BACKGROUND Colorectal cancer(CRC)is the third most prevalent form of cancer worldwide.Among patients with CRC,colorectal liver metastasis(CRLM)is the foremost direct contributor to mortality.In recent years,immunother...BACKGROUND Colorectal cancer(CRC)is the third most prevalent form of cancer worldwide.Among patients with CRC,colorectal liver metastasis(CRLM)is the foremost direct contributor to mortality.In recent years,immunotherapy has swiftly risen to prominence as a vital approach for treating a range of solid tumors,including CRC.We present a unique case of a patient suffering from CRLM,with the goal of offering an insightful example and relevant references for the treatment of CRLM.CASE SUMMARY We report a patient who experienced liver metastasis after undergoing successful surgical removal of CRC,with the postoperative pathological stage identified as pT4N2aM0.The patient has been receiving a combination treatment of Western and Traditional Chinese Medicine.Regular assessments of the patient’s condition have been conducted,encompassing evaluations of serum carcinoembryonic antigen levels,carbohydrate antigen 199,and observations of the tongue complexion and its coating.The patient achieved clinical remission after anti-programmed death-1 immunotherapy when various systemic therapies failed.Since the diagnosis of CRLM,the patient has survived for more than 6 years,surpassing the expected survival time for those with advanced CRC.CONCLUSION This case illustrates the considerable promise of anti-programmed death-1 immunotherapy in managing CRLM,especially in scenarios of drug resistance and disease progression.展开更多
Background:Previous experiments have demonstrated that hypofractionated radiation therapy(HFRT),low-dose radiation therapy(LDRT),and combined anti-programmed cell death protein 1(αPD-1)can enhance the abscopal effect...Background:Previous experiments have demonstrated that hypofractionated radiation therapy(HFRT),low-dose radiation therapy(LDRT),and combined anti-programmed cell death protein 1(αPD-1)can enhance the abscopal effect.Combined with the phenomenon of low prognosis in patients with breast cancer lung metastasis,our study establishes a mouse model and changes the irradiation regimen of LDRT to explore its preventive effect on breast cancer lung metastasis.Methods:The breast cancer subcutaneous graft tumor model was developed.Two-lung prophylactic LDRT was performed prior to the onset of lung metastases,in combination with HFRT(8 Gy,3f),andαPD-1(200μg,4f)therapy.We watched and documented the tumor volume,survival duration,and number of lung metastases.Furthermore,after labeling the corresponding cells using markers,we detected immune-related cell infiltration by immunohistochemistry and flow cytometry,such as T cells.We also determined the expression of cytokines(IFN-γand TNF-α)by enzyme-linked immunosorbent assay.Result:The triple therapy(HFRT+LDRT+αPD-1)resulted in tumor shrinkage and prolonged survival in mice,with median survival extending from 35 to 52 days.The most notable decrease in the quantity of advanced lung metastatic nodules in breast cancer was observed with the triple therapy(HFRT+LDRT+αPD-1)(p<0.05).Furthermore,according to immunohistochemistry and flow cytometry,the triple treatment(HFRT+LDRT+αPD-1)showed the greatest expression of CD8^(+)T cells.Additionally,the ratio of CD8^(+)/CD4^(+)T cells was considerably greater than that of the groups(p<0.0001).Triple therapy(HFRT+LDRT+αPD-1)increased the recruitment of DCs cells,promoted IFN-γand TNF-αexpression,and curbed the aggregation of MDSCs cells(p<0.05).Conclusion:Prophylactic LDRT to the lungs,based on HFRT andαPD-1,can enhance anti-tumor efficacy and prevent advanced lung metastases from breast cancer.The process involves boosting the recruitment of DCs and CD8^(+)T cells,preventing MDSC cell aggregation,and lessening the tumor microenvironment’s immunosuppressive effects.展开更多
BACKGROUND Ovarian cancer is the most common malignant tumor of the female reproductive system,and the survival rate of patients with relapsed and refractory ovarian cancer is very low.CASE SUMMARY Here,we report a ca...BACKGROUND Ovarian cancer is the most common malignant tumor of the female reproductive system,and the survival rate of patients with relapsed and refractory ovarian cancer is very low.CASE SUMMARY Here,we report a case of high-grade serous papillary adenocarcinoma of the ovary that was successfully treated with immunotherapy.Radical surgery and adjuvant chemotherapy for the 56-year-old patient were successful;however,her tumor relapsed.Subsequent second-line chemotherapy,targeted agents,and other treatments were ineffective,as the tumor continued to recur and metastasize.Anti-programmed cell death-1(PD-1)monotherapy(tislelizumab)completely alleviated the tumor,and the multiple metastatic tumors disappeared.To date,the patient has used anti-PD-1 for 32 months,experiencing no disease progression and maintaining good health without additional treatment.CONCLUSION This case suggests that anti-PD-1 immunotherapy may have long-term positive effects on outcomes in some refractory recurrent solid tumors.Further research is needed to identify patients most likely to respond to anti-PD-1 therapy.展开更多
