Targeting Immune Checkpoints for Cancer Therapies

合集下载

Immune Checkpoint Targeting in Cancer Therapy

Leading EdgeReviewImmune Checkpoint Targetingin Cancer Therapy:Toward CombinationStrategies with Curative PotentialPadmanee Sharma1,2,*and James P.Allison1,*1Department of Immunology2Department of Genitourinary Medical OncologyMD Anderson Cancer Center,Houston,TX77030,USA*Correspondence:padsharma@(P.S.),jallison@(J.P.A.)/10.1016/j.cell.2015.03.030Research in two fronts has enabled the development of therapies that provide signiﬁcant beneﬁt to cancer patients.One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development.This work triggered the development of tar-geted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation,although responses are often of limited duration.In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular im-mune responses.These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses,resulting in durable long-lasting responses but only in a frac-tion of patients.In this Review,we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents repre-sent a path forward for the development of curative therapies for the majority of cancer patients.IntroductionThe scientiﬁc community united against a common enemy in 1971when President Nixon signed a bill initiating the‘‘War on Cancer,’’which provided funding for scientiﬁc research focused on improving our understanding and treatment of cancer. Without doubt,the intervening years were followed by great advances in the elucidation of the molecular mechanisms that regulate growth and death of normal cells,including a deep understanding of how these pathways progressively go awry during the development of cancer.This understanding led to the era of genomically targeted therapies and‘‘precision medi-cine’’in the treatment of cancer.Genomically targeted therapies can result in remarkable clinical responses.The ability of cancer cells to adapt to these agents by virtue of their genomic insta-bility and other resistance mechanisms eventually leads to disease progression in the majority of patients nonetheless. Unraveling the mechanisms by which cancer cells become resis-tant to drugs and developing new agents to target the relevant pathways have become logical next steps in this approach for cancer treatment.However,given the genetic and epigenetic instability of cancer cells,it is likely that each new drug or com-bination of drugs targeting the tumor cells will meet with more complex mechanisms of acquired resistance.Recentﬁndings suggest that T cells,bearing antigen receptors that are gener-ated by random rearrangement of gene segments,followed by selective processes that result in a vast repertoire of T cell clones,provide sufﬁcient diversity and adaptability to match the complexity of tumors.Discoveries regarding regulation of T cell responses have provided key principles regarding immune checkpoints that are being translated into clinical success,with durable responses and long-term survival greater than10years in a subset of patients with metastatic melanoma,as well as yielding promising results in several other tumor types.Now, with the perspective of combining genomically targeted agents and immune checkpoint therapies,we areﬁnally poised to deliver curative therapies to cancer patients.To support this goal and accelerate these efforts,changes in directions of research support and funding may be required.Precision Medicine:Targeting the DriversIn the past three decades,enormous strides have been made in elucidating the molecular mechanisms involved in the develop-ment of cancer(Hanahan and Weinberg,2011).It is now clear that the oncogenic process involves somatic mutations that result in activation of genes that are normally involved in regula-tion of cell division and programmed cell death,as well as inac-tivation of genes involved in protection against DNA damage or driving apoptosis(Bishop,1991;Solomon et al.,1991;Weinberg, 1991;Knudson,2001).These genetic links led to the decision early in the war on cancer to undertake sequencing of cancer genomes to provide a comprehensive view of somatic muta-tional landscapes in cancer and identify possible therapeutic tar-gets.Infrastructure and funding were provided to coordinate the sequencing efforts.It has become apparent that the level of somatic mutations differs widely between and within different tumor types ranging from very low rates in childhood leukemias to very high rates in tumors associated with carcinogens(Alex-androv et al.,2013).Cell161,April9,2015ª2015Elsevier Inc.205Mutations can be divided into two broad classes:those whose products‘‘drive’’tumorigenesis in a dominant fashion and‘‘pas-sengers’’with no obvious role in the tumor causation.The Can-cer Genome Atlas(TCGA)projects have enabled identiﬁcation of many of these mutations(Chen et al.,2014;Cancer Genome Atlas Research Network,2014).This has allowed for the rational design of drugs that target and selectively interfere with onco-genic signaling pathways.This approach has revolutionized cancer medicine by moving away from the‘‘one sizeﬁts all’’approach—for instance,traditional chemotherapy,which attacks all dividing cells,including both cancer-differentiating or regenerating normal cells—to a more personalized strategy of treating patients with a speciﬁc drug only if their cancer bears particular molecular mutations that are target of that drug.As an example of genomically targeted therapies,an inhibitor against BRAF was developed when it was discovered that 40%–60%of cutaneous melanomas carry mutations in BRAF,which induces constitutive activation of the MAPK pathway(Curtin et al.,2005;Davies et al.,2002).In a randomized phase III trial comparing a BRAF inhibitor(vemurafenib)versus dacarbazine,the vemurafenib treatment group had a response rate of 48%versus5%in the dacarbazine arm(Chapman et al.,2011).However,the median duration of response was short,only6.7months(Sosman et al.,2012).Another oncogenic pathway that has been targeted is the tyrosine kinase chromo-somal rearrangement,which results in the fusion oncogene EML4-ALK that is found in 5%of NSCLC patients(Soda et al.,2007).The EML4fusion partner mediates ligand-indepen-dent oligomerization and/or dimerization of anaplastic lym-phoma kinase(ALK),resulting in constitutive kinase activity. Standard chemotherapies in this subgroup of patients have been associated with response rates of up to10%(Hanna et al.,2004).Crizotinib,a tyrosine kinase inhibitor targeting ALK(Kwak et al.,2010),was shown to elicit a response rate of 65%with a median duration of response of less than8months in a phase III trial(Shaw et al.,2013).Although there was a signif-icant increase in progression-free survival for patients treated with crizotinib,regrettably,there was no overall survival beneﬁt in the interim analysis.Therefore,although the concept of target-ing‘‘driver mutations’’has great merit and has demonstrated clinical responses,the reality remains that the majority of patients treated with these agents will derive short-term clinical responses with eventual development of resistance mecha-nisms that lead to disease progression and death. Mechanisms operative in acquired resistance fall into three main categories:alterations in the targeted gene(as a result of mutation,ampliﬁcation,or alternative splicing);other changes that do not affect the original target but re-activate the signaling pathway involved(i.e.,NRAS and MEK mutations in BRAF mutant melanoma);and changes that activate alternate path-ways(such as activation of growth factor receptors).Consider-able effort has gone intoﬁnding ways to enhance efﬁcacy of genomically targeted therapies.One effort involves multiple agents that target different molecules in the same pathway, such as the combination of a BRAF inhibitor and a MEK-inhibitor (Larkin et al.,2014;Robert et al.,2015a).This approach helps to reduce compensatory feedback loops,as well as to block the development of resistance due to mutations downstream that pathway.A different strategy consists of blocking parallel path-ways to prevent emerging resistance(Martz et al.,2014).Still, the chief challenge of these combinatorial approaches is the multiplicity of resistance mechanisms and the fact that different mechanisms may be in operation in different cells due to intratu-mor heterogeneity.Given these observations,it is difﬁcult to envision realistic approaches to effectively overcome the myriad of resistance mechanisms that may arise in the course of cancer treatment.The continued evolvability of the tumor cells and their mechanisms of escape from targeted therapies raise the ques-tion as to whether combinations of genomically targeted agents will ever be curative.Advantages of Mobilizing T Cells for Cancer TherapyAs the knowledge of the intricate biology of cancer has pro-gressed,so has the understanding of the fundamental cellular and molecular mechanisms that orchestrate the interplay of the innate and adaptive arms of the immune system.In a simplistic way,the innate system is composed primarily of cyto-kines,the complement system,and phagocytes such as macro-phages,neutrophils,dendritic cells,and natural killer(NK)cells. Cells of the innate immune system have hard-wired receptors to detect products of infectious microorganisms and dying cells. Macrophages and neutrophils provide an early defense against microorganisms,whereas dendritic cells provide a key interface to the adaptive immune system,composed of B and T cells with their somatically generated,clonally expressed repertoire of antigen receptors.The understanding of the basic principles governing the con-trolling immunity provided the rational for the development of powerful strategies to actively engage the immune system for cancer therapy.Strategies to unleash T cells against tumors are particularly compelling,as the activity of these cells presents important features that are advantageous over other cancer therapies.Theﬁrst is their speciﬁcity.T cells express antigen re-ceptors that recognize cell-surface complexes of MHC mole-cules and peptides sampled from virtually all the proteins in the cell and are not limited to peptide antigens derived from cell-surface molecules.The second feature is memory.Primary T cell responses are generally followed by the production of long-lived memory T cells with accelerated kinetics of secondary response if the antigen recurs.Finally,the T cell response is adaptable and can accommodate not only tumor heterogeneity but also responses to novel antigens expressed by recurring tumors.It has been calculated that the somatic recombination process that generates the antigen receptors of T cells can generate as many as1015different receptors(Davis and Bjork-man,1988).Of this theoretical number,each individual human has perhaps109different receptors.The immense size of the repertoire suggests that the immune system is indeed well equipped to deal with mutability and adaptability of cancer. Harnessing T Cell Responses to Tumor AntigensWith the advent of genomic and cDNA expression cloning methods and sequencing of peptides eluted from tumor cell MHC molecules,an avalanche of tumor antigens deﬁned by tumor-speciﬁc T cells has been identiﬁed in both mice and in hu-mans.Most of these are shared between cancer cells of different206Cell161,April9,2015ª2015Elsevier Inc.individuals and fall into four groups:products of oncogenic viruses(Epstein-Barr virus in certain leukemias and human papilloma virus in cervical and some head and neck cancers); antigens related to tissue-speciﬁc differentiation molecules (tyrosinase and related proteins in melanoma and prostate-spe-ciﬁc antigen and prostatic acid phosphatase in prostate cancer); molecules normally expressed only during fetal development (carcino-embryonic antigen in colon cancer,a-fetoprotein in liver cancer);and cancer-testes(CT)antigens,which are normally ex-pressed during gametogenesis but are found in many cancer cells as a result of changes in epigenetic regulation(MAGE and NY-ESO-1).Additionally,somatic mutations also can result in the genera-tion of tumor-speciﬁc peptides with the potential to bind major histocompatibility complex(MHC)molecules and therefore be recognized by the immune system as neoantigens(Sjo¨blom et al.,2006;Segal et al.,2008).The analysis of the epitope land-scape of breast and colon carcinoma cells revealed that the products of seven to ten mutant genes in colorectal and breast cancer,respectively,have the potential for binding to HLA-A*0201alone.Because each heterozygote individual carries as many as6different HLA class I genes,this means an average of42–60potential neoantigens that can be presented to T cells.In support of these estimates,recent studies have demonstrated that neoantigens generated by somatic mutation are recognized by T cells in both mouse and human cancers(Lin-nemann et al.,2015;Gros et al.,2014;Tran et al.,2014;Gubin et al.,2014).Atﬁrst,as a result of earlier studies identifying shared anti-gens,theﬁeld of cancer immunotherapy became focused on developing therapeutic vaccines to expand T cells against these shared antigens expressed on tumors.Many studies focused on stimulating T cell responses with peptides,proteins,whole-tumor cells including those modiﬁed to express cytokines, DNA,recombinant viral-based vaccines,or antigen-pulsed den-dritic cells given alone or in combination with various adjuvants or cytokines.Although these trials were conducted with the best available science at the time and provided promising anec-dotal evidence that induction of immune responses could elicit clinical beneﬁt,they remained largely negative and generally failed to show objective clinical responses(see Rosenberg et al.,2004for review).Enthusiasm waned somewhat as the number of failed clinical trials mounted.Many reasons might have contributed to the failure of these vaccination strategies,including choice of antigen,failure to pro-vide adequate costimulation,or functional inactivation of tumor-reactive T cells(Melero et al.,2014).A number of T-cell-extrinsic suppressive mechanisms such as TGF b,FoxP3+regulatory T cells(Treg),and tryptophan metabolites(IDO)that can hamper anti-tumor responses have also been identiﬁed,and there have been efforts to minimize the suppressive effects of these in pre-clinical and clinical studies.Unraveling the Complexity of T Cell ActivationAnother contributing factor to the failure of earlier cancer vaccine trials was perhaps the lack of understanding and appreciation of the full complexity of cell-intrinsic pathways that regulate T cell activation.By the late1980s,it was known that simple engage-ment of peptide/MHC complexes by the antigen receptor is insufﬁcient for activation of T cells and may render them anergic (Jenkins and Schwartz,1987;Mueller et al.,1989).In order to become fully activated,T cells must encounter antigen in the context of antigen-presenting cells(APCs)such as dendritic cells,which provide costimulatory signals mediated by B7mol-ecules(B7-1and B7-2)that will engage their ligand,CD28,in the T cell(Greenwald et al.,2005).Thus,T cells speciﬁc for a tumor antigen will not be activated by an initial encounter with tumor cells or may even be rendered anergic because,with the exception of a few lymphomas,tumors do not express costimu-latory B7molecules(Townsend and Allison,1993).Thus,tumors are essentially invisible to T cells until the T cells are activated as a result of cross-priming by dendritic cells that present tumor antigens acquired from dying tumor cells.Simultaneous recogni-tion of antigen/MHC complexes and costimulatory ligands by T cells initiates a complex set of genetic programs that result in cytokine production,cell-cycle progression,and production of anti-apoptotic factors that result in proliferation and functional differentiation of T cells.Consistent with the importance of both antigen receptor and costimulatory signals in initiating anti-tumor responses,many therapeutic vaccines now incorpo-rate both antigen and dendritic cells or agents that enhance cos-timulatory signaling.By the mid-90s,it became clear that T cell priming elicits not only programs leading to induction of T cell responses but also a parallel program that will eventually stop the response.The crit-ical inhibitory program is mediated by CTLA-4,a homolog of CD28that also binds B7-1and B7-2,although with much greater avidity than that CD28.Expression of the ctla-4gene is initiated upon T cell activation,and it trafﬁcs to and accumulates in the immunological synapse,eventually attenuating or preventing CD28costimulation by competition for B7binding and negative signaling(Walunas et al.,1994;Krummel and Allison,1995).The fact that ctla-4knockout mice suffer from a rapid and lethal lymphadenopathy(Waterhouse et al.,1995;Tivol et al.,1995; Chambers et al.,1997)speaks for a negative role for CTLA-4in limiting T cell responses to prevent damage to normal tissues. Thus,activation of T cells as a result of antigen receptor signaling and CD28costimulation is followed not only by induc-tion of genetic programs leading to proliferation and functional differentiation but also by induction of an inhibitory program mediated by CTLA-4,which will ultimately stop proliferation. Extrapolating this paradigm to anti-tumor T cell responses,if eradication of the tumor has not been completed by the time that the inhibitory signal of CTLA-4is triggered,the T cells will be turned off and will be unable to complete the task.Impor-tantly,this also suggests that,after this program is initiated, vaccines used to stimulate antigen receptor signaling may actually serve to strengthen the‘‘off’’signal as a result of addi-tional induction of ctla-4expression by antigen receptor signaling.In any event,this suggests the importance of shifting strategies for cancer immunotherapy from activating T cells to unleashing them.Inactivating the Brakes to Increase Anti-tumor Immunity Consistent with the observations that CD28and CTLA-4had opposing effects on T cell responses in vitro,in the late90s,itCell161,April9,2015ª2015Elsevier Inc.207was found that,although blocking antibodies to CD28impaired anti-tumor responses in mice,blocking antibodies to CTLA-4 enhanced anti-tumor responses in mouse tumor models(Leach et al.,1996).In fact,the treatment of mice with anti-CTLA-4 antibodies as monotherapy results in complete tumor rejection and long-lived ter on,mechanistic studies revealed that anti-tumor activity was associated with increased ratio of both CD4and CD8effector cells to FoxP3+regulatory T cells (Quezada et al.,2006).The success of CTLA-4blockade in these initial studies raised two compelling points.First,because the target molecule was on the T cell and not the tumor cell,it was feasible to imagine that the same strategy would work on many different histologic tumors,as well as on tumors caused by different genetic lesions.Second,taking into consideration that CTLA-4inhibited CD28-mediated costimulation by a cell-intrinsic mechanism(Peggs et al.,2009),its blockade could allow for enhanced T cell costimulation,which in turn would increase the efﬁcacy of tumor vaccines,as well as agents that kill tumor cells under conditions that promote inﬂammatory responses. These possibilities were further supported by the results of a series of studies in different mouse models,including the demonstration that blockade of CTLA-4was not limited to any particular tumor type but was rather broadly effective.CTLA-4 also was able to synergize with a vaccine consisting of tumor cells engineered to express the cytokine GM-CSF to eradicate tumors(Hurwitz et al.,1998;van Elsas et al.,1999).Finally, CTLA-4could be combined with local delivery of irradiation, cryoablation,or an oncolytic virus to induce systemic tumor im-munity and eradication of distant metastases(Zamarin et al., 2014;Waitz et al.,2012;Tang et al.,2014).These preclinical studies supported the development of clinical anti-CTLA-4 therapy.Immune Checkpoint Therapy:The Clinical Success CTLA-4blockade was translated to the clinic with a fully human antibody to human CTLA-4(ipilimumab,Medarex,Bristol-Myers Squibb).Tumor regression was observed in phase I/II trials in patients with a variety of tumor types,including melanoma,renal cell carcinoma,prostate cancer,urothelial carcinoma,and ovarian cancer(Yang et al.,2007;Hodi et al.,2008;Carthon et al.,2010;van den Eertwegh et al.,2012).Two phase III clinical trials with ipilimumab were recently completed in prostate can-cer,theﬁrst in patients with castrate-resistant prostate cancer who had not received prior chemotherapy treatment and the second in a more advanced disease setting,in which patients with castrate-resistant prostate cancer presented disease that had progressed on chemotherapy treatment.The former trial is yet to be reported.The latter trial reports the lack of statistical signiﬁcance(p value of0.053)to indicate a survival beneﬁt for patients who received ipilimumab treatment.However,subset analyses indicate that patients who have favorable clinical char-acteristics such as lack of liver metastases do beneﬁt from ipili-mumab therapy(Kwon et al.,2014).Two phase III clinical trials with anti-CTLA-4(ipilimumab)were also conducted in patients with advanced melanoma and demonstrated improved overall survival for patients treated with ipilimumab(Hodi et al.,2010; Robert et al.,2011).Importantly,these trials indicate long-term durable responses with greater than20%of treated patients living for more than4years,including a recent analysis indicating survival of10years or more for a subset of patients(Schadendorf et al.,2015).The FDA approved ipilimumab as treatment for patients with melanoma in2011.The clinical success of anti-CTLA-4opened a newﬁeld termed ‘‘immune checkpoint therapy’’as additional T cell intrinsic path-ways were identiﬁed and targeted for clinical development (Sharma et al.,2011;Pardoll,2012).Another T-cell-intrinsic inhibitory pathway identiﬁed after CTLA-4was that mediated by PD-1(programmed death1)and its ligand PD-L1.PD-1was initially cloned in1992in a study of molecules involved in nega-tive selection of T cells by programed cell death in the thymus (Ishida et al.,1992).Its function as an immune checkpoint was not established until2000upon identiﬁcation of its ligands (Freeman et al.,2000).PD-L1was then shown to protect tumor cells by inducing T cell apoptosis(Dong et al.,2002).Later, preclinical studies in animal models evaluated anti-PD-1and anti-PD-L1antibodies as immune checkpoint therapies to treat tumors(Keir et al.,2008).Much like CTLA-4,PD-1is expressed only in activated T cells. However,unlike CTLA-4,PD-1inhibits T cell responses by inter-fering with T cell receptor signaling as opposed to outcompeting CD28for binding to B7.PD-1also has two ligands,PD-L1and PD-L2.PD-L2is predominantly expressed on APCs,whereas PD-L1can be expressed on many cell types,including cells comprising the immune system,epithelial cells,and endothelial cells.Antibodies targeting PD-L1have shown clinical responses in multiple tumor types,including melanoma,renal cell carci-noma,non-small-cell lung cancer(Brahmer et al.,2012),and bladder cancer(Powles et al.,2014).Similarly,phase I clinical trials with a monoclonal antibody against PD-1demonstrated clinical responses in multiple tumor types,including melanoma, renal cell carcinoma,non-small-cell carcinoma(Topalian et al., 2012),Hodgkin’s lymphoma(Ansell et al.,2015),and head and neck cancers(Seiwert et al.,2014,J.Clin.Oncol.,abstract). Recently,a large phase I clinical trial with an anti-PD-1antibody known as MK-3475showed response rates of 37%–38%in patients with advanced melanoma,including patients who had progressive disease after prior ipilimumab treatment(Hamid et al.,2013),triggering the approval of MK-3475(pembroluzi-mab,Merck)by the FDA in September2014.A phase III clinical trial that treated patients with metastatic melanoma with a different anti-PD-1antibody(nivolumab,Bristol-Myers Squibb, BMS)also demonstrated improved responses and overall sur-vival beneﬁt as compared to chemotherapy treatment(Robert et al.,2015b).Nivolumab was FDA approved for patients with metastatic melanoma in December2014.In addition,nivolumab was FDA approved in March2015for patients with previously treated advanced or metastatic non-small-cell lung cancer based on a phase III clinical trial,which reported an improvement in overall survival for patients treated with nivolumab as compared to patients treated with docetaxel chemotherapy. Because CTLA-4and PD-1regulate different inhibitory path-ways on T cells,combination therapy with antibodies targeting both molecules was tested and found to improve anti-tumor re-sponses in a pre-clinical murine model(Curran et al.,2010).A recently reported phase I clinical trial with anti-CTLA-4in combi-nation with anti-PD-1also demonstrated tumor regression208Cell161,April9,2015ª2015Elsevier Inc.in 50%of treated patients with advanced melanoma,in most cases with tumor regression of80%or higher(Wolchok et al., 2013).There are ongoing clinical trials with anti-CTLA-4 (ipilimumab,BMS or tremelimumab,MedImmune/Astrazeneca) plus anti-PD-1or anti-PD-L1in other tumor types,with prelimi-nary data indicating promising results(Hammers et al.,2014, J.Clin.Oncol.,abstract;Callahan et al.,2014,J.Clin.Oncol., abstract)that highlight this combination as an effective immuno-therapy strategy for cancer patients.As with other cancer therapies,immune checkpoint therapies may lead to side effects and toxicities(see Postow et al.,2015; Gao et al.,2015for recent reviews).Brieﬂy,these side effects consist of immune-related adverse events that are deﬁned by in-ﬂammatory conditions,including dermatitis,colitis,hepatitis, pancreatitis,pneumonitis,and hypophysitis.These side effects can be managed and usually involve administration of immuno-suppressive agents such as corticosteroids,which do not appear to interfere with clinical beneﬁt that is derived from the immune checkpoint agents.The proﬁle of side effects that occur with both anti-CTLA-4and anti-PD-1/PD-L1antibodies is similar;however,the side effects appear to occur more frequently in the setting of anti-CTLA-4therapy as compared to anti-PD-1and anti-PD-L1therapies.The continued success of immune checkpoint therapies in the clinic will require educa-tion of the oncology community regarding recognition and treat-ment of the side effects elicited by these agents.Novel Immunologic Targets for Cancer Immunotherapy Although blockade of the CTLA-4and PD-1/PD-L1pathways is furthest along in clinical development,it only represents the tip of the iceberg in the realm of potential targets that can serve to improve anti-tumor responses.Ongoing studies on regulation of immune responses have led to the identiﬁcation of multiple other immunologic pathways that may be targeted for the devel-opment of therapies,either as monotherapy or in combination strategies,for the successful treatment of cancer patients.These include immune checkpoints or inhibitory pathways,as well as co-stimulatory molecules,which act to enhance immune re-sponses.A partial list of new immune checkpoints that are being evaluated in pre-clinical tumor models and/or in the clinic with cancer patients includes LAG-3(Triebel et al.,1990),TIM-3 (Sakuishi et al.,2010),and VISTA(Wang et al.,2011),whereas co-stimulatory molecules include ICOS(Fan et al.,2014),OX40 (Curti et al.,2013),and4-1BB(Melero et al.,1997).Of these emerging immune checkpoints,LAG-3is the furthest along in clinical development with a fusion protein(IMP321, Immuntep)and an antibody(BMS-986016,BMS)in clinical trials. The fusion protein was tested as monotherapy in patients with renal cell carcinoma,which was well tolerated and led to stabili-zation of disease in some patients(Brignone et al.,2009). IMP321was also tested in combination with paclitaxel chemo-therapy in patients with metastatic breast cancer,which led to an objective response rate of50%(Brignone et al.,2010). Based on these promising results,a phase III clinical trial is expected to begin accrual in2015.Other clinical trials are ongoing with an antibody against LAG-3(BMS-986016),which is also being tested in combination with anti-PD-1(nivolumab) (NCT01968109,).TIM-3is another immune checkpoint for which agents are being developed for clinical testing.Pre-clinical studies indicate that TIM-3is co-expressed with PD-1on tumor-inﬁltrating lymphocytes,and combination therapy targeting these two pathways improves anti-tumor immune responses(Sakuishi et al.,2010).Finally,an antibody targeting VISTA was recently shown to improve anti-tumor immune responses in mice(Le Mercier et al.,2014),with clinical development soon to follow.Again,these agents repre-sent only a partial list of the immune checkpoint agents that are currently under development for clinical testing,with expec-tations that they will be tested in combination strategies based on in-depth analyses of human tumors to provide an understand-ing of co-expression of these,and other immunologic targets,to guide rational combinations.Regarding the co-stimulatory molecules,OX40and41BB, which are members of the TNF-receptor superfamily,are furthest along in clinical development.A murine anti-OX40anti-body,given as a single dose,was tested in a phase I clinical trial and found to have an acceptable safety proﬁle,as well as evi-dence of anti-tumor responses in a subset of patients(Curti et al.,2013).Humanized antibodies against OX40are expected to enter clinical trial in2015.Anti-41BB(BMS-663513)is a fully humanized monoclonal antibody that has been tested in a phase I/II study in patients with melanoma,renal cell carcinoma,and ovarian cancer,with promising clinical responses,as well as toxicities,especially at higher doses,which led to re-evaluation of the dose and schedule of treatment(Sznol et al.,2008, J.Clin.Oncol.,abstract).Currently,there areﬁve clinical trials with anti-41BB(urelumab,BMS-663513)that are recruiting pa-tients with various tumor types(), including combination with anti-PD-1(nivolumab),with data ex-pected to be presented from these trials during the next1to2 years.The third co-stimulatory molecule is inducible co-stimu-lator(ICOS),a member of the CD28/B7family whose expression increases on T cells upon T cell activation.ICOS+effector T cells (Teff),as opposed to ICOS+regulatory T cells(Treg),increase after patients receive treatment with anti-CTLA-4(Liakou et al., 2008),correlating with clinical beneﬁt in a small retrospective study(Carthon et al.,2010).ICOS thus may serves as a pharma-codynamic biomarker to indicate that anti-CTLA-4has‘‘hit its target’’enhancing T cell activation(Ng Tang et al.,2013).Also, the association of agonistic targeting of ICOS and blockade of CTLA-4can lead to improved anti-tumor immune responses and tumor rejection in mice(Fan et al.,2014).Anti-ICOS anti-bodies are expected to enter into clinical trials in2015.It is likely that combination therapy to simultaneously engage co-stimula-tory pathways and limit inhibitory pathways will be a successful path forward to provide clinical beneﬁt.Importantly,based on the proﬁle of toxicities observed to date,it will be critical to closely monitor these combination strategies for potential adjustments of dosage and management of toxicities that may arise.Reconciliation:Curative Therapeutic CombinationsThe last few decades have witnessed the emergence of two effective but fundamentally different strategies for cancer ther-apy,each with its own strengths and weaknesses.Genomic-guided identiﬁcation of mutations that drive cancer has led toCell161,April9,2015ª2015Elsevier Inc.209。

