Immune Checkpoint Blockade:
A Common Denominator Approach to Cancer Therapy
Suzanne L.Topalian,1,*Charles G.Drake,2,3and Drew M.Pardoll3
1Department of Surgery
2The Brady Urological Institute
3Department of Oncology
Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine,Baltimore,MD21287,USA
*Correspondence:stopali1@https://www.doczj.com/doc/7f5893906.html,
https://www.doczj.com/doc/7f5893906.html,/10.1016/https://www.doczj.com/doc/7f5893906.html,ell.2015.03.001
The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands.These immune checkpoint pathways,which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses,can be co-opted by cancer to evade immune destruction.Drugs interrupting immune checkpoints,such as anti-CTLA-4,anti-PD-1,anti-PD-L1,and others in early development,can unleash anti-tumor immunity and mediate durable cancer regressions.The com-plex biology of immune checkpoint pathways still contains many mysteries,and the full activity spectrum of checkpoint-blocking drugs,used alone or in combination,is currently the subject of intense study.
In the current era in oncology emphasizing personalized therapy, immune checkpoint blockade is distinguished by its‘‘common denominator’’approach.Although the vast somatic mutational diversity found in most human cancers creates challenges for therapies targeting individual mutations,it exposes a panoply of new antigens for potential immune recognition.However,cells of the adaptive and innate immune systems that recognize and are poised to attack cancer are held in check by molecular pathways that suppress their activation and effector functions. The seminal observation that blocking the prototypical immune checkpoint receptor cytotoxic T lymphocyte antigen4(CTLA-4) could mediate tumor regression in murine models(Leach et al., 1996)led to the clinical development and approval of anti-CTLA-4as a treatment for patients with advanced melanoma (Hodi et al.,2010).Subsequently,drugs blocking the distinct checkpoints Programmed Death1(PD-1)and its major ligand PD-L1have shown great promise in treating many diverse cancer types,fueling the intensive examination of a growing cohort of unique checkpoint molecules as potential therapeutic targets. This has revealed new treatment options for patients and has revolutionized our approach to cancer therapy.
Biology of Immune Checkpoints:The Basics
The rapid-?re clinical successes from blocking CTLA-4and PD-1, the?rst checkpoint receptors to be discovered,have opened prospects for extending the potential of cancer immunotherapy by inhibiting more recently discovered checkpoint ligands and re-ceptors.It is clear that,despite some commonalities,CTLA-4and PD-1have distinct patterns of expression,signaling pathways, and mechanisms of action.Although discovered over20years ago,there are still many unanswered questions about their biology,particularly in the context of cancer.
The CD28/CTLA-4System of Immune Modulation
The conventional wisdom underlying our vision of how CTLA-4 blockade mediates tumor regression is that it systemically acti-vates T cells that are encountering antigens.CTLA-4represents the paradigm for regulatory feedback inhibition.Its engagement down-modulates the amplitude of T cell responses,largely by in-hibiting co-stimulation by CD28,with which it shares the ligands CD80(B7.1)and CD86(B7.2)(Figure1;Lenschow et al.,1996). As a‘‘master T cell co-stimulator,’’CD28engagement ampli?es TCR signaling when the T cell receptor(TCR)is also engaged by cognate peptide-major histocompatibility complex(MHC) (Schwartz,1992).However,CTLA-4has a much higher af?nity for both CD80and CD86compared with CD28(Linsley et al., 1994),so its expression on activated T cells dampens CD28 co-stimulation by out-competing CD28binding and,possibly, also via depletion of CD80and CD86via‘‘trans-endocytosis’’(Qureshi et al.,2011).Because CD80and CD86are expressed on antigen-presenting cells(APCs; e.g.,dendritic cells and monocytes)but not on non-hematologic tumor cells,CTLA-4’s suppression of anti-tumor immunity has been viewed to reside primarily in secondary lymphoid organs where T cell activation occurs rather than within the tumor microenvironment(TME). Furthermore,CTLA-4is predominantly expressed on CD4+‘‘helper’’and not CD8+‘‘killer’’T cells.Therefore,heightened CD8responses in anti-CTLA-4-treated patients likely occur indi-rectly through increased activation of CD4+cells.Of note,a few studies suggest that CTLA-4can act as a direct inhibitory recep-tor of CD8T cells(Fallarino et al.,1998;Chambers et al.,1998), although this role in down-modulating anti-tumor CD8T cell re-sponses remains to be directly demonstrated.
The speci?c signaling pathways by which CTLA-4inhibits T cell activation are still under investigation,although activation of the phosphatases SHP2and PP2A appears to be important in counteracting both tyrosine and serine/threonine kinase sig-nals induced by TCR and CD28(Rudd et al.,2009).CTLA-4 engagement also interferes with the‘‘TCR stop signal,’’which maintains the immunological synapse long enough for extended or serial interactions between TCR and its peptide-MHC ligand (Schneider et al.,2006).Naive and resting memory T cells ex-press CD28,but not CTLA-4,on the cell surface,allowing co-stimulation to dominate upon antigen recognition.However, CTLA-4is rapidly mobilized to the cell surface from
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protein stores,allowing feedback inhibition to occur within an hour after antigen engagement.The central role of CTLA-4in maintaining immune tolerance is dramatically demonstrated by the rapidly lethal systemic immune hyperactivation pheno-type of Ctla-4knockout mice (Tivol et al.,1995;Waterhouse et al.,1995).In humans,anti-CTLA-4treatment induces ex-pression of activation markers on circulating T cells (Maker et al.,2005)and a high rate of in?ammatory side effects (Phan et al.,2003).However,because melanoma patients appear to possess an unusually high proportion of tumor-reactive T cells,anti-tumor responses balance autoimmune toxicity and provide a clinical bene?t to roughly 20%of patients with this disease (see below).
PD-1:Similarities to and Differences from CTLA-4
The PD-1system of immune modulation bears similarities to CTLA-4as well as key distinctions (Parry et al.,2005).Similar to CTLA-4,PD-1is absent on resting naive and memory T cells and is expressed upon TCR engagement.However,in contrast to CTLA-4,PD-1expression on the surface of activated T cells requires transcriptional activation and is therefore delayed (6–12hr).Also in contrast to CTLA-4,PD-1contains a conven-tional immunoreceptor tyrosine inhibitory motif (ITIM)as well as an immunoreceptor tyrosine switch motif (ITSM).PD-1’s ITIM and ITSM bind the inhibitory phosphatase SHP-2.PD-1engage-ment can also activate the inhibitory phosphatase PP2A.PD-1engagement directly inhibits TCR-mediated effector functions and increases T cell migration within tissues,thereby limiting the time that a T cell has to survey the surface of interacting cells for the presence of cognate peptide-MHC complexes.
Therefore,T cells may ‘‘pass over’’target cells expressing lower levels of peptide-MHC complexes (Honda et al.,2014).
In contrast to CTLA-4,PD-1blockade is viewed to work predominantly within the TME,where its ligands are commonly overexpressed by tumor cells as well as in?ltrating leukocytes (Keir et al.,2008).This mechanism is thought to re?ect its im-portant physiologic role in restraining collateral tissue damage during T cell responses to infection.In addition,tumor-in?ltrating lymphocytes (TILs)commonly express heightened levels of PD-1and are thought to be ‘‘exhausted’’because of chronic stimulation by tumor antigens,analogous to the exhausted phenotype seen in murine models of chronic viral infection,which is partially reversible by PD-1pathway blockade (Barber et al.,2006).
Importantly,the phenotypes of murine knockouts of PD-1and its two known ligands are very mild,consisting of late-onset organ-speci?c in?ammation,particularly when crossed to auto-immune-prone mouse strains (Nishimura et al.,1999,2001).This contrasts sharply with the Ctla-4knockout phenotype and highlights the importance of the PD-1pathway in restricting pe-ripheral tissue in?ammation.Furthermore,it is consistent with clinical observations that autoimmune side effects of anti-PD-1drugs are generally milder and less frequent than with anti-CTLA-4.
Despite the conventional wisdom that CTLA-4acts early in T cell activation in secondary lymphoid tissues whereas PD-1in-hibits execution of effector T cell responses in tissue and tumors,this distinction is not absolute.Beyond its role in dampening acti-vation of effector T cells,CTLA-4plays a major role in driving the suppressive function of T regulatory (Treg)cells (Wing et al.,2008;Peggs et al.,2009).Tregs,which broadly inhibit effector T cell responses,are typically concentrated in tumor tissues and are thought to locally inhibit anti-tumor immunity.Therefore,CTLA-4blockade may affect intratumoral immune responses by inactivating tumor-in?ltrating Treg cells.Recent evidence has demonstrated anti-tumor effects from CTLA-4blockade even when S1P inhibitors block lymphocyte egress from lymph nodes (Spranger et al.,2014),indicating that this checkpoint exerts at least some effects directly in the TME as opposed to secondary lymphoid tissues.Conversely,PD-1has been shown to play a role in early fate decisions of T cells recognizing antigens pre-sented in the lymph node.In particular,PD-1engagement limits the initial ‘‘burst size’’of T cells upon antigen exposure and can partially convert T cell tolerance induction to effector differentia-tion (Goldberg et al.,2007).
Complex Receptor-Ligand Interactions in the PD-1Pathway:Links and Analogies to the CD28/CTLA-4System
The receptor-ligand interactions of the PD-1system appear to be even more complex than the CD28/CTLA-4system (Figure 1).The two ligands for PD-1are PD-L1(B7-H1,CD274)and PD-L2(B7-DC,CD273),which share 37%sequence homology and arose via gene duplication (Dong et al.,1999,Latchman et al.,2001;Tseng et al.,2001).However,their regulation is highly divergent.PD-L1is induced on activated hematopoietic cells and on epithelial cells by the in?ammatory cytokine interferon (IFN)-g ,which is produced by some activated T and natural killer (NK)cells.PD-L2has much more selective expression on acti-vated dendritic cells and some macrophages.It is induced to
a
Figure https://www.doczj.com/doc/7f5893906.html,plex Interactions between the CTLA-4/CD28and PD-1Families of Receptors and Ligands
Shown are the de?ned interactions between the co-inhibitory (checkpoint)receptors CTLA-4and PD-1and their ligands and related receptors.The two known ligands for CTLA-4are CD80(B7.1)and CD86(B7.2).CD86can ‘‘backward-signal’’into APCs when engaged by CTLA-4,inducing the immune inhibitory enzyme IDO.CD80and CD86also bind the co-stimulatory receptor CD28on T cells.Recently,another B7family member,inducible costimulator ligand (ICOS-L),which was discovered as the ligand for the co-stimulatory receptor ICOS (not shown),has been reported to bind to CD28,leading to co-stimulation independent of CD80or CD86.The two de?ned ligands for PD-1,PD-L1(B7-H1)and PD-L2(B7-DC),bind to additional molecules.PD-L1binds CD80molecules expressed on activated T cells,mediating inhibition.Addi-tionally,PD-L1on APCs appears to provide inhibitory signals (backward signaling)when it is engaged by PD-1.PD-L2binds another molecule,RGMb,which is expressed on macrophages and some epithelial cell types and ap-pears to deliver an inhibitory immune signal through an as yet unde?ned mechanism.Although not identi?ed,genetic evidence from PD-1knockout T cells and knockout mice suggests the existence of another receptor for PD-L2that is co-stimulatory.