BACKGROUND Since the advent of the 20th century,alongside the progression of medical science and technological advancements,immunotherapy has emerged as a pivotal thera-peutic approach for tumor patients subsequent to...BACKGROUND Since the advent of the 20th century,alongside the progression of medical science and technological advancements,immunotherapy has emerged as a pivotal thera-peutic approach for tumor patients subsequent to undergoing radiotherapy and chemotherapy.Arimab(camrelizumab),a flagship drug in the realm of immuno-therapy,functions as a monoclonal antibody specifically targeting the progra-mmed death protein 1(PD-1).This drug engages with the human PD-1 receptor,effectively inhibiting the PD-1/programmed death ligand 1 signaling pathway.This inhibition results in the restoration of T cell activity and the induction of an anti-tumour response.However,it is noteworthy that such interference could lead to immune-related adverse events resembling autoimmune reactions.The grow-ing availability and clinical use of immune checkpoint inhibitors have raised sig-nificant clinical concerns regarding their safety.Numerous instances of immune-related adverse reactions and the associated management strategies have been extensively reported.Timely identification and diagnosis,coupled with multidi-sciplinary consultation and the prompt administration of immunosuppressants,can effectively address severe immune-related adverse reactions.CASE SUMMARY Arimab(camrelizumab),a monoclonal antibody targeting programmed death protein 1(PD-1),disrupts the PD-1/programmed death ligand 1(PD-L1)inter-action,reactivating T cell function and triggering anti-tumor immunity.However,this disruption may trigger immune-mediated adverse events akin to autoim-mune disorders.Approximately 2.8%of such events manifest as immune-related dermatologic reactions,with 0.7%classified as grade 3,which are infrequently documented.Here,this study describes a case of grade 3 bullous dermatitis occur-ring 15 days after initiating camrelizumab therapy.The patient,a 67-year-old male with oesophageal squamous cell carcinoma,received camrelizumab plus paclitaxel alongside chemotherapy and radiotherapy in early 2022.Due to disease progression,maintenance monotherapy with camrelizumab(200 mg)commenced in June 2022.On the fourth cycle,15 days into treatment,the patient presented with an immune-checkpoint inhibitor-related rash,despite unremarkable test results.Dermatology and pharmacy consultations were conducted,leading to glucocorticoid therapy,topical interventions,and supportive care.Gastric mucosal protection,nutritional supplementation,and other adjunctive treatments were also provided.The patient's symptoms resolved within 15 days post-discharge,resulting in discontinuation of camrelizumab.Like other PD-1 inhibitors,camrelizumab is associated with immune-mediated dermatitis.Thus,optimal management of these events requires a multidisciplinary approach,vigilant monitoring,regular evalua-tions,prompt glucocorticoid administration,and specialized dermatologic care.CONCLUSION The increasing adoption of immune checkpoint inhibitors in clinical practice has prompted substantial concerns about their safety profile.A wide range of immune-related adverse events and corresponding management stra-tegies have been well-documented.Early recognition and accurate diagnosis,combined with interdisciplinary collaboration and swift initiation of immunosuppressive therapy,are essential in managing severe immune-related adverse reactions effectively.This report details the treatment trajectory and outcome of a case involving immune-related cutaneous adverse reactions,providing pertinent clinical insights for future cases.展开更多
The“obesity paradox”in hepatocellular carcinoma(HCC)suggests patients with obesity may experience better treatment outcomes compared to patients without obesity.Wang et al highlighted this paradox in HCC immunothera...The“obesity paradox”in hepatocellular carcinoma(HCC)suggests patients with obesity may experience better treatment outcomes compared to patients without obesity.Wang et al highlighted this paradox in HCC immunotherapy,demonstrating superior progression-free survival and overall survival in patients with overweight and obesity treated with lenvatinib and camrelizumab,focusing on hepatitis B virus-related HCC.Mechanisms such as better nutritional reserves,leptin-mediated immune modulation,and reduced protein breakdown may explain these outcomes.Obesity’s role in anti-programmed cell death protein-1 therapy appears could have a benefit,while its effects on other treatments,such as anti-vascular endothelial growth factor therapy,may reduce efficacy.Further research is needed to explore how obesity influences the effectiveness of other most common immunotherapies like nivolumab,pembrolizumab,and bevacizumab,and whether weight loss as well as weight-loss related sarcopenia impacts these benefits.展开更多
Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-s...Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival.Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant importance.Recent Food and Drug Administration approvals of immune checkpoint inhibitors(ICI)for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors.Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease,drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.展开更多
Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients wh...Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.展开更多
Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CC...Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA.The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis.This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1(PD-1)in CCA mouse model.Methods:We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro,including both intrahepatic CCA and extrahepatic CCA cells.We examined the in vitro effect of verteporfin on cell proliferation,apoptosis,and stemness.We evaluated the in vivo efflcacy of verteporfin,anti-PD-1,and a combination of both in subcutaneous CCA mouse model.Results:Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion.Nevertheless,verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation,decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers(all P<0.05).The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.Conclusions:Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.展开更多
BACKGROUND Camrelizumab(SHR-1210),an immune checkpoint inhibitor,is clinically used as a therapeutic option for various types of tumors.However,reports of adverse reactions associated with camrelizumab are gradually i...BACKGROUND Camrelizumab(SHR-1210),an immune checkpoint inhibitor,is clinically used as a therapeutic option for various types of tumors.However,reports of adverse reactions associated with camrelizumab are gradually increasing.Anaphylactic shock due to camrelizumab has not been reported previously,until now.We report here,for the first time,a case of anaphylactic shock associated with camrelizumab in a patient with esophageal squamous cell carcinoma.CASE SUMMARY An 84-year-old male esophageal cancer patient received radiotherapy and chemotherapy 11 years ago.He was diagnosed with advanced esophageal squamous cell carcinoma with liver metastasis(Tx N1 M1)and received the first immunotherapy(camrelizumab 200 mg/each time,once every 3 wk)dose in December 2020,with no adverse reactions.Three weeks later,a generalized rash was noted on the chest and upper limbs;palpitations and breathing difficulties with a sense of dying occurred 10 min after the patient had been administered with the second camrelizumab therapy.Electrocardiograph monitoring revealed a 70 beats/min pulse rate,69/24 mm Hg(1 mm Hg=0.133 k Pa)blood pressure,28 breaths/min respiratory rate,and 86%pulse oximetry in room air.The patient was diagnosed with anaphylactic shock and was managed with intravenous fluid,adrenaline,dexamethasone sodium phosphate,calcium glucosate,and noradrenaline.Approximately 2 h after treatment,the patient’s anaphylactic shock symptoms had been completely relieved.CONCLUSION Due to the widespread use of camrelizumab,attention should be paid to anti-programmed cell death 1 antibody therapy-associated hypersensitivity or anaphylactic shock.展开更多
Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States,with poor response to current standard of care,short progression-free and overall survival.Immunotherapies th...Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States,with poor response to current standard of care,short progression-free and overall survival.Immunotherapies that target cytotoxic T lymphocyte antigen-4,programmed cell death protein-1,and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma,renal cell carcinoma,and nonsmall cell lung cancer due to high numbers of somatic mutations,combined with cytotoxic T-cell responses.However,single checkpoint blockade was ineffective in pancreatic cancer,highlighting the challenges including the poor antigenicity,a dense desmoplastic stroma,and a largely immunosuppressive microenvironment.In this review,we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy,radiotherapy,and targeted therapy.These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.展开更多
After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrat...After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.展开更多
In recent years,studies have explored different combinations of immunotherapy and chemotherapy.The rationale behind these is the improved survival outcomes of new immunologic therapies used in first-line-treatment of ...In recent years,studies have explored different combinations of immunotherapy and chemotherapy.The rationale behind these is the improved survival outcomes of new immunologic therapies used in first-line-treatment of advanced non-small cell lung cancer.Moreover,for the most-studied combinations of anti-programed death-1(PD-1)/programed death ligand-1(PD-L1)with the addition of platinumbased chemotherapy,recent research is investigating whether combining different immunologic antitumoral mechanisms of action,such as anti-PD-1/PD-L1 and anti-CTLA-4,or anti-PD-L1 and anti-TIGIT,with or without chemotherapy,can improve efficacy outcomes compared with more classical combinations,or compared with standard chemotherapy alone.Here,we present the data of the main randomized studies that have evaluated these combinations,focusing on the basic rationale behind the different combinations,and the efficacy and tolerability data available to date.展开更多
Immunotherapy remains one of the most promising strategies for cancer treatment,with ICIs at the forefront of this innovation1.However,patient response to ICIs is highly variable,highlighting the urgent need to enhanc...Immunotherapy remains one of the most promising strategies for cancer treatment,with ICIs at the forefront of this innovation1.However,patient response to ICIs is highly variable,highlighting the urgent need to enhance their efficacy in clinical settings2.Addressing this challenge is critical for advancing the impact of immunotherapy in oncology.展开更多