疾病靶点英语

疾病靶点英语The field of disease research has seen remarkable advancements in recent decades, with the identification of specific molecular targets playing a crucial role in the development of effective treatments. These disease targets, often referred to as "druggable targets," are biomolecules or cellular processes that can be modulated by therapeutic interventions to alleviate the symptoms or underlying causes of various health conditions.At the heart of this research lies the fundamental understanding that diseases are not merely a collection of symptoms but rather complex biological phenomena driven by intricate pathways and dysregulated mechanisms. By unraveling these intricate webs of molecular interactions, scientists can pinpoint the key players responsible for the onset and progression of diseases, thereby opening up new avenues for targeted therapies.One of the most extensively studied disease targets is the family of protein kinases. Protein kinases are enzymes that play a pivotal role in cellular signaling cascades, regulating a wide range ofphysiological processes, from cell growth and differentiation to metabolism and immune response. Aberrant kinase activity has been implicated in the development of numerous diseases, including cancer, autoimmune disorders, and neurodegenerative conditions. As a result, kinase inhibitors have become a mainstay in the pharmaceutical industry, with several FDA-approved drugs targeting specific kinases to disrupt the pathological signaling pathways.Another important class of disease targets are G-protein coupled receptors (GPCRs). These membrane-bound receptors are responsible for translating extracellular signals into intracellular responses, making them crucial players in a variety of physiological and pathological processes. GPCRs have been the focus of extensive research, as they are involved in the regulation of diverse functions, such as neurotransmission, hormone signaling, and immune system modulation. Targeting specific GPCR subtypes has led to the development of numerous therapeutic agents, including drugs for the treatment of neurological disorders, cardiovascular diseases, and metabolic conditions.In addition to proteins, genetic targets have also emerged as promising avenues for disease intervention. The rapid advancements in our understanding of the human genome and the role of genetic variations in disease predisposition have paved the way for the development of personalized medicine. By identifying specificgenetic mutations or dysregulated gene expression patterns associated with particular diseases, researchers can design targeted therapies that address the underlying genetic drivers of the condition.One notable example of a genetic target is the BRCA1 and BRCA2 genes, which are known to play a crucial role in DNA repair mechanisms. Mutations in these genes are strongly linked to an increased risk of breast and ovarian cancer. The discovery of this genetic association has led to the development of targeted therapies, such as PARP inhibitors, which selectively target cancer cells harboring BRCA mutations, sparing healthy cells and reducing the adverse effects of traditional chemotherapy.Furthermore, the field of immunotherapy has seen a remarkable surge in recent years, with the identification of immune system-related targets becoming a key focus in the treatment of various diseases, particularly cancer. Immune checkpoint proteins, such as PD-1 and CTLA-4, have emerged as prime targets for immunotherapeutic interventions. These proteins act as natural "brakes" on the immune system, preventing an excessive or misdirected immune response. By blocking these checkpoint proteins, immunotherapies can unleash the power of the body's own immune system to recognize and attack cancer cells, leading to remarkable clinical outcomes in patients with previously intractablemalignancies.The identification of disease targets is not limited to the realm of pharmaceuticals; it also plays a crucial role in the development of diagnostic tools and biomarkers. By pinpointing specific molecules or cellular processes that are altered in the context of a particular disease, researchers can develop sensitive and accurate diagnostic assays to facilitate early detection and monitoring of disease progression. These disease-specific biomarkers can also serve as valuable tools for personalized medicine, allowing healthcare providers to tailor treatment strategies to the unique molecular profile of an individual patient.The pursuit of disease targets is an ongoing and dynamic field of research, with new discoveries and advancements continually expanding our understanding of the complex mechanisms underlying various health conditions. As our knowledge of the human body and its intricate biological networks continues to grow, the identification of novel disease targets will undoubtedly lead to the development of more effective, targeted, and personalized therapies, ultimately improving patient outcomes and transforming the landscape of healthcare.In conclusion, the identification of disease targets is a fundamental aspect of modern biomedical research, driving the development ofinnovative therapeutic strategies and diagnostic tools. By unraveling the molecular underpinnings of diseases, researchers can unlock new avenues for targeted interventions, paving the way for a future where personalized and precision medicine becomes the standard of care.。

阻断肺腺癌细胞A2aR抑制肿瘤相关巨噬细胞迁移及极化

精品文档供您编辑修改使用专业品质权威编制人：______________审核人：______________审批人：______________编制单位：____________编制时间：____________序言下载提示：该文档是本团队精心编制而成，希望大家下载或复制使用后，能够解决实际问题。

文档全文可编辑，以便您下载后可定制修改，请根据实际需要进行调整和使用，谢谢!同时，本团队为大家提供各种类型的经典资料，如办公资料、职场资料、生活资料、学习资料、课堂资料、阅读资料、知识资料、党建资料、教育资料、其他资料等等，想学习、参考、使用不同格式和写法的资料，敬请关注!Download tips: This document is carefully compiled by this editor. I hope that after you download it, it can help you solve practical problems. The document can be customized and modified after downloading, please adjust and use it according to actual needs, thank you!And, this store provides various types of classic materials for everyone, such as office materials, workplace materials, lifestylematerials, learning materials, classroom materials, reading materials, knowledge materials, party building materials, educational materials, other materials, etc. If you want to learn about different data formats and writing methods, please pay attention!阻断肺腺癌细胞A2aR抑止肿瘤相关巨噬细胞迁移及极化摘要：阻断肺腺癌细胞中的A2aR可能是肿瘤免疫治疗的一个重要治疗策略。