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much greater extent by interleukin 4(IL-4)than by IFN-g ,further emphasizing differences in regulation of expression of PD-L1and PD-L2.
Beyond their role as ligands for PD-1,PD-L1and PD–L2appear to have additional partners,indicating additional layers of immune modulation.An unexpected molecular interaction be-tween PD-L1and CD80has been discovered (Butte et al.,2007;Park et al.,2010)whereby CD80expressed on activated T cells (and possibly APCs)can function as a receptor rather than a ligand,delivering inhibitory signals when engaged by PD-L1.The relevance of this interaction in tumor immune resistance has not yet been determined.Recently,PD-L2has been shown to bind to repulsive guidance molecule b (RGMb),which itself binds at least three other molecules in cis (neogenin and BMP receptors type I and II)(Xiao et al.,2014).This interaction ap-pears to be inhibitory independent of PD-1,as demonstrated in a pulmonary tolerance model.Finally,evidence from murine models suggests that PD-L2and,possibly,PD-L1may bind to a co-stimulatory T cell receptor (Shin et al.,2003,2005),an arrangement reminiscent of the CD80/CD86ligand pair for the co-stimulatory CD28and co-inhibitory CTLA-4receptors.Understanding the roles of these various interactions in cancer is highly relevant for the development of immunomodulatory drugs and the discovery of biomarkers predictive of therapeutic response.
Mechanisms of PD-1Ligand Induction:Implications for Cancer Immunotherapy
A key ?nding that encouraged the development of drugs block-ing the PD-1pathway for cancer immunotherapy was that PD-1ligands are upregulated in many human cancers (Dong et al.,2002),whereas PD-1is highly expressed on tumor-in?ltrating lymphocytes (Ahmadzadeh et al.,2009;Sfanos et al.,2009).
Indeed,PD-L1appears to be the major ligand expressed in solid tumors,whereas PD-L2(together with PD-L1)is highly ex-pressed in certain subsets of B cell lymphomas (Ansell et al.,2015).Exploration of this phenomenon as a central process by which cancers resist elimination by endogenous tumor-speci?c T cells revealed two mechanisms for PD-1ligand upregulation in cancer,known as intrinsic and adaptive immune resistance (Figure 2).These mechanisms are not mutually exclusive and may co-exist in the same TME.Intrinsic resistance refers to the constitutive expression of PD-L1by tumor cells because of ge-netic alterations or activation of certain signaling pathways,such as the AKT pathway and STAT3,which are commonly acti-vated in many cancers (Parsa et al.,2007;Marzec et al.,2008).Although PD-L1induction by AKT and STAT3signaling has been demonstrated in some tumor cell lines,the importance of this intrinsic pathway in PD-L1expression by tumors in vivo re-mains to be determined.Genetic alterations in B cell lymphoma subtypes can drive expression of either or both PD-L1and PD-L2.Primary mediastinal lymphomas commonly display gene fu-sions between MHC class II transactivator (CIITA)and PD-L1or PD-L2,placing PD-1ligands under the transcriptional control of the CIITA promoter,which is highly active in B cell lymphomas (Steidl et al.,2011).A signi?cant subset of Hodgkin’s lymphoma has ampli?cation of chromosome 9p23-24,where PD-L1and PD-L2reside,resulting in overexpression of both ligands.Other cancers,such as a subset of Epstein-Barr virus-induced gastric cancers,also display gene ampli?cation with consequent induc-tion of PD-L1and PD-L2.
The second mechanism,adaptive resistance,refers to the induction of PD-L1expression on tumor cells in response to spe-ci?c cytokines,in particular IFN-g .Because IFN-g is only pro-duced by activated Th1-type helper CD4cells,activated
CD8
Figure 2.Two General Mechanisms for Expression of Checkpoint Ligands in the TME
The examples in this ?gure use the PD-1ligand PD-L1for illustrative purposes,although the concept likely applies to multiple checkpoint ligands.Top:innate immune resistance.In some tumors,consti-tutive oncogenic signaling,such as through activa-tion of the AKT pathway or gene ampli?cation,can upregulate PD-L1expression on tumor cells inde-pendently of in?ammatory signals in the TME.Bot-tom:adaptive immune resistance refers to PD-L1induction in tumors as an adaptation to the sensing of an immune attack.In adaptive resistance,PD-L1is not constitutively expressed but,rather,is induced by in?ammatory signals,such as IFN-g produced by T cells attempting to execute an active anti-tumor response.Expression of PD-L1in a non-uniform distribution associated with lymphocyte in?ltrates suggests adaptive induction in response to immune reactivity within the TME.Adaptive resistance can be generated by cytokine-induced PD-L1expression on either tumor cells themselves or on leukocytes (macrophages,myeloid suppres-sor cells,dendritic cells,or even lymphocytes)in the TME.Inhibition of tumor-speci?c T cells by PD-L1-or PD-L2-expressing leukocytes may in-volve cross-presentation of tumor antigens so that PD-1-dependent inhibition is in cis .Adaptive resis-tance may be a common mechanism for the intra-tumoral expression of multiple immune checkpoint molecules.
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cells,and NK cells,this mechanism represents an adaptation of tumor cells upon‘‘sensing’’an in?ammatory immune microenvi-ronment that‘‘threatens’’the tumor.Indeed,human tumors show signi?cant correlations between PD-L1expression,levels of T cell in?ltration,and IFN-g in the TME(Taube et al.,2012; Spranger et al.,2013).Other inhibitory molecules in the TME, such as indoleamine2030dioxygenase(IDO),which inhibits immu-nity locally via conversion of tryptophan to kynurenines,are also induced by IFN-g and coordinately upregulated with PD-L1.The concept of adaptive resistance does not solely apply to induction of PD-L1on tumor cells.Early studies demonstrated that PD-L1 expression on myeloid cells,including dendritic cells,can signi?-cantly impair activation of tumor-speci?c T cells.Inhibition of T cell responses can be mediated by PD-L1+suppressive myeloid cells or dendritic cells(DCs)in the TME as well as in tu-mor-draining lymph nodes(Curiel et al.,2003).In some tumors, such as microsatellite instability(MSI)colon cancer,myeloid rather than tumor cells are the major cell type expressing PD-L1 (Llosa et al.,2015).A recent report suggests that PD-L1expres-sion by in?ltrating myeloid cells rather than tumor cells is more predictive of response to PD-1pathway blockade(Herbst et al., 2014).The relative importance of PD-L1expression on leukocytes in the TME,which would provide‘‘third-party’’inhibition,versus direct expression by the tumor cells,remains to be determined. Implications of Adaptive Immune Resistance
The adaptive resistance mechanism of intratumoral PD-L1in-duction,together with the broad therapeutic activity of PD-1 pathway blockade in human cancer,validates one of the most important tenets underlying cancer immunology and immuno-therapy,namely,that many cancer patients contain a signi?cant repertoire of tumor-speci?c T cells capable of killing their tumor save for the adaptive induction of immune checkpoints in the TME.It also implies that PD-L1expression in the tumor repre-sents a measure of the potential for a patient’s immune system to recognize the tumor.One of the major unanswered questions is this:what are the dominant antigenic targets that T cells recog-nize when checkpoints are blocked?Circumstantial evidence supports the notion that neoantigens created by the multiple somatic mutations in cancers provide such targets.Indeed,a recent report has demonstrated that melanomas with higher mutational loads were more responsive to anti-CTLA-4therapy (Snyder et al.,2014).Also,the tumor types that have been shown to respond to anti-PD-1/PD-L1therapy tend to be those with higher median mutational loads(i.e.,carcinogen-induced can-cers such as melanoma,lung,bladder,and head and neck can-cers).However,there has been much evidence over the past20 years that shared self-antigens upregulated in tumors by epige-netic mechanisms(e.g.,cancer-testis antigens)are also able to provide selective tumor targeting.The relative importance of mutation-dependent,tumor-speci?c neoantigens versus tumor-associated self-antigens as T cell targets remains to be determined.
Finally,the adaptive resistance mechanism has profound im-plications for developing synergistic combinatorial cancer im-munotherapies.One of the most promising general approaches to immunotherapy utilizes positive drivers of anti-tumor immune responses,such as vaccines,intratumoral injection of immune activators,and co-stimulatory receptor agonists.These modal-ities with the potential to enhance anti-tumor responses would also be expected to enhance the adaptive induction of check-points like PD-1ligands.This has,in fact,been demonstrated in animal models of vaccination(Fu et al.,2014).Therefore,pos-itive drivers of anti-tumor immunity may be synergistic with PD-1 pathway inhibitors.Such approaches are just beginning to enter the clinic.
Clinical Impact of Drugs Blocking CTLA-4and PD-1
Anti-CTLA-4
The anti-CTLA-4monoclonal antibodies(mAbs)ipilimumab,a fully human IgG1(Bristol-Myers Squibb),and tremelimumab,a fully human IgG2(P?zer,MedImmune),were the?rst immune checkpoint-blocking drugs to enter clinical testing in oncology. Although designed as CTLA-4-blocking mAbs,these drugs have recently been postulated to have unique functions en-dowed by their speci?c isotypes,with evidence suggesting that ipilimumab may deplete Tregs overexpressing CTLA-4 (Selby et al.,2013).In2011,ipilimumab was approved in the United States and Europe as therapy for advanced unresectable melanoma based on results from two phase III trials showing signi?cant extensions in overall survival(OS)(Hodi et al.,2010; Robert et al.,2011).Long-term follow-up in a pooled meta-anal-ysis of1,861melanoma patients receiving ipilimumab in phase II or III trials revealed durable survival in approximately20%,in some cases extending to10years(Schadendorf et al.,2015). Interestingly,this survival rate is approximately double the observed rate of tumor regressions measured by standard oncologic criteria( 10%complete responses[CRs]and partial responses[PRs]).Factors contributing to this phenomenon may include prolonged disease stabilization,unconventional ‘‘immune-related’’response patterns,or a heightened respon-siveness of ipilimumab-refractory patients to subsequent thera-pies.Although tremelimumab,a distinct CTLA-4-blocking mAb, showed promise in early-phase melanoma trials,it did not meet its designated endpoint when randomized against standard chemotherapy in a?rst-line phase III melanoma trial(Ribas et al.,2013).