Background and aims:Radiofrequency ablation(RFA)is the first-line treatment for early-stage hepatocellular carcinoma(HCC).However,recurrence after curative RFA remains a significant challenge for HCC patients.Although...Background and aims:Radiofrequency ablation(RFA)is the first-line treatment for early-stage hepatocellular carcinoma(HCC).However,recurrence after curative RFA remains a significant challenge for HCC patients.Although RFA induces an immune response,the anti-tumor effect is often limited by the immunosuppressive tumor microenvironment.Enhancing anti-tumor immunity is essential to improve treatment efficacy and prevent recurrence.In this study,we explore the efficacy and underlying mechanisms of the combination of RFA and anti-PD-1 in suppressing abscopal and recurrent tumors.Methods:We established a bilateral subcutaneous HCC mouse model and performed complete RFA on the right-flank tumor.Anti-PD-1 or anti-IgG was administered post-RFA.Tumor growth,immune cell profiles,and molecular pathways were assessed using flow cytometry,immunohistochemistry staining,RNA-sequencing,and Western blot.Chemokines released by the tumor were detected by ELISA.An in vivo tumor rechallenge experiment was performed after a complete tumor regression to evaluate the immune memory induced by the RFA+anti-PD-1 treatment.Results:RFA combined with anti-PD-1 significantly suppressed abscopal tumor growth and prolonged survival.Compared with RFA monotherapy,the infiltration of CD8^(+)T cells and dendritic cells was significantly increased in the combined treatment group,while PMN-MDSCs were markedly reduced.Mechanistically,the chemokine signaling pathway and JAK-STAT signaling pathway were activated in the tumor of the RFA+anti-PD-1 group with upregulation of CXCL10 to recruit CD8^(+)T cells.In addition,the combination therapy induced durable immune memory that inhibited rechallenge tumor outgrowth.Conclusions:Our study discovered that RFA combined with anti-PD-1 induced anti-tumor immunity to inhibit abscopal tumors and durable immune memory to prevent recurrence,suggesting RFA+anti-PD-1 as a potential therapeutic strategy for multifocal HCC and preventing recurrence.展开更多
Precision medicine just witnessed two breakthroughs in oncology in 2017.Pembrolizumab(Keytruda),Merck’s anti-programmed cell death-1(PD-1)monoclonal antibody(mAb),received accelerated approval in May 2017 by the US F...Precision medicine just witnessed two breakthroughs in oncology in 2017.Pembrolizumab(Keytruda),Merck’s anti-programmed cell death-1(PD-1)monoclonal antibody(mAb),received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high(MSI-H)or deficient DNA mismatch repair(dMMR).Shortly after,nivolumab(Opdivo),Bristol-Myers Squibb’s anti-PD-1 mAb,gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy.These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated,and therefore established a precedent for tumor type-agnostic therapy.In the 2017 American Society for Clinical Oncology annual meeting,larotrectinib(LOXO-101),Loxooncology’s oral,potent,and selective inhibitor of tropomyosin receptor kinases(TRK),demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase(NTRK)-fusion proteins in adult and pediatric patients.Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features:(a)biomarker-based,well-defined rare patient population;(b)exceptionally high clinical efficacy,e.g.,near 40%overall response rate(ORR)for pem-brolizumab across 15 tumor types with MSI-H/dMMR and 75%ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins;(c)durable responses lasting at least 6 months with complete responses observed;and(d)parallel development in adult and pediatric populations.With increasing accessibility to genetic analysis tools such as next-generation sequencing,tumor type-agnostic therapy has become a reality,both during clinical development and in clinical practice.Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.展开更多
Immune checkpoint inhibitors are generally contraindicated for post-transplant patients.However,we report two patients with metastatic hepatocellular carcinoma(HCC)treated with camrelizumab(SHR-1210),an anti-programme...Immune checkpoint inhibitors are generally contraindicated for post-transplant patients.However,we report two patients with metastatic hepatocellular carcinoma(HCC)treated with camrelizumab(SHR-1210),an anti-programmed cell death 1(PD-1)agent,after liver transplant.Before undergoing immunotherapy,both patients underwent liver allograft biopsy and obtained negative PD-L1 expression in tumor and liver graft specimens by immunohistochemistry.Then,camrelizumab(200 mg)was administered once every 3 weeks.During immunotherapy,the targeted therapy was continued,and the immunosuppression regimen was adjusted to a low-dose level.No graft rejection or other severe adverse reactions were observed.The disease remained stable(SD,mRECIST)for 3 months in one patient and 10 months in the other.Therefore,camrelizumab may have safety and potential benefits in advanced HCC after liver transplant.展开更多
基金Supported by the National Key R and D Program of China,No.2022YFC3500200 and No.2022YFC3500204Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine,No.ZYYCXTD-C-202208+3 种基金NATCM’s Project of Highlevel Construction of Key TCM Disciplines,No.[2023]85Qing Lan Project of Jiangsu Higher Education Institutions,No.[2023]27Jiangsu Postgraduate Practice Innovation Plan,No.SJCX22_0706General Project of Universities’Philosophy and Social Science in Jiangsu Province,No.2024SJYB0564.
