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SO THE STORY WITH PAPILLOMA VIRUS
IS MANY THEMES THAT INTERSECT
WITH IT.
SO THESE ARE JUST SOME OF THE
QUESTIONS THAT WENT THROUGH MY
MIND AND I HOPE AS YOU HEAR THE
PRESENTATIONS TODAY, YOU'LL
CERTAINLY FEEL FREE AND
ENCOURAGED TO SPEAK UP AT ANY
TIME, AND THEN ASK YOUR
QUESTIONS.
SO ONE OF THE THINGS THAT I
WONDERED IS 50% OF WOMEN ACQUIRE
PAPILLOMAVIRUS INFECTION WITHIN
A FEW YEARS OF FIRST
INTERCOURSE, WHY IS THE CANCER
INCIDENCE MUCH LESS?
WHAT'S THE DIFFERENCE?
AND WHAT'S RESPONSIBLE FOR THE
LARGE GROUP DIFFERENCES IN THE
INCIDENCE OF CARCINOMA
ASSOCIATED WITH THE
PAPILLOMAVIRUS?
HOW IS PAPILLOMAVIRUS ASSOCIATED
WITH HEAD AND NECK CANCERS?
HOW EFFECTIVE IS THE VACCINE?
HOW SAFE IS IT?
HOW LONG IS IT EFFECTIVE?
WHY DON'T WE VACCINATE MALES?
AND WHY DO THEY RECOMMEND
VACCINATING GIRLS AT AGE 12?
DOES VACCINATION REDUCE THE
FREQUENCY WITH WHICH WOMEN GET
PAP SMEARS?
*** MA BEHAVIOR?
IS THERE ANY EVIDENCE THAT IF A
YOUNG WOMAN IS VACCINATED --
[INAUDIBLE]
ONE OWHAT ARE THE NATIONAL AND EVEN
INTERNATIONAL CHALLENGES?
AND AS ALWAYS IS IN MEDICINE,
WHAT'S NEXT?
SO WE'RE VERY FORTUNATE TO HAVE
TWO SPEAKERS TODAY WHO DEAL WITH
ON ONE HAND PARTICULARLY THE
CLINICAL AND TO SOME EXTENT THE
CELL BIOLOGICAL MECHANISM OF
HEAD AND NECK CANCER, THAT'S
CARTER VAN WAES, HE RECEIVED
HIS DEGREE AT THE UNIVERSITY OF
CHICAGO, AND HERE AT THE NIH IS
THE DIRECTOR OF THE SURGERY
BRANCH OF WHAT I REFER TO AS THE
DENTAL INSTITUTE BECAUSE I CAN'T
REMEMBER ALL --
CRANIOPHARYNGEAL -- RIGHT.
THANK YOU.
OUR SECOND SPEAKER IS DOUGLAS
LOWY, WHO TRAINED AT STANFORD,
CAME HERE TO THE NIH, HAS BEEN
INTERESTED THROUGHOUT HIS CAREER
IN ONCOGENIC VIRUSES.
IT'S THROUGH THE WORK THAT HE
AND JOHN SCHILLER AND THE CANCER
INSTITUTE THAT GAVE RISE TO THE
DEVELOPMENT OF THE VACCINE
AGAINST HUMAN PAPILLOMAVIRUS,
THAT FORM CLOSELY RELATED CANCER
IN MEN AND WOMEN, BUT
PARTICULARLY IN WOMEN.
SO WE'RE VERY GRATEFUL FOR YOU
AND IN ADDITION, DR. VAN WAES
HAS ASKED ONE OF HIS PATIENTS TO
COME, WHO HAS BEEN HERE ONCE
BEFORE.
AND WAS KIND ENOUGH TO SPEND HIS
TIME AND TELL YOU HIS STORY.
SO CARTER, WOULD YOU PLEASE?
THANK YOU VERY MUCH.
PLEASURE TO BE HERE TODAY AND TO
SHARE THE PODIUM WITH -- SPEAK A
LITTLE BIT TODAY ABOUT AN
EMERGING PROBLEM THAT'S RELATED
TO HUMAN PAPILLOMAVIRUS.
JENNINGS CANTRELL IS GOING TO
JOIN US TO TELL US ABOUT HIS
EXPERIENCE WITH HEAD AND NECK
CANCER.
I'M ON.
CAN PEOPLE HEAR ME IN THE BACK?
OKAY.
CAN YOU HEAR ME NOW?
ARE YOU ABLE TO TURN UP THE
MICROPHONE?
HOW IS THAT?
SO AS I WAS SAYING, MY PATIENT,
JENNINGS CANTRELL, HAS BEEN KIND
ENOUGH TO JOIN US TODAY, AND
THEN DOUG LOWY IS GOING TO TALK
ABOUT PREVENTION OF HPV RELATED
CANCERS.
SO THE SLIDES ARE NOT ADVANCING.
THERE WE GO.
SO TODAY I'M GOING TO SPEAK
ABOUT -- AND JUST GIVE AN
OVERVIEW ABOUT HUMAN
PAPILLOMAVIRUS AND CANCER IN THE
UNITED STATES.
DOUG IS GOING TO TALK ABOUT IT
AS A MUCH WIDER PROBLEM AS WELL,
AND ALSO SPEAK ABOUT HPV AND
OVEREAT LOGIC FACTORS FOR HEAD
AND NECK CANCER, BECAUSE THERE
MAY BE SOME EXCLUSIVE ROLE OF
HPV AND OTHER FACTORS IN CERTAIN
SUBSETS OF THESE CANCERS, BUT
THERE ALSO MAY BE SOME OVERLAP
IN THE SUSCEPTIBILITY TO THESE
HEAD AND NECK CANCERS.
AND MR. CANTRELL WILL DISCUSS
HIS CASE WITH US.
I'LL BRIEFLY TALK ABOUT HIS NIH
PROTOCOL TREATMENT, ALTHOUGH
THAT'S NOT REALLY THE FOCUS OF
THE TOPIC TODAY, AND THEN DOUG
WILL SPEAK ABOUT VACCINES.
SO DOUG WAS KIND ENOUGH TO
PROVIDE A SLIDE THAT SUMMARIZES
THE PROBLEM IN THE UNITED
STATES.
IN THE PAST, HPV WAS IMPLICATED
INITIALLY IN CERVICAL CARCINOMA
IN WOMEN, AND THIS IS NOW NOT
THE ONLY PROBLEM IN THE UNITED
STATES.
THERE'S BEEN AN INCREASE IN THE
INCIDENCE OF A NUMBER OF OTHER
SITES THAT HAVE BEEN IMPLICATED
IN HPV RELATED MALIGNANCIES
INCLUDING THE ***, ***,
***, AND MORE RECENTLY IT'S
BECOME CLEAR IN THE LAST DECADE
OR SO THAT THE OROPHARYNX, WHICH
IS THE PART OF THE HEAD AND NECK
AT THE BACK OF THE MOUTH, WHERE
THE TONSILS LIE RIGHT BEFORE THE
PHARYNX, IS ALSO A SITE FOR
INFECTION AND DEVELOPMENT OF
CANCERS THAT ARE RELATED TO THIS
DISEASE.
IN THE U.S., IT'S EMERGED TO BE
IMPLICATED IN ABOUT 70 TO 80% OF
OR OWOROPHARYNGEAL CANCERS, AND THIS
HAS INCREASED OVER THE PERIOD OF
1988 TO 2004 APPROXIMATELY THREE
FOLD.