Ipilimumab has so far shown only modest anti-tumor effects in non-melanoma cancers,and tremelimumab is still in early testing for these indications(reviewed in Weber,2014).Kidney,lung, and prostate cancer have been the most intensively studied. In a phase II study of metastatic renal cell carcinoma(RCC, n=61),a partial response rate of10%was observed with ipilimu-mab monotherapy(Yang et al.,2007).In lung cancer,treatment-naive patients with non-small-cell lung cancer(NSCLC)(n=204) or extensive disease small-cell lung cancer(ED-SCLC)(n=130) received standard chemotherapy alone or combined with ipili-mumab during initial(‘‘concurrent’’)or later(‘‘phased’’)chemo-therapy cycles in a phase III trial(Lynch et al.,2012;Reck et al.,2013).For both diseases,a brief but statistically signi?cant 1-month extension of progression-free survival measured by im-mune-related criteria(irPFS)was observed in patients receiving phased ipilimumab plus chemotherapy compared with chemo-therapy alone.In NSCLC,there was also a signi?cant1-month extension of PFS measured by standard criteria in the phased ipilimumab arm.Although ipilimumab did not have a signi?cant impact on OS in either NSCLC or ED-SCLC,a subset analysis appeared to show improved activity in patients with squamous NSCLC,providing the basis for an ongoing phase III trial of Cancer Cell27,April13,2015a2015Elsevier Inc.453
ipilimumab plus chemotherapy in this histology.Similarly,trials of ipilimumab in metastatic castration-resistant prostate cancer (mCRPC)have yielded weak but positive signals of activity.In phase I/II trials in which patients received ipilimumab alone or combined with systemic granulocyte-macrophage colony-stim-ulating factor or focal radiotherapy,prostate-speci?c antigen re-ductions of R 50%were observed in some patients,and isolated examples of measurable tumor regression were reported (Fong et al.,2009;Slovin et al.,2013),supporting further study.In a phase III trial of ipilimumab versus placebo after bone-directed radiotherapy in 799patients with docetaxel-refractory mCRPC,median OS was 11.2versus 10.0months,respectively (p =0.053),failing to meet the trial’s primary endpoint (Kwon et al.,2014).However,there was a statistically signi?cant 1-month improvement in PFS and a suggestion that OS was prolonged in a subgroup of patients with favorable prognostic features.A separate phase III trial of ipilimumab in chemotherapy-naive pa-tients with asymptomatic or minimally symptomatic mCRPC without visceral metastases has recently completed accrual.Valuable clinical experience gained from studies of anti-CTLA-4mAbs paved a path for accelerated development of other drugs in class by providing a framework for treatment strat-egy,toxicity management,and ef?cacy evaluation.New princi-ples emerged that distinguished immune checkpoint blockade from traditional cancer therapies.First,a new category of side effects,so-called ‘‘immune-related adverse events’’(irAEs),was recognized and characterized,leading to algorithm devel-opment for early detection and management.Drug-related irAEs were severe in 15%–30%of patients receiving anti-CTLA-4,sometimes resulting in fatalities.These irAEs were associated with in?ammation in normal tissues such as the gut,skin,and endocrine glands and resembled phenotypes observed in hu-man CTLA-4heterozygotes with reduced CTLA-4expression (Topalian and Sharpe,2014).Their occurrence in individuals with no prior history of autoimmunity validates the mechanism of action of anti-CTLA-4in ‘‘releasing the brakes’’on immune re-sponses and underscores the precarious balance that normally
exists between self-tolerance and autoimmunity.Second,a new category of clinical response termed ‘‘immune-related response’’was recognized in which major and durable tumor regressions could occur after apparent initial disease progres-sion on treatment (Wolchok et al.,2009).Tumor enlargement measured by conventional radiologic scans may result from drug-induced in?ammation at tumor sites or could re?ect actual tumor growth followed by delayed regression.Such phenomena pose challenges for the appropriate management of individual patients and the selection of informative endpoints for trials of immune checkpoint-blocking drugs.Drugs Blocking the PD-1Pathway
Information garnered from trials of anti-CTLA-4agents fast-for-warded the development of drugs blocking PD-1or its major ligand,PD-L1.As predicted by murine models,these drugs have heightened tumor selectivity and reduced toxicity com-pared with anti-CTLA-4,supporting their administration in an outpatient setting.Furthermore,although they are effective against advanced treatment-refractory melanoma,with recent regulatory approvals for two anti-PD-1drugs in this setting,they also appear to have a much broader spectrum of anti-tumor activity than anti-CTLA-4.Reproducible and durable regressions of epithelial cancers (lung,head and neck,and bladder cancers,among others)have catapulted the launching of hundreds of ongoing clinical trials in diverse disease indications.Although several different anti-PD-1/PD-L1-blocking mAbs are currently in clinical testing (Table 1),the fact that anti-tumor activity has been observed with all of them highlights the PD-1pathway as a dominant intratumoral immunosuppressive pathway and a key target in cancer therapy.
The ?rst-in-human trial of nivolumab anti-PD-1provided sem-inal evidence that this treatment approach could potentially impact diverse cancer types,including common epithelial can-cers,with objective responses reported in patients with mela-noma,kidney,and colorectal cancer (Brahmer et al.,2010).A transient tumor regression in one patient with NSCLC provided the impetus for investigating a larger NSCLC
cohort
Table 1.Drugs in Clinical Development that Block PD-1or PD-L1Isotype and b
Fc-modi?ed mAbs were engineered to abrogate ADCC and complement-dependent cytotoxicity (CDC).
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in a follow-up multi-dose trial of nivolumab in multiple cancer types(Topalian et al.,2012).Results from this trial showed notable objective response rates in patients with advanced treat-ment-refractory NSCLC(17%,n=129),RCC(27%,n=34),and melanoma(31%,n=107).Importantly,responses were quite du-rable,with many persisting even after drug discontinuation,and long-term follow-up revealed OS of9.9,22.4,and16.8months, respectively(Topalian et al.,2014).These non-randomized data compared favorably to historical response rates in similar patient populations,spurring phase III testing of nivolumab in all three cancers.A recent phase III report showed the superiority of ?rst-line nivolumab versus standard chemotherapy in patients with advanced melanoma(Robert et al.,2015).These?ndings have incentivized the aggressive clinical development of PD-1 pathway-blocking drugs by multiple pharmaceutical and bio-technology companies(Table1),and the clinical activity of these drugs in melanoma,RCC,and NSCLC has been con?rmed (Brahmer et al.,2012;Hamid et al.,2013;Herbst et al.,2014; Motzer et al.,2014).Nivolumab was recently approved by the Food and Drug Administration for chemotherapy-refractory squamous NSCLC.However,the full activity spectrum of PD-1 pathway-blocking drugs is not yet known,with recent evidence of ef?cacy in advanced chemotherapy-refractory bladder cancer (Powles et al.,2014),Hodgkin’s lymphoma(Ansell et al., 2015),head and neck,gastric,triple-negative breast,and ovarian cancers.
Combination Therapies Based on PD-1Pathway Blockade
Despite these promising results,the majority of patients treated with anti-PD-1/PD-L1monotherapies do not achieve objective responses,and most tumor regressions are partial rather than complete.Animal models suggest that treatment combina-tions based on PD-1pathway blockade may be synergistic, including anti-CTLA-4or other checkpoint inhibitors,chemo-therapy,tyrosine kinase inhibitors,focal irradiation,cancer vac-cines,or immune agonist mAbs.Appropriate preclinical models are valuable in providing a basis for prioritizing clinical transla-tion.A wide variety of treatment combinations are now under clinical development in diverse cancer types.Early and substantial tumor regressions observed with a combination of anti-CTLA-4(ipilimumab)and anti-PD-1(nivolumab)in advanced melanoma have garnered attention,although associ-ated irAEs were also ampli?ed(Wolchok et al.,2013).Results from ongoing prospectively randomized trials will be needed to de?ne the role of this treatment combination in melanoma and other cancers.
Biomarkers of Response
As mentioned earlier,studies of peripheral blood have yielded pharmacodynamic evidence of global T cell activation in patients receiving anti-CTLA-4(Maker et al.,2006),although these changes do not appear to correlate with clinical outcomes.Pe-ripheral T cell activation does not occur to the same degree in patients receiving anti-PD-1/PD-L1(Brahmer et al.,2010),as might be anticipated because the TME is thought to be the main site of activity of this pathway.Accordingly,tumor tissue has become the focal point for exploring potential biomarkers of response to anti-PD-1drugs.Early studies revealed a correla-tion between pretreatment tumor cell expression of the ligand PD-L1by immunohistochemistry(IHC)and the likelihood of response to anti-PD-1(Brahmer et al.,2010;Topalian et al., 2012).With the advent of several new automated PD-L1IHC tests and interrogation of hundreds of patients with a variety of cancer types,a signi?cant but not absolute relationship between PD-L1expression in the TME and responsiveness to PD-1 pathway blockade has been con?rmed.The potential impor-tance of PD-L1expression by in?ltrating immune cells(Herbst et al.,2014),the presence and location of CD8+tumor-in?ltrating lymphocytes(Tumeh et al.,2014),and other factors(Taube et al., 2014)are currently under intense study individually and in com-bination to discern more sensitive and speci?c predictors of clin-ical outcomes.
On the Horizon:Targeting Novel Checkpoints
Although antibody blockers of CTLA-4and PD-1are the focus of clinical attention at this time,it is likely that blockade of additional checkpoints will result in even further clinical activity.This is because multiple checkpoints appear to be co-expressed with PD-L1and PD-1in tumors.We review here some of the most actively studied‘‘next-generation’’checkpoint molecules for which antibody blockers are already in the clinic or soon to be tested in clinical trials,many in combination with anti-PD-1or anti-PD-L1.
