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Anti–PD-1(ProgrammedCellDeathReceptor-1)Antibodies
In1992,PD-1(orCD279)wasfirstdescribedbyTasuku Honjoand colleagues.Thename
programmedcelldeathreceptorwaschosen,sincethereceptorwasbelievedtobeinvolved
in T-cell death (214). Later, PD-1 was found to be an immune checkpoint. The tyrosine
phosphatases SHP-1 and SHP-2 (src homology region 2 domain-containing phosphatase)
mediate PD-1’sinhibitory function, dephosphorylating signaling molecules downstream of
theT-cellreceptor(TCR)andtherebyinhibitingcytokineproduction,forexample,IL-2and
IFN-ɣ,andT-cellproliferation.
PD-1isacellsurfacereceptorandincontrasttoCTLA-4,isexpressedonawidevariety
ofcells, including CD4 andCD8T cells,Bcells,monocytes, natural killer(NK) cells,
anddendriticcells(215–217).PD-1isnotexpressedonrestingTcellsbutcanbeinduced
uponactivation(218).Itcanalsobeinducedonantigen-presentingcells(APCs)(219).PD-1
hastwoligands,PD-L1(orCD274orB7-H1)(220,221)andPD-L2(orCD273orB7-DC)
(222).PD-L1isexpressedbymany celltypesincludingepithelial,endothelial,andstromal
cells. Its expression is induced by proinflammatory cytokines such as interferons, tumor
necrosisfactor(TNF),andVEGF.PD-L2isexpressedbyantigen-presentingcells.
UponTCRactivation,TcellsproduceIFN-f,thestrongeststimulatorofreactivePD-L1
expression.RepeatedexposuretocognateantigenstherebyresultsinhighPD-L1expression
andcontinuousPD-1signalingwhichcontinuouslycounteractsthestimulatoryeffectofthe
antigenandeventuallyinducesT-cellexhaustion.T-cellexhaustionisastateofacquiredT-
celldysfunctionandahallmarkofchronicinfection(223)andcancer(224).Itisdefined
by progressive poor effector function and sustained expression of inhibitory receptors.
Immune checkpoint inhibition using PD-1 and PD-L1 inhibitors aims to reverse T-cell
exhaustion.
CurrentlyavailablemonoclonalantibodiesrecognizethereceptorPD-1andtheligand
PD-L1.Forthediscussionoftherelevantclinicaltrials,seeChapters9,10,and11.
Pembrolizumab(MK-3475,Keytruda)
Pembrolizumabisahumanizedmonoclonalanti–PD-1IgG4antibody.Itdoesnotactivate
complementorbindFcreceptors,andtherebyavoidscytotoxiceffectsonTcells.Itbindsto
thePD-1receptorandblockstheinteractionwithPD-L1.
Nivolumab(Opdivo)
Nivolumabis ahuman monoclonalanti–PD-1IgG4 antibody.Comparisonofthe amino
acid sequences of pembrolizumaband nivolumab shows that they are essentially identical
exceptforthevariableregionsthatbindtheantigen(225).CrystalstructuresofPD-L1bound
toPD-1(226)aswellascrystalstructuresofthePD-1ectodomainincomplexwiththeFab
fragmentsofpembrolizumabandnivolumabareavailable(227–229).Thesecrystalstructures
suggestasimilarmechanismforbothantibodies;theycompetitivelyblockPD-L1bindingby
sterichindrance.However,pembrolizumabshowsagreateroverlapwiththePD-L1–binding
site than nivolumab. In fact, there is apparently no overlap between the binding sites of
pembrolizumabandnivolumabonthePD-1molecule,sothatbasedonthecrystalstructure,
simultaneous binding of the two PD-1 antibodies is possible. For the discussion of the
pertinentclinicaldata,seeChapters9,10,and11.
There are emerging data on the combined use of the two different immune checkpoint
inhibitors,thatis,ipilimumab,aCTLA-4antibody,andnivolumab,aPD-1antibody.A
recent phase II trial of this combination treatment in patients with advanced rare
malignanciesincludedacohortof17patientswithgynecologicmalignancies.Theresponse
rate was reported to be 41%, with another 29% of patient having stable disease (230).
Another randomized phase II trial reported a response rate of 31.4% for this
combination treatment in patients with recurrent ovarian cancer (231). It has been
hypothesizedthat the differentmechanisms of thecheckpointimmune inhibitors potentiate
theireffect.Whileanti–CTLA-4antibodiesimproveearlyactivationandprimingofTcellsin
lymphnodes,antibodiestargetingthePD-(L)1systemactlaterintheprocessofT-celltumor
attackandlocallyinthetumormicroenvironment.
Anti–PD-L1(ProgrammedCellDeathReceptorLigand-1)
Antibodies
Durvalumab(Imfinzi)
Durvalumab is a human monoclonal IgG1 antibody. The crystal structure of the PDL1/durvalumabcomplexisavailable(232).
