
基金National Natural Science Foundation of China(No.81974577)。
文摘In recent years,immune checkpoint molecules have made breakthroughs in the fields of inducing graft tolerance,tumor immune escape and preventing autoimmunity.These immunoregulatory factors,when combined with ligand,can transduce the inhibitory signal into cells to negatively regulate the immune response,which brings new enlightenment for the immune research of pregnancy and pregnancy complications.In this review,we reviewed the immunomodulatory effects of CTLA-4,PD-1 and Tim-3 in pregnancy,in order to evaluate their potential effects in pregnancy,and to provide a new direction for the immunotherapy of pregnancy complications.
文摘This study determined the effect of orally fed polysaccharide-rich bioprocessed (fermented) black rice bran produced by culturing with shiitake (Lentinus edodes) mushroom mycelium on CT-26 colon cancer cells in vivo in an intracutaneously transplanted mouse tumor alone and in combination with intraperitoneally administered anti-PD-1 immune checkpoint inhibitor. Analysis of the isolated tumor weights at the end of the study shows that the average tumor size in control mice is 3.78 grams, and the average tumor size in mice treated with anti-PD-1 antibody is 2.16 grams. The average tumor size in mice treated with BRB-F alone is 2.25 grams, and the average tumor size in mice treated with anti-PD-1 antibody BRB-F combination is 1.38 grams. Thus, BRB-F or anti-PD-1 antibody alone each reduce tumor size by 40.5% or 42.9%, whereas the combination of BRB-F and anti-PD-1 antibody reduces tumor size by 63.5%, with their cooperative effect being statistically significant. The observed anti-tumor effects were accompanied by a series of biomarkers associated with cancer formation and inhibition. These results indicate that the reported potentiation of cancer therapy using drug-based medical chemotherapies with added checkpoint inhibitors in human patients are mechanistically similar with the functional food evaluated in the present study. These beneficial effects in mice challenge clinicians to investigate if the black rice bran food product can also protect against human cancer.
文摘Immune checkpoint inhibitors are today an immense hope in the management of cancers. However, since their widespread use, many cases of insulin-requiring diabetes appearing suddenly, as fulminant diabetes have been reported. Here, we describe 4 cases that occurred at different times after the beginning of immune checkpoint inhibitor therapy with Nivolumab alone or associated with Ipilimumab. There are 3 cases of newly diagnosed diabetes and 1 case of known type 2 diabetes formerly quite well balanced with Metformin. The clinical and biological characteristics of these patients are quite similar. They were all insulin-requiring at the discovery of diabetes and remained so throughout their follow-up. This type of diabetes which looks like type 1 diabetes seems rather to be a new entity.
文摘BACKGROUND With the wide application of immune checkpoint inhibitors(ICIs)in cancer treatment,immune-related adverse events occur frequently,involving almost all organs and systems.The incidence of ICI-associated arthritis(IA)is unknown.In most cases,IA is not serious and non-lethal.Higher checkpoint inhibitor arthritis disease activity may be associated with cancer progression.Here,we report a severe case of IA with high arthritis disease activity in advanced pulmonary adenocarcinoma,causing permanent withdrawal of pembrolizumab,but the patient remained in complete remission(CR)20 mo after the development of IA.CASE SUMMARY An 81-year-old smoking man was admitted to our hospital because of left chest pain for 9 mo.He was finally diagnosed with advanced pulmonary adenocarcinoma,with programmed cell death 1 ligand 1 expression of 70%.The patient responded to pembrolizumab treatment and achieved CR,but IA occurred after the 5th cycle of pembrolizumab administration.Although non-steroidal antiinflammatory drugs and disease-modifying anti-rheumatic drugs were prescribed,arthralgia and joint swelling occurred.The symptoms of arthritis were further aggravated when immunotherapy was given again after short-term withdrawal.Clinical Disease Activity Index(CDAI)score,a traditional measure of arthritis activity,was 43.Intravenous methylprednisolone was prescribed at 20 mg/d and then tapered over the subsequent 4 wk.The symptoms of arthritis steadily improved and completely resolved 4 mo after withdrawal of pembrolizumab.A recent follow-up in June 2022 revealed satisfactory clinical recovery of arthritis and the patient remained in CR.CONCLUSION This case report highlights that early recognition of IA and appropriate treatment are critical to improving the outcome of both ICI-arthritis and lung cancer.