Lymphocyte Activation Gene3
Lymphocyte activation gene3(LAG-3,CD223)is an immune checkpoint molecule expressed on activated T cells(Huard et al.,1994),NK cells(Triebel et al.,1990),B cells(Kisielow et al.,2005),and plasmacytoid dendritic cells(Workman et al., 2009).Structurally,LAG-3is highly homologous to the CD4 T cell co-receptor and lies proximal to the CD4gene on human chromosome12,but,at the amino acid level,it is less than 20%homologous to CD4,indicating that the two genes likely diverged early in evolution(Dijkstra et al.,2006).The only known ligand for LAG-3is MHC II(Huard et al.,1997),although its struc-tural interactions with MHC II are more limited than those of CD4 (Fleury et al.,1991;Moebius et al.,1993).Early studies showed that LAG-3was selectively upregulated on CD4+Tregs(Huang et al.,2004).Here a LAG-3-blocking antibody mitigated Treg ac-tivity in vivo,and transfection of antigen-speci?c CD4T cells with full length,but not truncated,LAG-3could confer in vitro Treg function.More recent studies have also suggest that LAG-3 blockade(or genetic knockout)affects the ability of conventional T cells(Tconv)to be suppressed by Tregs(Sega et al.,2014; Durham et al.,2014).Additionally,LAG-3has a CD8T cell-intrinsic role because LAG-3blocking antibodies were found to augment CD8T cell function in vivo in the absence of CD4T cells Grosso et al.,2007).As described above,exhausted or dysfunctional T cells can express multiple immune checkpoint molecules,and LAG-3and PD-1are commonly co-expressed in models of chronic infection Blackburn et al.,2009)as well as models of self-antigen recognition(Grosso et al.,2009).These studies have been extended to human tumors in that a signi?cant fraction of antigen-speci?c CD8T cells in patients with ovarian cancer and melanoma co-express LAG-3and PD-1(Matsuzaki et al.,2010; Baitsch et al.,2012).Evidence for synergistic immunosuppression mediated by LAG-3and PD-1comes from studies in which dou-ble-knockout mice were generated.Although neither LAG-3nor PD-1single knockout animals succumb to autoimmunity,com-bined knockout results in multi-organ lymphocytic in?ltration, Cancer Cell27,April13,2015a2015Elsevier Inc.455
and early death(Woo et al.,2012).Nearly identical results were obtained in models of autoimmunity(Okazaki et al.,2011),rein-forcing the notion that LAG-3and PD-1are potentially synergistic in regulating T cell function.A role for dual blockade of LAG-3and PD-1in tumor immunity is suggested by studies in which most tumors implanted in PD-1/LAG-3double-knockout mice were rejected,whereas PD-1single-knockout mice showed delayed tumor growth.Similarly,combined antibody-mediated blockade of LAG-3and PD-1resulted in tumor rejection in several models without any short-term evidence of autoimmune side effects.An anti-LAG-3blocking mAb has recently entered clinical testing in cancer(clinical trial NCT01968109)in a phase I trial that includes cohorts receiving anti-LAG-3monotherapy or combination ther-apy with anti-PD-1.
Killer Inhibitory Receptors
NK cells are a population of innate immune cells with well docu-mented roles in infectious and tumor immunity(Marcus et al., 2014).Like activated CD8T cells,NK cells mediate target cell apoptosis via secretion of preformed granules containing per-forin and granzymes.However,unlike CD8T cells,NK cells do not recognize unique peptides in the context of classical MHC I molecules.Instead,NK function is controlled by the complex interplay of a series of activating receptors and killer inhibitory re-ceptors(KIRs)and their ligands.In humans,KIR molecules are polymorphic and bind to certain MHC I alleles,and not all KIR/ ligand pairs are equally capable of inhibiting NK cell function. Indeed,bone marrow transplants in which donor NK cells lack the ability to be inhibited by host KIR ligands have been shown to result in lower relapse rates and improved OS,supporting the importance of this cell type in cancer immunity(Benson and Caligiuri,2014).The relative importance of NK cells in murine models of cancer immunotherapy has been documented by mul-tiple studies but is especially highlighted by studies in which NK cell activation via IL-15can eradicate fairly advanced tumors in the absence of CD8T cells(Liu et al.,2012).So,in a sense, KIRs can be thought of as immune checkpoint molecules,and blocking KIRs on NK cells could be exploited to augment anti-tu-mor immunity.To that end,a fully human anti-KIR mAb has entered clinical testing.This antibody(initially IPH-2101,Innate Pharma;now lirilumab,Bristol-Myers Squibb)binds to the hu-man KIR molecules KIR2DL-1,KIR2DL-2,and KIR2DL-3as well as to KIR2DS-1and KIR2DA-2,preventing their binding to HLA-C MHC I molecules(Romagne′et al.,2009).A phase I trial of anti-KIR in acute myelogenous leukemia has been completed. Several studies in hematologic and solid cancers are ongoing, but of particular interest are trials in which lirilumab is being com-bined with anti-PD-1(nivolumab,clinical trial NCT01714739)or with anti-CTLA-4(ipilimumab,clinical trial NCT01750580).These trials are important in that each seeks to combine innate immune activation via anti-KIR with activation of the adaptive immune system,therefore offering the potential for additive or synergistic anti-tumor ef?cacy.
B7-H3
B7-H3(CD276)was initially identi?ed using a bioinformatics approach in which human genome databases were queried for sequences with homology to previously identi?ed B7family members(Chapoval et al.,2001).It is a type I transmembrane protein with single variable and constant immunoglobulin do-mains.B7-H3mRNA is widely expressed in normal tissues (Sun et al.,2002),but protein expression is more restricted and is controlled by post-transcriptional mechanisms.The under-standing of B7-H3biology is complicated by the fact that it can be expressed on both immune and non-immune cells.On immune cells,B7-H3appears to exert a stimulatory role:down-regulation of B7-H3expression using anti-sense oligonucleo-tides inhibits T cell production of IFN-g(Chapoval et al.,2001). Therefore,B7-H3might be considered not as a classical immune checkpoint molecule but,rather,as a co-stimulatory receptor more analogous to CD28.Although this model is supported by numerous studies(Yi and Chen,2009),several studies suggest an alternative model in which B7-H3down-modulates T cell acti-vation.These studies include the?nding that B7-H3-blocking antibodies exacerbate disease in the experimental autoimmune encephalomyelitis(EAE)murine model as well as in several other models(Suh et al.,2003).In terms of cancer immunity,there is a similar lack of clarity in that the induction of expression of B7-H3 in tumor cell lines increases their immunogenicity and leads to more rapid rejection(Luo et al.,2004).But in many human tu-mors,expression of B7-H3in situ has been associated with a poor outcome.This is especially notable in RCC and prostate cancer,where expression correlates with an increased risk of death(Crispen et al.,2008;Chavin et al.,2009).Based on the notion that B7-H3protein is overexpressed in multiple tumor types,a mAb with enhanced antibody-dependent cellular cyto-toxicity(ADCC)function has been developed(Loo et al.,2012) and has entered clinical trials(clinical trial NCT01391143).This agent is not being deployed as an immune checkpoint-blocking antibody.Rather,it is being tested as a traditional tumor-target-ing antibody similar in concept to rituximab or trastuzumab.
T Cell Immunoglobulin and Mucin-3
T cell immunoglobulin and mucin-3(TIM-3)is an immune checkpoint molecule expressed on activated human T cells, NK cells,and monocytes.TIM-3knockout mice,similar to LAG-3knockouts,do not develop overt autoimmunity(Sa′n-chez-Fueyo et al.,2003),suggesting that TIM-3and LAG-3 may have similarly subtle effects in modulating immune cell function.Consistent with this hypothesis,TIM-3blockade accelerates the disease phenotype in murine models prone to developing autoimmunity,including non-obese diabetic(NOD) (Sa′nchez-Fueyo et al.,2003)and EAE models(Monney et al., 2002).Functionally,TIM-3binds to galectin-9(as well as several other ligands),as supported by data showing that administration of galectin-9in vitro causes cell death of Th1cells in a TIM-3-dependent manner(Zhu et al.,2005).Recent studies showed that TIM-3is co-expressed with and binds to CECAM1and that this interaction is important in TIM-30s regulatory function (Huang et al.,2015).In other work,the role of the TIM-3immune checkpoint was studied in several murine cancer models(Sa-kuishi et al.,2010),including the CT26colon carcinoma,4T1 mammary carcinoma,and B16melanoma.Interestingly,TIM-3 was nearly universally co-expressed with PD-1on the majority of TILs.Co-expression of both checkpoint molecules re?ected a more exhausted phenotype,functionally de?ned by a T cell’s reduced ability to proliferate and secrete IFN-g,IL-2,and tumor necrosis factor a(TNF-a).Combined blockade was more effec-tive in controlling tumor growth than blocking either checkpoint alone,con?rming the notion that combined immune checkpoint blockade offers a potential treatment strategy for a wide variety
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of cancers and that,besides CTLA-4and LAG-3,other check-points might synergize with PD-1to down-modulate T cell responses to tumors.Anti-human TIM-3blocking antibodies have not yet entered the clinic but are under development.
V-Domain Ig-Containing Suppressor of T Cell Activation V-domain Ig-containing suppressor of T cell activation(VISTA)is a relatively recently described negative regulator of T cell func-tion(Wang et al.,2011).Unlike PD-1and CTLA-4,VISTA is pre-dominantly expressed on myeloid and granulocytic cells,with only weak T cell expression in mice and humans(Lines et al., 2014;Wang et al.,2011).Functionally,VISTA blockade attenu-ates tumor outgrowth,especially when combined with a cancer vaccine(Wang et al.,2011).In terms of human cancers, VISTA expression has been described in colorectal tumors; here expression appears to be con?ned to CD11b+cells, whereas expression on CD8T cells was not detected(Lines et al.,2014).These early studies are relatively limited in scope, and a more comprehensive analysis of VISTA expression in various human tumor types is warranted.In addition,the relative ef?cacy of VISTA blockade compared with PD-1or CTLA-4 blockade awaits the development of suitable reagents,but,as is the case for the other checkpoint molecules discussed above, the notion that VISTA expression so far appears to be selective for the myeloid compartment of tumors suggests the possibility of clinical effects distinct from those mediated by currently available checkpoint blocking antibodies as well as the potential for additive or synergistic bene?ts.
T Cell ITIM Domain:TIGIT
Like B7-H3,TIGIT was initially identi?ed through a genomic search for structures shared among regulatory receptors,including a conserved ITIM motif(Yu et al.,2009).Initial studies suggested that TIGIT functions by transmitting a negative signal to DCs, decreasing IL-12secretion while simultaneously enhancing IL-10levels.A more recent study,however,shows that TIGIT func-tions as an immune checkpoint,downregulating proliferation of both murine and human T cells(Johnston et al.,2014).The ligand for TIGIT is the poliovirus receptor(PVR),but PVR also binds to the T cell surface molecule CD226.In this way,TIGIT biology is perhaps reminiscent of the interaction between B7molecules and CTLA-4/CD28.Binding of PVR to TIGIT mediates an inhibitory signal,whereas binding of PVR to CD226transmits a positive co-stimulatory signal to T cells.Blocking TIGIT with a speci?c mAb showed ef?cacy in both viral and tumor models,including an ad-ditive anti-tumor effect when both PD-L1and TIGIT were blocked simultaneously.The relevance of these data to human cancer awaits future clinical development,but it is worth noting that genomic pro?ling studies showed that CD8a expression corre-lates closely with TIGIT expression in tissue from lung cancer patients(Johnston et al.,2014).