Avelumab(Bavencio)
Avelumab is a human monoclonal IgG1 antibody. The crystal structure of the PDL1/avelumabcomplexisavailable.ThebindingsiteofavelumabonPD-L1partiallyoverlaps
with PD-L1’s binding site to PD-1, thereby ligand-receptor binding is sterically hindered
(233). In a phase II trial of patients with mismatch repair-deficient recurrent
endometrialcancer,avelumab showedan objectiveresponserate of26% regardlessof
PD-L1expressionstatus(234).
Atezolizumab(Tecentriq)
Atezolizumabisafully humanized monoclonal IgG1 antibody.The crystal structure ofthe
PD-L1/atezolizumabcomplexis available. Atezolizumab competes with PD-1 for the same
PD-L1surface(235).
ResistanceMechanismstoImmuneCheckpointInhibition
Variousresistancemechanismstoimmunecheckpointinhibitorshavebeendescribedandan
understandingoftheircomplexityisemerging.Theseinclude:
immunoediting,thatis,interactionsbetweentheimmunesystemandcancercells,results
in the selection of cell clones that lack neoantigens and exhibit poor immunogenicity
(236);
downregulationofthemajor histocompatibility complex-I (MHC-I) and thereby loss of
antigenpresentation(237), or loss of β2-microglobulin function, which disrupts proper
MHC-IfoldingandMHC-Itransporttothecellsurface(238);
establishment of an immunosuppressive and tumor promoting microenvironment
characterized by increased infiltration with regulatory T cells (Tregs) (239) and M2
macrophages(240) mediated by immune modulating cytokines, including TGF-β (241)
andVEGF-A(242);
expression of the indoleamine 2,3-dioxygenase 1 (IDO1) that converts tryptophan to
kynurenine. Kynurenine accumulation has been associated with suppression of T-cell
function(243);
enhanced co-expression of multiple immune checkpoints including TIM-3 (T-cell
immunoglobulinmucindomain-3 protein), LAG-3 (lymphocyte-activation gene 3), and
BTLA (B and T lymphocyte attenuator), which are associated with severe T-cell
exhaustion(244–246);
antibioticusecan shiftthe relativeabundanceof bacterialspecies intheintestinalflora,
reduceitsdiversityandtherebyinduceimmunecheckpointinhibitorresistance(247).This
is likely to be based on decreased cross-reactivity between microbiome and tumor
antigens,togetherwithdecreasedantigenpresentationandcytokineproduction(248,249).
TherapeuticCancerVaccines
Most cancer vaccines are designed to induce antitumor immune responses against
specifictumor-associatedantigens(TAA).TAAsmaybe(i)antigensthatareoverexpressed
in cancers, such as Her2/Neu, or mesothelin, (ii) cancer/germline antigens that are only
expressedingermlinecells,butcanbereexpressedincancercells,forexample,MAGE-A1
(melanomaassociatedantigen),NY-ESO-1(NewYorkesophagealsquamouscellcarcinoma
1),and(iii) celllineagedifferentiationantigens,suchas tyrosinaseand gp100.Therapeutic
cancer vaccines are classified by how the TAA is delivered. The classifications are (i)
peptide/protein-based,(ii)cell-based,(iii)DNA/RNA-based, or(iv) glycan-based.Vaccines
canbegivenaloneoralongwithcytokinesorotherstimulatingfactors.Thedevelopmentof
therapeuticcancervaccineshasfacedthefollowingchallenges:(i)lowimmunogenicity,
(ii)establisheddiseaseburden,and (iii)immunosuppressivetumormicroenvironment.
Examplesoftherapeutic cancervaccinesthathavebeen usedforgynecologicmalignancies
arepresented.
Peptide/Protein-BasedVaccines
Coley’sfirstvaccination,theColey’stoxin,fallsintothiscategory(182).Mixturesofovarian
cancer peptides (250) or peptide fragments of the Her/2Neu receptor have been tested,
mainlyinthepreclinicalsetting(251).
NY-ESO-1(NewYorkEsophagealSquamousCellCarcinoma1)
NY-ESO-1isaso-calledcancer-testisantigen(CTA).Itsexpressionisrestrictedtotesticular
germcellsandplacentaltrophoblastswithnooronlylowexpressioninnormaladultsomatic
cells.However,itisreexpressed innumerouscancer typesandtherebyisagoodtargetfor
cancerimmunotherapy(252).Forovariancancervaccinations,epitopesofNY-ESO-1aswell
asthe fullproteinhave beenused (253,254). PhaseItrials in ovarian cancerhave been of
limitedsuccess,possiblyrelatedtothelowimmunogenicityofthevaccine(255).