THIS SLIDE JUST HIGHLIGHTS SOME
OF THE MEASURES OF THAT USING
SAMPLES FROM TUMORS THAT WERE
TAKEN DURING FOUR-YEAR WINDOWS
FROM OVER THAT INTERVAL, SHOWING
AN INCREASE IN THE -- USING A
STANDARD ASSAY FOR HPV, USING
HPV 16 VIRAL LOAD, THE E6,
E7 MARKER, WHICH IS ONE OF THE
VIRAL O ONG ONCOGENES, YOU CAN SEE
THAT OVER THIS PERIOD, THERE'S
BEEN AN INCREASE UP TO THE RANGE
OF ABOUT 70% OF O OROPHARYNGEAL
SQUAMOUS E CELL CARCINOMAS.
ALSO IN THIS PUBLICATION, IT
SHOWS THAT THERE'S ALSO BEEN A
TREND IN DEVELOPING COUNTRIES,
PARTICULARLY IN THE TOP PANEL,
PANEL A, OROPHARYNGEAL CANCERS
ARE SHOWN IN YELLOW, THEN ORAL
CAVITY AND LUNG CANCERS ARE
SHOWN IN BLUE AND GRAY, AND
THOSE HAVE BEEN ASSOCIATED
PRIMARILY WITH THE
TOBACCO-RELATED SUBSET OF THESE
TYPES OF HEAD AND NECK CANCERS.
AND YOU CAN SEE IN THE
DEVELOPING COUNTRIES, PANEL A,
FOR EXAMPLE, THAT THE TREND OF
THE GRAY BARS FOR LUNG CANCER
HAS BEEN DECLINING, WHEREAS THE
TREND IN THE YELLOW BARS IS
MOVING TO THE RIGHT, INDICATING
AN INCREASE IN PREVALENCE.
THIS INCLUDES THE UNITED STATES,
BUT ALSO A NUMBER OF OTHER
DEVELOPING COUNTRIES.
AND THIS IS MORE CLEAR IN MEN
BECAUSE OF THE DIVERGENCE IN
HABITS RELATED TO TOBACCO USE
WITH A DECLINE IN MEN AND THE
INCREASE IN HPV IN MEN AND ON
THE OTHER HAND, WOMEN, SINCE THE
RISE OF TOBACCO USE HAS SOMEWHAT
TRAILED THAT OF MEN IN THE 20TH
CENTURY, THAT INCREASE IS STILL
UNDERWAY FOR LUNG CANCER AND
ORAL CAVITY CANCER, BUT ALSO
THERE'S AN INCREASE IN THE
HPV-RELATED OROPHARYNX CASES.
THE OTHER ETIOLOGIC FACTORS THAT
ARE INVOLVED IN DEVELOPMENT OF
HEAD AND NECK CANCER IS TOBACCO
USE, IS THE OTHER MAJOR
ETIOLOGIC AGENT, AND IN CONTRAST
TO MOST HEAD AND NECK CANCERS
WHERE 70% ARE CAUSED BY TOBACCO
AND ABOUT 30% OR 25 OR 30% ARE
RELATED TO HPV OVERALL, AT THE
SITE OF THE OROPHARYNX, IT'S THE
OTHER WAY AROUND.
MOST OF THESE 70 TO 80% ARE
RELATED TO HPV, AND 25% ARE
TOBACCO-RELATED WITHOUT EVIDENCE
FOR HPV AND ANOTHER 5% MAY
INVOLVE OTHER FACTORS INCLUDING
HEREDITARY SUSCEPTIBLE, CHEMICAL
EXPOSURE AND RADIATION, AND
ALTHOUGH WE SEPARATE THESE THIS
WAY FOR THE PURPOSE OF DEFINING
THOSE WHICH ARE HPV-POSITIVE AND
HPV-NEGATIVE, IN FACT MANY
PATIENTS THROUGH OUR HPV
POSITIVE ARE ALSO TOBACCO USERS
AT SOME POINT IN THEIR LIFE OR
HAVE OTHER TYPES OF EXPOSURES,
SO IT'S QUITE POSSIBLE THAT THE
DEVELOP.
THESE CANCERS WHICH DOESN'T
OCCUR TO EVERYONE WITH HPV MAY
ALSO BE ASSOCIATED WITH
ADDITIONAL ALTERATIONS THAT
OCCUR AS A RESULT OF THEIR
PERSONAL EXPOSURES.
SO WHERE DOES OROPHARYNGEAL
SQUAMOUS CELL CARCINOMA ARISE?
I MENTIONED THAT IT'S ASSOCIATED
WITH THE AREA OF THE TONSILS,
AND MOST TIMES WHEN WE THINK OF
THE TONSILS, WE THINK ABOUT
THOSE TWO LARGE THINGS ON EITHER
SIDE OF THE BACK OF OUR MOUTH
THAT WE SEE IN THE MIRROR, BUT
THERE ARE ALSO PARTS OF THAT
THAT YOU CAN'T SEE, AND THOSE
ARE AT THE BASE OF THE TONGUE.
THOSE ARE CALLED THE LINGUAL
TONSILS, AND THIS IS THE AREA
THAT OUR PATIENT WAS AFFECTED
BY, AND ALSO THERE IS TONSILLAR
TISSUE UP IN THE AREA OF THE
ADENOID, IN THE NASOPHARYNX, AND
IT'S INTERESTING THAT THESE ARE
THE SITES IN THE HEAD AND NECK
CANCER IN WHICH THERE IS A VIRAL
ETIOLOGY IN THE ADENOID AREA,
EPSTEIN-BARR VIRUS HAS BEEN
INVOLVED IN NASOPHARYNGEAL --
THOSE THAT ARE IN THE BASE OF
THE TONGUE, THE LINGUAL TONSILS,
ARE ASSOCIATED PRIMARILY WITH
HPV-RELATED CANCERS.
HOWEVER, THERE HAS BEEN SOME
RECENT REPORTS THAT HPV IS ALSO
IMPLICATED IN CERTAIN
NASOPHARYNGEAL CANCERS,
PARTICULARLY IN NORTH AMERICA,
SO THIS IS ALSO A SITE THAT MAY
BE IMPORTANT TO THIS.
THE REASON FOR THIS MAY HAVE TO
DO WITH THE STRUCTURE OF THE
TONSILS TO SOME DEGREE, THEY
HAVE A VERY THIN EPITHELIUM AND
THIS EPITHELIUM OVERLIES A
COMPARTMENT WHICH IS OUR IMMUNE
DEFENSES IN THAT AREA, MAY HAVE
SOME TYPE OF INTERACTION THAT
PRECIPITATES OR ENHANCES THE
EFFECTIVITY OF THE VIRUS AND ITS
ABILITY TO ESTABLISH ITSELF AND
PERHAPS CANCER.
SO WE'LL NOW SIT DOWN FOR A FEW
MINUTES TO MEET WITH
MR. CANTRELL ABOUT HIS CASE, AND
I HAVE SOME OF IT SUMMARIZED UP
ON THE SLIDE WHICH WE MAY BOTH
TURN TO BECAUSE OUR MEMORY MAY
NOT SERVE US COMPLETELY IN
PRESENTING HIS CASE, BUT I'LL
MOVE OVER HERE WITH HIM AND
WE'LL SIT DOWN AND TALK A LITTLE
BIT ABOUT HIS CASE PRESENTATION.
I'M GOING TO TURN THIS THIS WAY.
GOOD AFTERNOON.
THIS WAS IN NOVEMBER OF 2008, I
THINK WHEN YOU CAME TO SEE US.