IDO
Although not an immune checkpoint in the classical sense, several inhibitory pathways mediated by overexpression of IDO in various tumor types play an important role in downregulating anti-tumor immunity(Prendergast et al.,2014).As brie?y men-tioned above,IDO catabolizes the breakdown of tryptophan to kynurenine(and other metabolites).T cells require adequate tryptophan levels for survival and effector function,and,there-fore,IDO-mediated tryptophan de?ciency results in T cell toler-ance and lack of effector function and promotes the differentia-tion of naive CD4T cells into Tregs(Fallarino et al.,2006).In addition,IDO expression in a relatively small population of tumor-associated DC allows the suppression of effector T cell responses(Mellor and Munn,2004).Both the IDO pathway inhib-itor D-1MT and small-molecule enzymatic inhibitors of IDO1 (INCB024360and NLG919)have entered clinical trials,and phase I data from a trial combining D-1MT(indoximod)with chemotherapy were published recently,demonstrating tolera-bility for the combination as well as evidence of anti-tumor activ-ity(Soliman et al.,2014).
Conclusions
Recent years have seen a rapid expansion of our knowledge of immune regulation.Basic principles established in laboratory models of infection,autoimmunity,and transplantation have proved to be transportable to human cancer,supporting the development of drugs modulating anti-tumor immunity.The suc-cessful application of the immune checkpoint blockers anti-CTLA-4in melanoma and anti-PD-1/PD-L1in multiple cancer types has established immunotherapy as a viable treatment op-tion for patients with advanced cancers and has opened the doors to developing a new generation of immune modulators that may be most effective when employed in treatment combi-nations.Armed with a new understanding and unprecedented opportunities,the?eld of immunotherapy is now standing on the threshold of great advances in the war against cancer. AUTHOR CONTRIBUTIONS
All authors contributed to the design and writing of this manuscript. ACKNOWLEDGMENTS
The authors thank Dr.Julie Brahmer(Johns Hopkins University)for helpful discussions.This work was supported by research funding from Bristol-Myers Squibb(to S.L.T.,C.G.D.,and D.M.P.),the Melanoma Research Alliance (to S.L.T., C.G.D.,and D.M.P.),the National Cancer Institute/NIH(R01 CA142779[to S.L.T.and D.M.P.]and R01CA154555[to C.G.D.]),the Barney Family Foundation(to S.L.T.),the Laverna Hahn Charitable Trust(to S.L.T.), the Commonwealth Foundation(to D.M.P.),and Moving for Melanoma of Dela-ware(to S.L.T.and D.M.P.).S.L.T.and D.M.P.were also supported by a Stand Up To Cancer—Cancer Research Institute Cancer Immunology Translational Cancer Research Grant(SU2C-AACR-DT1012).Stand Up To Cancer is a pro-gram of the Entertainment Industry Foundation administered by the American Association for Cancer Research.The authors have declared the following ?nancial relationships.S.L.T.:research grants from Bristol-Myers Squibb and consulting for Five Prime Therapeutics,GlaxoSmithKline,and Jounce Therapeutics;C.G.D.:research grants from Bristol-Myers Squibb and Jans-sen;consulting for Bristol-Myers Squibb,Compugen,Janssen,Novartis, and Roche/Genentech;stock options in Compugen,ImmuneXcite,NexIm-mune,and Potenza Therapeutics;and patent royalties through his institution, Bristol-Myers Squibb,and Potenza.D.M.P.:research grants from Bristol-Myers Squibb;consulting for Five Prime Therapeutics,GlaxoSmithKline, Jounce Therapeutics,MediImmune,P?zer,Potenza Therapeutics,and Sano?; stock options in Jounce and Potenza;and patent royalties through his institu-tion,Bristol-Myers Squibb and Potenza.
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第一部分参数选取 根据钻探揭露，滑带土为黄褐色粉质亚粘土夹少量砂板岩角砾，位于人工堆积层与下层基岩之间，深度在2-7m不等，厚约0.2-0.3m，断面光滑。 2、滑带土参数的取值 （1）参数反演 滑坡中的滑带土为基覆交界面的亚粘土层，由于野外取样时，所取滑带土样为已经扰动过的土样，因此在进行岩土试验参数统计及经验类比的取值时，滑带土的C、φ值采用滑坡在暴雨工况下，取稳定系数为1.03时反演取值，其反演计算模型，选定H1滑坡的2-2’剖面。反演计算剖面及内容见计算书。 采用反演公式和 经反演，滑坡滑带土在暴雨条件下C、φ值见下表。 （2）工程类比经验：借鉴蜀通公司对H2滑坡所做的勘查工作，天然条件下C 值为6.7KPa，φ为18.5°，暴雨条件下C值为3.3-4.6KPa，φ为12.3°。 （3）试验值： （4）综合取值： 根据滑带土的试验、剖面反演及工程类比的结果，滑带土而天然工况下的取值主要依据试验结果，在暴雨工况下参数取值主要采取加权平均，对试验值、反演值和工程类比值采取加权平均方法从而得出暴雨工况下的滑带土的c、φ值。目前各滑坡处于蠕动变形阶段，因此对试验值取较高的权重。三种取值的权重分别是0.5、0.3、0.2。据此得出暴雨工况下的滑带土的参数值。 滑带土参数取值为天然重度为19.0 kN/m3，饱和重度为20.5kN/m3，天然条件下C值为7.0KPa，φ为18.5°；饱和条件下c值为3.8KPa，φ为13.0°。 一、2-2’反演 滑坡剩余下滑力计算 计算项目： 2-2暴雨 ===================================================================== 原始条件: 滑动体重度= 19.000(kN/m3) 滑动体饱和重度= 20.500(kN/m3) 安全系数= 1.030 不考虑动水压力和浮托力 不考虑承压水的浮托力 不考虑坡面外的静水压力的作用 不考虑地震力 坡面线段数: 41, 起始点标高 0.000(m) 段号投影Dx(m) 投影Dy(m) 附加力数 1 0.144 0.351 0 2 0.386 1.579 0 3 0.279 0.673 0 4 0.541 0.977 0 5 0.232 0.793 0 6 0.601 0.846 0 7 0.475 0.781 0 8 0.266 0.496 0 9 0.353 0.812 0 10 0.518 0.658 0 11 0.110 0.265 0 12 0.102 0.204 0 13 0.197 0.490 0 14 0.234 0.464 0 15 0.197 0.147 0
