Immunotherapy has shown great promise in treating various types of malignant tumors.However,some patients with gastrointestinal cancer have been known to experience rapid disease progression after treatment,a situatio...Immunotherapy has shown great promise in treating various types of malignant tumors.However,some patients with gastrointestinal cancer have been known to experience rapid disease progression after treatment,a situation referred to as hyperprogressive disease(HPD).This minireview focuses on the definitions and potential mechanisms of HPD,natural disease progression in gastrointestinal malignancies,and tumor immunological microenvironment.展开更多
In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the differen...In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the different time of following and response,between this new therapy compared to the standard one.However,even if the iRECIST are worldwide accepted,to date,different aspects should be better underlined and well reported,especially in clinical practice.Clinical experience has demonstrated that in a non-negligible percentage of patients,it is challenging to determine the correct category of response(stable disease,progression disease,partial or complete response),and consequently,to define which is the best management for those patients.Approaching radiological response in patients who underwent immunotherapy,a new uncommon kind of target lesions behavior was found.This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug.Therefore,new groups of response have been described in clinical practice,defined as“atypical responses,”and categorized into three new groups:pseudoprogression,hyperprogression,and dissociated response.This review summarizes and reports these patterns,helping clinicians and radiologists get used to atypical responses,in order to identify patients that respond best to treatment.展开更多
BACKGROUND Immune checkpoint inhibitors,including programmed death-ligand 1(PD-L1)and programmed death-1(PD-1)have recently been approved to treat locally advanced and metastatic urothelial carcinoma(UC).However,some ...BACKGROUND Immune checkpoint inhibitors,including programmed death-ligand 1(PD-L1)and programmed death-1(PD-1)have recently been approved to treat locally advanced and metastatic urothelial carcinoma(UC).However,some patients experience rapid tumor progression rather than any clinical benefit from anti-PDL1/PD-1 therapy.CASE SUMMARY A 73-year-old woman with bladder UC showed the progression of multiple metastases after surgery and chemotherapy for over 12 mo.The patient could not tolerate further chemotherapy.Next-generation sequencing was performed,and the results indicated that the tumor mutational burden was 6.4 mutations/Mb.The patient received the anti-PD-L1 agent toripalimab combined with albuminbound paclitaxel.Compared with the baseline staging before immunotherapy,the patient had a treatment failure time of<2 mo,an increase in tumor burden of>50%,and a>2-fold increase in progression,indicating hyperprogression.CONCLUSION Selecting patients most likely to respond to treatment with immunotherapeutic agents remains challenging.For older patients with advanced UC who have already exhausted multi-line chemotherapy options,immunotherapy should be used prudently if no effective biomarker is available.Further studies are required to clarify the causes and mechanisms of hyperprogression.展开更多
Murine double minute 2(MDM2)plays an essential role in the cell cycle,apoptosis,DNA repair,and oncogene activation through p53-dependent and p53-independent signaling pathways.Several preclinical studies have shown th...Murine double minute 2(MDM2)plays an essential role in the cell cycle,apoptosis,DNA repair,and oncogene activation through p53-dependent and p53-independent signaling pathways.Several preclinical studies have shown that MDM2 is involved in tumor immune evasion.Therefore,MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention.In recent years,im-mune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic.Howev-er,the effectiveness of a single agent is only approximately 20%-40%,which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins.Here,we reviewed the role of MDM2 in regulating the immune microenvironment,tumor immune evasion,and hyperprogression during immunotherapy.In addition,we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tu-mors with MDM2 overexpression or amplification.The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.展开更多