MAYBE YOU COULD TELL EVERYONE A
LITTLE BIT ABOUT HOW LONG BEFORE
THAT YOU OR YOUR WIFE NOTICED
WHAT WAS GOING ON AND WHAT YOU
THOUGHT AT THE TIME.
>> WELL, IN THE SUMMER OF 2008,
I DEVELOPED A SORE THROAT, WHICH
IS UNLIKE ANY SORE THROAT THAT I
HAD EVER HAD BEFORE.
AND IT WAS VERY STRANGE.
BUT I JUST DIDN'T MAKE THE
CONNECTION TO ANY KIND OF
SERIOUS ILLNESS.
MY WIFE TELLS ME SINCE THEN THAT
ABOUT EIGHT TO NINE MONTHS
BEFORE THAT, SHE HAD NOTICED MY
BREATH CHANGED, THE SMELL OF MY
BREATH CHANGED.
IT DEVELOPED SORT OF A MUSTY
SMELL, LIKE THE SMELL OF OLD
BOOKS.
BUT SHE DIDN'T -- SHE THOUGHT IT
WAS ODD BUT SHE DIDN'T MAKE A
CONNECTION TO ANY KIND OF
SERIOUS ILLNESS EITHER.
SO I'M IN THE CATASTROPHE
BUSINESS AND I FOUND MYSELF
WORKING IN NEBRASKA, IN OCTOBER
OF 2008, AND WHILE I WAS THERE,
A NODE SPRANG OUT UNDERNEATH MY
JAW, RIGHT ABOUT HERE, AND I
WENT TO A SORT OF WHAT YOU MIGHT
THINK OF AS A DOC IN A BOX, YOU
KNOW, A LITTLE PRACTITIONER THAT
WORKED OUT OF A LITTLE OFFICE,
AND HE GAVE ME AN ANTIBIOTIC AND
HE SAID, IF THIS DOESN'T GO AWAY
IN 10 DAYS, YOU SHOULD SEE AN
ENT.
AND SO WITHOUT GIVING YOU TOO
MUCH OF THE PLAY-BY-PLAY OF HOW
THAT HAPPENED, WITHIN THE 10
DAYS, IT DIDN'T GO AWAY, I DID
SEE AN ENT, HE TOLD ME I SHOULD
IMMEDIATELY GET A CT SCAN, OR IT
WAS AN MRI, I CAN'T REMEMBER
WHICH ONE IT WAS, AND I DID HAVE
THAT TEST.
THAT SAME AFTERNOON, ACTUALLY.
AND HE CALLED ME THE NEXT DAY AT
WORK AND SAID THAT I HAD A MASS,
AND THAT HE WANTED TO SEE ME.
I WENT IN TO HIS OFFICE AND HE
SAID THAT I HAD A MASS WHICH
INDICATED A CANCER SOMEWHERE IN
THE NEIGHBORHOOD OF STAGE 2 TO
3, HE DIDN'T KNOW FOR SURE WHAT,
AND HE SAID HE DIDN'T KNOW
EXACTLY WHAT IT WAS, BUT HE SAID
IT WAS ABOUT AN 80% CHANCE THAT
IT WAS SQUAMOUS CELL CANCER.
SO I WAS ON A PLANE THE NEXT DAY
FOR HOME, AND THE DAY AFTER I
ARRIVED, WE'RE TALKING AGAIN
LATE OCTOBER STILL, BECAUSE
THESE EVENTS WERE HAPPENING, I
PUSHED THEM ALONG AS RAPIDLY AS
I COULD, AND I SAW A HEAD, NECK
ENT HERE IN FIR FAIRFAX, AND SHE
TOOK -- I HAD THE DISK THAT WAS
THE IMAGE OF THE TEST THAT HAD
BEEN DONE, AND SHE TOOK A LOOK
AT IT AND SHE EXAMINED ME AND
SHE SAID, WHAT I'M SEEING -- SHE
USED A SCOPE, AND DON'T KNOW THE
NAME OF IT, BUT I'M SURE THESE
FOLKS KNOW WHAT I'M TALKING
ABOUT.
AND SHE SAID, I DON'T SEE ON THE
SCOPE WHAT I SEE ON THE DISK,
AND I DON'T UNDERSTAND WHAT THAT
IS.
AND SHE COULDN'T SEE ANYTHING ON
THE SURFACE OF MY TONGUE.
AND SO SHE SCHEDULED A BIOPSY
AND SHE PERFORMED THE BIPS.
TURNS OUBIOPSY.
TURNS OUT THE CANCER WAS IN MY
TONGUE, COULD NOT BE SEEN WITH
THE AID OF A SCOPE.
APPARENTLY -- SHE NEVER ACTUALLY
SPOKE TO ME ABOUT IT, SHE TOLD
MY WIFE, THAT I WAS A STAGE IV.
AND SHE LEFT IT TO MY WIFE TO
TELL ME.
AND SHE HAD SOME CONNECTION
HERE, I BELIEVE WITH DR. VAN
WAES, AND SO I CONTACTED THEM
AND IT TURNS OUT THAT THEY HAD A
STUDY THAT INVOLVED TREATMENT
HERE, AND I CAME IN AND SAW HIM
AND THEY DECIDED TO ACCEPT ME IN
THE PROGRAM, AND THEY BEGAN A
PROGRAM OF RADIOLOGY AND
CHEMOTHERAPY, WHICH BEGAN, I
BELIEVE, ON DECEMBER 1 OF 2008.
AND I WAS TREATED THROUGH
JANUARY 26TH, 2009 WITH
CHEMOTHERAPY AND RADIATION, AND
IT WAS AN IMRT MACHINE THAT THEY
REFERRED TO AS A TOMO MACHINE,
WHICH IS APPARENTLY MORE
TISSUE-SPARING THAN STANDARD
IMRT MACHINE.
LATER THAT YEAR, THEY FOUND A
METASTASIS IN MY LEFT LUNG, A
NODE, AND IT WAS REMOVED HERE AT
NIH IN LATE SEPTEMBER OF 2009,
AND I'VE HAD A NUMBER OF PET
SCANS SINCE THEN, AND BIOPSIES
OF ONE THING OR ANOTHER.
IT LOOKS AS THOUGH THAT I AM
CANCER-FREE, AND I HAVE QUITE A
NUMBER OF RESIDUAL PROBLEMS
CAUSED BY THE TREATMENT, BUT IN
VIEW OF THE FACT THAT I AM STILL
HERE, I FEEL THAT IT'S PROBABLY
A GOOD IDEA TO VIEW THOSE AS IN A
SOMEWHAT FIL PHILOSOPHIC WAY.
>> THANKS.
[APPLAUSE]
>> IN TERMS OF WHAT YOU THINK
MAY HAVE BEEN SOME OF THE THINGS
YOU WERE EXPOSED TO OR MAY HAVE
CAUSED THIS, WHAT ARE SOME OF
THE THINGS YOU HAD TOLD US AT
THE TIME THAT YOU REMEMBER?
>> WELL, I SERVED IN VIETNAM AND
WAS EXPOSED TO AGENT ORANGE.
THERE WERE -- I OCCASIONALLY
SMOKED A PIPE OR CIGAR, AND WHEN
I SAY OCCASIONALLY, I MEAN IT
WAS NOT UNCOMMON FOR ME TO GO
SIX MONTHS WITHOUT SMOKING A
PIPE OR A CIGAR, SO
OCCASIONALLY
IN MY CASE MEANS VERY
OCCASIONALLY.