本文由ｎｏ１ｍｏｏｎｂｏｙ贡献 ｄｏｃ１。 双 ＣｈｅｃｋＰｏｉｎｔ 防火墙实施方案 目 录 第一章 客户环境概述…… ４ １．１ 概述 …… ４ １．２ 网络拓扑与地址分配表 …… ４ １．３ 安装前准备事宜 …… ６ 第二章 Ｎｏｋｉａ ＩＰ３８０ 安装与配置 …… ７ ２．１ 概述 …… ７ ２．２ 初始化 ｎｏｋｉａ３８０ …… ７ ２．３ 设置 ｎｏｋｉａ 基本信息 …… ８ ２．３．１ Ｎｏｋｉａ 端口 ＩＰ 地址设定 …… ８ ２．３．２ 设置网关路由 …… ８ ２．３．３ 设置 Ｎｏｋｉａ 平台时间 …… ９ ２．３．４ 设定 Ｎｏｋｉａ 高可用 ＶＲＲＰ 参数 …… ９ ２．４ 初始化 ｃｈｅｃｋｐｏｉｎｔ …… １４ ２．４．１ 在 ｎｏｋｉａ 平台上 ｃｈｅｃｋｐｏｉｎｔ 的安装与卸载 …… １４ ２．４．２ 初始化 ｃｈｅｃｋｐｏｉｎｔ …… １６ 第三章 管理服务器的安装与配置…… １７ ３．１ｃｈｅｃｋｐｏｉｎｔ ｓｍａｒｔｃｅｎｔｅｒ 的安装…… １８ ３．１．１ 安装前的准备 …… １８ ３．１．２ 安装步骤 …… １８ ３．２ 配置 ｃｈｅｃｋｐｏｉｎｔ 对象和参数 …… ２０ ３．２．１ 建立 ｓｉｃ …… ２０ ３．２．２ 定义防火墙对象拓扑结构 …… ２１ ３．２．３ 使用同样的步骤按照表 １ 的参数建立 ＩＰ３８０Ｂ ｃｈｅｃｋｐｏｉｎｔ ｇａｔｅｗａｙ 对象。 …… ２１ ３．３ 基于 ｎｏｋｉａ ｖｒｒｐ 或者 ｃｌｕｓｔｅｒ 的设置…… ２２ ３．３．１ 基于 Ｎｏｋｉａ ＶＲＲＰ 的设置 …… ２２ ３．３．２ 为 ｎｏｋｉａ ｖｒｒｐ 定义策略 …… ２２ ３．３．３ 高可用性的检查 …… ２３ ３．４ｎｏｋｉａ ｃｌｕｓｔｅｒ 的设置 …… ２３ ３．５ 暂时没有 …… ２３ 第四章 策略设定…… ２４ ４．１ 概述 …… ２４ ４．２ ｎｅｔｓｃｒｅｅｎ 的策略 …… ２４ ４．３ 经过整理后转换成 ｃｈｅｃｋｐｏｉｎｔ 的策略 …… ２４ ４．４ 设定策略 …… ２４ ４．４．１ 定义主机对象 …… ２４ ４．４．２ 定义网络对象 …… ２５ ４．４．３ 定义组 …… ２６ ４．４．４ 定义服务 …… ２６ ４．４．５ 添加标准策略 …… ２７ ４．４．６ 添加 ＮＡＴ 策略…… ２７ 第五章 切换与测试…… ２９ ５．１ 切换 …… ２９ ５．２ 测试 …… ２９ ５．３ 回退 …… ３０ 第六章 日常维护…… ３１ ６．１ 防火墙的备份与恢复 …… ３１ ６．１．１ ｎｏｋｉａ 防火墙的备份与恢复方法 …… ３１ ６．１．２ ｃｈｅｃｋｐｏｉｎｔ ｍａｎａｇｅｍｅｎｔ 上的备份与恢复 …… ３３ 第一章 客户环境概述 １．１ 概述 ＸＸＸＸＸＸ 公司因应企业内部的网络需求，对总部网络进行扩容改动，中心 防火墙从原来的 ｎｅｔｓｃｒｅｅｎ 换成两台 Ｎｏｋｉａ ＩＰ３８０，两台 ｎｏｋｉａ 互为热备。维持原 有的服务不变。 由于这次网络改动比较大，所以先离线进行安装和测试，最后再进行切换 １．２ 网络拓扑与地址分配表 ＸＸＸＸＸＸ 改造前网络拓扑如下 改动后，ＸＸＸ 将按照以下图进行实施 改动后， 给个设备及端口的地址分配入下表所示 ＩＰ 地址分配表（表 １） 管理服务器参数 ＩＰ 地址 防火墙各端口参数 端口 Ｅｔｈ１ 用途 外网 口 Ｅｔｈ２ Ｅｔｈ３ Ｅｔｈ４ ？ ＤＭＺ 内网 同步 口 ｇａｔｅｗａｙ 静态路 由 １７２．１６．１００．５／３０ １７２．１６．１００．６／３０ １７２．１６．１００．１／３０ １０．１０１．１．１０１／２４ １０．１０１．１．１０２／２４ １０．１０１．１．１／２４ １９２．１６８．１１．１／２４ １９２．１６８．１１．２／２４ Ｎｏｋｉａ３８０Ａ Ｎｏｋｉａ３８０Ｂ 虚拟地址 １．３ 安装前准备事宜 １．管理服务器硬件平台 ＣＰＵ 奔腾 ３ ５００ 以上 内存 １２８ 以上 硬盘 ６０Ｍ 以上 操作系统，ｗｉｎｄｏｗｓ ２０００ ｓｅｒｖｅｒ ＋ＳＰ４ 补丁 ２．网络连线 ３．Ｃｈｅｃｋｐｏｉｎｔ 及 ｎｏｋｉａ 管理软件 Ｃｈｅｃｋｐｏｉｎｔ ＮＧ ＡＩ Ｒ５５ 安装包 ｆｏｒ ｗｉｎｄｏｗｓ ｈｏｔｆｉｘ０９ 或以上 ４．Ｎｏｋｉａ ＩＰ３８０ 设备两台 内置 ＩＰＳＯ３．８ ｂｕｉｌｄ ３９ 内置 ｃｈｅｃｋｐｏｉｎｔ ＮＧ ＡＩ Ｒ５５ 安装包 第二章 Ｎｏｋｉａ ＩＰ３８０ 安装与配置 ２．１ 概述 首先我们可以对两台 Ｎｏｋｉａ ＩＰ３８０ 进行安装与配置，由于 Ｎｏｋｉａ 防火墙将会 替代 Ｎｅｔｓｃｒｅｅｎ，所以 Ｎｏｋｉａ 防火墙可以进行离线配置。配置步骤如下。 ２．２ 初始化 ｎｏｋｉａ３８０ １． 使用 ｎｏｋｉａ ｃｏｎｓｏｌｅ 线，连接 ｎｏｋｉａ ｃｏｎｓｏｌｅ 口和管理 ｐｃ 的串行端口，
燃气轮机性能指标主要影响因素及提高性能途径研究 摘要: 本文以9e燃机为例，概括介绍了国内已经投产的燃气轮机的主要性能指标，并通过对不同设计和运行条件下技术性能指标的对比，分析对燃气轮机性能指标产生影响的主要影响因素，从而总结和简述了提高性能指标的主要途径。 关键词: 燃气轮机；性能指标；功率；热耗率；影响因素；abstract：illustrated by 9e gas turbine, the main technical performance parameters of gas turbine in china are described, and with the comparison of the technical parameters under different design and operation condition, an analysis on the main influencing factors is presented, so as to summarizethe major way to improve the performance parameters. keywords: gas turbine; performance parameter; power; heat rate; influencing factor 中图分类号：th138.23 文献标识码：a文章编号：2095-2104（2012） 1.引言 燃气轮机是从本世纪50年代开始逐渐登上发电工业舞台的。但是由于当时机组的单机容量较小，而热效率又比较低，因而在电力系统中只能作为紧急备用电源和调峰机组使用。 60年代时欧美的大电网曾发生过电网瞬时解列的大事故，这些事
win7防火墙设置指南、多重作用防火墙策略以及设置方法 214小游戏https://www.doczj.com/doc/7f5893906.html,/ windows XP集成防火强常被视为鸡肋，不过随着vista和WIN7的发布，微软对于防火墙的两次升级让windows的firewall不再是系统的累赘，特别是win7的firewall，强悍的功能让微软的防火墙也有了“专业”的味道。 本文就教大家来了解一下windows7下的 firewall设置以及向你展示怎样对多重作用防火墙策略下对Firewall进行配置。Windows Firewall的演变过程。 一、windows防火墙的演变 Windows XP中的防火墙是一款简单、初级仅保护流入信息，拦截任何不是由你主动发启入站连接的软件－－它是默认关闭的。SP2后它才被默认启动并可以通过组策略的方式由管理员进行配置。而 Vista Firewall 是建立在一个新的Windows Filtering Platform （WFP、Windows过滤平台）上、并通过Advanced Security MMC嵌入式管理单元添加了新的过滤外发信息的能力。在Windows 7中MS对firewall做了进一步的微调，使其更具可用性，尤其针对移动计算机，更是舔加了对多重作用防火墙策略的支持。 二、windows 7 firewall（防火墙）设置方法 与Vista相同的是，可以通过访问控制面板程序对Windows 7 firewall进行基础配置。与Vista不同的是，你还可以通过访问控制面板的方式对其进行高级配置（包括对出站连接过滤器的配置），而不是一定要创建空白MMC并加入嵌入式管理单元来实现。只是点击一下左侧面板里的高级配置选项。 更多的网络配置 Vista firewall允许你去选择是在公共网格上还是在专用网络中，而在Windows 7中你有三个选择－－公用网络、家庭网络、办公网络。后两个选项是专用网络的细化。 如果你选择了“家庭网络”选项，你将可以建立一个“家庭组”。在这种环境中，“网路发现”会自动启动，你将可以看到网络中其它的计算机和设备，同时他们也将可以看到你的计算机。隶属于“家庭组”的计算机能够共享图片、音乐、视频、文档库以及如打印机这样的硬件设备。如果有你不想共享的文件夹在文档库中，你还可以排除它们。 如果你选择的是“工作网络”，“网路发现”同样会自动启动，但是你将不能创建或是加入“家庭组”。如果你的计算机加入了Windows域（通过控制面板－－系统和安全－－系统－－高级系统配置－－计算机名选项卡）并通过DC验证，那么防火墙将自动识别网络类型为域环境网络。 而“公用网络”类型是当你在机场、宾馆、咖啡馆或使用移动宽带网络联通公共wi-fi 网络时的适当选择，“网路发现”将默认关闭，这样其它网络中的计算机就不会发现你的共享而你也将不能创建或加入“家庭组”。 在全部的网络模式中，Windows 7 firewall都将在默认情况下拦截任何发送到不属于白名单中应用程序的连接。Windows 7允许你对不同网络类型分别配置。 多重作用防火墙策略 在Vista中，尽管你有公用网络和私用网络两个配置文件，但是只会有一个在指定的时间内起作用。所以如果你的计算机发生要同时连接两个不同网络的情况，那你就要倒霉啦。最严格的那条配置文件会被用户到所有的连接上，这意味着你可能无法在本地（私用）网络中做你想做的事，因为你是在公用网络在规则下操作。而在Windows 7 （和 Server 2008 R2）中，不同网络适配器上可以使用不同的配置文件。也就是说专用网络之间的网络连接受专用网络规则支配，而与公用网络之间的流量则应用公用网络规则。 起作用的是那些不显眼的小事 在很多事例中，更好的可用性往往取决于小的改变，MS听取了用户的意见并将一些“不
Check point 防火墙基本操作手册 CheckPoint(中国) TEL:(86)10 8419 3348 FAX:(86)10 8419 3399 ?2010 Check Point Software Technologies Ltd. All rights reserved. Classification:
目录 目录 (2) 防火墙架构 (3) 防火墙的Web管理 (3) 配置IP： (4) 配置DNS和Host: (5) 配置路由: (5) 通过防火墙的管理客户端管理 (5) 添加防火墙 (7) 添加策略步骤 (10) IP节点添加 (10) 添加网段 (11) IPS的配置 (13) 更新IPS库 (14) 新建IPS动作库 (14) 应用控制 (16) 更新数据库 (16) 添加应用控制策略 (17) App Wike (18) 自定义添加应用 (18) QOS配置 (20) Qos策略的添加 (20) 日志工具的使用 (20) 筛选日志 (21) 临时拦截可以连接 (22) ?2010 Check Point Software Technologies Ltd. All rights reserved. Classification:
?2010 Check Point Software Technologies Ltd. All rights reserved. Classification: 防火墙架构 Check point 防火墙的管理是通过一个三层架构来实现的。首先我们可以在任意的机器上安装防火墙客户端控制台，然后利用控制台的图形化界面登录check point 的管理服务器，定义出各个网络对象，定义企业各条策略，最后下发到防火墙执行模块。具体实现过程见图示： 防火墙的Web 管理 首先打开Web 管理界面，出现登录界面：
防火墙基本操作及应急措施陈世雄安全工程师 CCSE
议程 ?智能边界安全解决方案?CheckPoint 配置基础?常见问题及应急措施
Check Point 简介 ?最受信赖、最可依靠的互联网安全厂商 –我们致力发展安全领域——并且比任何厂商更优秀! –全球财富100企业中，100%企业使用我们的产品 –在防火墙和虚拟专用网络（VPN）市场中占有领导 地位 ?在全球 VPN/防火墙软件市场销售额中占70%份额 （Infonetics提供数据） ?VPN/防火墙软件市场占有率超过 54% （IDC提供数据） ?安全硬件设备市场份额中有 36% 为 Check Point 产品（由 Infonetics 提供） ?以客为本的企业原则 –业界领先的技术合作伙伴关系 –强大且广泛的渠道合作伙伴关系
状态检测 / FireWall-1 1993 OPSEC 1997 VPN-1 1998 Next Generation 2001 SmartDefense 2002 应用智能 2003 Check Point: 一直走在客户现实需求的前面 创新历程 1994 1995 1996 1999 2000 Web 智能 2004
我们的策略 2004上半年提供! ? 安全远程访问 ? Web 服务器保护 ? 统一认证 ? 一致性策略管理 ? 市场领先 ? 十年的成功史 ? 最新发布 - InterSpect 2.0 - Connectra 2.0 - Intergrity 6.0 ? Check Point InterSpect ? Zone Labs SMART 管理 无忧保护 边界 深入检查 智能 安全解决方案
本篇要为大家介绍一些实用的知识，那就是如何配置防火中的安全策略。但要注意的是，防火墙的具体配置方法也不是千篇一律的，不要说不同品牌，就是同一品牌的不同型号也不完全一样，所以在此也只能对一些通用防火墙配置方法作一基本介绍。同时，具体的防火墙策略配置会因具体的应用环境不同而有较大区别。首先介绍一些基本的配置原则。 一. 防火墙的基本配置原则 默认情况下，所有的防火墙都是按以下两种情况配置的： ?拒绝所有的流量，这需要在你的网络中特殊指定能够进入和出去的流量的一些类型。 ?允许所有的流量，这种情况需要你特殊指定要拒绝的流量的类型。可论证地，大多数防火墙默认都是拒绝所有的流量作为安全选项。一旦你安装防火墙后，你需要打开一些必要的端口来使防火墙内的用户在通过验证之后可以访问系统。换句话说，如果你想让你的员工们能够发送和接收Email，你必须在防火墙上设置相应的规则或开启允许POP3 和SMTP 的进程。 在防火墙的配置中，我们首先要遵循的原则就是安全实用，从这个角度考虑，在防火墙的配置过程中需坚持以下三个基本原则：（1）. 简单实用：对防火墙环境设计来讲，首要的就是越简单越好。其实这也是任何事物的基本原则。越简单的实现方式，越容易理解和使用。而且是设计越简单，越不容易出错，防火墙的安全功能越容易得到保证，管理也越可靠和简便。 每种产品在开发前都会有其主要功能定位，比如防火墙产品的初衷就是实现网络之间的安全控制，入侵检测产品主要针对网络非法行为进行监控。但是随着技术的成熟和发展，这些产品在原来的主要功能之外或多或少地增加了一些增值功能，比如在防火墙上增加了查杀病毒、入侵检测等功能，在入侵检测上增加了病毒查杀功能。但是这些增值功能并不是所有应用环境都需要，在配置时我们也可针对具体应用环境进行配置，不必要对每一功能都详细配置，这样一则会大大增强配置难度，同时还可能因各方面配置不协调，引起新的安全漏洞，得不偿失。 （2）. 全面深入：单一的防御措施是难以保障系统的安全的，只有采用全面的、多层次的深层防御战略体系才能实现系统的真正安全。在防火墙配置中，我们不要停留在几个表面的防火墙语句上，而应系统地看等整个网络的安全防护体系，尽量使各方面的配置相互加强，从深层次上防护整个系统。这方面可以体现在两个方面：一方面体现在防火墙系统的部署上，多层次的防火墙部署体系，即采用集互联网边界防火墙、部门边界防火墙和主机防火墙于一体的层次防御；另一方面将入侵检测、网络加密、病毒查杀等多种安全措施结合在一起的多层安全体系。 3）. 内外兼顾：防火墙的一个特点是防外不防内，其实在现实的网络环境