文摘BACKGROUND Colorectal cancer(CRC)is the third most prevalent form of cancer worldwide.Among patients with CRC,colorectal liver metastasis(CRLM)is the foremost direct contributor to mortality.In recent years,immunotherapy has swiftly risen to prominence as a vital approach for treating a range of solid tumors,including CRC.We present a unique case of a patient suffering from CRLM,with the goal of offering an insightful example and relevant references for the treatment of CRLM.CASE SUMMARY We report a patient who experienced liver metastasis after undergoing successful surgical removal of CRC,with the postoperative pathological stage identified as pT4N2aM0.The patient has been receiving a combination treatment of Western and Traditional Chinese Medicine.Regular assessments of the patient’s condition have been conducted,encompassing evaluations of serum carcinoembryonic antigen levels,carbohydrate antigen 199,and observations of the tongue complexion and its coating.The patient achieved clinical remission after anti-programmed death-1 immunotherapy when various systemic therapies failed.Since the diagnosis of CRLM,the patient has survived for more than 6 years,surpassing the expected survival time for those with advanced CRC.CONCLUSION This case illustrates the considerable promise of anti-programmed death-1 immunotherapy in managing CRLM,especially in scenarios of drug resistance and disease progression.
基金supported by a grant from the Southwest Medical University’s Program for Creating Popular Science Works(No.00160580).
文摘Background:Previous experiments have demonstrated that hypofractionated radiation therapy(HFRT),low-dose radiation therapy(LDRT),and combined anti-programmed cell death protein 1(αPD-1)can enhance the abscopal effect.Combined with the phenomenon of low prognosis in patients with breast cancer lung metastasis,our study establishes a mouse model and changes the irradiation regimen of LDRT to explore its preventive effect on breast cancer lung metastasis.Methods:The breast cancer subcutaneous graft tumor model was developed.Two-lung prophylactic LDRT was performed prior to the onset of lung metastases,in combination with HFRT(8 Gy,3f),andαPD-1(200μg,4f)therapy.We watched and documented the tumor volume,survival duration,and number of lung metastases.Furthermore,after labeling the corresponding cells using markers,we detected immune-related cell infiltration by immunohistochemistry and flow cytometry,such as T cells.We also determined the expression of cytokines(IFN-γand TNF-α)by enzyme-linked immunosorbent assay.Result:The triple therapy(HFRT+LDRT+αPD-1)resulted in tumor shrinkage and prolonged survival in mice,with median survival extending from 35 to 52 days.The most notable decrease in the quantity of advanced lung metastatic nodules in breast cancer was observed with the triple therapy(HFRT+LDRT+αPD-1)(p<0.05).Furthermore,according to immunohistochemistry and flow cytometry,the triple treatment(HFRT+LDRT+αPD-1)showed the greatest expression of CD8^(+)T cells.Additionally,the ratio of CD8^(+)/CD4^(+)T cells was considerably greater than that of the groups(p<0.0001).Triple therapy(HFRT+LDRT+αPD-1)increased the recruitment of DCs cells,promoted IFN-γand TNF-αexpression,and curbed the aggregation of MDSCs cells(p<0.05).Conclusion:Prophylactic LDRT to the lungs,based on HFRT andαPD-1,can enhance anti-tumor efficacy and prevent advanced lung metastases from breast cancer.The process involves boosting the recruitment of DCs and CD8^(+)T cells,preventing MDSC cell aggregation,and lessening the tumor microenvironment’s immunosuppressive effects.
