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Open Journal of
Clinical & Medical
Case Reports
Volume3(2017)
Issue2
ISSN2379-1039
Clinicalbene itsinpatientswithadvancedsolidtumorsafter
long-termimmunizationwithaVEGFtherapeuticvaccine
Katty-Hind Selman-Housein*; Ana de la Torre; Francisco Herná ndez-Bernal; Yenima Martın
́ ; Acralys
Garabito;Jesú sPiñ ero;YanelysMorera;JavierSá nchez;Mó nicaBequet;CimaraBermú dez;Josué dela
Torre;MartaAyala;JorgeVGavilondo
*Katty-HindSelman-Housein
CenterofMedicalandSurgicalResearch,216and11BStreets,Siboney,Playa,Havana,Cuba.
Email:[email protected]
Abstract
CIGB-247 is cancer vaccine candidate that uses a recombinant variant of the human Vascular
EndotheliumGrowthFactor(VEGF)isoform121asantigen,incombinationwithVSSP,abacteriallyderivedadjuvant.Fouryearsago,CIGB-247wasstudiedinaphaseIclinicaltrial(codenameCENTAURO),
wherethevaccinewasadministeredtothirtypatientswithadvancedsolidtumorsatthreeantigendose
level (50, 100 or 400 µg), all combined with 200 µg of VSSP. The vaccine was administered
subcutaneouslyonceaweek,for8weeks,witha inalre-immunizationonweek12.Evaluationofpatients
ontheirweek16provedthatCIGB-247wassafe,withmainlylow-gradelocaladverseevents,andelicited
anti-VEGFneutralizingantibodies,andgammaIFNproducingT-cellsafterinvitrostimulationwitha
mutatedVEGFversion.
Startingonweek16,survivingtrialpatientsreceivedsupervisedvoluntaryoff-trialre-immunizations
every4weeks,using400µgofantigenand200µgofVSSP.Thepresentarticleisacaseseriespresentation
ofthesafetyandclinicalfollowupofeightCENTAUROpatientsthathavereceivedbetween62and66
immunizationswithCIGB-247,withnootheronco-speci ictreatment,andhaveshownanaccumulated
survivaltimerangingbetween4.5to4.9yearsaftertrialinclusion.Noimportantadverseeventshave
beenreportedduringlongtermvaccination.Oftheeightpatients,twoovarycancersandoneNSCLChave
achieved complete response status. A patient with a duodenum adenocarcinoma with pancreas
in iltrationhasrecentlyrelapsedaftertwoyearsfreeofdisease.Anindividualwithapureseminomahas
adocumentedpartialresponse.Theotherthreepatients(ametastaticalveolarsoft-partsarcoma,asmall
intestine carcinoid tumor, and a metastatic pancreas neuroendocrine carcinoma) have maintained a
stablediseasestatusalreadyforseveralyears.Thesesafetyandclinicalevolutionevidencesjustifythe
continuationoftheclinicaldevelopmentprogramofCIGB-247.
Abbreviations
CIGB: Center for Genetic Engineering and Biotechnology; CECMED: Cuban State Center for Medicament
Control; ECOG: Eastern Cooperative Oncological Group; ELISA: enzyme linked immunosorbent assay;
ELISPOT: enzyme-linked immunospot; RECIST: Response Evaluation Criteria in Solid Tumors; VEGF:
vascular endothelial growth factor; VSSP: very small-sized particles; VEGFR2: VEGF receptor 2; IFN:
interferon;PFS:ProgressionFreeSurvival;PFI:ProgressionFreeInterval;NSCLC:non-smallcelllungcancer
OpenJClinMedCaseRep:Volume3(2017)
Selman-HouseinKH
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Keywords
cancer;activeimmunotherapy;VEGF;angiogenesis;clinicaltrial;therapeuticvaccine
Background
VEGFisakeymoleculeinphysiologicalneo-angiogenesisandinthemaintenanceofnormalblood
vessels,butthisgrowthfactorhasbeenalsoassociatedwiththeoccurrenceofpathologicalangiogenesis
inawidespectrumofhumandiseases[1].Inthecaseofcancer[2],VEGFisproducedbytumorcellsin
responsetohypoxia,stimulatingvascularendothelialcellsofnearbynormalbloodvessels,aswellas
theirbonemarrowprecursors,andeventuallyleadingtothedevelopmentoftumorbloodvesselsthatare
necessary for cancer growth and metastasis. Additionally, VEGF produced by cancer cells is also a
powerfulinhibitoroftheimmuneresponseagainsttumors[2].