Checkpoint R65 Test Plan Revision 0.1 2009-10-14 Author: Peng Gong
Revision History
1‘FW MONITOR’ USAGE (7) 2TEST SUITES (7) 2.1R65I NSTALL &U NINSTALL (7) 2.1.1Create a v3 vap-group with vap-count/max-load-count set >1, Confirm R65 and related HFA could be installed on all vap within vap-group successfully (7) 2.1.2Create a v4 vap-group, confirm XOS would prompt correctly message and failure install would cause unexpected issue to system (9) 2.1.3Create a v5 vap-group, confirm XOS would prompt correctly message and failure install would cause unexpected issue to system (10) 2.1.4Create a v5_64 vap-group, confirm XOS would prompt correctly message and failure install would cause unexpected issue to system (11) 2.1.5Try to install R65 on a v3 vap-group and abort the install process, confirm nothing is left afterwards12 2.1.6Reduce max-load-count down to 1, confirm only one Vap is allowed to run R65 accordingly (13) 2.1.7Increase vap-count and max-load-count to maximum vap count and executing "application-update", confirm all the Vap are running R65 properly (14) 2.1.8Reduce vap-count to 3, Confirm the surplus Vap is stopped from running R65 and related partitions are removed from CPM (15) 2.1.9Enable/Disable IPv6 in vap-group and w/o ipv6-forwarding, confirm R65 wouldn't be affected. (16) 2.1.10Confirm the installed R65 could be stopped through CLI (17) 2.1.11Confirm the installed R65 could be started through CLI (18) 2.1.12Confirm the installed R65 could be restarted through CLI (18) 2.1.13Confirm the installed R65 could be reconfigured through CLI (19) 2.1.14Confirm checkpoint could be upgraded to R70 by CLI: application-upgrade (19) 2.1.15Confirm R65 could run properly while reload vap-group totally (20) 2.1.16Confirm R65 could run properly while reload all chassis totally (20) 2.1.17Create 2 vap groups, install R65 on both. Confirm R65 are running on both vap-groups without any mutual impact. (21) 2.1.18Confirm configure operation couldn't be allowed if some Vap don't run R65 properly. (23) 2.1.19Confirm uninstall/Configure operation couldn't be allowed if some Vap don't run properly. (24) 2.1.20Confirm start/stop/restart operation could works prope rly if R65 doesn’t run properly on some Vaps.25 2.1.21Confirm configure operation couldn't be allowed if vap-count>max-load-count causing some Vap don't run properly (26) 2.1.22Confirm uninstall operation couldn't be allowed if vap-count>max-load-count causing some Vap don't run properly (27) 2.1.23Confirm start/stop/restart operation couldn't be allowed if vap-count>max-load-count causing some Vap don't run properly (28) 2.1.24Confirm R65 could be uninstalled from vap-group (29) 2.1.25Confirm R65 installation package could be remove from XOS by CLI: application-remove (30) 2.2C HECKPOINT F EATURES (31) 2.2.1Create GW and Set SIC, get topology from Smart Dashboard (31) 2.2.2Configure Policy and push policy (31) 2.2.3Confirm R65 could be started/stoped/restarted by cp-command (32) 2.2.4Confirm different kinds of rule actions could work - allow/drop/reject (33) 2.2.5Verify different kinds of tracking actions could work properly - log/alert/account (33) 2.2.6Verify static NAT and hide NAT work properly (34) 2.2.7Verify default license is installed automatically (34) 2.2.8Verify some usual fw commands output - fw ver -k/ fw ctl pstat/ fw tab/ fw stat/ cphaprob stat /fw fetch /fw unloadlocal / fwaccel stat (34) 2.2.9Verify SXL status if enable/disable it (36) 2.2.10Verify the log information in SmartViewer are displayed correctly. (37) 2.2.11Verify the GW and its member information in SmartViewer are displayed correctly (37) 2.2.12Define a VPN Community between two GW; Confirm traffic can pass (37) 2.2.13Create a VPN client tunnel, make sure client can login and traffic is encrypted as it should (38) 2.2.14Enabling/Disabling SXL during connections (39) 2.2.15Fail over the active member during connections (39) 2.3I NTERFACE T EST-T RAFFIC MIXED WITH IPV6 AND IPV4 (39) 2.3.1Verify traffic pass through the interface without SXL - non vlan<--->vlan (tcp+udp+icmp) (39)
第一讲：燃气轮机基本原理及9E燃机性能型号参数授课内容： 第一章：绪论 1）：燃气轮机发电装置的组成 2）：燃气轮机发展史 3）：我国燃气轮机工业慨况 4）：GE公司燃气轮机产品系列及其编号 第二章：燃气轮机热力学基础知识 1）：工质的状态参数 2）：理想气体状态方程 3）：功和热量 第三章：燃气轮机热力循环 1）：燃气轮机热力循环的主要技术指标 2）：燃气轮机理想简单循环 3）：燃气—蒸汽联合循环 第四章：9E燃机性能型号参数 1）：PG9171E型燃机型号简介 2）：PG9171E型燃机性能参数简介
第一章绪论 第一节燃气轮机发电装置的组成 燃气轮机是近几十年迅速发展起来的热能动力机械。现广泛应用的是按开式循环工作的燃气轮机。它不断地由外界吸入空气，经过压气机压缩，在燃烧室中通过与燃料混合燃烧加热，产生具有较高压力的高温燃气，再进入透平膨胀作功，并把废气排入大气。输出的机械功可作为驱动动力之用。因此，由压气机、燃烧室、透平再加上控制系统及基本的辅助设备，就组成了燃气轮机装置。如果用以驱动发电机供应电力，就成了燃气轮机发电装置。 (幻灯)
第二节 燃气轮机发展史 燃气轮机是继汽轮机和内燃机问世以后，吸取了二者之长而设计出来的，它
是内燃的，避免了汽轮机需要庞大锅炉的缺点;又是回转式的，免去了内燃机中将往复式运动转换成旋转运动而带来的结构复杂，磨损件多，运转不平稳等缺点。但由于燃气轮机对空气动力学和高温材料的要求超过其他动力机械，因此，发展燃气轮机并使之实用化，人们为之奋斗了很长时间。如果从1791年英国人约翰·巴贝尔(John Baber)申请登记第一个燃气轮机设计专利算起，经过了半个世纪的奋斗，到1939年，一台用于电站发电的燃气轮机(400OkW)才由瑞士BBC公司制成，正式投运。同时Heinkel工厂的第一台涡轮喷气式发动机试飞成功，这标志着燃气轮机发展成熟而进入了实用阶段·在此以后，燃气轮机的发展是很迅速的。由于燃气轮机本身固有的优点和其技术经济性能的不断提高，它的应用很快地扩展到了国民经济的很多部门· 首先在石油工业中，由于油田的开发和建设，用电量急剧增加·建造大功率烧煤电站不具备条件(没有煤炭，交通不便，水源紧张，施工困难等)，周期也不能满足要求·而燃气轮机电厂功率不受限制，建造速度抉，对现场条件要求不高，油田有充足的可供燃用的气体和液体燃料·不少油田还利用开发过程中一时难以利用的伴生气作燃气轮机燃料，价格便宜，发电成本低，增加了燃气轮机的竞争力，所以在油田地区，燃气轮机装置被广泛应用，除用于发电外，还在多种生产作业申用燃气轮机带动压缩机(例如天然气管道输送，天然气回注，气田采油等)和泵(例如原油管道输送和注水等)。 其他工业部门，如炼油厂、石油化工厂、化工厂、造纸厂等等;它们不仅需要机械动力，而且需要大量热(例如蒸汽)。这时用燃气轮机来功热联供，在满足这两方面需要的同时，还能有效地节能，故应用发展较快。 实践证明，燃气轮机作为舰船推进动力，其优点显著，特别是排水量为数千