DPX-Survivac
DPX-survivac is a mix of HLA (human leukocyte antigen) class I peptides designed to
trigger T-cell responses against survivin. This vaccine has been used for recurrent ovarian
cancerincombinationwithlow-dosecyclophosphamideandepacadostat(256).Thevaccine
was well tolerated and showed antitumor response, with disease control in 9 of 13
patients. A correlation between tumor size and response was noted with lesions ≤5 cm
displayingincreasedtumorregression.ThisphaseIb/IItrialisongoing,withaphaseIIpart
that randomizes DPX-survivac and cyclophosphamide with and without epacadostat. The
latterisaninhibitorofIDO-1(indoleamine2,3-dioxygenase-1)thatmayenhanceeffectorTcell proliferation. Preliminary results have revealed that DPX-survivac with
cyclophosphamideinducesastrongT-cellresponse,evenwithoutepacadostat(257).
Cell-BasedVaccines
Themajorityofcell-basedvaccineshaveuseddendriticcells.Theseantigen-presenting
cellscanbederivedfromapatient’sownmonocytes.Afterleukapheresis,themonocytes
aredifferentiatedexvivointoimmaturedendriticcells,whicharethenstimulatedand
loadedwithantigensandtherebymatured. Thematuredendritic cells present tumor
antigens on their major histocompatibility complexes. Finally, these mature dendritic
cells are administered to the patient. Once reinfused, the mature dendritic cells will
migratetolymphoidorgansandactivateeffectorcellsoftheimmunesystem,primarilyTand
B cells. In this way, it is hoped that cancer immunosuppression might be overcome and
immunosurveillance reinstated. Dendritic cells have been loaded with (i) tumor lysates
(258,259)or(ii)syntheticpeptides,forexample,fusionproteinsofHer2/NeuandGM-CSF
(260)orpeptidesderivedfromWT-1,MUC-1,andCa-125(261).
DendriticCellVaccine(DCVAC)
Forthe DCVAC/OvCarandomized phaseII trial,dendriticcellswereloaded withantigens
obtainedfromovariancancercelllinelysates(262).Theinterimanalysisofthistrialhas
shown a 6-month increase in the progression-free survival, and a trend toward an
increasedoverallsurvival inthegroupthat receivedchemotherapyplusdendriticcell
vaccinemaintenanceafterprimarydebulkingsurgery(263).
DNA/RNA-BasedVaccines
Recombinant vaccinia and fowlpox vectors for prime and booster vaccinations have been
usedtoinduceinvivoexpressionofthetumor-associatedantigensinsomaticcellssuchas
keratinocytesormyocytes.Thisapproachhasbeentestedinovariancancerusingthegenetic
information of NY-ESO-1 (264) and the combination of CEAand MUC-1 combined with
costimulatoryproteins(265).
EngineeredListeriaMonocytogenes
Attenuated live Listeria monocytogenes have been used as bacterial vectors. Listeria are
facultativeintracellular bacteria. Inthecytoplasm, Listeria can induce MHC classIand II
pathwaysandtherebyT-cellresponses(266)anddecreasedregulatoryTcells(267).Inearly
cervical cancer studies, Listeria was used to deliver an HPV E7 plasmid, but the risk of
plasmid loss or antibiotic resistance was noted (268). More recently, Listeria has been
engineeredtoexpressalisteriolysin-E7fusionproteinwhichhasbeensuccessfullyappliedin
preclinicalmodels(269).InaphaseIItrialoflisteriolysin-E7fusionproteininpatients
with recurrentand persistent cervical cancer, overall survival with vaccination alone
wasthesame as when combined with cisplatin (8.8 vs. 8.3 months, respectively), and
therewasapromising34.9%combined12-monthoverallsurvivalrate(270).Inovarian
cancer,Listeriahasbeenusedtoexpressmesothelin(271).
Glycan-BasedVaccines
Most cancer cells display an altered glycosylation pattern (272). In fact, cancer cells are
likelytobeusinguniqueglycosylationpatternsforimmuneevasion(273).Pureglycan-based
vaccines,however,have shownonlymodest successbecause of poorimmunogenicity,and
needtobeconjugatedtohelperT-cellepitopes(274).
Lewis(y)
In a phase I trial, the synthetic pentasaccharide Lewis was coupled to the KLH (keyhole
limpet hemocyanin) carrier protein and used to vaccinate patients with recurrent and
persistent ovarian cancer. At 18 months follow-up, 5 of 24 patients showed a complete
response(275).
AdoptiveCellTherapy
Adoptivecelltherapyisalsoknownascellularimmunotherapy.Adoptivecelltherapy
usesthepatient’s own immune cells by (i) extracting Tinfiltrating lymphocytes from
tumor tissue (TILs), or by (ii) engineering autologous T cells with tumor antigen–
specific surface receptor molecules. T-cell receptor (TCR) therapy, chimeric antigen
receptor(CAR) T-celltherapy, andmorerecentlyengineered naturalkiller(NK) cells are
beingstudied in various clinicaltrials.Among the most commontargetsfor TCR orCAR
directedcelltherapyareNY-ESO1,mesothelin,andthefolatereceptor.