CIGB-247 is a therapeutic cancer vaccine candidate that combines a recombinant antigen
representativeofhumanVEGFisoform121,andVSSP,apowerfulbacterially-derivedadjuvant[3].The
vaccinewasdesignedtoelicitspeci icantibodiesabletoblocktheinteractionoftumor-producedVEGF
and vascular endothelial cell receptors, thus inhibiting neo-angiogenesis, andto stimulate the
developmentofspeci iccytotoxicTcellsthatcoulddirectlykilltumorandtumorstromalVEGF-secreting
cells.Inmouseexperimentalmodels,CIGB-247wasshowntobeimmunogenicandtoinhibittumor
growthandmetastasis[3,4].Thevaccinewasalsofoundtobesafeinpreclinicaltestsdoneinrats,
rabbits,andnon-humanprimates[5,6].
In2011,theCubanregulatoryauthority(CECMED)approvedthedevelopmentofamulti-center
phaseIclinicaltrialwithCIGB-247inadvancedcancerpatients(RPCEC00000102intheCubanPublic
ClinicalTrialRegistry;codenameCENTAURO).Thestudyinvolvedthirtypatientswithadvancedsolid
tumors, most of which had received all available onco-speci ic therapies without response. The
individualsweredistributedinthreesimilarcohortsthatreceivedeither50,100or400µgoftheantigen,
combinedinallcaseswith200µgofVSSP.Immunizationwasdonesubcutaneousinaweeklyfashion,for
upto8weeks,followedbyare-immunizationonweek12.
Inthe inaltrialevaluationmadein2012afterallpatientshadreachedweek16,CIGB-247was
foundtobesafe,tolerable,andimmunogenic.Positivespeci icIgGtiters,theabilityofserumtoblock
VEGF-VEGF Receptor 2 (VEGFR2) interaction, and positivity in a gamma-IFN ELISPOT were dose
dependent,andbestwiththehigherantigendosevaccinecombination.This,andthe indingofclinical
bene itsinsomepatients,ledtosupervisedvoluntaryoff-trialimmunizationsofindividualssurviving
afterthetrialtime,whichstartedonweek16,andweredonesubsequentlyevery4weeks,withthe
highestantigendose,untilsafetyissues,patientgeneralstateordeathwouldpreventfurthervaccination.
Ina irstpaperpublishedbyourgroupin2014[7]wedescribedtheCENTAUROtrialresults,as
well as the clinical and immunological follow-up of patients that had been submitted to off-trial reimmunizationsforclosetotwoyears.Thepresentarticlepresentsanddiscussesourclinical indingsin
eightoftheCENTAUROpatientsthathavesurvivedbetween4.5and4.9yearsaftertrialinclusion,withno
additionaltreatmentthanmonthlyre-immunizationswithCIGB-247.
Results
Table1presentsthegeneraldataoftheeightpatientsincludedinthispublication,startingwith
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theircodenameandfollowedbydiagnosisattrialonset,numberofimmunizationsreceived(including
vaccinationswithintheCENTAUROtrialperiod),accumulatedsurvivaltimesincetrialinclusion,and
responseevaluationaccordingtoRECISTcriteria[8]atdifferenttimesaftertrialstart.Inthemomentin
which this article was sent for publication (August 2016), three of the patients showed complete
responses,andanotherindividualhadrelapsedandrecentlypassedawayduetodiseaseprogression
aftertwoyearsfreeofdisease.Oftherestofthepatients,oneindividualshowedapartialresponseinhis
tumor,andthreeothershadmaintainedastablediseasestatusforseveralyears.
TheTablealsodepictsabasicclassi icationofthepatientswithrespecttotheirpositivityintwo
speci icimmuneresponsestests.Intheperiod2012-2016,alleightindividualshaveshownpositive
resultsinaninvitrocompetitiveELISAassay[9]thatspeci icallymeasurestheabilityofantibodiesin
serumtoblocktheinteractionbetweenVEGFandVEGFR2.ExceptionmadeofCQ-17,allindividualshave
alsoshowntobepositiveinagamma-IFNELISPOTtest[7],afterstimulationoftheirperipheralblood
lymphocyteswithaVEGFmutatedantigen.