文摘BACKGROUND Ovarian cancer is the most common malignant tumor of the female reproductive system,and the survival rate of patients with relapsed and refractory ovarian cancer is very low.CASE SUMMARY Here,we report a case of high-grade serous papillary adenocarcinoma of the ovary that was successfully treated with immunotherapy.Radical surgery and adjuvant chemotherapy for the 56-year-old patient were successful;however,her tumor relapsed.Subsequent second-line chemotherapy,targeted agents,and other treatments were ineffective,as the tumor continued to recur and metastasize.Anti-programmed cell death-1(PD-1)monotherapy(tislelizumab)completely alleviated the tumor,and the multiple metastatic tumors disappeared.To date,the patient has used anti-PD-1 for 32 months,experiencing no disease progression and maintaining good health without additional treatment.CONCLUSION This case suggests that anti-PD-1 immunotherapy may have long-term positive effects on outcomes in some refractory recurrent solid tumors.Further research is needed to identify patients most likely to respond to anti-PD-1 therapy.
文摘BACKGROUND Since the advent of the 20th century,alongside the progression of medical science and technological advancements,immunotherapy has emerged as a pivotal thera-peutic approach for tumor patients subsequent to undergoing radiotherapy and chemotherapy.Arimab(camrelizumab),a flagship drug in the realm of immuno-therapy,functions as a monoclonal antibody specifically targeting the progra-mmed death protein 1(PD-1).This drug engages with the human PD-1 receptor,effectively inhibiting the PD-1/programmed death ligand 1 signaling pathway.This inhibition results in the restoration of T cell activity and the induction of an anti-tumour response.However,it is noteworthy that such interference could lead to immune-related adverse events resembling autoimmune reactions.The grow-ing availability and clinical use of immune checkpoint inhibitors have raised sig-nificant clinical concerns regarding their safety.Numerous instances of immune-related adverse reactions and the associated management strategies have been extensively reported.Timely identification and diagnosis,coupled with multidi-sciplinary consultation and the prompt administration of immunosuppressants,can effectively address severe immune-related adverse reactions.CASE SUMMARY Arimab(camrelizumab),a monoclonal antibody targeting programmed death protein 1(PD-1),disrupts the PD-1/programmed death ligand 1(PD-L1)inter-action,reactivating T cell function and triggering anti-tumor immunity.However,this disruption may trigger immune-mediated adverse events akin to autoim-mune disorders.Approximately 2.8%of such events manifest as immune-related dermatologic reactions,with 0.7%classified as grade 3,which are infrequently documented.Here,this study describes a case of grade 3 bullous dermatitis occur-ring 15 days after initiating camrelizumab therapy.The patient,a 67-year-old male with oesophageal squamous cell carcinoma,received camrelizumab plus paclitaxel alongside chemotherapy and radiotherapy in early 2022.Due to disease progression,maintenance monotherapy with camrelizumab(200 mg)commenced in June 2022.On the fourth cycle,15 days into treatment,the patient presented with an immune-checkpoint inhibitor-related rash,despite unremarkable test results.Dermatology and pharmacy consultations were conducted,leading to glucocorticoid therapy,topical interventions,and supportive care.Gastric mucosal protection,nutritional supplementation,and other adjunctive treatments were also provided.The patient's symptoms resolved within 15 days post-discharge,resulting in discontinuation of camrelizumab.Like other PD-1 inhibitors,camrelizumab is associated with immune-mediated dermatitis.Thus,optimal management of these events requires a multidisciplinary approach,vigilant monitoring,regular evalua-tions,prompt glucocorticoid administration,and specialized dermatologic care.CONCLUSION The increasing adoption of immune checkpoint inhibitors in clinical practice has prompted substantial concerns about their safety profile.A wide range of immune-related adverse events and corresponding management stra-tegies have been well-documented.Early recognition and accurate diagnosis,combined with interdisciplinary collaboration and swift initiation of immunosuppressive therapy,are essential in managing severe immune-related adverse reactions effectively.This report details the treatment trajectory and outcome of a case involving immune-related cutaneous adverse reactions,providing pertinent clinical insights for future cases.
文摘The“obesity paradox”in hepatocellular carcinoma(HCC)suggests patients with obesity may experience better treatment outcomes compared to patients without obesity.Wang et al highlighted this paradox in HCC immunotherapy,demonstrating superior progression-free survival and overall survival in patients with overweight and obesity treated with lenvatinib and camrelizumab,focusing on hepatitis B virus-related HCC.Mechanisms such as better nutritional reserves,leptin-mediated immune modulation,and reduced protein breakdown may explain these outcomes.Obesity’s role in anti-programmed cell death protein-1 therapy appears could have a benefit,while its effects on other treatments,such as anti-vascular endothelial growth factor therapy,may reduce efficacy.Further research is needed to explore how obesity influences the effectiveness of other most common immunotherapies like nivolumab,pembrolizumab,and bevacizumab,and whether weight loss as well as weight-loss related sarcopenia impacts these benefits.