文摘BACKGROUND Immune checkpoint inhibitor-mediated colitis(IMC)is a common adverse event following immune checkpoint inhibitor(ICI)therapy for cancer.IMC has been associated with improved overall survival(OS)and progression-free survival(PFS),but data are limited to a single site and predominantly for melanoma patients.AIM To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.METHODS We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age,sex,ICI class,and malignancy to a cohort of ICI users without IMC,from May 2011 to May 2020.Using univariate and multivariate logistic regression,we determined association of presence of IMC on OS,PFS,and clinical predictors of IMC.Kaplan-Meier curves were gen-erated to compare OS and PFS between ICI users with and without IMC.RESULTS IMC was significantly associated with a higher OS(mean 24.3 mo vs 17.7 mo,P=0.05)but not PFS(mean 13.7 mo vs 11.9 mo,P=0.524).IMC was significantly associated with OS greater than 12 mo[Odds ratio(OR)2.81,95%confidence interval(CI)1.17-6.77].Vitamin D supplementation was significantly associated with increased risk of IMC(OR 2.48,95%CI 1.01-6.07).CONCLUSION IMC was significantly associated with OS greater than 12 mo.In contrast to prior work,we found that vitamin D use may be a risk factor for IMC.
文摘Immune checkpoint inhibitors(ICIs)are a new class of cancer pharmacotherapy consisting of antibodies that block inhibitory immune regulators such as cytotoxic T lymphocyte antigen 4,programmed cell death 1 and programmed death-ligand 1.Checkpoint blockade by ICIs reactivates a tumor-specific T cell response.Immune-related adverse events can occur in various organs including skin,liver,and gastrointestinal tract.Mild to severe colitis is the most common side effect with some experiencing rapid progression to more serious complications including bowel perforation and even death.Prompt diagnosis and management of ICI-induced colitis is crucial for optimal outcome.Unfortunately,its clinical,endoscopic and histopathologic presentations are non-specific and overlap with those of colitis caused by other etiologies,such as infection,medication,graftversus-host disease and inflammatory bowel disease.Thus,a definitive diagnosis can only be rendered after these other possible etiologies are excluded.Sometimes an extensive clinical,laboratory and radiologic workup is required,making it challenging to arrive at a prompt diagnosis.Most patients experience full resolution of symptoms with corticosteroids and/or infliximab.For ICI-induced colitis that is treatment-refractory,small scale studies offer alternative strategies,such as vedolizumab and fecal microbiota transplantation.In this review,we focus on the clinical features,differential diagnosis,and management of ICIinduced colitis with special attention to emerging treatment options for treatmentrefractory ICI-induced colitis.
基金This work was supported by a grant from the Wu Jieping Medical Foundation(Grant No.320675018288).
文摘Immune checkpoint inhibitors(ICIs)are new and promising therapeutic agents for non-small cell lung cancer(NSCLC).However,along with demonstrating remarkable efficacy,ICIs can also trigger immune-related adverse events.Checkpoint inhibitor pneumonitis(CIP)has been reported to have a morbidity rate of 3%to 5%and a mortality rate of 10%to 17%.Moreover,the incidence of CIP in NSCLC is higher than that in other tumor types,reaching 7%to 13%.With the increased use of ICIs in NSCLC,CIP has drawn extensive attention from oncologists and cancer researchers.Identifying high risk factors for CIP and the potential mechanism of CIP are key points in preventing and monitoring serious adverse events.In this review,the results of our analysis and summary of previous studies suggested that the risk factors for CIP may include previous lung disease,prior thoracic irradiation,and combinations with other drugs.Our review also explored potential mechanisms closely related toCIP,including increasedT cell activity against associated antigens in tumor and normal tissues,preexisting autoantibodies,and inflammatory cytokines.