FromthepointofviewofthesafetyoflongtermCIGB-247vaccination,nonewadverseevents
attributabletovaccinationweredocumented,withrespecttothelocalgrade1painanderythemaat
injection site, and occasional fever, reported during the CENTAURO trial and irst follow-up [6].
Interestingly,injectionsitesignsandfevereventsprogressivelydisappearedwithchronicvaccination,
untilthepatientsmadenofurtherreportsinthissenseintheirroutineinterviewsandimmunization
appointments.
A detailed description of the individual patient clinical evolution since their inclusion in the
CENTAUROtrial,isnowpresented.
RECISTstatus(***)
AS(**)
(month
s)
Initial 2012 2013 2015
-14
-16
Patient
code
Diagnosis
attrialonset
Total
numberof
immunizati
onswith
CIGB-247(*)
CH-11
Peritonealmetastasesfroman
ovarianadenocarcinoma
66
58
SD
SD
CR
CR
+/+
CH-19
Peritonealmetastasesfroman
adenocarcinomaofuterus-ovary
64
56
PD
SD
CR
CR
+/+
CH-18
NSCLCwithmetastasesinbothlungs
64
56
PD
SD
CR
CR
+/+
CH-25
Duodenumadenocarcinomawith
pancreasin iltration
64
57
SD
SD
CR
CR,
R,†
+/+
CH-28
Lungandbonemetastasesfromalveolar
soft-partsarcoma
62
54
PD
SD
SD
SD
+/+
CH-07
Liver,lymphnodes,andovarianmetastases
fromSmallintestinecarcinoidtumor
66
59
SD
SD
SD
SD
+/+
CH-15
Pancreaticneuroendocrinecarcinomawith
adrenal,lymphnodeandspleenmetastases
62
58
PD
SD
SD
SD
+/+
CQ-17
Puremediastinumseminoma
64
57
SD
SD
PR
PR
+/−
Immune
Response
Blocking
ability/
ELISPOT(****)
Table1:PatientCharacteristics
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Notes: (*)number includes the 9 vaccinations made during the 12 weeks of the CENTAURO trial; (**)
accumulated survival since the beginning of immunizations with CIGB-247; (***) Response Evaluation
CriteriainSolidTumors(RECIST)classi ication:CR–CompleteResponse,PR–PartialResponse,SD–Stable
Disease, PD – Progressive Disease, R – Relapse, † patient dies of disease progression; (****) for tests
descriptions, please check reference [9] and text; “+”sign indicatesreports of positive results in tests
conductedduringtheperiod2011-2016.
PatientCH-11:
This24yearsoldwomanwasdiagnosedinMayof2010withovarianadenocarcinoma.Shewas
submitted to hysterectomy and double oophorectomy, followed by chemotherapy with 6 cycles of
Paclitaxel and Carboplatin. During her irst follow up after chemotherapy, she was re-diagnosed by
laparoscopyandbiopsyaswithastageIIIBperitonealcarcinomatosis.Thepatientreceivedasecond
treatmentlinewith4cyclesofCyclophosphamide/Adriamycin,withoutresponse,andwasconsidered
chemotherapyresistant.
PatientCH-11wasincludedintheCENTAUROclinicaltrialinSeptemberof2011,withprogressive
diseaseandanECOG1score[10],threemonthsafterherlastchemotherapytreatment.Afterher irst
yearofCIGB-247vaccinationsthepatientwasabletoreturntowork.Onthesecondyearevaluation,the
patientwasreportedasinstablediseasestatus,andfromherthirdyearonanduntilpresent,incomplete
response,withanECOGof0.NolesionshavebeendetectedinCT-scans,andtumormarkersCA125and
HE4[11]havebeennegative.ByAugust2016,CH-11hadreceivedatotalof66immunizations,withan
overallsurvivalof59monthssinceherinclusionintheCENTAUROtrial.
PatientCH-19:
CH-19was52yearsoldinOctoberof2010whendiagnosedofauterus-ovaryadenocarcinoma
(double primary tumors). She was submitted to hysterectomy, oophorectomy, and omentectomy.
Omentummetastaticlesionswerefoundandthepatientwasclassi iedasinstageIIIB.CH-19received6
cyclesofPaclitaxelandCarboplatin.Onlaparoscopyevaluationaftertreatment,peritonealcarcinosisand
liver metastatic lesions were diagnosed (stage IV). A second chemotherapy line was added
(Cisplatin/Adriamycin;6cycles)withoutresponse.