Tumor-InfiltratingLymphocytes(TILs)Therapy
Inthe1980s,StevenRosenbergandcolleaguesperformedthefirstpreclinicalstudiesinmice
withtumor-infiltratinglymphocytes(TILs).TheTILswereisolated,exvivostimulated,and
reinfused(276). Similarto theoriginalexperiments, thecurrentTIL therapyincludesex
vivo expansion of TILs from resected primary tumor material, and reinfusion of
expanded TILs. Cell infusion is preceded by a lymphocyte-depleting conditioning
regimenandfollowedbyhigh-doseinterleukin-2support.Earlyclinicalstudiesusingthis
approachforcervicalcancerhavebeenpromising(277).A recenttwo-cohort phaseIItrial
hasreporteda28%responserateintherecurrentmetastaticcervicalcancercohort(278).The
interimanalysisof anongoingphaseIItrialshoweda 44%objectiveresponseratein
recurrent,metastatic,orpersistentcervicalcancer(279).
EngineeredT-CellReceptor(TCR)Therapy
PeripheralbloodTcellscanalsobeisolated.IfT-cellreceptorsdonotrecognizetumor
antigens,T cells canbegeneticallymodified so that theirTCRsspecifically recognize
and target tumor antigens. In order to be recognized by the TCR, antigens have to be
presented by the major histocompatibility complex (MHC). Many cancer cells, however,
escapeT-cellimmuneresponsebydownregulationorlossofMHCs,whichlimitsthebenefit
ofTCRtherapy(280).
NY-ESO-1
c259
Tcells
There is a clinical trial evaluating different lymphodepleting regimens, that is,
cyclophosphamideversuscyclophosphamideplusfludarabine,inrecurrentplatinum-resistant
ovariancancerthat showedthefeasibilityofthe approach(281).Twoof sixpatientshada
completeresponse(282).
EngineeredT-CellChimericAntigenReceptor(CAR)Therapy
IncontrasttoTCRtherapy,CARTcellsrecognizeandtargettumorcellsindependent
of MHC expression in tumor cells(283). CARs comprise four parts: (i) an extracellular
antigen recognition region derived from a specific antibody, (ii) an extracellular stalk
domain,(iii)a transmembranedomain,and(iv)an intracellularsignalingcomponent.CAR
structureshavenowevolvedintofourgenerations,withthemaindifferencebeingadditional
intracellular costimulatory domains. The first generation of CAR T cells showed only
minimalefficacyanddurability(284).Toimprovetheefficacy,acostimulatorydomainwas
addedtothesecond-generation,dual-fusionCARreceptors.Forthethird-generation,triplefusionreceptorsofCARs,twocostimulatorydomainswereadded.Costimulatorymolecules
includeCD28orCD27,4-1BB,andOX-40(285).ThefourthgenerationofCARscomprises
an inducible element such as the NFAT-responsive (nuclear factor of the activated T cell)
expression cassette that facilitates expression and secretion of transgenic cytokines,
particularlyIL-12(interleukin-12)uponT-cell activation.SecretedIL-12helpsregulatethe
tumor microenvironment (286) (see Fig. 3.4). Preclinical studies of CAR-T cells have
demonstratedefficacyinovariancancermodels(287).
Figure 3.4 T-cell receptors (TCRs) and CAR (chimeric antigen receptors) T cells.
EngineeredT-cellreceptorsto specifically recognize andtarget tumor antigens. CAR T cells
comprisetheextracellularantigenrecognitionregionderivedfroma specificantibody.Forthe
secondandthirdgeneration,co-stimulatorydomainswere added, for example, CD28 and 41BB,toincreasedurabilityoftheCARTcells.ThefourthgenerationofCARTcells,alsocalled
TRUCKs(Tcellsredirectedforuniversal cytokine-mediatedkilling),arearmedwithadditional
cytokine expression. Upon antigen recognition and T-cell response, an inducible response
element, here for example NFAT (nuclear factor of the activated T cell), will activate the
expressionoftransgenicinterleukin-12(IL-12).
NaturalKiller(NK)CellTherapy
Morerecently,otherimmunecellshavebeenusedforadoptivecelltherapy,includingnatural
killercells. Sometrials havestudied intravenousinfusions ofallogeneicnaturalkillercells
fromhaplo-identicalrelateddonorsafterlymphodepletingregimens(288).OnephaseIItrial
has shown a response rate of 29% and stable disease in 57% in patients with platinumrefractory ovarian cancer (289). Studies are ongoing to equip NK cells efficiently with
cancer-specificCARs(290).
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