免疫细胞学英语

IntroductionImmunocytology, a specialized branch of cellular biology, delves into the intricate world of immune cells, their structure, function, and interactions within the complex network of the immune system. These cells, often referred to as leukocytes or white blood cells, play a pivotal role in defending our bodies against a myriad of pathogens, foreign substances, and even aberrant cells that arise from within. This essay provides a comprehensive, high-quality analysis of immunocytology, examining various aspects of immune cells, including their classification, development, activation mechanisms, effector functions, and the emerging therapeutic applications that harness their power.Classification and Development of Immune CellsThe immune system is composed of a diverse array of cell types, each with distinct roles and characteristics. Broadly, immune cells can be classified into two main categories: innate immune cells and adaptive immune cells. Innate immune cells, such as neutrophils, monocytes/macrophages, dendritic cells (DCs), natural killer (NK) cells, and mast cells, provide the first line of defense against invading pathogens. They recognize conserved pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) and respond rapidly but non-specifically.In contrast, adaptive immune cells, comprising B cells and T cells, offer a highly specific, long-lasting defense. B cells produce antibodies, while T cells execute cytotoxic or helper functions depending on their subsets (CD4+ T helper cells, CD8+ cytotoxic T cells, regulatory T cells, etc.). The development of these immune cells occurs primarily in the bone marrow (for B cells and myeloid cells) and the thymus (for T cells). A tightly regulated process involving hematopoietic stem cell (HSC) differentiation, gene rearrangements, positive and negative selection, and maturation ensures the generation of a diverse and self-tolerant immune repertoire.Activation Mechanisms and Signal TransductionThe activation of immune cells is a finely orchestrated process triggeredby the recognition of antigens or danger signals. For innate immune cells, PRR engagement initiates signaling cascades involving adaptor proteins like MyD88 and TRIF, leading to the activation of transcription factors such as NF-κB and IRF3/7, which drive the expression of pro-inflammatory cytokines, chemokines, and antimicrobial peptides.Adaptive immune cells, particularly T and B cells, require antigen recognition through their unique antigen receptors (TCR for T cells, BCR for B cells). This interaction, when accompanied by appropriate co-stimulatory signals, activates intracellular signaling pathways involving kinases such as Lck, Zap70, and PI3K, ultimately leading to the activation of transcription factors like NF-κB, AP-1, and NFAT. These transcription factors orchestrate the expression of genes involved in cell proliferation, differentiation, and effector function.Effector Functions of Immune CellsInnate immune cells execute various effector functions to combat infections. Neutrophils phagocytose and kill pathogens through the release of reactive oxygen species (ROS) and granule contents. Monocytes/macrophages display similar phagocytic abilities and also present antigens to T cells, produce inflammatory cytokines, and participate in tissue repair. DCs are professional antigen-presenting cells (APCs) that capture, process, and present antigens to naïve T cells, initiating adaptive immune responses. NK cells directly eliminate virus-infected or transformed cells without prior sensitization, relying on the balance of activating and inhibitory receptors interacting with cell surface ligands.Adaptive immune cells contribute to immunity through antibody production and cell-mediated responses. B cells differentiate into plasma cells that secrete antibodies, which neutralize pathogens, opsonize them for enhanced phagocytosis, or activate complement. T cells, upon activation, differentiate into effector subsets: CD4+ T helper cells (Th1, Th2, Th17, Tfh, etc.) that provide help to other immune cells, and CD8+ cytotoxic T cells that directlykill infected or transformed cells. Regulatory T cells (Tregs) maintain immune homeostasis by suppressing excessive immune responses and preventing autoimmunity.Emerging Therapeutic ApplicationsRecent advances in immunocytology have paved the way for innovative therapeutic strategies targeting immune cells. Cancer immunotherapy, for instance, has revolutionized cancer treatment, with approaches such as immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4 antibodies) that unleash the cytotoxic potential of T cells suppressed by tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy involves engineering patient's T cells to express CARs, enabling targeted recognition and destruction of tumor cells. Additionally, adoptive transfer of ex vivo expanded or genetically modified NK cells is being explored for cancer therapy due to their inherent ability to recognize and kill malignant cells.In autoimmune diseases and transplant rejection, therapies targeting immune cells aim to suppress pathogenic immune responses. These include the use of monoclonal antibodies against pro-inflammatory cytokines or their receptors, T cell-depleting agents, and Treg-based therapies. Moreover, modulation of innate immune cells, particularly DCs, through targeted delivery of antigens or immunomodulatory molecules, holds promise for the induction of tolerance in autoimmune and allergic disorders.ConclusionImmunocytology offers a rich tapestry of knowledge, elucidating the complexities of immune cells and their integral role in maintaining host defense. From the classification and development of these cells to the intricate mechanisms governing their activation and effector functions, understanding immunocytology is crucial for both fundamental biological insights and translational applications. The ongoing advancements in this field continue to fuel the development of novel therapeutic strategies that harness the power of immune cells, transforming the landscape of modern medicine in the fight againstinfectious diseases, cancer, and autoimmune disorders.。

非小细胞肺癌免疫检查点抑制剂疗效预测标志物研究进展

非小细胞肺癌免疫检查点抑制剂疗效预测标志物研究进展孔文翠，余宗阳Ｒｅｖｉｅｗｏｆｐｒｅｄｉｃｔｉｖｅｂｉｏｍａｒｋｅｒｓｆｏｒｔｈｅｉｍｍｕｎｏｌｏｇｉｃａｌｃｈｅｃｋｐｏｉｎｔｉｎｈｉｂｉｔｏｒｓｒｅｌａｔｅｄｅｆｆｉｃａｃｙｉｎｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒＫＯＮＧＷｅｎｃｕｉ，ＹＵＺｏｎｇｙａｎｇＭｅｄｉｃａｌＯｎｃｏｌｏｇｙＤｅｐａｒｔｍｅｎｔ，ｔｈｅ９００ｔｈＨｏｓｐｉｔａｌｏｆｔｈｅＪｏｉｎｔＳｕｐｐｏｒｔＦｏｒｃｅｏｆｔｈｅＣｈｉｎｅｓｅＰｅｏｐｌｅ＇ｓＬｉｂｅｒａｔｉｏｎＡｒｍｙ，ＦｕｊｉａｎＦｕｚｈｏｕ３５００２５，Ｃｈｉｎａ．【Ａｂｓｔｒａｃｔ】Ｉｎｒｅｃｅｎｔｙｅａｒｓ，ｉｍｍｕｎｏｔａｒｇｅｔｉｎｇｔｈｅｒａｐｙｈａｓｂｅｅｎａｎｅｗｆｉｅｌｄｆｏｒｔｈｅｉｎｔｅｒｖｅｎｔｉｏｎｏｆｔｕｍｏｒｍｉｃｒｏｅｎｖｉｒｏｎｍｅｎｔｔｒｅａｔｍｅｎｔ．Ｃｈｅｃｋｐｏｉｎｔｉｎｈｉｂｉｔｏｒｓｈａｖｅｄｅｍｏｎｓｔｒａｔｅｄａｃｃｅｐｔａｂｌｅｔｏｘｉｃｉｔｉｅｓ，ｐｒｏｍｉｓｉｎｇｃｌｉｎｉｃａｌｒｅｓｐｏｎｓｅｓ，ｄｕｒａｂｌｅｄｉｓｅａｓｅｃｏｎｔｒｏｌ，ａｎｄｉｍｐｒｏｖｅｄｓｕｒｖｉｖａｌｉｎｔｈｅｓｅｌｅｃｔｅｄｐａｔｉｅｎｔｓｗｉｔｈａｄｖａｎｃｅｄｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ（ＮＳＣＬＣ）．Ｈｏｗｅｖｅｒ，ｏｎｌｙａｂｏｕｔｔｗｅｎｔｙｐｅｒｃｅｎｔｐａｔｉｅｎｔｓｃａｎｒｅａｌｌｙｂｅｎｅｆｉｔｆｒｏｍｔｈｅｓｅｔｈｅｒａｐｉｅｓ．Ｈｏｗｔｏｓｃｒｅｅｎｔｈｅｓｅｌｅｃｔｅｄｐａｔｉｅｎｔｓ？Ｂｉｏｍａｒｋｅｒｓａｓｔｈｅｈｉｇｈｌｉｇｈｔｅｄｐｒｅｄｉｃｔｉｖｅｍａｒｋｅｒｓｈａｖｅｂｅｅｎｅｘｐｌｏｒｅｄ，ａｎｄｐｏｔｅｎｔｉａｌｌｙｈｅｌｐｓｃｒｅｅｎｔｈｅｆａｖｏｒｐａｔｉｅｎｔｓｂｅｎｅｆｉｔｆｒｏｍｃｈｅｃｋｐｏｉｎｔｉｎｈｉｂｉｔｏｒｓ．Ｔｈｅｒｅｖｉｅｗｆｏｃｕｓｏｎｔｈｅｈｉｇｈｌｉｇｈｔｅｄｂｉｏｍａｒｋｅｒｓ，ｉｎｃｌｕｄｉｎｇＰＤ－Ｌ１ｅｘｐｒｅｓｓｉｏｎ，ｔｕｍｏｒｍｕｔａｔｉｏｎｌｏａｄ（ＴＭＢ），ｍｉｃｒｏｓａｔｅｌｌｉｔｅｉｎｓｔａｂｉｌｉｔｙ（ＭＳＩ），ｄｒｉｖｉｎｇｇｅｎｅｍｕｔａｔｉｏｎｓｔａｔｕｓ，ａｎｄＤＮＡｄａｍａｇｅｒｅｐａｉｒｒｅｌａｔｅｄｇｅｎｅｍｕｔａｔｉｏｎｓｉｎＮＳＣＬＣｐａｔｉｅｎｔｓ．【Ｋｅｙｗｏｒｄｓ】ｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ，ｃｈｅｃｋｐｏｉｎｔｉｎｈｉｂｉｔｏｒｓ，ｂｉｏｍａｒｋｅｒｓ，ｉｍｍｕｎｏｔｈｅｒａｐｙＭｏｄｅｒｎＯｎｃｏｌｏｇｙ２０２０，２８（２２）：４０１７－４０２０【指示性摘要】近年来，免疫靶向治疗成为针对肿瘤微环境干预治疗异军突起的新领域。

免疫治疗在膀胱癌中的最新研究进展和未来展望

免疫治疗在膀胱癌中的最新研究进展和未来展望曹达龙;叶定伟【摘要】膀胱癌已成为泌尿男生殖系统中常见的恶性肿瘤.自1976年将卡介苗(Bacillus Calmette-Guerin,BCG)膀胱灌注成功地用于非肌层浸润性膀胱癌治疗之后,膀胱癌的治疗未见显著进步,尤其是局部进展和转移性膀胱癌的治疗效果仍不理想.近年来,膀胱癌免疫治疗取得了重大突破,尤其是针对程序性细胞死亡分子1(programmed death-1,PD-1)、程序性细胞死亡分子配体1(programmed death-ligand 1,PD-L1)和细胞毒 T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4,CTLA-4)的免疫检查点抑制剂已被证实不仅具有良好的耐受性,而且能显著改善局部进展和晚期膀胱癌患者的预后.PD-1、PD-L1和CTLA-4抑制剂主要通过阻断负向调控信号,恢复T细胞活性,从而增强T细胞的抗肿瘤免疫应答.其他免疫治疗还包括嵌合抗原受体 T细胞免疫疗法(chimeric antigen receptor T-cell immunotherapy,CAR-T)等也具有良好的发展前景.该研究将对免疫治疗在膀胱癌治疗中的作用机制、疗效等进行综述.%Bladder cancer is one of the common genitourinary malignancies. Since the discovery of intravesical Bacillus Calmette-Guerin (BCG) in the 1970s for non-muscle invasive bladder cancer, there have not been any major breakthrough drugs especially for locally advanced and metastatic bladder cancer. Recently, the immunotherapy for bladder cancer has made great breakthrough. Immune-checkpoint inhibitors targeting the programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways have shown significant long-term responses and tolerable safety profiles for locallyadvanced and metastatic bladder cancer. Inhibitors targeting PD-1, PD-L1 and CTLA-4 are mainly used to restore T cell activity by blocking negative regulation signal, and to enhance the anti-tumor activities of T cells. Other immunotherapies including chimeric antigen receptor T-cell (CAR-T) therapy also have great prospects. In this review, the effect of immunotherapeutic agents and the mechanisms in the treatment of bladder cancer are summarized.【期刊名称】《中国癌症杂志》【年(卷),期】2018(028)002【总页数】7页(P81-87)【关键词】膀胱癌;免疫治疗;卡介苗;PD-1;PD-L1;CTLA-4【作者】曹达龙;叶定伟【作者单位】复旦大学附属肿瘤医院泌尿外科,复旦大学上海医学院肿瘤学系,上海200032;复旦大学附属肿瘤医院泌尿外科,复旦大学上海医学院肿瘤学系,上海200032【正文语种】中文【中图分类】R737.14膀胱癌是泌尿男生殖系统中常见的恶性肿瘤，已成为欧美国家的第九位常见恶性肿瘤［1-2］。

肿瘤突变负荷应用于肺癌免疫治疗的专家共识

肿瘤突变负荷应用于肺癌免疫治疗的专家共识Cancer Immunotherapy: Expert Consensus on the Application of Tumor Mutation Burden in Lung Cancer TreatmentIntroduction:In recent years, immunotherapy has emerged as a promising treatment option for lung cancer patients. Harnessing the power of the immune system to recognize and destroy cancer cells, this revolutionary approach has shown remarkable success in extending survival rates and improving overall outcomes. One important aspect of lung cancer immunotherapy is the utilization of tumor mutation burden (TMB) as a predictive biomarker. This article will delve into TMB's significance in guiding treatment decisions and explore the expert consensus surrounding its application in lung cancer immunotherapy.Understanding TMB:Tumor mutation burden refers to the number of mutations present within a tumor cell's genome. These mutations can broadly be categorized as either synonymous (not affecting protein function) or non-synonymous (affecting protein function). TMB serves as an indicator of genomicinstability and has been found to correlate with the likelihood of neoantigen creation, which plays a crucial role in triggering an immune response against tumors.Expert Consensus on TMB in Lung Cancer Immunotherapy:1. Predictive Value for Immune Checkpoint Inhibitors (ICI):Immune checkpoint inhibitors have revolutionized lung cancer treatment by targeting proteins that hinder immune responses against tumors. Research studies haveconsistently demonstrated that higher TMB levels are associated with improved response rates and increased efficacy of ICIs such as pembrolizumab and nivolumab. As a result, experts widely agree that TMB can serve as a reliable predictive biomarker for selecting suitable candidates for ICI therapy.2. Combination Therapies:Due to intrinsic heterogeneity within tumors, utilizing a single biomarker might not capture the complexity of tumor-immune interactions accurately. Experts propose combining TMB assessment with other biomarkers, such as programmed death-ligand 1 (PD-L1) expression, to enhance patient stratification and optimize treatment decisions. This approach allows for a more comprehensive understanding of the tumor microenvironment and helps identify patients who are most likely to benefit from immunotherapy.3. Potential Utility in Small Cell Lung Cancer (SCLC):While TMB has been extensively studied in non-small cell lung cancer (NSCLC), its role in SCLC remains under investigation. Preliminary findings show promise, suggesting that TMB may have predictive value in SCLC patients as well. Expert consensus acknowledges the need for further research in this area to establish the true potential of TMB as a biomarker for SCLC immunotherapy.4. Challenges and Future Directions:Though significant progress has been made, challenges remain in standardizing TMB assessment methods, ensuring reproducibility, and defining optimal cutoff values for clinical decision-making. Experts emphasize the importance of collaborative efforts to establish guidelines and validate TMB as a standard biomarker across different laboratories and institutions. Additionally, ongoing research aims to identify additional genomic alterations beyond single nucleotide variants that could enhance the predictive power of TMB.Conclusion:In conclusion, tumor mutation burden has emerged as an important biomarker in lung cancer immunotherapy, particularly when considering immune checkpoint inhibitor therapy. Expert consensus supports its use as a predictive tool for treatment selection and patient stratification. Collaboration among researchers, clinicians, and regulatoryauthorities is crucial in establishing standardized protocols for TMB assessment and refining its application to further improve patient outcomes. With continued advancements in genomic profiling techniques, precise targeting of therapies based on individual tumor characteristics holds great promise for the future of lung cancer treatment.。