文摘Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival.Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant importance.Recent Food and Drug Administration approvals of immune checkpoint inhibitors(ICI)for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors.Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease,drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.
基金Supported by The United Kingdom Charity pancreatic Cancer Research Fundpancreatic Cancer Research United Kingdom+1 种基金Ministry of Sciences and Technology of ChinaNo.2013DFG32080
文摘Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.
基金supported by the Physician-Scientist Early Investigator Program at National Cancer Institute,National Institute of Health(ZIA BC 011888)。
文摘Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA.The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis.This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1(PD-1)in CCA mouse model.Methods:We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro,including both intrahepatic CCA and extrahepatic CCA cells.We examined the in vitro effect of verteporfin on cell proliferation,apoptosis,and stemness.We evaluated the in vivo efflcacy of verteporfin,anti-PD-1,and a combination of both in subcutaneous CCA mouse model.Results:Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion.Nevertheless,verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation,decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers(all P<0.05).The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.Conclusions:Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.
基金Supported by the National Natural Science Foundation of China,No.81873317the Natural Science Foundation of Zhejiang,No.LSY19H030002the Science and Technology Projects of Hangzhou City,No.20181228Y22。
文摘BACKGROUND Camrelizumab(SHR-1210),an immune checkpoint inhibitor,is clinically used as a therapeutic option for various types of tumors.However,reports of adverse reactions associated with camrelizumab are gradually increasing.Anaphylactic shock due to camrelizumab has not been reported previously,until now.We report here,for the first time,a case of anaphylactic shock associated with camrelizumab in a patient with esophageal squamous cell carcinoma.CASE SUMMARY An 84-year-old male esophageal cancer patient received radiotherapy and chemotherapy 11 years ago.He was diagnosed with advanced esophageal squamous cell carcinoma with liver metastasis(Tx N1 M1)and received the first immunotherapy(camrelizumab 200 mg/each time,once every 3 wk)dose in December 2020,with no adverse reactions.Three weeks later,a generalized rash was noted on the chest and upper limbs;palpitations and breathing difficulties with a sense of dying occurred 10 min after the patient had been administered with the second camrelizumab therapy.Electrocardiograph monitoring revealed a 70 beats/min pulse rate,69/24 mm Hg(1 mm Hg=0.133 k Pa)blood pressure,28 breaths/min respiratory rate,and 86%pulse oximetry in room air.The patient was diagnosed with anaphylactic shock and was managed with intravenous fluid,adrenaline,dexamethasone sodium phosphate,calcium glucosate,and noradrenaline.Approximately 2 h after treatment,the patient’s anaphylactic shock symptoms had been completely relieved.CONCLUSION Due to the widespread use of camrelizumab,attention should be paid to anti-programmed cell death 1 antibody therapy-associated hypersensitivity or anaphylactic shock.
文摘Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States,with poor response to current standard of care,short progression-free and overall survival.Immunotherapies that target cytotoxic T lymphocyte antigen-4,programmed cell death protein-1,and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma,renal cell carcinoma,and nonsmall cell lung cancer due to high numbers of somatic mutations,combined with cytotoxic T-cell responses.However,single checkpoint blockade was ineffective in pancreatic cancer,highlighting the challenges including the poor antigenicity,a dense desmoplastic stroma,and a largely immunosuppressive microenvironment.In this review,we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy,radiotherapy,and targeted therapy.These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.
文摘After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.
文摘In recent years,studies have explored different combinations of immunotherapy and chemotherapy.The rationale behind these is the improved survival outcomes of new immunologic therapies used in first-line-treatment of advanced non-small cell lung cancer.Moreover,for the most-studied combinations of anti-programed death-1(PD-1)/programed death ligand-1(PD-L1)with the addition of platinumbased chemotherapy,recent research is investigating whether combining different immunologic antitumoral mechanisms of action,such as anti-PD-1/PD-L1 and anti-CTLA-4,or anti-PD-L1 and anti-TIGIT,with or without chemotherapy,can improve efficacy outcomes compared with more classical combinations,or compared with standard chemotherapy alone.Here,we present the data of the main randomized studies that have evaluated these combinations,focusing on the basic rationale behind the different combinations,and the efficacy and tolerability data available to date.
基金supported by grants from the National Key R&D Program of China(2022YFA1206100 and 2021YFA1201100)the National Natural Science Foundation of China(32271449)+1 种基金CAS Project for Young Scientists in Basic Research(YSBR-036,China)Beijing Natural Science Foundation(Z230008,China).