Primary or secondary(i.e.,acquired)resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory(T_(reg))cells(CD4^(+)CD25^(+)FOXP3^(+)).The approval of ipilimumab and ...Primary or secondary(i.e.,acquired)resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory(T_(reg))cells(CD4^(+)CD25^(+)FOXP3^(+)).The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on T_(reg)cells demonstrates that such intervention may overcome resistance in cancer patients.Hence,the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4(CTLA-4)targeting agents can serve as a prototype for similar agents.Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory(T_(eff)/T_(reg))ratio.While clinical development with large molecules has shown the greatest advancement,small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation.These new small molecule inhibitors often target specific intracellular signaling pathways[e.g.,phosphoinositide-3-kinase delta(PI3K-δ)]that play an important role in regulating the function of T_(reg)cells.This review will summarize the lessons currently applied to develop novel clinical agents that target T_(reg)cells.展开更多
Cancer greatly affects the quality of life of humans worldwide and the number of patients suffering from it is continuously increasing.Over the last century,numerous treatments have been developed to improve the survi...Cancer greatly affects the quality of life of humans worldwide and the number of patients suffering from it is continuously increasing.Over the last century,numerous treatments have been developed to improve the survival of cancer patients but substantial progress still needs to be made before cancer can be truly cured.In recent years,antitumor immunity has become the most debated topic in cancer research and the booming development of immunotherapy has led to a new epoch in cancer therapy.In this review,we describe the relationships between tumors and the immune system,and the rise of immunotherapy.Then,we summarize the characteristics of tumor-associated immunity and immunotherapeutic strategies with various molecular mechanisms by showing the typical immune molecules whose antibodies are broadly used in the clinic and those that are still under investigation.We also discuss important elements from individual cells to the whole human body,including cellular mutations and modulation,metabolic reprogramming,the microbiome,and the immune contexture.In addition,we also present new observations and technical advancements of both diagnostic and therapeutic methods aimed at cancer immunotherapy.Lastly,we discuss the controversies and challenges that negatively impact patient outcomes.展开更多
After more than one hundred years of documented trials,immunotherapy has become a standard of care in the treatment of human cancer.Much of the knowledge that led to recent breakthroughs seems quite logical from today...After more than one hundred years of documented trials,immunotherapy has become a standard of care in the treatment of human cancer.Much of the knowledge that led to recent breakthroughs seems quite logical from today’s point of view.However,what we now cite as facts were originally considered paradoxes,meaning something contrary to expectations or perceived opinion at the time.In order to make gains in the field of immunotherapy,one had to be willing to confront ideas and concepts that seemed to contradict one another,and reconcile how each could be true.This is what led to new knowledge and advances.Here,we highlight some of these paradoxes and the milestone discoveries that followed,each one critical for our understanding of immune checkpoint pathways.By outlining some of the steps that we took and the challenges that we overcame,we hope to inspire and encourage future generations of researchers to confront the paradoxes that still permeate the field.展开更多
文摘Immunotherapy has shown great promise in treating various types of malignant tumors.However,some patients with gastrointestinal cancer have been known to experience rapid disease progression after treatment,a situation referred to as hyperprogressive disease(HPD).This minireview focuses on the definitions and potential mechanisms of HPD,natural disease progression in gastrointestinal malignancies,and tumor immunological microenvironment.
文摘In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the different time of following and response,between this new therapy compared to the standard one.However,even if the iRECIST are worldwide accepted,to date,different aspects should be better underlined and well reported,especially in clinical practice.Clinical experience has demonstrated that in a non-negligible percentage of patients,it is challenging to determine the correct category of response(stable disease,progression disease,partial or complete response),and consequently,to define which is the best management for those patients.Approaching radiological response in patients who underwent immunotherapy,a new uncommon kind of target lesions behavior was found.This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug.Therefore,new groups of response have been described in clinical practice,defined as“atypical responses,”and categorized into three new groups:pseudoprogression,hyperprogression,and dissociated response.This review summarizes and reports these patterns,helping clinicians and radiologists get used to atypical responses,in order to identify patients that respond best to treatment.
基金Supported by the National Natural Science Foundation,No.81973640.