防火墙基础知识 3.3 包过滤包过滤技术(Ip Filtering or packet filtering) 的原理在于监视并过滤网络上流入流出的Ip包，拒绝发送可疑的包。由于Internet 与Intranet 的连接多数都要使用路由器，所以Router成为内外通信的必经端口，Router的厂商在Router上加入IP Filtering 功能，这样的Router也就成为Screening Router 或称为Circuit-level gateway. 网络专家Steven.M.Bellovin认为这种Firewall 应该是足够安全的，但前提是配置合理。然而一个包过滤规则是否完全严密及必要是很难判定的，因而在安全要求较高的场合，通常还配合使用其它的技术来加强安全性。Router 逐一审查每份数据包以判定它是否与其它包过滤规则相匹配。(注：只检查包头的内容，不理会包内的正文信息内容) 过滤规则以用于IP顺行处理的包头信息为基础。包头信息包括: IP 源地址、IP目的地址、封装协议(TCP、UDP、或IP Tunnel)、TCP/UDP源端口、ICMP包类型、包输入接口和包输出接口。如果找到一个匹配，且规则允许这包，这一包则根据路由表中的信息前行。如果找到一个匹配，且规则允许拒绝此包，这一包则被舍弃。如果无匹配规则，一个用户配置的缺省参数将决定此包是前行还是被舍弃。*从属服务的过滤包过滤规则允许Router取舍以一个特殊服务为基
础的信息流，因为大多数服务检测器驻留于众所周知的TCP/UDP端口。例如，Telnet Service 为TCP port 23端口等待远程连接，而SMTP Service为TCP Port 25端口等待输入连接。如要封锁输入Telnet 、SMTP的连接，则Router 舍弃端口值为23,25的所有的数据包。典型的过滤规则有以下几种： .允许特定名单内的内部主机进行Telnet输入对话 .只允许特定名单内的内部主机进行FTP输入对话 .只允许所有Telnet 输出对话 .只允许所有FTP 输出对话 .拒绝来自一些特定外部网络的所有输入信息* 独立于服务的过滤 有些类型的攻击很难用基本包头信息加以鉴别，因为这些独立于服务。一些Router可以用来防止这类攻击，但过滤规则需要增加一些信息，而这些信息只有通过以下方式才能获
防火墙安装操作手册By Shixiong Chen
一、准备安装介质和服务器 安装CheckPoint防火墙基于开放的服务器平台需要准备两点: 如果选用的是Checkpoint的硬件，UTM-1则不需要考虑这些问题。 第一，准备好服务器，服务器最好选择IBM\HP\或者其他大品牌厂商的硬件平台，并且事先确认该品牌和型号的服务器与CheckPoint软件兼容性，将网卡扩展至与真实火墙一致，服务器需要自带光驱。 第二，准备好CheckPoint防火墙安装介质，注意软件的版本号与真实环境火墙一致，同时准备好最新的防火墙补丁。 二、SecurePlatform系统安装过程 硬件服务器初始状态是裸机，将服务器加电后，设置BIOS从光盘启动，将CheckPoint软件介质放入光驱，然后出现如下界面: 敲回车键盘开始安装。出现如下界面，选择OK,跳过硬件检测。
选择安装的操作系统类型，根据自己防火墙操作系统的版本选择。SecurePlatform Pro是带有高级路由和支持Radius的系统版本。 选择键盘支持的语言，默认选择US，按TAB键，继续安装。 配置网络接口，初始我们配置外网接口即可，选择eth0配置IP, 输入IP地址、子网掩码、以及默认网关，然后选择OK,继续。 选择OK.开始格式化磁盘。
格式化完成后开始拷贝文件，最后提示安装完成，按照提示点击OK.系统会自动重新启动。然后出现登陆界面，如下所示。 第一次登陆系统，默认账号和密码都是admin，登陆后需要出入新的密码和管理员账号。 三、CheckPoint防火墙软件安装过程
运行sysconfig 命令，启动安装防火墙包。选择n,继续安装。 打开网络配置页面，选择1,配置主机名，选择3配置DNS服务器，选择4配置网络，选择5配置路由，注意要与生产线设备的配置保持一致，特别是路由要填写完整，主机名、接口IP和子网掩码要填写正确。 配置完成后，选择n,下一步继续配置，如下图所示，选择1配置时区(选择5，9，1)，选择2配置日期，选择3配置本地系统时间，选择4查看配置情况。注意配置时间和日期的格式。完成后选择n， 然后会出现提示是否从tftp服务器下载安装软件，选择n.然后出现如下界面，选择N,继续安装。 选择Y,接受安装许可协议。
(一) 防火墙概念 防火墙不只是一种路由器、主系统或一批向网络提供安全性的系统。相反，防火墙是 一种获取安全性的方法；它有助于实施一个比较广泛的安全性政策，用以确定允许提供的服务和访问。就网络配置、一个或多个主系统和路由器以及其他安全性措施(如代替 静态口令的先进验证)来说，防火墙是该政策的具体实施。防火墙系统的主要用途就是 控制对受保护的网络(即网点)的往返访问。它实施网络访问政策的方法就是逼使各连接 点通过能得到检查和评估的防火墙。 ____________ ___________ | | | | | Computer | | Computer | |__________| |___________| ____________ ________ | | |应| |Packet | ______|________________|__________| 用|_____|Filter |___Internet | 网| |Router | 网点系统| 关| |________| |__________| 路由器和应用网关防火墙范例 防火墙系统可以是路由器，也可以是个人主机、主系统和一批主系统，专门把网 络或子网同那些可能被子网外的主系统滥用的协议和服务隔绝。防火墙系统通常位于等级较高的网关如网点与Internet的连接处，但是防火墙系统可以位于等级较低的网关, 以便为某些数量较少的主系统或子网提供保护。 防火墙基本上是一个独立的进程或一组紧密结合的进程，运行于Router or Server 来控制经过防火墙的网络应用程序的通信流量。一般来说，防火墙置于公共网络(如Inter- -net)人口处。它可以看作是交通警察。它的作用是确保一个单位内的网络与Internet之间所有的通信均符合该单位的安全方针。这些系统基本上是基于TCP/IP,并与实现方法有关，它能实施安全路障并为管理人员提供对下列问题的答案： * 谁在使用网络? * 他们在网上做什么? * 他们什么时间使用过网络?
文章编号：1009-6825（2013）01-0048-02 临界状态滑坡土层参数反演在工程中的应用 收稿日期：2012-10-26作者简介：王树州（1983-），男，硕士，工程师； 刘强（1978-），男，工程师 王树州 刘强 （安徽省交通规划设计研究院有限公司，安徽合肥230008） 摘 要：针对芜湖至铜陵高速K51+354 K51+500段出现的裂缝及下挫现象，分析了其产生变形的原因，通过不平衡推力法算出 滑坡剩余下滑力， 提出了采用抗滑桩结合挡土墙支护边坡的方案，并在工程运用中得到了很好的效果。关键词：滑坡，临界状态，反演，裂缝及下挫，不平衡推力法 中图分类号：TU435 文献标识码：A 0引言 随着国民经济的飞速发展，大量铁路、公路、矿山等设施的修建，特别是丘陵和山区建设中，人类工程活动中开挖和堆填的边坡数量会越来越多， 高度也将越来越大。如北京—福州高速公路福建段200余千米内高度大于30m 的边坡多达150多处。由于地质条件复杂， 加之人类改造自然规模愈来愈大，设计施工方法不当，高边坡开挖后发生变形和造成灾害的事故频繁发生，给工程运营和人身安全带来很大隐患。 芜湖至铜陵高速K51+354 K51+500为开挖路段，右侧挖方较长，坡高较大，最大坡高31m 。该项目已建成运营近三年时间，于2010年4月K51+420 K51+480段右侧一级坡出现裂缝宽2cm 5cm ，一级坡护面墙局部开裂，二级坡裂缝宽10cm 30cm ，二级坡平台下挫20cm 40cm ，估计松动方量4000m 3，坡 脚未出现剪出口。该滑坡体处于蠕动变形阶地， 若遇到暴雨天气，雨水下渗，有可能会加速下滑，危及人的生命安全。 1滑坡区工程地质概况1．1地形地貌 边坡区地貌属低山丘陵区，区内地形较简单，岗凹相间内，岗丘顶部浑圆，坡面平缓，覆盖层主要为残坡积层，凹地上部覆盖第四系全新统冲积层。 1．2地层结构及岩土体特征 滑坡区上部覆盖层为第四系中更新统残坡积层（Q el +dl 2 ）的粗粒土和高液限粘土，粗砾土层厚7．5m 10．7m ，高液限粘土层厚8．0m 12．4m ，工程性质差；下伏基岩为三叠系下统南陵湖组（T 1n ）灰岩。 1．3水文地质特征 滑坡区主要赋存少量残坡积松散层孔隙水，主要来源于大气 降水补给，季节性变化较大，但由于上部的碎石土夹砂砾石及少量细粒土，渗透性较好，降雨时大量的地表水下渗，而中部高液限 粘土及下部基岩为相对不透水层，致使高液限粘土含水量增高， 而高液限粘土遇水后性质变差，形成软弱层，对边坡稳定不利，滑坡区应设置好防渗及排水措施。 2滑坡基本特征及成因分析2．1 滑坡基本特征 滑坡区位于K51+354 K51+500的右侧，整体坡度为36?， 坡形整体呈上缓下陡，只有护面墙护坡，如图1所示。该滑坡分三级台阶，第三级台阶的护面墙已经损坏，可能是导致降雨入渗的主要原因。第一、第二级台阶的护面墙也有拉裂地方。滑坡区右侧一级坡出现裂缝宽2cm 5cm ，二级坡裂缝宽10cm 30cm ，二级坡平台下挫20cm 40cm ，如图2所示。 图1 滑坡区地貌特征 图2第二级台阶开裂下挫 2．2滑坡成因分析 1）雨水下渗。边坡排水沟、截水沟日渐淤积堵塞，护面墙开裂，导致降雨下渗不能及时的排出坡体，使得坡体含水率增高。而第一级、第二级台阶主要分布着高液限粘土，富含高岭土，具有膨胀性，当坡体含水率增高时，坡体内土体膨胀，膨胀力使得护面墙开裂，同时土体的抗剪强度降低。三级坡的粗粒土夹有少量的 砾石， 渗透性较好，又是雨水下渗的良好通道。2）支挡不足。该边坡坡度较高，1?1 1?1．3的坡率只能保证每一级台阶是安全的，整体边坡是欠稳定的。整个边坡缺乏有效的支挡， 仅仅修筑护面墙是不能抵抗坡体变形产生的下滑力櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅櫅 。On engineering features of collapsible loess ZHANG Ai-fang （Shanxi Jinzheng Construction Engineering Program Management ，Co．，Ltd ，Hejin 043304，China ） Abstract ：According to the distribution regions ，the horizontal and vertical distribution features of the collapsible loess of Shanxi Aluminum Plant ，the paper illustrates the conditions for the self-weight collapsibility ，features for the moment of the self-weight collapsible deformation after being soaked in water ，as well as the scopes for the deformation ，identifies the deformation features of the natural and compacted foundation un-der the measurement of additional collapsible volume ，and concludes the measured self-weight collapsible volume is less than the one of the in-door test calculation ，and the adopted correction factors in the new regulation is fundamentally consistent．Key words ：collapsibility deformation ，subsidiary stress ，self-weight collapsible volume · 84·第39卷第1期2013年1月 山西 建筑 SHANXI ARCHITECTURE Vol．39No．1Jan．2013