I NEVER SMOKED CIGARETTES OF
EVER IN MY LIFE.
AND SO THOSE, AND NORMAL LIVING,
OR WHAT I WOULD GUESS BE
POSSIBLE AGENTS OF
CAUSATION.
>> SO YOU HAD ALSO HAD AN HPV
TEST DONE ON THE TUMOR SPECIMEN
WHEN YOU HAD THE OUTSIDE
EVALUATION?
>> YES.
THE ENT THAT I SAW HERE, WHEN I
GOT BACK TO FAIRFAX, DID AS PART
OF HER EXAMINATION OF ME A TEST
FOR HPV AND IT WAS NEGATIVE.
AND SO WHEN SHE TOLD MY WIFE
ABOUT THE STAGE IV, SHE SAID
WELL, OF COURSE IF HE WERE -- IF
HE HAD BEEN POSITIVE WITH THE
HPV, HE WOULD HAVE A HIGHER
LIKELIHOOD OF BEING CURED, OR
ACHIEVING A STATUS OF NO FURTHER
CANCER.
BECAUSE, OF COURSE, USING THE
WORD CURED IS A SERIOUS NO-NO
APPARENTLY.
BUT SHE SAID HE'S NEGATIVE FOR
HPV.
SO WE CAN'T COUNT ON THAT.
>> OKAY.
SO I THINK WITH THAT, I'LL GO
AHEAD AND GO BACK UP AND TELL
THE REST OF THE THE STORY AND A
LITTLE BIT ABOUT -- OH, SURE,
SURE.
>> DOES ANYONE HAVE ANY
QUESTIONS?
YES, SIR.
[INAUDIBLE]
>> APPARENTLY.
>> [INAUDIBLE]
>> I NEVER HAD ANYONE SAY THAT.
IT IS TRUE THAT WHEN I WAS
YOUNGER, MY WIFE USED TO
COMPLAIN THAT MY SNORING RATTLED
THE WINDOWS, LITERALLY.
BUT IN LATER YEARS, LAST 25, 30
YEARS, THAT PROBLEM DIMINISHED
AND WENT AWAY, SO NO ONE HAS
SUGGESTED THAT THAT WAS A CAUSE.
>> SO THAT'S WHERE WE LEFT
THINGS.
BY THE OUTSIDE SCAN AND THE
BIOPSY, IT APPEARED TO BE A
STAGE -- THE PRIMARY SIZE OF
THIS TUMOR WAS WHAT WE CALL A T2
ON A SCALE OF 4, AND HAVING A
NECK NODE AND ALSO ON SCAN
HAVING MORE THAN ONE NODE, ONE
ON ONE SIDE AND ONE ON THE
OTHER, IT WAS CALLED AN N2C.
THERE WE GO.
SO AT THAT TIME, THERE WAS ALSO
NO EVIDENCE THAT THIS HAD SPREAD
ANYWHERE ELSE BEYOND THE HEAD
AND THE NECK REGION.
SO WHEN HE WAS SCANNED HERE, A
MONTH LATER, PRETTY MUCH THE
SAME STORY, ALTHOUGH THERE WERE
MULTIPLE LYMPH NODES IN THE NECK
AND THIS TUMOR WAS ACTUALLY
FAIRLY LARGE, IT EXTENDED ACROSS
THE BACK OF THE TONGUE FROM ONE
SIDE ACROSS THE MIDLINE.
IN TERMS OF IMPLICATIONS FOR
THERAPY, THE BACK OF THE TONGUE
IS A FAIRLY UNFOR GIVING AREA
FOR SURGICAL TREATMENT, WHEN IT
GOES ACROSS MORE THAN HALF OF
THE TONGUE AND REALLY REQUIRES
REMOVAL OF THE WHOLE TONGUE.
AND LEAVES PEOPLE BASICALLY
CRIPPLED IN TERMS OF THEIR
SPEECH.
SO OVER THE LAST 20 YEARS OR SO,
THE TREATMENT OF COMBINING
CHEMOTHERAPY OR DRUG TREATMENT
WITH RADIATION HAS EVOLVED AND
HAS BEEN SHOWN TO BE FAIRLY
ACTIVE IN THIS AREA, IN PART
WE'RE LEARNING NOW PERHAPS
BECAUSE THESE ARE HPV-RELATED
CANCERS.
AND SO HE UNDERWENT TREATMENT
WITH AN INVESTIGATIONAL REGIMEN
WHICH COMBINED TWO DRUGS, ONE
CALLED BORTESIMIB AND SER TUCKS
MIB, I'LL GIVE A LITTLE
BACKGROUND FOR THE RATIONALE OF
THAT, CETUXIMAB IS AN ANTIBODY
THERAPY FIRST DEVELOPED FROM AN
ANTIBODY THAT WAS FOUND IN THE
1980s TO BLOCK THE EPIDERMAL
GROWTH FACTOR RECEPTOR, WHICH IS
SEEN IN THE UPPER RIGHT-HAND
CORNER THERE ON THE CELL
SURFACE, AND IT'S AN IMPORTANT
GROWTH SIGNAL FOR HEAD AND NECK
AND OTHER EPITHELIAL CANCERS AND
IT SIGNALS INTO THE CELL THROUGH
A NUMBER OF PATHWAY, INCLUDING
MITOGEN ACTIVATED PROTEASE -- IN
THESE CANCERS, THE ROLE OF
INFLAMMATION I MENTIONED TO YOU
EARLIER THAT THESE CANCERS HAVE,
THEY DEVELOP IN LYMPHOID TYPE
TISSUE IN THE BASE OF THE TONGUE
AND THE TONSILS AND ALSO APPEAR
TO HAVE FAIRLY STRONG SIGNALS OF
A NUMBER OF DIFFERENT CYTOKINES
THAT ALSO SIGNAL TO ACTIVATE
DOWNSTREAM PATHWAYS INCLUDING
THE NF KA PA B PATHWAY.
SO THE TWO DRUGS USED IN THE
STUDY WERE DESIGNED TO TARGET
WITH -- AND ITS ACTIVATION AND
EGF AND ITS DOWNSTREAM PATHWAYS
USING CETUXIMAB.
AND RADIATION TO ACTIVATE THE
P53 FAMILY, WHICH IS INVOLVED IN
INDUCING CELL DEATH AND IS ALSO
INHIBITORY FOR GROWTH.
AND THERE'S JUST A NUMBER OF THE
TARGET GENES WITH THE OBJECT TV
OF THESE DRUGS, WAS TO INHIBIT
THE PHENOTYPE OR THE CANCER
CELL, ITS PROLIFERATION,
SURVIVAL OF THE CELLS AND THE
BLOOD VESSEL FORMATION AND
INFLAMMATION.
SO THE STUDY DESIGN WAS OH TO
GIVE THE CETUXIMAB DRUG WEEKLY
AND TO GIVE THE VOR TEASE MIB
TWICE WEEKLY, FOR THREE WEEKS,
WITH WITH TIME OFF IN BETWEEN OF
ONE WEEK, AND THIS WAS COMBINED
DURING THE TIME WITH RADIATION
THERAPY.
THIS WAS REPORTED AS -- THE
STUDY WAS REPORTED IN CLINICAL
CANCER RESEARCH IN 2011.