AURKA对肿瘤免疫影响的研究进展

• 726 •国际免疫学杂志2020年1丨月第43卷第6期Int J Immunol，Nov. 2020，VoL 43，No. 6•综述•AURKA对肿瘤免疫影响的研究进展单宝聪王天真李晓波哈尔滨医科大学基础医学院病理教研室150081通信作者：李晓波，Email:lixiaobo@e m .c n，电话**************【摘要】AURKA是一种丝氨酸/苏氨酸激酶，在细胞有丝分裂过程中发挥重要调控作用。

AURKA的上调在人类恶性肿瘤中普遍存在。

大量研究已经证实，AURKA作为一种癌基因，影响了众多肿瘤生物学过程，如增殖、基因组不稳定、非整倍体核型的产生和侵袭转移等。

近年来,一些研究发现AURKA与肿瘤免疫之间也存在密切关联。

人们对AURKA影响免疫反应的最初认识来源于其在免疫治疗中的应用。

AURKA的抗原决定簇可以启动抗AURKA免疫反应，借以杀伤高表达AURKA的肿瘤细胞。

另外，有研究发现抑制AURKA可以通过诱导细胞转化、T细胞活化和免疫细胞浸润而直接干预免疫反应。

文章对AURKA参与免疫调控的相关发现进行了回顾和总结。

【关键词】AURKA;癌症;免疫D0I ： 10. 3760/cma. j. issn. 1673^394. 2020. 06. 021The effect of AURKA on cancer immunityShan Baocong，Wang Tianzhen^ Li XiaoboDepartment of Pathology, College of Basic Medicine, Harbin Medical University, Harbin150081 , ChinaCorresponding author：LI Xiaobo^ Email：******************f7e/：*************[Abstract】AURKA is a serine/threonine kinase and has a key role in regulation of mitosis. Moreover,upregulation of AURKA has been identified in a wide range of human malignancy. Functioning as an oncogene,AURKA influences multiple biological processes of tumor, including proliferation, genomic instability, aneu-ploid karyotype, and metastasis. In recent years, there are some studies which explore the association betweenAURKA and immune activity. The initial understanding of AURKA’s effect on immune response came from itsuse in immunotherapy. AURKA epitopes activate an anti-AURKA immune response that kills tumor cells withhigh level of AURKA. In addition, It has been found that AURKA inhibition can directly interfere with immuneresponse by inducing cell transformation, T cell activation and immune cell infiltration. This review summarizedthese findings of AURKA involvement in immune regulation.【K eywords】AURKA; Cancer; ImmunityDOI： 10. 3760/cma. j. issn. 1673-4394. 2020. 06. 021A U R K A(aurora kinase A)是 Aurora激酶家族成员之一，该家族目前已经发现Aurora A，B和C三个成员m。

A_Review_of_Recently_Approved_PD-1_Inhibitors_for_

A Review of Recently Approved PD-1 Inhibitors for the Treatment of Gastric CancerKeru ChenCollege of Life Science of Sichuan Agricultural University, Ya'an Sichuan 625014, P.R. China ABSTRACTGastric cancer is a formidable adversary in the realm of human health,posing a serious threat to those who are afflicted by it. However, there ishope on the horizon as research into its treatment has been progressingsteadily in recent years. Up to now, there are three kinds of immunecheckpoint inhibitors approved by NMPA that can be used in treatingGastric cancer, all of which target PD-1. They are Sintilimab, Tislelizumab,and Nivolumab. While they share similarities in their approach tocombating gastric cancer, there are also notable differences betweenthem that warrant closer examination. This review highlights the cost-effectiveness of Sintilimab and Tislelizumab compared with Nivolumab.By analyzing these differences more closely, we can gain valuable insightsinto which drug may be most suitable for individual patients based ontheir unique circumstances. And with continued progress in this field, wecan look forward to even more effective treatments being developed thatwill help us overcome this challenging disease once and for all.KEYWORDSPD-1 inhibitors; Gastric cancer; Nivolumab; SintilimabDOI: 10.47297/taposatWSP2633-456915.202304011 IntroductionHuman health is seriously threatened by gastric cancer, one of the world's most common forms of malignant tumor. IARC reported 1089103 new cases of gastric cancer worldwide in 2020, which accounts for 5.6% of all new tumors. And the incidence rate among males is more than double that of females. Aging and population growth are expected to significantly increase new cases and deaths of GC despite declining incidence and mortality rates [1].In addition to starting in the stomach, gastric cancer can spread to the esophagus and small intestine. It can also spread to nearby organs and lymph nodes. Almost all gastric malignancies are adenocarcinomas, which refer to adenocarcinomas of the stomach. Early gastric cancer typically presents with no symptoms or signs, making early detection challenging. Advanced-stage diagnosis is common in gastric cancer (80-90%), and 30% miss out on radical surgery, with frequent recurrence within 5 years post-surgery. There is an urgent need for research into treatments.A Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo in 2018. This was for their discovery of cancer therapy by inhibiting the negative immune system. Then we saw a breakthrough milestone has been reached in tumor therapy with immunotherapy. In recent years, the research of immune checkpoints has developed rapidly as one of the most promising immunotherapy strategies for treating malignant tumors.Theory and Practice of Science and TechnologyTumor cells can be distinguished from normal cells by the immune system using the myriad of genetic and epigenetic changes that are unique to all cancers. Through antigen-specific signals from TCRs as well as antigen-independent signals from cosignaling receptors, T-cells will be activated, followed by cosigning receptors on their surface: costimulatory receptors and coinhibitory receptors, whose functions are essential to T cell signaling and activation.[2].T cells are influenced by co-signaling molecules. Over-expression of programmed death-1 (PD-1) may contribute to immune evasion in cancer patients, suggesting the potential for immune checkpoint inhibitors in the treatment of gastric cancer. Additionally, the possibility of immunotherapy as a first-line treatment option for gastric and gastroesophageal adenocarcinomas could be offered by these two randomized trials presented at ESMO 2020 [3].In contrast to traditional therapies that target cancer cells, immune checkpoint therapy activates the body's immune system which has been suppressed by tumors to eliminate cancer cells. Due to GC’s high heterogeneity and complex molecular mechanism, it is still of research significance for the selection of treatment methods for different types of gastric cancer. Immune checkpoint therapy, considered a targeted treatment, can also be a more appropriate treatment.PD-1/PD-L1 immune drugs have been widely commercialized in China in just five years since they were first approved in June 2018. According to the NMPA, 17 immune checkpoint inhibitors are available on the Chinese market. In addition, three immune checkpoint inhibitors have been approved for gastric cancer treatment: Nivolumab, Tislelizumab, and Sindillimab. This review may get a relatively better treatment option by comparing the differences between the three drugs.Table 1. Three clinic indications of PD-1 mAbs approved for gastric cancer listed in ChinaTarget Structure Agent indicationsPD-1Nivolumab( Opdivo®)Lung cancer, SCCHN, gastric or gastro-oesophageal junction cancer,malignant pleural mesothelioma, advanced or metastatic gastric cancer,esophageal cancer or esophagogastric junction cancer, advanced ormetastatic esophageal squamous cell carcinomaPD-1Sintilimab(Sintilimab Injection)Hodgkin's lymphoma, lung cancer, liver cancer, esophageal cancer, gastric orgastro-oesophageal junction cancerPD-1Tislelizumab(Tislelizumab Injection)Hodgkin's lymphoma, lung cancer, liver cancer, MSI-H/dMMR SolidTumor, esophageal cancer, nasopharyngeal carcinoma, gastric or gastro-oesophageal junction cancer2 Approved PD-1 Monoclonal Antibodies in Gastric CancerIn peripheral tissues, the PD-1/PD-L1 checkpoint is functional and a negative regulator of T cells, both with regards to regulating local inflammatory responses and maintaining self-tolerance.[4]. PD-1 is expressed in T cells, natural killer cells, and B cells of the immune system.PD-1 intracellular domains contain two separate phosphorylation sites in both their N- and C-terminal amino acid residues: immunoreceptor tyrosine-based switch motif (ITSM) and immunoreceptor tyrosine inhibition motif (ITIM). Among these structural sites, ITSM plays an essential role in PD-1's biological actions: it is phosphorylated when PD-1 binds to PD-L1, resulting in the activation of a number of intracellular signaling pathways and effective immunosuppression[5].There are two types of PD-1 Ligands, which are PD-L1 and PD-L2. Although the interaction of PD-L2 and PD-1 can inhibit T-cell effector function, PD-L2 is expressed less than PD-L1, with expression in macrophages and dendritic cells. In this way, PD-L1 seems to be more effective and widely expressed,Vol.4 No.1 2023suggesting a more prominent role for it in the regulation of peripheral T-cell responses [6].Figure 1. Antibodies against PD-1 inhibit the function of the brake leading to activation of T cells and highly efficientattack on cancer cells the from 2018 Nobel Prize in Physiology or Medicine(1) NivolumabThe anti-PD-1 antibody Nivolumab belongs to the family of IgG4 monoclonal antibodies. It is a monoclonal antibody jointly developed by two companies named Ono Pharmaceutical (Ono) and Bristol-Myers Squibb (BMS). It functions on T cells by binding to the PD-1 protein. This prevents cancer cells from suppressing the immune system. Thus, cancer cells can be attacked by the immune system.1) Nivolumab plus chemotherapyAn international, randomized, CheckMate 649 phase 3 study found that Combining Nivolumab with chemotherapy significantly enhanced overall survival compared to chemotherapy when treating gastric, gastro-esophageal junction, or esophageal cancers. A 30% reduction in mortality is achieved, with a 31% versus 19% survival rate at 24 months. This outcome has led many countries, including China, to approve Nivolumab plus chemotherapy as the primary therapy for these patients.2) Nivolumab plus ipillimumabCombination therapy simultaneously targeting PD-1 and CTLA-4 immune checkpoints made remarkable and efficient effects on antitumor. The research shows that the blockade of each immune checkpoint or the combination of the two has distinct but complementary mechanisms of action.As shown in the Checkmate-032 study, Nivolumab plus ipilimumab was effective against chemotherapy-refractory esophagogastric cancer and had durable responses, long OS periods, and manageable safety. It was also reported that overall survival was lower for patients who received ipillimumab plus nivolumab (combination of PD-L1 positive scores ≥ 5) than for patients who received only chemotherapy. In order to treat gastroesophageal adenocarcinoma effectively, nivolumab plus chemotherapy should be the standard first-line treatment.Theory and Practice of Science and Technology3) PriceNivolumab has different specifications and prices: 100mg/10ml CNY 9260 and 40mg/4ml CNY 4591. According to BMS, nivolumab is used for intravenous Opdivo 3mg/kg every two weeks. Dosage is related to body weight.(2) TislelizumabTislelizumab, a humanized monoclonal antibody directed against PD-1, demonstrates high affinity and specificity.It is well documented that tislelizumb has longer t1/2 and slower dissociation rate from PD-1 than nivolumab[7], showing a hidden mechanism for clearing T cells and resisting anti-PD-1 treatments.1) Tislelizumab plus chemotherapyIn a phase II clinical trial (NCT03469557), tislelizumab plus chemotherapy was evaluated in patients with localized or metastatic G/GEJ adenocarcinoma. A study found that Tislelizumab plus chemotherapy achieved durable responses and was safe for patients without new safety signals. NACT plus tislelizumab has improved LAGC efficacy and R0 resection rate without causing perioperative complications in recently published studies. And Another phase II clinical trial(NCT03469557[8]) demonstrated that tislelizumab together with chemotherapy could control adverse events associated with advanced G/GEJ adenocarcinomas in the first-line treatment showing the possibility of this combination therapy.2) PriceOn March 1, 2021, after the official implementation of national medical insurance, the price of tislelizumab was reduced to CYN 2180 per tube (100mg), a reduction of up to 80%, and the down payment for self-paid treatment was only CYN 4360 per cycle, which is in the low-price range among immunological drugs of the same specification.(3) SintilimabThe recombinant anti-PD-1 antibody sintilimab has a higher affinity than both nivolumab and pembrolizumab.Sintilimab could bind to human PD-1 strongly and specifically. A powerful antitumor effect was observed along with a high level of tumor-infiltrating CD8/CD4 T cells and CD8/Treg ratios. In addition, it can block PD-1 interaction with PD-L1 and PD-L2, elevate interferon (IFN)-γ and interleukin (IL)-2, and increase anticancer activity. There are several combination therapies.1) Sintilimab plus chemotherapyPFS was significantly prolonged by PD-1 inhibitors plus oxaliplatin-based chemotherapy but did not prolong OS statistically significantly when compared to PD-1 inhibitors plus cisplatin. Combining PD-1 inhibitors with oxaliplatin-based chemotherapy may represent a superior first-line treatment option for AGC both As far as efficacy and safety are concerned [9], especially for patients with CPS ≥ 1. In comparison with The combination of sintilimab and oxaliplatin, nivolumab plus oxaliplatin did not show a significant difference.Vol.4 No.1 20232) Sintilimab plus oxaliplatin/capecitabineDuring a phase Ib clinical trial, Sintilimab plus CapeOx demonstrated promising outcomes in treating advanced or metastatic G/GEJ adenocarcinomas[10]. However, Currently, the Phase III clinical trial is being conducted on a large, randomized, double-blinded scale because of the small sample size.We still know that multiple advantages can be gained by delivering neoadjuvant therapy to patients with G/GEJ adenocarcinomas beyond surgery alone. In neoadjuvant settings, sintilimab plus oxaliplatin/capecitabine showed encouraging efficacy and safety profile[11].3) PriceAfter 2022, Sintilimab began to implement the latest price of CYN 1080 per unit (100mg) in China. Until disease progression or intolerable toxicity occurs, 200 mg is recommended every 3 weeks.3 ConclusionThis paper has given three different approved PD-1 mAbs in China that can be used in the treatment of G/GEJ cancer and showed the recent combination therapy used recently. Although α - PD-1/PD-L1 therapy has shown strong anti-tumor effects in some patients, due to primary or acquired treatment resistance, most patients cannot benefit from α- PD-1/PD-L1 treatment.Compared with monotherapy, combination therapy has better anti-tumor effects, OS, and other advantages, and its adverse resolution is within the controllable range. The most used combination therapy is chemotherapy and in combination with other immune checkpoint inhibitors that have increased its effectiveness.As a drug with a long research period, Nivolumab has many related research trials showing that the combination with chemotherapy is safer and more controllable than in combination with CTLA-4 inhibitors and is more suitable as the main first-line treatment. For the latter two drugs, although showing controllability and safety, the research is still temporarily stuck in combination with chemotherapy, due to various reasons, further trials are needed to obtain more accurate data.Considering the cost, it is noteworthy that except for Nivolumab, both other two approved drugs have been incorporated into China's medical insurance system and their prices have been significantly reduced even without insurance coverage. In summary, the research of the three drugs on the market still needs to be strengthened, among which most of the effects of Sintilimab and Tislelizumab are better than nivolumab and more cost-effective, but their studies need to be continuously expanded to determine their safety and efficacy.Table 2. Price comparison of three drugsAgent Nivolumab Sintilimab TislelizumabPrices in China CNY 9260/100mgCNY 4591/40mgCYN 2180/100mg CYN 1080/100mgRecommended dose3 mg/kg is givenintravenously every 2 weeksfor 60 minutes until diseaseprogression or unacceptabletoxicityThe recommended doseis 200 mg every 3 weeksuntil disease progression orintolerable toxicity.It is given intravenously at arecommended dose of 200mg every 3 weeks.Theory and Practice of Science and TechnologyAbout the AuthorKeru Chen is undergraduate of School of Life Science, Sichuan Agricultural University, and her research field is biology.References[1] Yan, C., Shan, F., Ying, X., Li, Z. (2023). Global burden prediction of gastric cancer during demographic transition from2020 to 2040. Chin. Med. J. (Engl.), 136: 397–406.[2] Hui, E., Cheung, J., Zhu, J., et al. (2017) .T cell costimulatory receptor CD28 is a primary target for PD-1-mediatedinhibition. Science, 355: 1428-+.[3] Smyth, E.C., Cervantes, A. (2020) .Addition of nivolumab to chemotherapy in patients with advanced gastric cancer: arelevant step ahead, but still many questions to answer. Esmo Open, 5: e001107.[4] Sunshine, J., Taube, J.M. (2015). PD-1/PD-L1 inhibitors. Curr. Opin. Pharmacol. 23: 32–38.[5] Hofmeyer KA, Jeon H, Zang X. (2011) The PD-1/PD-L1 (B7-H1) Pathway in Chronic Infection-Induced Cytotoxic TLymphocyte Exhaustion. J. Biomed. Biotechnol., 451694.[6] Sundar, R., Cho, B.C., Brahmer, J.R., et al. (2015) .Nivolumab in NSCLC: latest evidence and clinical potential. Ther. Adv.Med. Oncol., 7: 85–96.[7] Hong, Y., Feng, Y., Sun, H., et al. (2021). Tislelizumab uniquely binds to the CC’ loop of PD-1 with slow-dissociated rateand complete PD-L1 blockage. FEBS Open Bio, 11: 782–92.[8] Qiu, H.B. (2020). Safety and efficacy of tislelizumab plus chemotherapy for first-line treatment of advanced esophagealsquamous cell carcinoma and gastric/gastroesophageal junction adenocarcinoma. Thorac. Cancer, 11: 3419–21. [9] Guo, X., Yang, B., He, L., et al. (2022). PD-1 inhibitors plus oxaliplatin or cisplatin-based chemotherapy in first-linetreatments for advanced gastric cancer: A network meta-analysis. Front. Immunol., 13: 905651.[10] Jiang, H., Zheng, Y., Qian, J., et al. (2020). Safety and efficacy of sintilimab combined with oxaliplatin/capecitabine asfirst-line treatment in patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma in a phase Ib clinical trial. BMC Cancer, 20: 760.[11] Jiang, H., Yu, X., Li, N., et al. (2022). Efficacy and safety of neoadjuvant sintilimab, oxaliplatin and capecitabine inpatients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: early results of a phase 2 study. J. Immunother. Cancer, 10: e003635.。