PatientCH-19wasincludedintheCENTAUROclinicaltrialinNovemberof2011,8weeksafterher
lastchemotherapytreatment.ShewasreportedlyinprogressionandherECOGscorewas1.Similarto
patientCH-11,shewasreportedasinstablediseaseafterhersecondyearevaluation,andhasbeenin
completeresponsesinceherthirdyearevaluation.TumormarkersCA125andHE4arenegative.Patient
CH-19isaworkinguniversityteacher,andbyAugust2016shehadreceived64immunizationswith
CIGB-247,withanoverallsurvivalof56monthssincetrialinclusion.
PatientCH-18:
Thisfemalepatientwas44yearsoldinFebruaryof2011whendiagnosedthroughbronchoscopy
andimagingashavingaNSCLCwithbilateralmetastases(T4N2M0-IIIB).Shereceiveda irstlineof
treatmentwith6cyclesofCisplatin/Etoposide(VP-16)andradiotherapy,withoutresponse.
PatientCH-18wasincludedintheCENTAUROclinicaltrialinNovemberof2011,withprogressive
diseaseandanECOG1score.Thepatientwasclassi iedasincompleteresponseandECOGscoreof0after
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thesecondyearevaluationandhasremainedsincefreeofdiseaseaccordingtoclinicalandimaging
criteria. She is an active housewife that exercises daily. By August 2016, CH-18 had received 64
immunizationswithCIGB-247,withanoverallaccumulatedsurvivalof56months. PatientCH-25:
This58yearsoldmalepatientwasdiagnosedinFebruaryof2011byendoscopyofhavinganonsurgicalduodenumadenocarcinoma,withpancreasin iltration(T4NxM1–stageIV).Thepatientwas
submittedtobypasspalliativesurgeryandreceived12cyclesof5- luorouracil/Leucovorin.
CH-25wasincludedintheCENTAUROclinicaltrialinDecemberof2011,twomonthsafterthelast
chemotherapycycle,withstablediseasebutECOG1score.Hemaintainedhisstablediseasestatusforthe
irsttwoyearsafterenteringthetrial,improvinghisECOGscore,andreturningtoworkasafarmerin
2013.Onhisthirdyearevaluation(2014),CH-25wasclassi iedasincompleteresponse.AbdominalCTscan,upperendoscopywithbiopsy,andtumormarkers[10]CEAandCA19-9werenegative.
Onhisfourthyearevaluation(2015)newhepaticlesionswerefoundincontrastedCT-scantests,
suggestingrelapse.CEAwasslightlyovernormalrange,butCA19-9continuedtobenormal.Anupper
endoscopywasnegativeofcancerandthepatientwasasymptomatic,withanECOG0score.However,the
patientshowedarapidprogressionofhisdiseaseinthefollowing6months,whicheventuallyledtohis
demise.Thispatienthadreceived64immunizationswithCIGB-247,andshowedanaccumulatedoverall
survivalof57months,sincehisinclusionintheCENTAUROtrial.
PatientCH-28:
This34yearsoldmalepatientwasincludedintheCENTAUROclinicaltrialinDecemberof2011.
Hehadbeenoriginallydiagnosedwithadeepalveolarsoft-partssarcomaofhisrightarm,andsubmitted
to surgery in November 2007. The tumor had a diameter smaller than 5 cm, and negative margins
(T1bN0M0-GradeII).CH-28receivedpostsurgicaladjuvanttreatmentwith6cyclesofMAID(Mesna,
Doxorubicin,Ifosfamide,Dacarbazine),andradiotherapy.Thepatientwasfollowedupevery3months
and in June 2011, large and numerous metastatic pulmonary lesions were detected. He then was
submitted to Dacarbazine/Carboplatin/Actinomycin D chemotherapy without response. The patient
enteredtheCENTAUROclinicaltrialinprogressionandwithanECOG1score,4weeksafterthelast
chemotherapycycle.CH-28hasbeeninstablediseasestatusandECOG0scoresinceOctober2012,with
noevidencesofnewmetastaticlesions.Hereturnedtoworktwoyearsago.ByAugust2016,CH-28had
received62immunizationswithCIGB-247.