SO THE OUTCOME IN MR. CANTRELL'S
CASE IS THAT HE HAD CT SCANS
THREE MONTHS AFTER TREATMENT
THAT SHOWED A COMPLETE RESPONSE
OR ELIMINATION OF THIS MASS IN
THE BASE OF HIS TONGUE WHICH WE
COULD ALSO SEE BOTH IN THE
CLINIC AND IN THE OPERATING ROOM
AND ENDOSCOPICALLY IN THE BIOPSY
OF THAT AREA DIDN'T SHOW ANY
SIGN OF CANCER LEFT AT THAT SITE
SITE.
SO HE WAS CONSIDERED A COMPLETE
RESPONSE AT THAT POINT, BUT ONLY
A FEW MONTHS LATER, HE HAD A NEW
LUNG NODULE WHICH HAD NOT BEEN
SEEN UP TO THAT TIME, AND THIS
WAS RESECTED BY OUR THORACIC
SURGEONS HERE, A SINGLE NODULE,
AND THIS SHOWED A POORLY
DIFFERENTIATED SQUAMOUS CELL
CARCINOMA THAT WAS VERY SIMILAR
TO THE ONE IN THE BACK OF HIS
TONGUE, AND WHAT WAS INTERESTING
ABOUT THIS WAS WE ASKED THEM TO
STAIN IT FOR A MARKER, WHICH IS
A MARKER THAT IS USUALLY
INCREASED IN HPV POSITIVE
CANCERS AND THIS CAME UP
POSITIVE FOR P16, WHICH IS A
MARKER THAT'S CONSISTENT WITH AN
HPV POSITIVE PRIMARY TONGUE
TUMOR.
AND MR. CANTRELL IS NOW
APPROACHING FIVE YEARS OF
DISEASE-FREE SURVIVAL FROM THE
TIME OF HIS LAST TREATMENT.
WHAT WE'VE LEARNED ABOUT
PHARYNGEAL SQUAMOUS CELL
CARCINOMA IS THAT IT IS A
DIFFERENT DISEASE THAN THE TO
TOBACCO-RELATED CANCERS WHICH
HAVE A MUCH WORSE PROGRES PROGNOSIS OF
THE ONE OF THE DIFFERENCES ALSO
HIGHLIGHTED IN THE SAME ARTICLE
WE WERE TALKING ABOUT EARLIER
AND WE'RE PICKING BACK UP ON
AGAIN IS THAT THE MEDIAN
SURVIVAL IS MUCH CLOSER TO FIVE
YEARS FOR HALF THE PATIENTS
SURVIVING FIVE YEARS OR LONGER
COMPARED WITH TWO YEARS FOR THE
TOBACCO RELATED MALIGNANCIES,
AND AGAIN THIS IMPROVEMENT IN
SURVIVAL IN OR OW OROPHARYNGEAL CANCER
HAS TRENDED OVER THE YEARS TO
OCCUR IN PATIENTS IN THE SAME
INTERVAL IN WHICH WE'VE SEEN
THIS INCREASE IN POSITIVITY IN
OROPHARYNGEAL CARCINOMAS IN
PLACE OF TOBACCO-RELATED
OROPHARYNGEAL CARCINOMAS.
SO I'M GOING TO END MY TALK JUST
BY TALKING A LITTLE ABOUT SOME
OF THE EMERGING DATA THAT WE'RE
GETTING FROM THE NEW CANCER
GENOME AT LAS INITIATIVE IN
WHICH ALMOST 300 HEAD AND NECK
CANCERS HAVE NOW BEEN SEQUENCED
USING THE NEXT GENERATION
SEQUENCING TECHNOLOGY THAT'S
ALLOWED US TO MAKE A ROAD MAB OR
A CIRCUIT DIAGRAM OF THE TYPES
OF ALTERATIONS IN THESE
DIFFERENT CANCERS AND FOR HUMAN
PAPILLOMAVIRUS SUBSET OF THESE
CANCERS, WHAT WE KNOW IS THAT
THE VIRUS SERVES AS ONE OF THE
KEY ON COPROTEINS INACTIVATE A
COUPLE OF THE TUMOR SUPPRESSOR
GENES POSH IN THIS TYPE OF IMPORTANT IN TH IS TYPE OF
CANCER, AND IN ADDITION TO THAT,
AS A RESULT OF THAT, THESE
CANCERS HAVE A DIFFERENT GENETIC
ALTERATIONS THAN THE
TOBACCO-RELATED MALIGNANCIES,
WHICH IN MOST CASES RESULT IN
INACTIVATION OF AN UPSTREAM
CYCLIN DEPENDENT KINASE WHICH IS
THE GENE THAT ENCODES P16.
SO THAT'S PATIENTS WHO HAVE
HPV-RELATED CANCERS TEND TO HAVE
IP16 IN MOST CASED, AND AS WELL
THESE CANCERS SHOW MUCH FEWER
GENETIC ALTERATIONS THAN
TOBACCO-RELATED PLAGU MALIGNANCIES
WHICH HAVE GENETIC ALTERATIONS
IN MOST OF THESE OTHER MOLECULES
THAT IN HPV, THERE APPEAR TO BE
IN THESE CANCERS A MUCH MORE
FOCUSED ALTERATION IN THE
PI3 KINASE CATALYTIC STUB UNIT,
WHICH IS AFFECTED IN ABOUT 60%
OF THESE CANCERS, AND ALSO THE
P63, ANOTHER P53 FAMILY MEMBER,
THIS GENE IS AMPLIFIED ALONG
WITH PI3 KINASE IN ABOUT 30% OF
THESE CANCERS AND ADDITIONAL
MUTATIONS AND ANOTHER 30% IN THE
CATALYTIC SUBUNIT.
SO ACROSS THESE PATHWAYS,
PATHWAYS INVOLVED IN CELL
GROWTH, CELL SURVIVAL AND DEATH,
IMMUNITY, AND IN DIFFERENTIATION
APPEAR TO BE AFFECTED BY GENETIC
ALTERATIONS.
ONE OF THE ONES THAT'S
PARTICULARLY NOTEWORTHY IN THE
HPV POSITIVE CANCERS IS A LOSS
OF A GENE CALLED TRAF3, EITHER A
LOSS OR MUTATION, AND THIS
OCCURS IN ABOUT ONE-FIFTH OF THE
HPV-RELATED CANCERS, BUT NOT IN
THE TOBACCO RELATED PLAGUE
NANCYS.
THIS IS OFF PARTICULAR INTEREST
BECAUSE TRAF3 IS NOT ONLY A
NEGATIVE RE REGULATOR FOR ONE OF
THE TRANSCRIPTION FACTORS THAT
ACTIVATES MANY GENES INVOLVED IN
PROLIFERATION, CELL SURVIVAL
INFLAMMATION -- GENESIS BUT IT'S
ALSO A PROTEIN THAT'S INVOLVED
IN INTRODUCING INTERFERON
RESPONSE FACTORS AND INTERFERONS
WHICH ARE INVOLVED IN THE
IMMUNITY TO THE N.A. VIRUSES, SO
WE THINK THIS MAY BE ONE OF THE
IMPORTANT EVENTS THAT
DIFFERENTIATES HPV-POSITIVE
CANCERS FROM TOBACCO-RELATED
CANCERS.