文摘Immunotherapy remains one of the most promising strategies for cancer treatment,with ICIs at the forefront of this innovation1.However,patient response to ICIs is highly variable,highlighting the urgent need to enhance their efficacy in clinical settings2.Addressing this challenge is critical for advancing the impact of immunotherapy in oncology.
基金funded by the National Natural Science Foundation of China to Xuezhen Zeng(No.82372777)the Kelin Foundation for Distinguished Young Scholars to Xuezhen Zeng(No.R07014).
文摘Background and aims:Radiofrequency ablation(RFA)is the first-line treatment for early-stage hepatocellular carcinoma(HCC).However,recurrence after curative RFA remains a significant challenge for HCC patients.Although RFA induces an immune response,the anti-tumor effect is often limited by the immunosuppressive tumor microenvironment.Enhancing anti-tumor immunity is essential to improve treatment efficacy and prevent recurrence.In this study,we explore the efficacy and underlying mechanisms of the combination of RFA and anti-PD-1 in suppressing abscopal and recurrent tumors.Methods:We established a bilateral subcutaneous HCC mouse model and performed complete RFA on the right-flank tumor.Anti-PD-1 or anti-IgG was administered post-RFA.Tumor growth,immune cell profiles,and molecular pathways were assessed using flow cytometry,immunohistochemistry staining,RNA-sequencing,and Western blot.Chemokines released by the tumor were detected by ELISA.An in vivo tumor rechallenge experiment was performed after a complete tumor regression to evaluate the immune memory induced by the RFA+anti-PD-1 treatment.Results:RFA combined with anti-PD-1 significantly suppressed abscopal tumor growth and prolonged survival.Compared with RFA monotherapy,the infiltration of CD8^(+)T cells and dendritic cells was significantly increased in the combined treatment group,while PMN-MDSCs were markedly reduced.Mechanistically,the chemokine signaling pathway and JAK-STAT signaling pathway were activated in the tumor of the RFA+anti-PD-1 group with upregulation of CXCL10 to recruit CD8^(+)T cells.In addition,the combination therapy induced durable immune memory that inhibited rechallenge tumor outgrowth.Conclusions:Our study discovered that RFA combined with anti-PD-1 induced anti-tumor immunity to inhibit abscopal tumors and durable immune memory to prevent recurrence,suggesting RFA+anti-PD-1 as a potential therapeutic strategy for multifocal HCC and preventing recurrence.
文摘Precision medicine just witnessed two breakthroughs in oncology in 2017.Pembrolizumab(Keytruda),Merck’s anti-programmed cell death-1(PD-1)monoclonal antibody(mAb),received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high(MSI-H)or deficient DNA mismatch repair(dMMR).Shortly after,nivolumab(Opdivo),Bristol-Myers Squibb’s anti-PD-1 mAb,gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy.These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated,and therefore established a precedent for tumor type-agnostic therapy.In the 2017 American Society for Clinical Oncology annual meeting,larotrectinib(LOXO-101),Loxooncology’s oral,potent,and selective inhibitor of tropomyosin receptor kinases(TRK),demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase(NTRK)-fusion proteins in adult and pediatric patients.Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features:(a)biomarker-based,well-defined rare patient population;(b)exceptionally high clinical efficacy,e.g.,near 40%overall response rate(ORR)for pem-brolizumab across 15 tumor types with MSI-H/dMMR and 75%ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins;(c)durable responses lasting at least 6 months with complete responses observed;and(d)parallel development in adult and pediatric populations.With increasing accessibility to genetic analysis tools such as next-generation sequencing,tumor type-agnostic therapy has become a reality,both during clinical development and in clinical practice.Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.
基金Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province of China(CXPJJH12000001-2020218).
文摘Immune checkpoint inhibitors are generally contraindicated for post-transplant patients.However,we report two patients with metastatic hepatocellular carcinoma(HCC)treated with camrelizumab(SHR-1210),an anti-programmed cell death 1(PD-1)agent,after liver transplant.Before undergoing immunotherapy,both patients underwent liver allograft biopsy and obtained negative PD-L1 expression in tumor and liver graft specimens by immunohistochemistry.Then,camrelizumab(200 mg)was administered once every 3 weeks.During immunotherapy,the targeted therapy was continued,and the immunosuppression regimen was adjusted to a low-dose level.No graft rejection or other severe adverse reactions were observed.The disease remained stable(SD,mRECIST)for 3 months in one patient and 10 months in the other.Therefore,camrelizumab may have safety and potential benefits in advanced HCC after liver transplant.