我的心愿希望科学家发明新药治愈癌症英语作文

我的心愿希望科学家发明新药治愈癌症英语作文Cancer has long been one of the most formidable adversaries in the field of medicine. Its pervasive nature, with the ability to affect virtually any part of the human body, and its complex mechanisms of progression and resistance to treatment, make it a particularly challenging disease to combat. The desire for a cure is universal, transcending borders, cultures, and socioeconomic statuses. As such, the hope that scientists will one day develop a new drug capable of curing cancer is a profound and pervasive aspiration that drives much of contemporary biomedical research.The scientific community has made significant strides in understanding the biology of cancer. The discovery of oncogenes and tumor suppressor genes has elucidated some ofthe genetic foundations of cancer. Researchers have identified pathways and molecular mechanisms that drive the uncontrolled growth of cancer cells. These advances have paved the way for targeted therapies, which are designed to specifically inhibit the function of molecules critical for cancer cell survival and proliferation. Drugs like Imatinib (Gleevec) for chronic myeloid leukemia and Trastuzumab (Herceptin) for HER2-positive breast cancer are prime examples of how understanding cancer at the molecular level can lead to effective treatments.However, despite these advances, the quest for a universal cure for cancer remains elusive. One of the significant challenges in developing a cure is the heterogeneity of cancer. Each type of cancer, and even each patient's cancer, can have a unique genetic and molecular profile. This heterogeneity makes it difficult to develop a one-size-fits-all treatment. Moreover, cancer cells canevolve and develop resistance to treatments, rendering many drugs ineffective over time.Immunotherapy has emerged as a promising approach in the fight against cancer. By harnessing the body's immune system to recognize and destroy cancer cells, immunotherapy offers a different angle of attack compared to traditional treatments like chemotherapy and radiation. Drugs such as Pembrolizumab (Keytruda) and Nivolumab (Opdivo) have shown remarkable success in treating certain cancers by targeting immune checkpoints, proteins that normally help keep immune responses in check but are exploited by cancer cells to avoid being attacked by the immune system. The development of CART-cell therapy, where a patient's T cells are genetically modified to target cancer cells, has also shown promising results, particularly in blood cancers like leukemia and lymphoma.Another exciting area of research is the development of personalized medicine. By analyzing a patient's genetic makeup and the specific characteristics of their cancer, scientists can tailor treatments that are more effective and have fewer side effects. This approach not only improves the efficacy of treatment but also helps in minimizing the adverse effects associated with conventional therapies. Personalized medicine is already being implemented in some areas of cancer treatment, and continued advancements in genomic sequencing and bioinformatics are likely to expandits applicability.In addition to these biological and technological advancements, the role of early detection and prevention cannot be overstated. Early detection of cancer significantly increases the chances of successful treatment and survival. Techniques such as liquid biopsies, which detect cancer-related genetic mutations and proteins in blood samples, are becoming more refined and could revolutionize cancerscreening and diagnosis. Preventative measures, including lifestyle modifications and vaccinations, such as the HPV vaccine to prevent cervical cancer, also play a crucial role in reducing cancer incidence.While the scientific and medical communities continue to make progress, it is important to recognize the broadersocial and economic factors that impact the fight against cancer. Access to healthcare, affordability of treatments, and disparities in healthcare quality are significant issues that need to be addressed to ensure that advancements in cancer treatment benefit all segments of society. Moreover, the psychological and emotional support for cancer patients and their families is a critical component of comprehensive cancer care.The quest for a cure for cancer is not just a scientific challenge but a human one. It requires the collective efforts of researchers, clinicians, policymakers, patients, andadvocates. Continued investment in cancer research, support for innovative and interdisciplinary approaches, and a commitment to equitable healthcare access are essential to make the dream of curing cancer a reality.In conclusion, the hope that scientists will one day develop a new drug capable of curing cancer is a powerful and motivating force. While significant challenges remain, the advancements in our understanding of cancer biology, the development of targeted therapies and immunotherapies, and the promise of personalized medicine provide a strong foundation for optimism. The journey towards a cure is ongoing, and with continued dedication and collaboration, the dream of a world without cancer may one day be realized.。

治愈癌症的方法英语作文

治愈癌症的方法英语作文Title: Exploring Methods for Cancer Treatment and Healing。

Cancer is one of the most daunting diseases humanity faces, and finding effective methods for its treatment and cure remains a paramount challenge in medical research. Various approaches have been explored over the years, each with its own merits and limitations. In this essay, we will delve into some of the methods used in the quest to cure cancer.Chemotherapy is one of the most common treatments for cancer. It involves the use of drugs to kill cancer cells or stop them from growing and spreading. These drugs can be administered orally or intravenously and work by targeting rapidly dividing cells, which are characteristic of cancerous growths. While chemotherapy can be effective in shrinking tumors and controlling cancer, it often comes with side effects such as nausea, hair loss, and fatigue.Another widely used method is radiation therapy, which uses high doses of radiation to kill cancer cells andshrink tumors. This treatment is localized, meaning it targets specific areas of the body affected by cancer. Radiation therapy can be used as a primary treatment or in combination with surgery or chemotherapy. Like chemotherapy, it can cause side effects such as skin irritation and fatigue, but advancements in technology have led to more targeted and precise delivery of radiation, minimizing damage to healthy tissues.Surgery remains a cornerstone in the treatment of many types of cancer. It involves the removal of canceroustumors and surrounding tissues to prevent the spread of cancer cells. Surgery can be curative if the cancer has not spread beyond the primary site, or it can be palliative to relieve symptoms and improve quality of life. With advancements in surgical techniques and technology, such as minimally invasive procedures and robotic-assisted surgery, outcomes for cancer patients undergoing surgery have improved significantly.Immunotherapy is a relatively newer approach to cancer treatment that harnesses the power of the immune system to fight cancer. It works by stimulating the body's immune response or by enhancing it with substances such as immune checkpoint inhibitors, monoclonal antibodies, or cancer vaccines. Immunotherapy has shown promising results in treating various types of cancer, including melanoma, lung cancer, and certain types of leukemia and lymphoma. While it can be highly effective, not all patients respond to immunotherapy, and it can also cause immune-related side effects.Targeted therapy is another precision medicine approach that targets specific molecules involved in cancer growth and progression. Unlike chemotherapy, which affects all rapidly dividing cells, targeted therapy specifically targets cancer cells while sparing normal cells. This approach can result in fewer side effects and improved outcomes for patients with certain types of cancer, such as breast cancer and leukemia. However, resistance to targeted therapy can develop over time, limiting its long-termeffectiveness.Complementary and alternative therapies, such as acupuncture, herbal supplements, and mind-body practiceslike yoga and meditation, are also used by some cancer patients to manage symptoms and improve well-being. While these therapies may offer benefits such as pain relief and stress reduction, it's important for patients to discuss them with their healthcare providers and ensure they complement rather than replace conventional cancer treatments.In conclusion, the quest to cure cancer involves a multifaceted approach that encompasses various treatment modalities, from conventional therapies like chemotherapy, radiation therapy, and surgery to newer approaches such as immunotherapy and targeted therapy. Each method has its own strengths and limitations, and the optimal treatment approach may vary depending on the type and stage of cancer, as well as individual patient factors. Continued research and innovation are essential to improving cancer outcomes and ultimately finding a cure for this devastating disease.。

肿瘤微环境与结直肠癌预后的相关性

肿瘤微环境与结直肠癌预后的相关性【摘要】肿瘤浸润免疫细胞（tumor infiltrating immune cell，TIC）是肿瘤微环境中对结直肠癌的发生发展起到至关重要的成分，包括：淋巴细胞、单核巨噬细胞等。

他们通过不同方式抑制炎症反应及抗肿瘤反应发生，逃离免疫监视发生免疫逃逸，诱导肿瘤的发生发展和转移。

因此，了解肿瘤浸润免疫细胞功能及其诱导结肠癌发生的机制，是这篇综述的主要内容。

【关键词】肿瘤免疫浸润细胞肿瘤微环境免疫逃逸结直肠癌（Colorectal Cancer，CRC）是常见的消化道恶性肿瘤，其发病率及死亡率逐年增加。

据世界卫生组织国际癌症研究署（WHO IARC）发布的癌症负担数据显示，结直肠癌全球发病率仅次于乳腺癌、肺癌，居第3位，死亡率居癌症相关死亡率的第2位。

仅2020年一年，全球就报告了大约193万新发结直肠癌病例，占全球新确诊癌症人数的9.7%。

据统计，约三分之一的CRC死亡患者发生转移及术后复发，致使生存率不到10%，是结直肠癌死亡率上升的主要原因[1]。

随着内镜技术的快速发展及靶向药物的研发和广泛应用，对CRC的诊断与治疗有了明显的提高。

但由于内镜下诊断治疗需进行禁食和肠道清洁，过程中伴随不同程度的痛苦，且禁忌症较多，导致患者依从性差，从而错过最佳治疗时间，预后不佳。

准确的预后评估对于提高疗效，改善患者生存质量具有重大意义。

现临床广泛采用结直肠癌TNM分期系统，即浸润深度、淋巴结数目、远处转移，来预测患者预后。

然而大量的临床数据显示出II期患者生存率低于IIIA期患者的反常现象，且在相同组织学肿瘤分期的患者中观察到的临床结果也具有显著差异，这表明了TNM分期系统的局限性，以及其作为CRC预后评估手段的不准确性[2]。

随着二代测序技术的发展与应用，基于基因水平对患者预后评估得到了广泛认可，从一定程度上既可以避免内镜检查依从性差的相关问题，也可以避免TNM分期预测预后差异性较大的局限性。

科研成果英文表达

科研成果英文表达Scientific Research Achievements: A Breakthrough in Cancer Treatment。

Introduction。

Cancer is a global health concern, affecting millions of lives each year. In recent years, significant advancements have been made in cancer research, leading to breakthroughs in treatment options. This article aims to highlight some of the remarkable scientific research achievements in the field of cancer treatment.Immunotherapy: Harnessing the Power of the Immune System。

One of the most promising areas of cancer research is immunotherapy. This innovative approach focuses on utilizing the body's immune system to target and destroy cancer cells. Unlike traditional treatments such as chemotherapy or radiation therapy, immunotherapy is designed to specifically target cancer cells while leaving healthy cells unharmed.One remarkable breakthrough in immunotherapy is the development of immune checkpoint inhibitors. These inhibitors work by blocking proteins that prevent immune cells from attacking cancer cells. This mechanism effectively "releases the brakes" on the immune system, allowing it to recognize and destroy cancer cells more efficiently. Immune checkpoint inhibitors have shown remarkable success in treating various types of cancer, including melanoma, lung cancer, and bladder cancer.Precision Medicine: Tailoring Treatment to Individuals。