WE'VE KNOWN FOR MANY YEARS THAT
CISPLATIN IS AN ACTIVE AGENT IN
HEAD AND NECK CANCER AND
PARTICULARLY IN HPV-RELATED
OROPHARYNGEAL CARCINOMAS IN
COMBINATION WITH RADIATION, AND
THESE TWO STANDARD THERAPIES
APPEAR TO HAVE SOME OF THEIR
EFFECTS IN DNA DAMAGING EFFECTS
ON CELL PROLIFERATION, ALSO
APPEAR TO CAUSE THE DEGRADATION
OF ONE OF THOSE ON COPROTEINS
P63 AND ALSO BECAUSE THESE
HPV-RELATED CANCERS MAY HAVE
SOME RESIDUAL P53, IT MAY BE
THAT RADIATION IS EFFECTIVE
THROUGH THE -- OF THE VIRAL
ONCOPROTEIN'S INCOMPLETE
INHIBITION OF P53 IN THESE
TUMORS.
IN ADDITION WITH OUR KNOWLEDGE
ABOUT PI3 KINASE, IT MAY BE
POSSIBLE TO TARGET THESE WITH --
INHIBITORS AND PERHAPS REDUCE
THE NEED FOR SOME OF THE MORE
TOXIC AGENTS WHICH WE USE
CURRENTLY IN THOSE TYPES OF
CANCERS.S. SO IN SUMMARY,
INCIDENCE IS INCREASING IN THE
U.S. AND WORLDWIDE.
THESE CANCERS ARE ASSOCIATED
WITH IMPROVED SURVIVAL.
THEY HAVE FEWER ALTERATIONS THAN
HPV NEGATIVE SQUAMOUS CELL
CARCINOMAS, ONE OF THE MARKERS
FOR THIS WE CAN USE CLINICALLY
IS THE RETENTION OF P16, AND
BECAUSE THEY HAVE DECREASED BUT
NOT MUTANT P53 IN CONTRAST TO
THE TOBACCO-RELATED
MALIGNANCIES, THEY MAY HAVE A --
MAY ONE OF THE GREATER FACTORS
RESPONSIVENESS TO OUR STANDARD
THERAPIES, BUT WE'RE LEARNING
ABOUT THE ALTERATION
SPECIFICALLY AFFECTING THESE
CANCERS IN THE CELL CYCLE, AND
THE TRAF -- INTERFERON PATHWAYS
MAY DEFINE SOME NEW POTENTIAL
TARGETS FOR PREVENTION AS WELL
AS THERAPY.
ANY QUESTIONS RELATED TO THAT?
>> THANK YOU VERY MUCH.
[APPLAUSE]
THE SAME PATHWAYS INVOLVED IN
HPV-RELATED TUMORS IN THE ***
AND OTHER ORGANS?
>> JUST IN TERMS OF THE OVERALL
GENOMIC ALTERATIONS BETWEEN THE
TWO CANCERS, PARTICULARLY THE
HPV SUBSET OF HEAD AND NECK --
IT DOESN'T APPEAR THAT
TRAF3 LOSS IS AS COMMON IN
CERVICAL CANCER, FROM WHAT WE
KNOW.
>> SO THE THERAPIES THAT ARE
SOMEWHAT SI SIMILAR?
ALL RIGHT.
WELL, THANK YOU.
>> GOOD AFTERNOON, EVERYONE.
IT'S REALLY A PLEASURE AND AN
HONOR TO HAVE BEEN INVITED AND
ALSO TO BE ABLE TO PARTICIPATE
WITH DR. VAN WAES AND WITH
MR. CANTRELL.
YOU'VE REALLY HEARD, I THINK, A
VERY GOOD INTRODUCTION AS WELL
AS A STRIKING EXAMPLE OF HOW
IMPROVED TREATMENT CAN ACTUALLY
HELP PATIENTS, AND IN ADDITION,
CAN ALSO IMPROVE QUALITY OF
LIFE.
MR. CANTRELL DIDN'T DISCLOSE TO
US EXACTLY WHAT HIS SIDE EFFECTS
WERE, BUT I THINK IT WAS
INSTRUCTIVE THAT THE
EXTENSIVENESS OF HIS CANCER LED
ACTUALLY TO A DECISION TO DO
CHEMOTHERAPY PLUS RADIATION
RATHER THAN SURGERY IN ORDER TO
TRY TO PRESERVE HIS ABILITY TO
SPEAK, ET CETERA.
I AM GOING TO CONTINUE AND TO
SWITCH GEARS A BIT TO REALLY TRY
TO TALK MORE IN THE PREVENTION A
AREA THAN IN THE THERAPEUTIC
AREA, BUT ALSO TO TRY TO ADDRESS
SOME ALTHOUGH PERHAPS NOT ALL OF
THE QUESTIONS THAT -- WAS ASKING
AT THE BEGINNING.
FIRST A LITTLE BIT OF
HOUSEKEEPING DISCLOSURES.
I HAVE BEEN INVOLVED IN THE
DEVELOPMENT OF THE LICENSED
VACCINES AND OUR TECHNOLOGY HAS
BEEN LICENSED TO THE TWO
COMPANIES THAT MAKE THE VACCINES
AND I WILL DISCUSS POTENTIAL
OFF-LABEL USE OF THE TWO
FDA-APPROVED VACCINES.
WHAT I'M GOING TO TALK ABOUT IS
GO BACK BRIEFLY OVER THE NOTION
OF HPV INFECTION AND DE, AND
THEN TALK ABOUT PREVENTION BOTH
BY SCREENING AND VACCINATION,
AND THEN AFTER WE TALK ABOUT
THAT A BIT, TO MOVE TO HPV-BASED
SCREENING AND TO FEWER THAN
THREE VACCINE DOSES, WHICH IS
WHAT THE VACCINES HAVE BEEN
APPROVED FOR UP TO NOW, AND THEN
END WITH A LITTLE BIT ABOUT
SECOND GENERATION VACCINES.
AS WE MENTIONED, I'VE WORKED
VERY CLOSELY WITH JOHN SCHILLER
NOW FOR CLOSE TO 30 YEARS, AND
WE'VE HAD WONDERFUL
COLLABORATORS BOTH WITHIN THE
LABORATORY, WITHIN THE NIH
EXTRAMURALLY, AND IMPORTANTLY,
INTERNATIONALLY.
THE IMPLICATIONS OF -- HPV AS --
HAVE REALLY BEEN PROFOUND AND
EVEN HARVEY ALTAR WOULD APPROVE,
I THINK, R.
WITH THE IDENTIFICATION -- HPV
16 AND 18 IN THE 1980s, LED
FINALLY TO HIS RECEIVING A NOBEL
PRIZE 25 YEARS AFTER THE
DISCOVERY OF THESE TWO VIRUSES.
AND AS WITH ANY OTHER INFECTIOUS
AGENT THAT IS THE CAUSE OF AN
IMPORTANT DISEASE, I HOACH THAT YOU HOPE T HAT
THE DISCOVERY OF THE AGENT WILL
LEAD TO TARGETS AT INTERVENTIONS
AGAINST THE AGENT BECAUSE IN
PRINCIPLE, THAT MIGHT BE EASIER
THAN TRYING TO DEVELOP TREATMENT
THAT IS SPECIFICALLY TARGETED TO
THE DISEASE.
AND I MUST CONFESS THAT WHAT
DR. VAN WAES WAS TALKING ABOUT
FOR MR. CANTRELL IS REALLY
TRYING TO TARGET THE DISEASE AS
OPPOSED TO TARGETING THE HPV IN
THE DISEASE.
IN THIS SITUATION, OF COURSE,
SINCE THERE WASN'T AN OBVIOUS
PRESENCE OF HPV, THE OPTION
DIDN'T SEEM TO BE THERE ANYWAY,
AND WE DON'T HAVE ANY APPROVED
TREATMENT AGAINST HPV ENCODED
PROTEINS, FOR EXAMPLE, FOR THESE
CANCERS.