文摘BACKGROUND Immune checkpoint inhibitors,including programmed death-ligand 1(PD-L1)and programmed death-1(PD-1)have recently been approved to treat locally advanced and metastatic urothelial carcinoma(UC).However,some patients experience rapid tumor progression rather than any clinical benefit from anti-PDL1/PD-1 therapy.CASE SUMMARY A 73-year-old woman with bladder UC showed the progression of multiple metastases after surgery and chemotherapy for over 12 mo.The patient could not tolerate further chemotherapy.Next-generation sequencing was performed,and the results indicated that the tumor mutational burden was 6.4 mutations/Mb.The patient received the anti-PD-L1 agent toripalimab combined with albuminbound paclitaxel.Compared with the baseline staging before immunotherapy,the patient had a treatment failure time of<2 mo,an increase in tumor burden of>50%,and a>2-fold increase in progression,indicating hyperprogression.CONCLUSION Selecting patients most likely to respond to treatment with immunotherapeutic agents remains challenging.For older patients with advanced UC who have already exhausted multi-line chemotherapy options,immunotherapy should be used prudently if no effective biomarker is available.Further studies are required to clarify the causes and mechanisms of hyperprogression.
基金supported by the National Natural Science Foundation of China (No.82202869,82260491,82160459)Jiangxi Province"Double Thousand Program" (China) (No.jxsq 2023201108)+1 种基金China Postdoctoral Science Foundation (No.338937)the Jiangxi Provincial Natural Science Foundation (China) (No.20232ACB206044).
文摘Murine double minute 2(MDM2)plays an essential role in the cell cycle,apoptosis,DNA repair,and oncogene activation through p53-dependent and p53-independent signaling pathways.Several preclinical studies have shown that MDM2 is involved in tumor immune evasion.Therefore,MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention.In recent years,im-mune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic.Howev-er,the effectiveness of a single agent is only approximately 20%-40%,which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins.Here,we reviewed the role of MDM2 in regulating the immune microenvironment,tumor immune evasion,and hyperprogression during immunotherapy.In addition,we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tu-mors with MDM2 overexpression or amplification.The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.
文摘Primary or secondary(i.e.,acquired)resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory(T_(reg))cells(CD4^(+)CD25^(+)FOXP3^(+)).The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on T_(reg)cells demonstrates that such intervention may overcome resistance in cancer patients.Hence,the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4(CTLA-4)targeting agents can serve as a prototype for similar agents.Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory(T_(eff)/T_(reg))ratio.While clinical development with large molecules has shown the greatest advancement,small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation.These new small molecule inhibitors often target specific intracellular signaling pathways[e.g.,phosphoinositide-3-kinase delta(PI3K-δ)]that play an important role in regulating the function of T_(reg)cells.This review will summarize the lessons currently applied to develop novel clinical agents that target T_(reg)cells.
基金National Natural Science Foundation of China,Grant/Award Number:81930065。
文摘Cancer greatly affects the quality of life of humans worldwide and the number of patients suffering from it is continuously increasing.Over the last century,numerous treatments have been developed to improve the survival of cancer patients but substantial progress still needs to be made before cancer can be truly cured.In recent years,antitumor immunity has become the most debated topic in cancer research and the booming development of immunotherapy has led to a new epoch in cancer therapy.In this review,we describe the relationships between tumors and the immune system,and the rise of immunotherapy.Then,we summarize the characteristics of tumor-associated immunity and immunotherapeutic strategies with various molecular mechanisms by showing the typical immune molecules whose antibodies are broadly used in the clinic and those that are still under investigation.We also discuss important elements from individual cells to the whole human body,including cellular mutations and modulation,metabolic reprogramming,the microbiome,and the immune contexture.In addition,we also present new observations and technical advancements of both diagnostic and therapeutic methods aimed at cancer immunotherapy.Lastly,we discuss the controversies and challenges that negatively impact patient outcomes.
基金Acknowledgements and conflicts of interestThe authors declare no conflicts of interest.
文摘After more than one hundred years of documented trials,immunotherapy has become a standard of care in the treatment of human cancer.Much of the knowledge that led to recent breakthroughs seems quite logical from today’s point of view.However,what we now cite as facts were originally considered paradoxes,meaning something contrary to expectations or perceived opinion at the time.In order to make gains in the field of immunotherapy,one had to be willing to confront ideas and concepts that seemed to contradict one another,and reconcile how each could be true.This is what led to new knowledge and advances.Here,we highlight some of these paradoxes and the milestone discoveries that followed,each one critical for our understanding of immune checkpoint pathways.By outlining some of the steps that we took and the challenges that we overcame,we hope to inspire and encourage future generations of researchers to confront the paradoxes that still permeate the field.