免疫检查点抑制剂在肿瘤治疗中的不良反应及毒性管理

㊃综述㊃免疫检查点抑制剂在肿瘤治疗中的不良反应及毒性管理张璐洁李斌李瑞娟丁翠敏河北医科大学第四医院呼吸内科,石家庄050011通信作者:丁翠敏,E m a i l w jw d c m@s i n a c o m ʌ摘要ɔ 免疫检查点抑制剂(I C P i )历经数十年,目前已成为癌症治疗领域最成功的方法之一㊂I C P i 通过靶向T 细胞的调节途径来增强抗肿瘤免疫应答,而非直接对肿瘤细胞产生细胞毒作用,提高了许多难治性肿瘤的生存率,改善了晚期癌症患者的生存质量㊂这些单克隆抗体具有重新激活免疫系统的能力,同时也可能引发无数的自身免疫不良反应,称为免疫相关不良反应(i r A E s )㊂i r A E s 可累及全身各个系统,且发生特点与传统化疗及靶向药物有很大差异㊂现就I p i l i m u m a b ㊁N i v o l u m a b 和P e m b r o l i z u m a b 等药物在肺脏㊁肝脏㊁肾脏㊁胃肠道系统㊁内分泌系统㊁皮肤等组织和器官的i r A E s 的发生率㊁临床表现及治疗原则等方面进行综述㊂ʌ关键词ɔ 肿瘤;免疫疗法;免疫检查点抑制剂;免疫相关不良反应D O I 10 3760 c m a ji s s n 1673-436X 2019 04 012T o x i c i t i e s a n dm a n a g e m e n t o f i m m u n e c h e c k p o i n t i n h i b i t o r s i n c a n c e r i m m u n o t h e r a p yZ h a n g L u j i e L iB i n L iR u i j u a n D i n g Cu i m i n D e p a r t m e n to f R e s p i r a t o r y M e d i c i n e t h e F o u r t h H o s p i t a l o f H e b e i M e d i c a l U n i v e r s i t y S h i j i a z h u a n g 050011 C h i n a C o r r e s p o n d i n g a u t h o r D i n g C u i m i n E m a i l w jw d c m@s i n a c o m ʌA b s t r a c t ɔ I mm u n e c h e c k po i n t i n h i b i t o r s I C P i h a v e n o wb e c o m e o n e o f t h em o s t s u c c e s s f u l t h e r a p i e s i nt h ef i e l do fc a n c e ra f t e rd e c a d e s I C P ie n h a n c e st h ea n t i -t u m o r i mm u n er e s p o n s eb yt a r g e t i n g Tc e l l r e g u l a t o r yp a t h w a y s r a t h e rt h a n p r o d u c i n g c y t o t o x i c i t y d i r e c t l y o nt u m o rc e l l s w h i c h i m p r o v e s t h es u r v i v a l r a t eo fm a n y r e f r a c t o r y t u m o r sa n di m p r o v e st h e q u a l i t y of l i f ef o r p a t i e n t s w i t h a d v a n c e d c a n c e r T h e s e m o n o c l o n a la n t i b o d i e s h a v et h ea b i l i t y t o r e a c t i v a t et h e i mm u n e s y s t e m b u tm a y a l s o c a u s e v a r i o u s a u t o i mm u n e s i d e e f f e c t s c a l l e d i mm u n e -r e l a t e d a d v e r s e e v e n t s i r A E s I r A E sc a n a f f e c ta l m o s ta l lo r ga n sa n di t sc h a r a c t e r i s t i c sa r e d i f f e r e n tf r o m c o n v e n t i o n a lc h e m o t h e r a p y a n d t a r g e t e d t h e r a p y T h i s a r t i c l e r e v i e w t h e i n c i d e n c e c l i n i c a l p r e s e n t a t i o na n dm a n a g e m e n t o f i r A E s i nt h e l u n g l i v e r k i d n e y g a s t r o i n t e s t i n a l s ys t e m e n d o c r i n e s y s t e m s k i na g a i n s t I p i l i m u m a b N i v o l u m a ba n dP e m b r o l i z u m a b ʌK e y w o r d s ɔ N e o p l a s m s I mm u n o t h e r a p y I mm u n ec h e c k p o i n ti n h i b i t o r s I mm u n e -r e l a t e d a d v e r s e e v e n t sD O I 10 3760 c m a j i s s n 1673-436X 2019 04 012近年来,肿瘤的免疫治疗备受瞩目,其中最成功的治疗方法之一当属免疫检查点抑制剂(i mm u n ec h e c k p o i n t i n h i b i t o r s ,I C P i)㊂目前研究主要针对细胞毒性T 淋巴细胞相关抗原4(c y t o t o x i cTl y m p h o c y t e -a s s o c i a t e da n t i ge n4,C T L A -4),程序性死亡受体1(p r o g r a mm e d d e a t h r e c e pt o r -1,P D -1)/程序性死亡配体1这2个免疫检查点通路㊂抗C T L A -4单抗I pi l i m u m a b ,抗P D -1单抗N i v o l u m a b ,P e m b r o l i z u m a b 以及最近批准的抗程序性死亡配体-1单抗A t e z o l i z u m a b ,A v e l u m a b 和D u r v a l u m a b 已由美国F D A 批准用于黑色素瘤㊁非小细胞肺癌㊁肾细胞癌㊁尿路上皮癌㊁头颈部鳞癌等恶性肿瘤的治疗[1]㊂I C P i 与传统化疗及靶向药物的作用机制不同㊂在正常情况下,免疫检查点可以通过调节自身免疫反应的强度来维持免疫耐受,肿瘤细胞利用这种机制,抑制免疫细胞,从人体免疫系统中逃逸㊂I C P i 可解除这种抑制作用,使免疫细胞重新激活工作,从而杀伤肿瘤细胞㊂而传统的化疗以及靶向治疗则通过快速分解肿瘤细胞和正常细胞㊁特定的靶向分子来抑制肿瘤生长㊂因此,不同的治疗方式,其不良反应机制也是不同的㊂对于免疫相关不良反应(i mm u n e -r e l a t e da d v e r s ee v e n t s ,i r A E s)的发生机制,目㊃213㊃国际呼吸杂志2019年2月第39卷第4期 I n t JR e s p i r ,F e b r u a r y 2019,V o l .39,N o .4Copyright ©博看网. All Rights Reserved.前还不十分清楚,可能与免疫检查点维持免疫稳态有关㊂研究表明,i r A E s可能与T细胞,自身抗体和炎症性细胞因子有关[2],且大多程度较轻㊁易于管理㊂下面我们对常见的以及重要器官的i r A E s作一综述㊂1i r A E s概述总体而言,与传统化疗相比,i r A E s通常为1~2级[3-4]㊂在接受单药治疗的患者中的发生率为90%,3级以上的发生率为15%~42%,且多发生在接受抗C T L A-4单抗的患者中[5]㊂i r A E s大多发生在治疗的最初几周至几个月内,但也可能随时发生[1]㊂任何器官都可能受累,最常见的是皮肤和胃肠道[3]㊂2i r A E s的发生率及临床表现21免疫相关性肺炎I C P i相关性肺炎发生率较低,多个研究报道,单药治疗时发生率小于5%㊂在接受抗P D-1治疗时,其发生率较高为27%,3级以上发生率为08%[6]㊂临床表现主要是干咳和呼吸困难㊂此类肺炎进展十分迅速,一旦出现低氧血症,将很快导致呼吸衰竭[6]㊂22肝毒性I C P i相关性肝炎较少见,总发生率为5%~ 10%,3级以上的发生率为1%~2%㊂当联合治疗时3~4级发生率显著增加达59%[7]㊂其临床表现多种多样,患者一般无症状,常表现为转氨酶升高,可伴/不伴胆红素轻度升高[8]㊂此外,还可表现为乏力㊁肌痛㊁头痛㊁腹痛㊁恶心㊁呕吐㊁精神错乱和/或黄疸[9]㊂23肾毒性肾脏系统的i r A E s比较罕见,在接受P e m b r o l i z u m a b或N i v o l u m a b治疗的患者中,肾功能衰竭/肾炎的发生率为1%[10]㊂I p i l i m u m a b引起的肾脏相关不良反应主要为肾炎㊁肾功能衰竭和狼疮性肾炎[11-13]㊂24胃肠道毒性在抗C T L A-4治疗相关的不良反应中,胃肠道i r A E s是最常见和最严重的,常导致治疗中断[14]㊂主要表现为腹泻㊁恶心和呕吐,发生率分别为33%~ 51%㊁24%~35%和12%~24%[15]㊂另一常见的不良反应是小肠结肠炎㊂M a r t h e y等[16]报道,在接受I p i l i m u m a b治疗的患者中,7%~22%的患者出现了结肠炎,92%患者出现腹泻,其他症状还包括腹痛㊁便血㊁呕吐㊁发热和体质量减轻㊂此外,一些患者还出现了结肠炎相关的肠外表现,如关节痛㊁垂体炎㊁肾炎㊁心包炎等㊂25内分泌系统毒性内分泌系统i r A E s常常不可逆转[4],甲状腺㊁垂体是最易受到影响的内分泌器官[17]㊂甲状腺功能紊乱一般早期就可发现,患者并无明显症状或仅有轻微症状[18]㊂主要表现为甲状腺功能亢进症和甲状腺功能减退症㊂据报道,在I p i l i m u m a b㊁N i v o l u m a b和P e m b r o l i z u m a b中的发生率分别为38%㊁65%和79%,而联合治疗时的发生率为132%[19]㊂I C P i引起的垂体炎通常发生在接受I p i l i m u m a b治疗的年龄偏大的男性患者中[20]㊂最近一项Ⅲ期临床试验证实, I p i l i m u m a b相关的垂体炎的发生率,高剂量组(10m g/k g)是低剂量组(3m g/k g)的2倍,分别为66%和33%[21],表明其毒性特征呈剂量依赖性㊂临床表现主要为全垂体功能减退或垂体前叶功能减退,伴或不伴垂体增大,而很少出现与垂体占位相关的症状[20]㊂最常见的症状是头痛和疲劳[22-23]㊂其他罕见症状包括神经精神症状(意识模糊㊁幻觉㊁记忆力减退)㊁视觉障碍㊁失眠㊁厌食㊁恶心等[24]㊂26皮肤毒性在I C P i治疗所引起的不良反应中,皮肤相关的不良反应是最常见的,多见于抗C T L A-4治疗中,发生率为43%~45%,可表现为皮疹㊁瘙痒和白癜风㊂皮疹多呈网状分布,可累及四肢及躯干,伴有红斑㊁水肿㊁斑丘疹等表现[25]㊂在黑色素瘤患者中,皮肤相关i r A E s比较特殊,常表现为白癜风,在接受抗P D-1治疗的患者中,其发生率高达11%,且与黑色素瘤患者预后良好相关[26]㊂此外,比较罕见的皮肤i r A E s包括药物超敏反应综合征㊁S w e e t综合征㊁S t e v e n s-J o h n s o n综合征和中毒性表皮坏死松解症等,且已有相关的致死性报道[26]㊂3诊断及鉴别诊断在开始接受I C P i治疗前,应考虑对所有患者行治疗前评估和诊断性检查㊂包括询问病史(详细询问自身免疫性疾病㊁传染病㊁内分泌疾病和器官特异性疾病史以及基线排便习惯史),血液检查(血常规㊁生化全项㊁糖化血红蛋白㊁甲状腺功能㊁垂体功能㊁甲乙肝炎检查㊁巨细胞病毒抗体㊁人类免疫缺陷病毒抗原及抗体㊁结核检查㊁心肌酶㊁肌钙蛋白Ⅰ㊁B型钠尿肽)㊁心电图㊁全身皮肤黏膜检查㊁基线氧饱和度㊁肺功能检查㊁6分钟步行试验等[27]㊂在接受I C P i治疗时出现新发呼吸系统症状的患者,应高度怀疑I C P i相关性肺炎的可能㊂其影像学特征为:隐源性机化性肺炎样表现㊁磨玻璃样变㊁间质性肺炎和过敏性肺炎等[28]㊂而免疫相关肝炎在C T上主要表现为肝脏肿大㊁门静脉周围水肿㊁肝实质体积缩小,在M R I上表现为门静脉周围在T2W I呈高信号,以及门静脉周围淋巴结增大[29-31]㊂诊断时需与病毒性肝炎㊁酒精性肝炎㊁自身免疫性肝炎等疾病相鉴别[32]㊂对于治疗过程中出现肾功能损害的患者,应立即停用可能引起肾损伤的一切药物,并除外泌尿系感染㊁梗阻以及肾前性肾损伤等病因㊂当患者在治疗期间出现腹泻时,应考虑到药物引起的腹泻/结肠炎或感染性结肠炎的可能㊂由于这些症状及影像学表现均缺乏特异性,在诊断时应仔细鉴别,必要时可穿刺活检㊂4毒性管理目前i r A E s的评估尚无定论,国内外学者均参照美国国家癌症研究所制定的常见不良反应事件评价标准(C T C A E)v40对I C P i的不良反应进行评估㊂对于i r A E s的治疗,目前也并无明确的循证医学证据,目前的专家共识基本参照临床经验治疗㊂对于轻度i r A E s,通常给予对症支持㊁口服皮质类固醇激素治疗,而中重度的i r A E s,则需暂停I C P i治疗,静脉应用皮质类固醇激素,根据患者临床症状酌情加用其他免疫抑制剂(如英夫利昔单抗),必要时请专科医师会诊,待患者症状好转后,皮质类固醇激素可改为口服,再缓慢逐渐减量[27]㊂此外,以下几点需特别指出:由于I C P i相关性肺炎有致死性风险,对于高度怀疑或确诊的患者应立刻接受激素治疗;因英夫利昔单抗的潜在肝毒性,不推荐其用于I C P i㊃313㊃国际呼吸杂志2019年2月第39卷第4期I n t JR e s p i r,F e b r u a r y2019,V o l.39,N o.4Copyright©博看网. All Rights Reserved.相关性肝炎的治疗;内分泌系统i r A E s 比较特殊,常不可逆转,因此需要长期的激素替代治疗[1]㊂具体各系统不良反应毒性管理见表1㊁2[1,27]㊂表1 肺㊁肝㊁肾㊁胃肠道㊁皮肤毒性管理分级免疫相关性肺炎描述处理肝毒性描述处理肾毒性描述处理腹泻/结肠炎描述处理皮疹描述处理1级无症状,仅有影像学改变暂停I C P i 治疗,每2~3天监测症状A S T 或A L T >U L N 至3ˑU L N 和/或T B I L >U L N ~1 5ˑU L N 继续I C P i 治疗,监测肝功能(1次/周)肌酐水平增加>0 3m g /d,或肌酐>1 5~2ˑ基线水平继续I C P i 治疗,监测肌酐水平(1次/周)腹泻:排便次数超过基线水平<4次/d ;结肠炎:无症状继续I C P i 治疗,清淡饮食,1~2d 监测病情变化覆盖率<10%体表面积继续I C P i 治疗,对症治疗(如抗组胺药㊁外用类固醇激素)2级轻度至中度新发症状暂停I C P i 治疗,每日监测症状,1 0m g㊃k g-1㊃d -1甲泼尼龙静脉或等效剂量口服㊂考虑支气管镜检查㊁肺活检A S T 或A L T >3至ɤ5ˑU L N 和/或T B I L >1 5至ɤ3ˑU L N 暂停I C P i 治疗,监测肝功能(2次/周),0 5~1m g ㊃k g-1㊃d -1甲泼尼龙静脉或等效剂量口服,每4周递减,减至1级,恢复I C P i 治疗肌酐>2~3ˑ基线水平暂停I C P i 治疗,每2~3天监测一次肌酐水平,0 5~1 0m g ㊃k g -1㊃d-1甲泼尼龙静脉或等效剂量口服,考虑肾穿刺活检腹泻:排便次数超过基线水平4~6次/d ;结肠炎:腹痛;便血暂停I C P i 治疗,单纯腹泻:观察2~3d 无改善开始口服泼尼松1 0m g ㊃k g -1㊃d -1或等效剂量的甲泼尼龙/腹泻+结肠炎症状:立即口服泼尼松1 0m g ㊃k g -1㊃d -1或等效剂量的甲泼尼龙覆盖率10%~30%体表面积继续I C P i 治疗,对症治疗(如抗组胺药㊁外用类固醇激素)3级重度新发症状;新发/加重缺氧;威胁生命终止I C P i 治疗,2~4m g ㊃k g -1㊃d -1甲泼尼龙静脉或等效剂量静注,预防性应用抗生素,防止机会性感染,考虑支气管镜检查㊁肺活检A S T 或A L T >5ˑU L N 和/或T B I L >3ˑU L N 终止IC P i 治疗,每1~2天监测肝功能,1 0~2 0m g ㊃k g -1㊃d -1甲泼尼龙静脉或等效剂量静注,若症状改善,激素逐渐减量,若3d 后加重,加用吗替麦考酚酯,考虑肝活检肌酐>3ˑ基线水平或>4m g/d ,有住院指征暂停I C P i 治疗,每2~3天监测一次肌酐水平,0 5~1 0m g ㊃k g -1㊃d-1甲泼尼龙静脉或等效剂量口服,考虑肾穿刺活检腹泻:排便次数超过基线水平ȡ7次/d ;结肠炎:剧烈腹痛,排便习惯改变,有医疗干预指征,腹膜炎征象暂停I C P i 治疗,立即1 0~2 0m g ㊃k g -1㊃d-1甲泼尼龙静脉或等效剂量静注,症状改善激素可逐渐减量,若症状加重加用英夫利昔单抗,行结肠镜检查覆盖率>30%体表面积伴有或不伴有症状暂停或终止I C P i 治疗,口服抗组胺药,静脉应用泼尼松0 5~1 0m g ㊃k g -1㊃d -1或等效剂量的甲泼尼龙,请皮肤科会诊4级重度新发症状;新发/加重缺氧;威胁生命终止I C P i 治疗,2~4m g㊃k g -1㊃d -1甲泼尼龙静脉或等效剂量静注,预防性应用抗生素,防止机会性感染,考虑支气管镜检查㊁肺活检A S T 或A L T >5ˑU L N 和/或T B I L >3ˑU L N 终止IC P i 治疗,每1~2天监测肝功能,1 0~2 0m g㊃k g-1㊃d -1甲泼尼龙静脉或等效剂量静注,若症状改善,激素逐渐减量,若3d 后加重,加用吗替麦考酚酯,考虑肝活检危及生命,有透析指征终止I C P i 治疗,监测肌酐水平(1次/d ),1 0~2 0m g ㊃k g -1㊃d -1甲泼尼龙静脉或等效剂量静注,考虑肾穿刺活检危及生命,有指征进行紧急干预终止I C P i 治疗,立即1 0~2 0m g ㊃k g -1㊃d-1甲泼尼龙静脉或等效剂量静注,症状改善激素可逐渐减量,若症状加重加用英夫利昔单抗,行结肠镜检查覆盖率>30%体表面积或危及生命暂停或终止I C P i 治疗,口服抗组胺药,静脉应用泼尼松1 0~2 0m g ㊃k g -1㊃d -1或等效剂量的甲泼尼龙,请皮肤科会诊注:I C P i 为免疫检查点抑制剂;A S T 为天冬氨酸转氨酶;A L T 为丙氨酸转氨酶;U L N 为正常值上限;T B I L 为总胆红素5 i r A E s 毒性预测标志物尽管I C P i 在临床上的应用取得了显著的成效,但是这些药物的疗效在不同的肿瘤类型和个体患者之间差异很大,并非所有的患者都能获益,因此,通过生物标志物筛选潜在的获益人群,成为当前研究的重中之重㊂目前研究最多的是胃肠道不良反应的预测㊂有报道显示,肠道微生物群的组成可能是预测结肠炎发生的潜在生物标志物㊂D u b i n 等[33]报道,拟杆菌属细菌比例增加可减少结肠炎的发生,而多胺转运通道和B 族维生素生物合成遗传通路的缺失与结肠炎风险增加有关㊂此外,肠道微生物群还可以预测I C P i 的治疗效果㊂G o pa l a k r i s h n a n 等[34]观察到,将接受抗P D -1单抗治疗的黑色素瘤患者分为缓解组与非缓解组,2组在肠道微生物的多样性和组成方面存在显著差异㊂缓解组患者粪便样本中肠道细菌存在丰富的合成代谢途径,其内瘤胃菌科细菌的㊃413㊃国际呼吸杂志2019年2月第39卷第4期 I n t JR e s p i r ,F e b r u a r y 2019,V o l .39,N o .4Copyright ©博看网. All Rights Reserved.表2内分泌系统毒性管理甲状腺无症状患者有症状的甲状腺功能减退症有症状的甲状腺功能亢进症肾上腺疑似肾上腺危象原发性肾上腺皮质功能不全垂体炎处理继续I C P i治疗,定期检查甲状腺功能甲状腺激素治疗β受体阻滞剂(心得安㊁阿替洛尔),并进行甲状腺抗体㊁甲状腺核素扫描等检查㊂若促甲状腺激素受体抗体阳性:给予卡比马唑抗甲状腺治疗延迟或终止I C P i治疗,静注含有盐皮质激素成分的应激剂量的类固醇可能需要长期激素替代治疗出现症状的患者需中断I C P i治疗,评估垂体轴的功能,行垂体MR I除外脑转移,并给予激素替代治疗;若患者存在头痛㊁复视或其他神经系统症状,则需给予大剂量激素治疗注:I C P i为免疫检查点抑制剂α多样性和相对丰度较高㊂免疫分析显示,有良好肠道菌群的患者(比如菌群具有丰富的多样性并富含瘤胃菌科细菌),可增强患者的全身免疫和抗肿瘤免疫功能,并且将缓解组患者的粪便移植给无菌小鼠时,小鼠的免疫功能也得到增强㊂6结论相对于传统化疗,I C P i耐受性良好,大部分i r A E s是可逆的,关键在于早期识别并处理㊂由于可累及全身各个系统,不良反应种类较多,有些症状并不典型,需要临床医师仔细鉴别㊂目前尚缺乏可靠的用于筛选有效人群的生物标志物,相信随着研究的深入,I C P i会给患者带来更大的获益㊂利益冲突所有作者均声明不存在利益冲突参考文献1 H a a n e n J B A G C a r b o n n e lF R o b e r tC e t a l M a n a g e m e n to ft o x i c i t i e s f r o m i mm u n o t h e r a p y E S MO C l i n i c a l P r a c t i c eG u i d e l i n e sf o rd i a g n o s i s t r e a t m e n ta n df o l l o w-u p J A n nO n c o l201728S u p p l4i v119-i v142D O I101093a n n o n c m d x2252 P o s t o w MA S i d l o w R H e l l m a n n M D I mm u n e-r e l a t e da d v e r s e e v e n t sa s s o c i a t e d w i t hi mm u n ec h e c k p o i n tb l oc k ad eJ N E n g l J M e d20183782158-168D O I101056N E J M r a17034813 W e b e r J S K a h l e rK C H a u s c h i l dA M a n a g e m e n t o f i mm u n e-r e l a t e d a d v e r s e e v e n t s a n d k i n e t i c s o f r e s p o n s e w i t hi p i l i m u m a b J JC l i n O n c o l201230212691-2697D O I101200J C O 20124167504 W e b e r J S P o s t o w M L a oC D e t a l M a n a g e m e n to f a d v e r s ee v e n t sf o l l o w i ng t r e a t m e n t w i th a n t i-p r o g r a mm e d d e a t h-1a g e n t s J O n c o l o g i s t201621101230-1240D O I101634t h e o n c o l o g i s t2016-00555 D a v i e s M D u f f i e l d E A S a f e t y o fc h e c k p o i n ti n h i b i t o r sf o rc a n c e r t r e a t m e n t s t r a t e g i e s f o r p a t i e n t m o n i t o r i n g a n dm a n a g e m e n t o f i mm u n e-m e d i a t e d a d v e r s e e v e n t s JI mm u n o t a r g e t s T h e r2017651-71D O I102147I T TS1415776 C h u z i S T a v o r aF C r u z M e t a l C l i n i c a l f e a t u r e s d i a g n o s t i cc h a l l e n g e s a nd m a n a ge m e n t s t r a t e g i e s i n c h e c k p o i n ti n h i b i t o r-r e l a t e d p n e u m o n i t i s J C a n c e rM a n a g R e s20179207-213D O I102147C MA R S1368187 C a l l a h a n MK K l u g e rH P o s t o w MA e ta l N i v o l u m a b p l u si p i l i m u m a bi n p a t i e n t s w i t h a d v a n c e d m e l a n o m a u p d a t e ds u r v i v a l r e s p o n s e a n d s a f e t y d a t a i n a p h a s eⅠd o s e-e s c a l a t i o ns t u d y J JC l i nO n c o l2018364391-398D O I101200J C O 20177228508 H a h n AW G i l l D M A g a r w a l N e t a l P D-1c h e c k p o i n ti n h i b i t i o n t o x i c i t i e sa n d m a n a g e m e n t J U r o lO n c o l20173512701-707D O I101016j u r o l o n c2017080059 H u f f m a n B M K o t t s c h a d e L A K a m a t h P S e t a lH e p a t o t o x i c i t y a f t e r i mm u n ec h e c k p o i n t i n h i b i t o r t h e r a p y i nm e l a n o m a n a t u r a l p r o g r e s s i o na n d m a n a g e m e n t J A m JC l i n O n c o l2018418760-765D O I101097C O C000000000000037410 H o f m a n n L F o r s c h n e r A L o q u a i C e t a l C u t a n e o u sg a s t r o i n t e s t i n a l h e p a t i c e n d o c r i n e a n dr e n a ls i d e-e f f e c t so fa n t i-P D-1t h e r a p y J E u r JC a n c e r201660190-209D O I101016j e j c a20160202511 V o s k e n sC J G o l d i n g e r S M L o q u a iC e ta l T h e p r i c e o ft u m o r c o n t r o l a na n a l y s i s o f r a r e s i d e e f f e c t s o f a n t i-C T L A-4 t h e r a p y i nm e t a s t a t i c m e l a n o m a f r o mt h e i p i l i m u m a bn e t w o r kJ P L o S O n e201381e53745D O I101371j o u r n a lp o n e005374512 V o s k e n sC C a v a l l a r oA E r d m a n n M e t a l A n t i-c y t o t o x i cT-c e l l l y m p h o c y t ea n t i g e n-4-i nd u ce dr e g r e s s i o no fs p i n a lc o r dm e t a s t a s e s i n a s s o c i a t i o n w i t h r e n a l f a i l u r e a t y p i c a l p n e u m o n i a v i s i o nl o s s a n dh e a r i n g l o s s J JC l i n O n c o l20123033e356-e357D O I101200J C O 201141435913 F a d e l F E lK a r o u iK K n e b e l m a n nB A n t i-C T L A4a n t i b o d y-i n d u c e d l u p u s n e p h r i t i s J NE n g l JM e d20093612211-212D O I101056N E J M c090428314 H o r v a t T Z A d e l N G D a n g T O e t a l I mm u n e-r e l a t e da d v e r s ee v e n t s n e e df o rs y s t e m i ci mm u n o s u p p r e s s i o n a n de f f e c t s o ns u r v i v a la n dt i m et ot r e a t m e n t f a i l u r e i n p a t i e n t sw i t h m e l a n o m at r e a t e d w i t hi p i l i m u m a ba t m e m o r i a ls l o a n k e t t e r i n g c a n c e r c e n t e r J JC l i nO n c o l201533283193-3198D O I101200J C O 201560844815 C o u s i n S S e n e s c h a l J I t a l i a n o A T o x i c i t y p r o f i l e s o fi mm u n o t h e r a p y J P h a r m a c o l T h e r201818191-100D O I101016j p h a r m t h e r a20170700516 M a r t h e y L M a t e u s C M u s s i n i C e t a l C a n c e ri mm u n o t h e r a p y w i t h a n t i-C T L A-4m o n o c l o n a l a n t i b o d i e si n d u c e s a n i n f l a mm a t o r y b o w e l d i s e a s e J JC r o h n sC o l i t i s㊃513㊃国际呼吸杂志2019年2月第39卷第4期I n t JR e s p i r,F e b r u a r y2019,V o l.39,N o.4Copyright©博看网. All Rights Reserved.2016104395-401D O I101093e c c o-j c c j j v22717 C a l l a h a n MK W o l c h o kJ D A t t h eb e d s i d e C T L A-4-a n dP D-1-b l o c k i n g a n t i b o d i e s i n c a n c e r i mm u n o t h e r a p y J JL e u k o cB i o l201394141-53D O I101189j l b121263118 B a r r o s o-S o u s a R O t t P A H o d i F S e t a l E n d o c r i n ed y s f u n c t i o n i n d u ce d b y i mm u n e c h e c k p o i n t i n h i b i t o r sp r a c t i c a l r e c o mm e n d a t i o n s f o r d i a g n o s i s a n d c l i n i c a l m a n a g e m e n t J C a n c e r201812461111-1121D O I101002c n c r3120019 B a r r o s o-S o u s a R B a r r y WT G a r r i d o-C a s t r o A C e t a lI n c i d e n c e o f e n d o c r i n e d y s f u n c t i o n f o l l o w i n g t h e u s e o fd i f fe r e n t i mm u n e c h e c k p o i n t i n h i b i t o r r e g i m e n s a s y s t e m a t i cr e v i e wa n dm e t a-a n a l y s i s J J AMA O n c o l201842173-182D O I101001j a m a o n c o l2017306420 F a j e A T S u l l i v a n R L a w r e n c eD e ta l I p i l i m u m a b-i n d u c e dh y p o p h y s i t i s a d e t a i l e d l o n g i t u d i n a l a n a l y s i s i na l a r g e c o h o r to f p a t i e n t sw i t h m e t a s t a t i c m e l a n o m a J JC l i nE n d o c r i n o l M e t a b201499114078-4085D O I101210j c2014-230621 A s c i e r t oP A D e lV e c c h i o M R o b e r tC e ta l I p i l i m u m a b10m g k g v e r s u s i p i l i m u m a b3m g k g i n p a t i e n t s w i t h u n r e s e c t a b l eo r m e t a s t a t i c m e l a n o m a ar a n d o m i s e d d o u b l e-b l i n d m u l t ic e n t r e p h a s e3t r i a l J L a n c e t O n c o l2017185611-622D O I101016S1470-20451730231-022 M i nL H o d i F S G i o b b i e-H u r d e rA e t a l S y s t e m i ch i g h-d o s ec o r t i c o s t e r o i dt r e a t m e n td oe sn o ti m p r o v et h e o u t c o m e o fi p i l i m u m a b-r e l a t e dh y p o p h y s i t i s a r e t r o s p e c t i v e c o h o r t s t u d yJ C l i nC a n c e rR e s2015214749-755D O I1011581078-0432C C R-14-235323 A l b a r e lF G a u d y C C a s t i n e t t iF e t a l L o n g-t e r mf o l l o w-u po f i p i l i m u m a b-i n d u c e dh y p o p h y s i t i s a c o mm o na d v e r s e e v e n t o ft h e a n t i-C T L A-4a n t i b o d y i n m e l a n o m a J E u r JE n d o c r i n o l20151722195-204D O I101530E J E-14-084524J o s h i MN W h i t e l a w B C P a l o m a r M T e t a l I mm u n ec h e c k p o i n t i n h i b i t o r-r e l a t ed h y p o p h y s i t i s a n de n d o c r i n ed y s f u n c t i o n c l i n i c a l re v i e w J C l i nE n d o c r i n o l O x f2016853331-339D O I101111c e n1306325王巧红吴霞免疫检查点抑制剂治疗中免疫相关不良反应的临床表现及处理J中国免疫学杂志2017334615-620D O I103969j i s s n1000-484X 20170402926王雅坤张小田免疫检查点抑制剂的毒性风险分析J临床肿瘤学杂志2017228735-741D O I103969j i s s n1009-046020170801627 P u z a n o vI D i a b A A b d a l l a h K e ta l M a n a g i n g t o x i c i t i e sa s s o c i a t e d w i t h i mm u n e c h e c k p o i n t i n h ib i t o r sc o n s e n s u sr e c o mm e n d a t i o n sf r o m t h e S o c i e t y f o rI mm u n o t h e r a p y o fC a n c e r S I T C T o x i c i t y M a n a g e m e n t W o r k i n g G r o u p J JI mm u n o t h e rC a n c e r20175195D O I101186s40425-017-0300-z28 N a i d o o J W a n g X W o o KM e ta l P n e u m o n i t i s i n p a t i e n t st r e a t e d w i t h a n t i-p r o g r a mm e d d e a t h-1p r o g r a mm e d d e a t h l i g a n d1t h e r a p y J J C l i nO n c o l2017357709-717D O I101200J C O 201668200529 O'r e g a n K N J a g a n n a t h a nJ P R a m a i y a N e ta l R a d i o l o g i ca s p e c t s o f i mm u n e-r e l a t e d t u m o r r e s p o n s e c r i t e r i a a n dp a t t e r n s o f i mm u n e-r e l a t e d a d v e r s e e v e n t s i n p a t i e n t s u n d e r g o i n g i p i l i m u m a bt h e r a p y J A J R A m JR o e n t g e n o l20111972W241-W246D O I102214A J R 106032 30 T i r u m a n i S H R a m a i y a N H K e r a l i y a A e ta l R a d i o g r a p h i cp r o f i l i n g o f i mm u n e-r e l a t e d a d v e r s e e v e n t s i n a d v a n c e d m e l a n o m a p a t i e n t s t r e a t e d w i t h i p i l i m u m a b J C a n c e rI mm u n o lR e s20153101185-1192D O I1011582326-6066C I R-15-010231 K i m KW R a m a i y a N H K r a j e w s k i KM e ta l I p i l i m u m a ba s s o c i a t e d h e p a t i t i s i m a g i n g a n d c l i n i c o p a t h o l o g i cf i n d i n g sJ I n v e s t N e w D r u g s20133141071-1077D O I101007s10637-013-9939-632 M o r t e l eK J S e g a t t oE R o sP R T h e i n f e c t e d l i v e r r a d i o l o g i c-p a t h o l o g i c c o r r e l a t i o n J R a d i o g r a p h i c s2004244937-955D O I101148r g24403571933 D u b i nK C a l l a h a n MK R e n B e ta l I n t e s t i n a lm i c r o b i o m ea n a l y s e s i d e n t i f y m e l a n o m a p a t i e n t sa tr i s kf o rc h e c k p o i n t-b l oc k ad e-i n d u ce dc o l i t i s J N a tC o mm u n2016710391D O I101038n c o mm s1039134 G o p a l a k r i s h n a nV S p e n c e rC N N e z i L e t a l G u tm i c r o b i o m em o d u l a t e s r e s p o n s e t o a n t i-P D-1i mm u n o t h e r a p y i n m e l a n o m a p a t i e n t s J S c i e n c e2018359637197-103D O I101126s c i e n c e a a n4236收稿日期2018-08-25㊃613㊃国际呼吸杂志2019年2月第39卷第4期I n t JR e s p i r,F e b r u a r y2019,V o l.39,N o.4Copyright©博看网. All Rights Reserved.。