BUT THIS IDENTIFICATION LED TO
AN EXPLOSION IN UNDERSTANDING
THE NATURAL HISTORY OF HPV
INFECTION, THE PATHOGENESIS OF
CERVICAL CANCER AND ULTIMATELY
TO THE PATHOGENESIS OF OTHER
CANCERS, BUT THE IDENTIFICATION
OF OTHER HPV-ASSOCIATED CANCERS
IS A DIRECT OUTCOME OF THE
IDENTIFICATION OF THE VIRUS.
FOR EXAMPLE, WE DIDN'T REALLY
UNDERSTAND THAT HPV MIGHT BE AN
IMPORTANT CAUSE OF OROPHARYNX
CANCER PRY TO TH PRIOR TO THE DISCOVERY OF
HPV.
SO FIRST IN TERMS OF DISEASE
UNDERSTANDING, IT'S VERY
IMPORTANT.
THE SPECTRUM OF DISEASE I'M
GOING TO CONTRAST WHAT I'M
SHOWING YOU HERE ON THIS SLIDE
WITH THE NEXT SLIDE, WHICH
DR. VAN WAES -- HPV AFFECTS A
HIGH PERCENTAGE OF PEOPLE WHO
ARE SEXUALLY ACTIVE IT, BUT IN
THE DEVELOPING WORLD, IT MAINLY
CAUSES CERVICAL CANCER, AND I'LL
EXPLAIN WHY IN A LITTLE BIT.
THIS PROFILE SHOWS YOU THE
NUMBER OF CASES OF CERVICAL
CANCER THAT OCCUR IN THE
DEVELOPING WORLD ABOUT A HALF
MILLION CASES PER YEAR, AND THE
OTHER HPV-ASSOCIATED CANCERS ARE
MUCH LESS COMMON IN THE
DEVELOPING WORLD.
TO PUT THIS IN PERSPECTIVE, MORE
THAN 90% OF HPV-ASSOCIATED
CANCER IS CERVICAL CANCER, AND
GLOBALLY, ABOUT 85% OF THOSE
CANCERS OCCUR IN THE DEVELOPING
WORLD, AND ABOUT 88% OF THE
DEATHS, SO THAT FROM A GLOBAL
PERSPECTIVE, CERVICAL CANCER IS
THE NUMBER ONE PROBLEM, AND IT
IS A PARTICULAR PROBLEM IN THE
DEVELOPING WORLD AND IN MANY
COUNTRIES IN THE DEVELOPING
WORLD, CERVICAL CANCER IS THE
MOST COMMON CANCER OF WOMEN, AND
IT'S A PARTICULAR PROBLEM
BECAUSE IT TENDS TO STRIKE WOMEN
WHO STILL ARE RAISING CHILDREN,
ET CETERA, RATHER THAN OCCURRING
IN WOMEN WHO ARE GRANDPARENTS,
ET CETERA.
IF YOU CONTRAST THAT PROFILE
WITH WHAT IS SEEN IN THE UNITED
STATES, YOU CAN APPRECIATE THAT
THE OTHER CANCERS, THE
NON-CERVICAL CANCERS, ARE
APPROXIMATELY AS NUMEROUS AS THE
CERVICAL -- AS THE CERVICAL
CANCERS.
THESE WHITE AREAS ARE THE
CANCERS OF THESE TYPES THAT ARE
NOT HPV-ASSOCIATED.
ANOTHER IMPORTANT DIFFERENCE IS
THAT WHILE IN THE DEVELOPING
WORLD, APPROXIMATELY 95% OF
HPV-ASSOCIATED CANCERS OCCUR IN
WOMEN IN THE UNITED STATES, IT'S
MORE LIKE 70% OR SO OCCUR IN
WOMEN, SO THAT ON THE ORDER OF
THREE OUT OF 10 HPV-ASSOCIATED
CANCERS IN THE UNITED STATES ARE
OCCURRING IN MEN.
SO THIS IS ANOTHER CLEAR
DIFFERENCE, AND OROPHARYNX
CANCER, AS DR. VAN WAES HAS
MENTIONED, INCIDENCE HAS
INCREASED SUBSTANTIALLY OVER THE
LAST 25 YEARS, AND IT IS
PREDOMINANTLY MALES WHO DEVELOP
THIS DISEASE, ABOUT A 3:1 RATIO
OF MALES TO FEMALES DEVELOPING
THIS DISEASE.
THUS FAR, CERVICAL CANCER STILL
OCCURS ONLY IN WOMEN, EVEN IN
THE UNITED STATES.
I'M SORRY, THAT WAS A JOKE.
SO WHEN ASKED AT THE BEGINNING
IF HPV INFECTION IS SO COMMON IN
WOMEN, WHY IS CERVICAL CANCER
RELATIVELY UNCOMMON, AND FIRST I
WOULD POINT OUT THAT OUR
ESTIMATES NOW ARE THAT PROBABLY
75 TO 80% OF WOMEN WILL HAVE AT
LEAST ONE GENITAL HPV INFECTION
DURING THEIR LIFETIME.
SO IT'S A VERY COMMON -- IT'S A
VERY COMMON INFECTION, AND IT'S
ALMOST ALWAYS GOING TO BE A
SEXUALLY TRANSMITTED INFECTION.
LUCKILY, THE VAST MAJORITY OF
BOTH MEN AND WOMEN WHO ARE
INFECTED BY HPV, THE INFECTION
IS -- LIMITED, WHICH MEANS AFTER
A PERIOD OF BETWEEN SIX MONTHS
AND TWO YEARS, THE INFECTION
GOES AWAY SPONTANEOU SPONTANEOUSLY.
HOWEVER, THERE IS A SUBSET OF
INDIVIDUALS IN WHOM INSTEAD OF
GOING AWAY, THE INFECTION
PERSISTS, AND PERSISTENT
INFECTION IS A MAJOR RISK FACTOR
FOR THE DEVELOPMENT OF
HPV-ASSOCIATED CANCER, WHETHER
IT IS CERVICAL CANCER,
OROPHARYNX CANCER OR ANY OF THE
OTHER CANCERS.
AND WHAT THIS SHOWS HERE IS THAT
YOU CAN HAVE SPONTANEOUS
REGRESSION, AND SUBCLINICAL
INSPECTION IS MUCH MORE EXON IN
THE U.SCOMMONIN THE U.S. THAN CANCER.
PART OF THE DECREASE HERE IS
BECAUSE WE HAVE EFFECTIVE
SCREENING, PAP SMEAR SCREENING
WAS DEVELOPED APRO APPROXIMATELY 60
YEARS AGO AND HAS HAD A BIG
IMPACT IN REDUCING THE INCIDENCE
AND MORTALITY FROM CERVICAL
CANCER, AND I HAVE A SLIDE FOR
THAT LATER.
BUT THERE ARE STILL ABOUT 12,000
CASES PER YEAR IN THE UNITED
STATES.
ANOTHER ADVANCE THAT IS
ATTRIBUTABLE TO THE DISCOVERY OF
HPV AS A CAUSATIVE AGENT OF
CERVICAL CANCER AND THEN OF
THESE OTHER CANCERS, IS THE
DEVELOPMENT OF HPV-BASED
CERVICAL SCREENING AND HPV
INTERVENTIONS OF THE PREVENTIVE
VACCINE, AND THEORETICALLY,
DEVELOPMENT OF THERAPEUTIC
VACCINES OR ANTIVIRALS, BUT
THERE HAS BEEN LESS ACTIVITY IN
THESE AREAS.