PatientCH-07:
This60year-oldfemalewasincludedintheCENTAUROclinicaltrialinAugustof2011.Shehad
been diagnosed in 1999 with a small intestine carcinoid tumor, which was surgically resected, and
submitted subsequently to 6 cycles of chemotherapy (5- luorouracil, DTIC, Doxorubicin), and
recombinantalphaIFNfor12weeks.CH-07evolvedwelluntil2010,whenupperrightabdominalpain
appeared and was found to have multiple liver, lymph node, and ovarian metastasis. A biopsy by
laparotomy con irmed metastatic disease from a carcinoid tumor. She was submitted to 6 cycles of
chemotherapywithCisplatin/Etoposide(VP-16),andanother12weeksofrecombinantalphaIFN.She
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wasincludedintheCENTAUROclinicaltrial10monthsafterchemotherapyended,classi iedasinstable
disease,butwithliver,lymphnode,andovarianmetastasis,andaECOGscoreof1.
AfteroneyearoftreatmentwithCIGB-247,CH-07improvedherECOGscoreandreturnedbackto
work.Shehasmaintainedastablediseasestatus.ByAugust2016,CH-07hadreceived66immunizations
withCIGB-247,andshowed59monthsofaccumulatedsurvival,sinceenteringtheclinicaltrial.
PatientCH-15:
This63yearsoldmalepatientwasoriginallydiagnosedaswithapancreaticneuroendocrine
carcinomaandmetastaticdisease.Leftsuprarenalglandlaparotomyshowedalesioninvolvingtheportal
vein, and intra-abdominal lymph nodes. He was classi ied as T4N1M1, and in stage IV, with a nonfunctionaltumor.CH-15received6cyclesofAdriamycin/5- luorouracil.Sixteenmonthsaftertheendof
chemotherapy,thepatientwasindiseaseprogressionwithadrenal,lymphnodeandspleenmetastases,
andECOGscoreof1.Hewas inallyincludedintheCENTAUROtrialinOctoberof2011.Oneyearlater,the
patientshowedanimprovedRECISTstatusandwasclassi iedaswithstabledisease.Sincethen,the
patienthasbeenstableandcompletelyasymptomatic,withanECOGscoreof0.CH-15returnedbackto
workin2014.ByAugust2016,thepatienthadreceived62immunizationswithCIGB-247,andshowed58
monthsofaccumulatedsurvivalaftertrialinclusion.
PatientCQ-17:
This 37 years old male was diagnosed in February of 2010 as having a pure mediastinum
seminoma,basedonadirectbiopsytakenduringanunsuccessfultumorsurgery.Thetumorwasnot
removed because of in iltration and involvement of main blood vessels. The patient started with
chemotherapy (Bleomycin/Etoposide/Cisplatin) but treatment had to be stopped in June of 2010
becauseoftoxicity.Thepatientvoluntarilydeclinedanyotherpossibilitiesofoncologicaltreatment.CQ17 was included in the CENTAURO clinical trial in November of 2011, with an ECOG score of 1 and
classi iedasinstabledisease.
Afterremainingstablefor2years,imagingevidencesofareductionintumorsizewerefoundby
late2013.Hewasthen,andhasbeenthereafter,classi iedaswithapartialresponse.Areductionoftumor
massofmorethan50%hasbeenalreadydocumented.HCGinserumisnegativeandLDHlevelsareinthe
normal range. Symptoms (lack of breath after effort) described at the time of his inclusion in the
CENTAUROtrialhavedisappearedandhispresentECOGscoreis0.Thepatientwasbacktoworkin2015,
anddoesregularphysicalworkouts.ByAugust2016,thispatienthadreceived64immunizationswith
CIGB-247.
Discussion
Oneofthemostrelevant indingsinthisoff-trialre-immunizationfollowupstudyisthelong-term
safetypro ileofCIGB-247vaccination.Wehadalreadyreportednonewadverseeventsinanyofthe
survivingpatients,withrespecttothelocallow-gradeonesfoundduringthetrialprotocol,afterthe irst
twoyearsofsystematicoff-trialCIGB-247re-immunization[7].Now,after4.5to4.9yearsofmonthly
repeatedvaccination,theoccurrenceofinjectionsiteeventsandoccasionalfeverhaveprogressively
disappearedinalltreatedpatients.BecauseofthebacterialoriginofVSSP,andtheexistenceofprevious
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reportsoflocaladverseeventsproducedinhumansbyVSSP[13,14],wehadoriginallyhypothesizedthat
someofthelocaladverseeventsseenwithCIGB-247wereprobablyduetotheuseofthisadjuvantinour
vaccinecomposition[7].WethinkthatthelocaleffectsofVSSPhavebecomelessfrequent,and/orcanbe
physiologically adjusted better by the patients, during the off-trial vaccination period, because
immunizationsproceedeveryfourweeks,insteadoftheweeklyregimeusedduringtheCENTAUROtrial.