免疫检查点

strong TCR signal
Net negative
signal
T cell
CTLA-4是T细胞的“刹车”分子
免疫检查点 Immune Checkpoint
是在免疫应答过程中，调节T细胞的受体(TCR)抗原识别的共刺激或抑制信号。
CTLA-4的“刹车”作用，能为人类做些什么呢？
抗CTLA-4分子
B7
CTLA-4
Antigen presenting
cell B7
MHC
CD28 TCR
strong TCR signal
Net negative
signal
T cell
请大家思考为什么阻断CTLA-4可以抗癌？
免疫检查点分子PD1
和CTLA-4类似，是T细胞活化的一种负调节分子。与其配体：程序性死亡配体1 (PD-L1)和程序性死亡配体2 (PD-L2)结合。
再着眼于直接打击癌细胞，而是着力于研究整
个人体免免疫疫系系统统检检查查点点疗法”。
他们的发现是“我们在与癌症战斗过程中的一个里程碑”。
我们首先来看看T细胞攻击癌细胞
➢ T细胞识别癌细胞，接触，攻击
靶细胞
1核心:TCR --MHC-Ag 结合 2共刺激信号：CD28--B7 结合
Байду номын сангаас
B7 CD28
CD8
MHCⅠ类分子抗原多肽
TCR-CD3复合物
1 2
T
CD28是T细胞的
“油门”分子
CTLA-4表达在活化的T细胞膜上，竞争性结合B7。
阻止由CD28:B7结合提供的共刺激信号，同时向T细胞传递抑制信号。
B7
CTLA-4