Inthissense,ithasbeenshownthattheadministrationfrequencyofothersubcutaneousadjuvantshasto
dowiththeamountandintensityoflocaladverseevents[15].
Severe systemic adverse events have been reported after long term application of cancer
therapies that target VEGF, including Bevacizumab [16, 17], the anti-VEGF humanized monoclonal
antibody, commercially known as Avastin®. It is thought that outstanding suppression of cellular
signalizationpathwaysthatareimportantinphysiologicalmicrovasculaturemaintenance,regulation,
andrepairinnormaltissues,underlietheseadverseevents,whichcandifferbetweencancers.
Whileourpatientsampleisstillsmall,anotherpotentiallyrelevant indingderivedfromourlong
term CIGB-247 vaccination study is absence of events reported for other anti-angiogenic drugs. As
previouslymentionedbyusandbyothers[5-7,18-19],importantpharmacologicaldifferencesexist
between the application of externally infused antibodies, and active immunization strategies [20].
Therapeuticvaccinesleadtotheproductionoflower,albeitsustained,levelsofpolyclonalantibodies,a
verydifferentscenariotothatfoundwhentherapeuticmonoclonalimmunoglobulinsareadministered.
In the latter, very high doses of therapeutic antibodies have to be infused in order to achieve
pharmacologicallyactiveconcentrationsintumors,andreportedadverseeffectsinnormaltissuesare
probablyduetothesehighsystemiclevelsofspeci ictherapeuticimmunoglobulins.
Thispotentialverylowtoxicitypro ileopensinterestingpossibilitiesinthefutureuseofCIGB247incombinationwith,orafter,chemotherapy,radiotherapy,orevenotheranti-angiogenictreatments,
andinthechronicapplicationofthevaccineforlong-termcancercontrolpurposes.
TheCENTAUROclinicaltrialwasnotdesignedtoprovethepotentialanti-tumoreffectofCIGB247,soitisimperativetobecautiouswheninterpretingtheimplicationsofthevaccineintheclinical
indingsseenafterlong-termfollowupofsurvivingpatients.Therearehowever,notableevidencesthat
suggest that some clinical bene its could be associated with vaccination. Most of the patients were
symptomatic,withECOGscoresof1,andwithadvanceddisseminatedtumors,ontrialinclusion.Atthe
timethispaperwassentforpublication,threeoftheCIGB-247long-termimmunizedpatientsshowed
completeresponsesandwerebacktotheirnormallifeactivities.Anotherindividualhadonlyrecently
relapsed,afterbeingfortwoyearsfreeofdetectablediseaseandasymptomatic.A ifthpatient,that
rejectedchemotherapyduetohightoxicity,hadachievedapartialresponsestatus,andwasbacktowork.
Threeotherindividualswereinstabledisease,havingimprovedtheirfunctionalECOGscores.These
patientssurvivingtheCENTAUROphaseIclinicaltrialhavereceivedfrom62to66totalimmunizations
with CIGB-247, in the absence of any other speci ic oncological treatment. These evidences are
compelling,moreoverwhenaccumulatedsurvival,countingtimeaftertheirinclusioninthetrial,ranges
from55to59months,thatatleastduplicatingtheexpectedPFStimesforthesetypesoftumors.
PatientsCH-11andCH-19,bothwithadvancedovariancancers,haveshownsimilarpositiveand
noteworthyevolution,andarenowincompleteresponsewithnegativevaluesforrelatedtumormarkers.
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ThemajorityofpatientswithepithelialovariancancerarediagnosedinstageIIIorIVadvanceddisease.
Afterpostoperativetreatment,the5-yearsurvivalrateofpatientswithstageIIIoptimallyde-bulked
(withresidualdiseaselessthanorequalto1cmdiametertumors)rangebetween20%and30%,and
thesenumbersdecreasetolessthan10%forpatientswithsub-optimallyde-bulkedstageIIIdiseaseor
thosewithstageIVtumors[21].Mostpatientswithrecurrentovariancanceraredestinedtodieoftheir
tumors,regardlessofthesecond-linetreatmentmodalityused[22].PatientswithaPFI<6monthsare
lesslikelytorespondtosecond-lineplatinumandareoftenmanagedwithanalternativeagent[23].The
clinicalevolutionofCH-11andCH-19isnoteworthyandhasleadedustoconsiderovariancancerasa
potentialtargetforPhaseII/IIItrialswithCIGB-247.
Patient CH-18, with lung cancer and bilateral metastatic compromise, is de initively an
unexpectedcaseofcompleteresponse.ShewasadmittedtotheCENTAUROclinicaltrialinprogression,
andachievedstablediseaseafterayear,andacompleteresponseaftertwoyearsofvaccinationwith
CIGB-247.Theliteraturedescribesthatonly13%oflungcancerpatientsareexpectedtolive5years.In
thepast20years,inspiteofoncologicaltreatmentsadvances,overallsurvivalisnotimproving.Inthe
caseofIIIBstages,5yearoverallsurvivalisonly7%[24].AphaseIIclinicaltrialthatcompared irstline
carboplatin/paclitaxelversusanarmthatassociatedBevacizumabtochemotherapyinpatientswith
non-smallcelllungcancer,locallyadvancedormetastatic,describedadiscreetPFSimprovementof3.2
monthsintheBevacizumabarm,overthecontrolarm[25].
PatientCH-25(duodenumadenocarcinoma,withpancreasin iltration)wasclassi iedonhisthird
year evaluation as in complete response, only to relapse a year later, with new hepatic tumors. His
accumulatedoverallsurvivalatdeathtimewasof64monthssinceinitialtumordiagnosis.Duodenum
adenocarcinomaaccountsfor45%ofsmallintestinetumorsandoverallsurvivalinmetastaticdiseaseis
8.6months[6].Asreportedinasingleinstitutionalreviewof217patients,70%oftheindividualswith
stageIIIorgreatersmallbowelcancerhad20monthsasmedianoverallsurvival[27].
Oftheotherpatientsofthiscaseseries,CH-28,bearinglungmetastasesfromanalveolarsoftpartssarcoma,isaninterestingcase.Thispatientisinstablediseasesincelate2012,hasanECOGscoreof
0andisbacktowork.ConsideringPFSis7monthsforpatientswithtreatedalveolarsoft-partssarcoma
[28],furthercarefulfollowupofthispatientevolutionisimportant.
PatientCH-07,withliver,lymphnode,andovarianmetastasisfromasmallintestinecarcinoid
tumor,hasachievedasustainedstabledisease.Her4.83yearsofaccumulatedsurvivalsinceenteringthe
trialisnoteworthy,consideringthatinindividualswithboweldiseaseanddistantmetastases5-year
overallsurvivalisonly22%[29].
PatientCH-15,thatenteredthetrialinfrankprogressionwithadrenal,lymphnode,andspleen
metastasesofapancreaticneuroendocrinecarcinoma,isnowinstabledisease,andhasaccumulated
4.75 years of survival since trial inclusion. Median survival for patients with distant pancreatic
neuroendocrinecarcinomais25months,andforpatients60yearsorolder,asinourcase,prognosisis
worse[30].
Finally,patientCQ-17,diagnosedwithanin iltratingpuremediastinumseminoma,hasbeenin
partialresponseinthelast2yearlyevaluations.WithanECOG0score,heisbacktonormallifeactivities.
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Inthisparticularcase,thepatientinterruptedhis irstlinechemotherapycyclesduetohightoxicity,and
voluntarilydeclinedanyothertreatmentmodalities.Chemotherapyrefusalorabandonmentduetoside
effectsisnotararephenomenonincancerpatients.VaccinationwithCIGB-247washisonlypotentially
speci iconcologicaltherapyopportunity,duetotheabsenceofimportantside-effects.
Long-term follow up in this series shows that clinical bene its in patients started to be
documentedafterthe irstyearofvaccination.Thisisinlinewithliteraturethatdescribestheimportance
of chronic immunization to increase the probability of cancer patients to become good speci ic
responders[31].Resultsobtainedinthisinvestigationshowthepotentialofactiveimmunotherapyin
elicitingspeci icimmuneresponsestoaself-antigenlikeVEGF,andallpatientspresentedinthiscase
seriesshowedsomeevidenceofrespondingpositivelytovaccination,intermsofthespeci icimmune
testsdesignedbyustothiseffect[7,9].