CancerImmunotherapy治愈癌症新路径

CancerImmunotherapy治愈癌症新路径Cancer Immunotherapy: Opening New Avenues for Cancer Treatment Introduction:Cancer has been a global health concern for decades, causing significant morbidity and mortality worldwide. Traditional cancer treatments, such as surgery, radiation therapy, and chemotherapy, have played a crucial role in managing and treating cancer patients. However, these treatments often have limitations in terms of efficacy, side effects, and the potential for cancer recurrence. In recent years, a groundbreaking approach called cancer immunotherapy has emerged, offering a promising new pathway for cancer treatment. This article will explore the concept of cancer immunotherapy, its mechanisms of action, and the significant advancements it has brought in the fight against cancer.Understanding Cancer Immunotherapy:Cancer immunotherapy is a revolutionary treatment strategy that leverages the body's immune system to combat cancer. It is based on the premise that our immune system possesses the ability to identify and destroy cancer cells. However, cancer cells often develop mechanisms to evade immune detection, allowing them to proliferate unchecked. Immunotherapy aims to strengthen the immune response against cancer and restore its ability to recognize and target cancer cells.Mechanisms of Cancer Immunotherapy:1. Checkpoint Inhibitors:Checkpoint inhibitors are a class of immunotherapy drugs that target proteins on immune cells or cancer cells that control immune responses. Cancer cells exploit these checkpoints to prevent immune cells from recognizing and attacking them. By blocking these inhibitory signals, checkpoint inhibitors unleash the immune system, enabling it to identify and destroy cancer cells effectively. Prominent examples of checkpoint inhibitors include CTLA-4 inhibitors like ipilimumab and PD-1/PD-L1 inhibitors like pembrolizumab and nivolumab.2. CAR-T Cell Therapy:CAR-T cell therapy is an innovative approach that involves genetically modifying a patient's T cells (a type of immune cell) to express Chimeric Antigen Receptors (CARs) on their surface. These receptors allow T cells to recognize specific proteins on cancer cells, enhancing their ability to target and eliminate cancer cells. CAR-T cell therapy has shown remarkable success in treating hematological malignancies, such as acute lymphoblastic leukemia and certain types of lymphoma.3. Cancer Vaccines:Cancer vaccines are designed to stimulate the immune system to recognize and attack cancer cells. They are developed using antigens derived from cancer cells or tumor-associated antigens. By introducing these antigens into the body, cancer vaccines educate the immune system to identify cancer cells as foreign and mount a targeted immune response against them. Several cancer vaccines, such as the HPV vaccine and the prostate cancer vaccine sipuleucel-T, have shown efficacy in preventing and treating specific types of cancer.Advancements and Success Stories:1. Melanoma Treatment Breakthrough:One of the most remarkable success stories of cancer immunotherapy is its efficacy in treating advanced melanoma. Prior to the advent of immunotherapy, melanoma had very limited treatment options, and patients faced a grim prognosis. However, the introduction of checkpoint inhibitors revolutionized melanoma treatment. Drugs like pembrolizumab and nivolumab have demonstrated significant improvements in overall survival and long-term disease control in patients with advanced melanoma.2. Lymphoma Remissions with CAR-T Therapy:CAR-T cell therapy has shown remarkable success in treating certain types of lymphoma, particularly refractory or relapsed cases. Clinical trials have reported impressive response rates, with a significant proportion of patients achieving complete remissions. CAR-T therapies like axicabtagene ciloleucel and tisagenlecleucel have been approved for the treatment of relapsed or refractory lymphoma, offering new hope to patients who previously had limited treatment options.3. Targeting Solid Tumors:While initial success in immunotherapy was observed in hematological malignancies, recent advancements have expanded its applications to solid tumors. Drugs like pembrolizumab and nivolumab have been approved for various types of solid tumors, including lung cancer, kidney cancer, and head and neck cancer. The inclusion of immunotherapy in the treatment regimens of these cancers has resulted in significant improvements in patient outcomes.Conclusion:Cancer immunotherapy represents a paradigm shift in cancer treatment, offering remarkable potential for improved patient outcomes. By harnessing the power of the immune system, immunotherapy has demonstrated unprecedented success in various types of cancer. With the continued research and development in this field, it is anticipated that cancer immunotherapy will play an increasingly significant role in the fight against cancer, opening new avenues for patients previously left with limited treatment options.。

免疫checkpoint的研究进展及其在癌症治疗中的应用

免疫checkpoint的研究进展及其在癌症治疗中的应用在癌症治疗中，免疫治疗近年来备受关注。

免疫细胞是保持机体免疫稳态的关键，而某些癌症越来越被认为是免疫抑制的结果。

免疫检查点阻断剂是最近免疫治疗的一大突破，大大改善了某些类型的癌症的治疗效果。

本文将介绍免疫checkpoint的研究进展及其在癌症治疗中的应用。

一、免疫checkpoint的概念免疫checkpoint是指免疫系统中的调节机制。

在T细胞与抗原识别后，T细胞会释放多种抗体和细胞毒素来攻击异物，这就是免疫反应。

然而，当免疫系统反应过度或发生错误时，它可能会攻击身体健康细胞和组织，导致自身免疫疾病。

为了防止这种情况的发生，免疫系统中有一种叫做免疫检查点的负调节机制来限制免疫细胞的活性。

二、免疫checkpoint在癌症治疗中的应用在癌症治疗中，肿瘤细胞可以通过表达一些免疫检查点来干扰免疫系统的正常反应，从而逃避免疫控制。

福尔摩斯，J. M.等在2010年首先提出了双向的免疫checkpoint模型：肿瘤靶细胞表达的PD-L1（又叫做B7-H1）与T细胞表面的PD-1结合，抑制了T细胞的生长和分化，从而抑制了免疫系统。

目前，已经证实PD-1和PD-L1通路在多种癌症中都有高表达。

这包括黑色素瘤、黑色素肿瘤、肺癌、淋巴瘤、乳腺癌、结直肠癌等多种类型的癌症。

因此，阻断PD-1和PD-L1通路被认为是一种更广泛适用于癌症治疗的免疫治疗。

下面将详细介绍当前关于免疫checkpoint在癌症治疗中的应用。

1. PD-1免疫检查点阻断剂PD-1免疫检查点在癌症治疗中的表现时是治疗难度的一个主要因素。

因此，许多公司都在竞相研发PD-1免疫检查点阻断剂。

2015年最早获批的是Keytruda，它是由默克生产的PD-1抗体，可治疗黑色素瘤、非小细胞肺癌和淋巴瘤等。

之后，多家厂商陆续推出了各自的PD-1抗体，如Opdivo和Imfinzi 等。

2. PD-L1免疫检查点阻断剂在免疫检查点阻断治疗中，PD-L1的检测也很重要。

靶向免疫检查点的肿瘤免疫治疗现状与趋势

靶向免疫检查点的肿瘤免疫治疗现状与趋势李春【摘要】Immune checkpoint that the inhibition of signal transduction pathway exists in the immune system, the immune response strength, persistent adjusted in peripheral tissues, preventing tissue damage, and it plays a role in the maintenance of self antigen tolerance. If it does’ t want to have tumor immune destruction on immune checkpoint inhibitory signaling pathway to use, and then on the activity of T cells were fully inhibited. CTLA-4 (cytotoxic T lymphocyte associated antigen -4) is targeting immune checkpoint drug, can inhibit PD-1 (programmed cell death protein -1) and its ligand, the treatment of tumor and sustained remission. In anti-tumor immunotherapy targeting immune checkpoint is huge, and the future main trend for chemotherapy combined with immunotherapy.%免疫检查点即抑制性信号通路存在于免疫系统中，对外周组织中免疫反应强度、持续性予以调节，防止损伤组织，并在对自身抗原耐受性进行维持的过程中发挥作用。

拥有Immune Checkpoint Inhibitor的肿瘤治疗方法

拥有Immune Checkpoint Inhibitor的肿瘤治疗方法肿瘤治疗一直是医学领域的重大难题，由于肿瘤的复杂性和高致死率，对于患者来说这也是一种极大的考验。

然而，随着生物技术和药物治疗的不断发展，肿瘤药物研究领域也取得了巨大的进展。

而今天我们就来说说一种最近几年兴起的肿瘤治疗方法——Immune Checkpoint Inhibitor。

首先，我们来了解一下什么是Immune Checkpoint Inhibitor。

它是一种针对免疫检查点分子的药物。

免疫检查点分子是一种重要的调节因子，可以帮助人体免疫系统识别并攻击异常细胞，保护身体免受疾病侵害。

但是，在肿瘤细胞的发展过程中，它们往往能够通过某些机制，伪装成正常细胞，逃避身体的免疫攻击。

随着科学技术的不断发展，研究人员终于发现了某些肿瘤细胞可以通过操纵免疫检查点分子的表达，从而有效地抵御身体的攻击。

因此，通过研究免疫检查点分子的机制和调节药物的作用模式，开发出的Immune Checkpoint Inhibitor被视为一种新型抗肿瘤药物。

那么，Immune Checkpoint Inhibitor的作用原理是什么呢？在肿瘤的治疗过程中，人体免疫系统的主要任务就是找出肿瘤细胞并摧毁它们。

然而，由于肿瘤细胞能够伪装成正常细胞，免疫系统可能会被误导，从而不能有效地识别并摧毁这些异常细胞。

这时，Immune Checkpoint Inhibitor就可以发挥非常重要的作用。

通过抑制T细胞的负向调节因子，加倍提高T细胞的能力，从而使得它们能够在身体中自由地寻找和攻击肿瘤细胞。

目前，Immune Checkpoint Inhibitor的功效已经在很多特定类型的肿瘤治疗中得到了验证。

虽然Immune Checkpoint Inhibitor的使用在肿瘤治疗领域中取得了一定的成果，但是其安全性和有效性还需要进一步的研究。

由于与传统的化疗药物不同，Immune Checkpoint Inhibitor在用药过程中需要特别注意患者的免疫系统状况。

1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。

Targeting Immune Checkpoints for Cancer TherapiesShishuang LiuOne of the most promising approaches to stimulate the immune system is the blockade of immune checkpoints, which represent negative regulators of T cell immunity. Two notable immune checkpoint molecules, CTLA4 and PD1, have been sufficiently studied. Several checkpoint inhibitors have been approved in advanced melanoma and non small cell lung cancer. These agents also have promising activity in other solid tumors. We reviewed the studies about immune checkpoint therapies in tumors, hoping which can lead us to develop more effective therapies with stronger anti-tumor responses.IntroductionCancer is characterized by the accumulation of a variable number of genetic alterations and the loss of normal cellular regulatory processes. Recent years, the immunotherapy of cancer attracts people’s attention due to its merits of strong specialty, long action period and fewer side effects. The generation of immunity to cancer is a process leading to an accumulation of immune-stimulatory factors that in principle should amplify and broaden T cell responses. The process is also characterized by immune repressors that lead to immune regulatory feedback mechanisms, which can halt the development or limit the immunity (Chen and Mellman, 2013). Clinical studies indicate that inhibitors targeting on such repressors result in enhanced immune responses. Besides, Immune checkpoint therapies and combination strategies with other therapies such as radiotherapy, chemotherapy, or cancer vaccines also have a promising future (Mahoney et al., 2015).The biological study of the immune checkpointWhat is Immune checkpoint?T lymphocytes have an important role in orchestrating the immune system. However, this power of T lymphocytes to combat invading organisms/malignant cells must be controlled by the coordination of numerous factors, both stimulatory and inhibitory in nature (Abdel-Rahman, 2016). The stimulatory factors could promote immunity, whereas inhibitors help keep the process in check and reduce immune activity or prevent autoimmunity. These inhibitory factors in the immune system are known as the immune checkpoint (Chen and Mellman, 2013).The key molecules involved in immune checkpointCo-stimulatory and co-inhibitory receptors modulate the function of both the antigen-presenting and the antigen-sensing lymphocytes (figure 1). Examples of immune checkpoint are shown as follows: CTLA4 (cytotoxic T-lymphocyte protein 4); PD1 (programmed cell-death protein 1); PDL1 (programmed death-ligand 1); IL10 (interleukin10);VEGF (vascular endothelial growth factor); IDO (indole amine2,3-dioxygenase);TGF (transforming growth factor); BTLA (B-and T-lymphocyte attenuator); VISTA (V-domain Ig suppressor of T cell activation); LAG-3 (lymphocyte-activation gene 3 protein); MIC (MHC class I polypeptide-related sequence protein); TIM-3 (T cell immunoglobulin domain and mucin domain-3), B7H3; CD137; CD40; OX40; GITR (glucocorticoid-induced TNF receptor); CD27 and so on (Chen and Mellman, 2013; Guo and Wang, 2015; Melero et al., 2013).Figure 1. Schematic representation of immune synapses formed by atumor-reactive T lymphocyte with a dendritic cell, a tumor cell, and amacrophage in the tumor microenvironment (Melero et al., 2013).Among these immune checkpoints, two pathways involved CTLA4 and PD 1/PDL1 have been well studied and some inhibitors of them have been manufactured against cancer (Mahoney et al., 2015).CTLA4 was initially recognized as an inhibitory receptor expressed on the surface of activated T lymphocytes. In resting T cells, CTLA4 protein cycles from the Golgi apparatus to the cell surface, and this is followed then by rapid endocytosis. CTLA4 exerts its inhibitory effect through competitive inhibition with the inhibitory receptor CD28 on the surface of T cells (as both receptors share the same ligands; B7–1 and B7–2). Another inhibitory mechanism of CTLA4 seems to be mediated by its cytoplasmic portion which interacts with a number of signaling molecules that inhibit proximal signaling via the stimulatory receptor CD28. Thus, activation of T cellsresults in induction of expression of CTLA4, which accumulates in the T cell at the T cell–APC interface, reaching a level where it eventually blocks co-stimulation and abrogates an activated T cell response (Abdel-Rahman, 2016).Much like CTLA4, PD1 is expressed only in activated T cells. However, unlike CTLA4, PD1 inhibits T cell responses by interfering with T cell receptor signaling as opposed to outcompeting CD28 for binding to B7. PD1 also has two ligands, which include PDL1 (B7-H1) and PDL2 (B7-DC) and they are reported to be expressed on a wide variety of hematopoietic and non-hematopoietic tissues. Interestingly, it appears that PDL1 exerts its inhibitory effects not only through interaction with PD1 but also through interaction with B7-1 (independent of inter-action with PD1). Characteristically, PDL1 has been thought to be involved in immune evasion of tumors. This has been supported by the observation of the expression of PD1 by tumor-infiltrating lymphocytes together with the expression of PDL1 by many tumor types (Abdel-Rahman, 2016).The therapeutics targeting the immune checkpointImmune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer (Sharma and Allison, 2015a). Targeting immune checkpoints such as PD1, PDL1 and CTLA4 has achieved noteworthy benefit in multiple cancers by blocking immune inhibitory signals and enabling patients to produce an effective anti-tumor response. Three immune checkpoint inhibitors have already been marketed: ipilimumab, nivolumab, and pembrolizumab, all for the treatment of malignant melanoma and blocking immune checkpoints CTLA4 or PD1 (Webster, 2014). The list of inhibitors acting on immune checkpoints under development also includes PDL1 (B7-H1), KIR (The killer cell immunoglobulin-like receptor), IDO1, CD137 (4-1BB), CD134 (OX40), and so on (Sharma and Allison, 2015a, b).Table 1. Select immune checkpoint inhibitors in the pipeline (Webster, 2014).DiscussionAlthough the monotherapy has acquired gratifying effects for some kinds of cancers, there are still problems to be resolved such as the low efficiency in some therapies. It is intractable for cancer therapies. First of all, tumors show high heterogeneity not only existing in different tumors or patients, but also in the same tumor. Secondly, tumors have evolved diverse mechanism to escape from the surveillance of immune system (Sharma and Allison, 2015b). As a result, it’s difficult to overcome these challenges with monotherapy. However, combination strategies with immune checkpoint therapy provide a new approach to cure cancer, including dual checkpoint inhibition, integrating checkpoint inhibition with existing chemotherapy, integrating checkpoint inhibition with other investigationalimmunotherapeutic agents, tailored checkpoint inhibitor therapy and so on (Melero et al., 2013). For example, blocking CTLA4 and PD1 all at once gains the better curative effect in the tumor tissue (Sharma and Allison, 2015b). All in all, combination therapy may improve anti-tumor responses thus increasing clinical benefits, which indicate a tremendous potential to further improve efficacy (Hardwick et al., 2016). References艾斌(2015). 免疫检查点抑制剂在肿瘤治疗中的应用. 医学与哲学. 36, 18-21.李春(1998). 靶向免疫检查点的肿瘤免疫治疗现状与趋势. 中国继续医学教育. 7, 32-33.Abdel-Rahman, O. (2016). Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials. Crit Rev Oncol Hematol 97, 65-71.Chen, D.S., and Mellman, I. (2013). Oncology meets immunology: thecancer-immunity cycle. Immunity 39, 1-10.Guo, Y., and Wang, A.Y. (2015). Novel Immune Check-Point Regulators in Tolerance Maintenance. Front Immunol 6, 421.Hardwick, N., Frankel, P.H., and Cristea, M. (2016). New Approaches for Immune Directed Treatment for Ovarian Cancer. Curr Treat Options Oncol 17, 14. Mahoney, K.M., Rennert, P.D., and Freeman, G.J. (2015). Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14,561-584.Melero, I., Grimaldi, A.M., Perez-Gracia, J.L., and Ascierto, P.A. (2013). Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res 19, 997-1008.Sharma, P., and Allison, J.P. (2015a). The future of immune checkpoint therapy. Cancer Immunology and Immunotherapy 348, 56-62.Sharma, P., and Allison, J.P. (2015b). Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205-214. Webster, R.M. (2014). The immune checkpoint inhibitors: where are we now? Nat Rev Drug Discov 13, 883-884.。