Results described in this paper justify the continuation of CIGB-247 clinical development
program.ThevaccinecandidateisnowbeingconsideredforPhaseIIstudiesinspeci ictumors.Asshown
inthispaper,ovariancancerseemstobeaninterestingcandidate.Metastaticcolorectalcancermaybe
anotherrelevanttargettumortostudy,havinginmindthatBevacizumabhasbeenapprovedforthis
speci icniche[32].Futuretrialdesignswillalsotakeintoconsiderationtheinclusionofpatientsinearlier
tumorstages,andthepossibilityofcombinationswithotherdrugs,withconsequentcarefulvaccination
timingstrategies.Controlgroupswillbepartofthesestudies,andeffect/ef icacyofCIGB-247willmost
probablybasedonPFIorPFS,assuccesscriteria.
Basedontheresultswehaveshowninthispaperandotherssoontobepublished,vaccination
strategywillfollowasimilaronetothatusedintheCENTAUROtrial[7].i.e.,aninitialinductionphase
followedbychronicre-immunization.
NewCIGB-247trialswilladditionallytakeintoaccounttheuseofvalidatedtumormarkersthat
arecommonlyemployedinthefollowupoftreatedpatientswiththeaforementionedcancers[11,12].It
couldbethoughtthatblood/plateletVEGFshouldbeanotherpotentialbiomarkerofprognosiswhen
usinganti-angiogenicdrugs.However,itsusebeyondinvestigationpurposesisstillindiscussionbecause
therelationshipbetweenthemeasurementofVEGFlevelsandtreatmentresultshavebeeninconclusive
resultstodate,afterstudiesdonewithanti-angiogenicproducts[33].
Lastly,wewillcontinuemonitoringthespeci icimmuneresponsetothevaccineinfuturetrials,as
part of our efforts to characterize the potential anti-tumor mechanisms of CIGB-247, and to de ine
whetherthesetestscanhelpinpatientstrati icationand/orpredictionoftheresponsetovaccination,as
othershavedonewithothervaccinecandidates[31,34].Ofthethreebasicspeci icimmuneresponse
tests[7,9]thatwehavedevelopedforphaseIclinicaltrials,i.e.,themeasurementofanti-VEGFIgGand
otherimmunoglobulinclassesinserum,theidenti icationoftheabilityofthepatient'ssampletoblock
VEGF/VEGF receptors interaction, and cytokine ELISPOT tests where the patient's lymphocytes are
stimulatedwithamutatedformofVEGF,thetwo irsthumoralresponseassaysaremostprobablythe
onesthatcanberoutinelyemployedinphaseIIclinicaltrials,withemphasisinthosethatcouldprovide
uswithafunctionalcharacterizationoftheindividual'sspeci icantibodyresponse.
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ManuscriptInformation:Received:September20,2016;Accepted:January25,2017;Published:January28,2017
AuthorsInformation:Katty-HindSelman-Housein1*;AnadelaTorre2;FranciscoHerná ndez-Bernal3;YenimaMartın
́ 3;Acralys
2
1
3
3
3
3
Garabito ; Jesú s Piñ ero ; Yanelys Morera ; Javier Sá nchez ; Mó nica Bequet ; Cimara Bermú dez ; Josué de la Torre1; Marta
Ayala3;JorgeVGavilondo3
1
CenterofMedicalandSurgicalResearch,216and11BStreets,Siboney,Playa,Havana,Cuba
CelestinoHerná ndezHospital,564CubaStreet.SantaClaraCity,Cuba
3
CenterforGeneticEngineeringandBiotechnology,31Ave.between158and190Streets.Cubanacá n,Playa,Havana,Cuba
2
Citation:Selman-HouseinKH,delaTorreA,Herná ndez-BernalF,Martın
́ Y,GarabitoA,Piñ eroJ,Morera,etal.Clinicalbene its
inpatientswithadvancedsolidtumorsafterlong-termimmunizationwithaVEGFtherapeuticvaccine.OpenJClinMedCase
Rep.2017;1216
Copy right statement: Content published in the journal follows Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0). ©Selman-HouseinKH2017
Journal: Open Journal of Clinical and Medical Case Reports is an international, open access, peer reviewed Journal
focusingexclusivelyoncasereportscoveringallareasofclinical&medicalsciences.
Visitthejournalwebsiteatwww.jclinmedcasereports.com
Forreprints&otherinformation,contacteditorialof [email protected]
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