I WOULD POINT OUT THAT IN
ADDITION TO HEPATITIS B VIRUS,
WHERE THERE IS PREVENTIVE
VACCINATION, AND WITH HPV,
HEPATITIS C VIRUS IS ALSO AN
IMPORTANT CAUSE OF LIVER CANCER
AND BECOMING PROGRESSIVELY MORE
IMPORTANT IN THE UNITED STATES.
THERE HAVE RECENTLY BEEN MAJOR
ADVANCES IN THE EFFECTIVENESS OF
THE ANTIVIRAL TREATMENT OF HCV
INFECTION, AND SO WE HOPE THAT
THE INCIDENCE OF SERIOUS
SIRROSIS, LIVER FAILURE AND
LIVER CANCER, ATTRIBUTABLE TO
HCV INFECTION WILL GO DOWN OVER
TIME AS MORE PEOPLE ARE ABLE TO
BE TREATED.
WITH HCV INFECTION, THE
PROTECTIVE IMMUNE RESPONSES ARE
NOT WELL UNDERSTOOD SO IT HAS
TURNED OUT TO BE EASIER TO
DEVELOP APT VIRALS AGAINST HCV
INFECTION THAN TO DEVELOP A
PRIMARY PREVENTIVE VACCINE.
I JUST WANT TO POINT OUT THE WAY
HPV-BASED SCREENING IS DONE IN
THE UNITED STATES IS IN
CONJUNCTION WITH CYTOLOGY, AND
IT'S USED AS A A PRIMARY
SCREENING TEST IN SOME KUN
TRIES.
TWO WEEKS AGO, THE FDA ADVISORY
COMMITTEE SAID THAT THE TESTS
CAN BE USED FOR PRIMARY
SCREENING, DIFFERENT
FDA-APPROVED TESTS, SO I THINK
THAT PRIMARY HPV-BASED SCREENING
IS COMING TO THE U.S. AND WILL
PROBABLY BE AVAILABLE QUITE
SHORTLY.
I'LL EXPLAIN TO YOU PART OF THE
REASON.
THIS LOOKS AT THE INCIDENCE OF
CERVICAL CANCER OVER THE LAST 40
YEARS.
AND WHAT I HOPE YOU CAN
APPRECIATE IS THAT THERE'S BOTH
SQUAMOUS CELL CANCER AND
ADENOCARCINOMA.
THE DECREASED INCIDENCE IS
REALLY PRIMARILY ATTRIBUTABLE TO
THE DECREASE IN SQUAMOUS CELL
CARCINOMA, LESS SO WITH
ADENOCARCINOMA, CYTOLOGY IS A
MUCH BETTER SCREENING TEST FOR
SQUAMOUS CELL CANCER THAN FOR
ADENOCARCINOMA.
AND THE ADVENT OF HPV-BASED
SCREENING CAN IMPROVE THE
RECOGNITION OR THE DETECTION OF
THE INCIPIENT LEAGUES THAT MAY
GO AND PROGRESS TO
ADENOCARCINOMA, AND SO WE ARE
HOPING THAT THE USE OF HPV
TESTING NOT ONLY WILL BE ABLE TO
CONTINUE THIS DOWNWARD CYCLE
HERE FOR SQUAMOUS CELL
CARCINOMA, BUT ALSO TO HAVE AN
IMPACT ON THE INCIDENCE AND
ULTIMATELY THE MORTALITY FROM
ADENOCARCINOMA.
IT'S REALLY IMPORTANT TO
UNDERSTAND THAT ALTHOUGH THE
HEPATITIS B VIRUS VACCINE WAS
FIRST INTRODUCED IN THE 1980s,
THE EVIDENCE FOR REDUCTION OF
LIVER CANCER IS QUITE LIMITED UP
TO THIS TIME BECAUSE THERE'S
SUCH A LONG INTERVAL BETWEEN THE
TIME OF THE INFECTION AND THE
DEVELOPMENT OF THE CANCER THAT
YOU ARE TRYING TO PREVENT.
AND THE SITUATION IS VERY
SIMILAR WITH HPV TO THE EXTENT
THAT YOU'RE TRYING TO PREVENT
CANCER.
HPV INFECTION ALSO LEADS TO SOME
NON-MALIGNANT INFECTION, FOR
EXAMPLE, GENITAL WARTS, AND
THERE, THE IMPACT CAN BE SEEN
MUCH FASTER.
BUT WE HAVE TWO MODALITIES OF
TRYING TO PREVENT CANCER.
ONE IS SCREENING AND THE OTHER
IS VACCINATION, AND I HAVE THIS
SLIDE HERE TO TRY TO IMPRESS ON
YOU THAT ACTUALLY THERE ARE SOME
THEORETICAL ADVANTAGES OF
SCREENING COMPARED TO
VACCINATION.
AND THAT IS, IN PRINCIPLE, YOU
CAN HAVE AN IMPACT ON REDUCING
INCIDENCE OF MORTALITY
ATTRIBUTABLE TO CANCER MUCH
FASTER IF YOU DO SCREENING THAN
IF YOU DO VACCINATION.
BECAUSE VACCINATION IS
PREVENTING THE INITIAL
INFECTION.
WHEREAS SCREENING, YOU ALREADY
HAVE THE INITIAL INFECTION, IT'S
GONE ON FOR SOME PERIOD OF TIME,
AND YOU THEN ARE IDENTIFYING THE
PRECANCERS, AND THIS THEN LEADS
TO THE REDUCTION IN CANCER.
SO WHILE VACCINATION MAY BE AS
EFFICIENT AS SCREENING, IT TAKES
LONGER TO SEE THE IMPACT IF THE
END POINT THAT YOU'RE LOOKING
FOR IS A REDUCTION OF CANCER OR
A REDUCTION IN MORTALITY
ATTRIBUTABLE TO CANCER.
NOURISH AND THIS SHOWS YOU THE
RESULT OF A RANDOMIZED CONTROL
TRIAL OF SCREENING THAT WAS
CARRIED OUT IN RURAL INDIA AND
RECORDED ABOUT FOUR YEARS AGO,
IT WAS SPONSORED BY THE
INTERNATIONAL AGENCY FOR
RESEARCH ON KEAN SER CANCER, WHICH IS AN
ARM OF THE WORLD HEALTH
ORGANIZATION.
AND WHAT I WOULD HOPE YOU WILL
SEE HERE IS THAT THIS IS LOOKING
AT THE MORTALITY RATE OF THE
WOMEN WHO WERE IN THE TRIAL,
WOMEN OF AGE BETWEEN 30 AND 59,
THEY WERE SCREENED ONCE.
AND THEN FOLLOWED UP BASED ON
THE RESULTS OF THE SCREEN.
THESE ARE THE WOMEN WHO RECEIVE
HPV-BASED TESTING.
THE OTHER WOMEN IN THE OTHER
GROUPS WERE EITHER ESSENTIALLY
STANDARD CONTROL GROUP,
CYTOLOGY, OR WHAT'S CALLED
VISUAL INSPECTION WITH ACETIC
ACID, WHICH VERY RECENTLY HAS
BEEN SHOWN TO HAVE SOME IMPACT.
BUT FOR CYTOLOGY AND -- TO HAVE
IMPACT, YOU NEED TO DO SEVERAL
ROUNDS OF SCREENING, WHICH
LOGISTICALLY IS OFTEN VERY
DIFFICULT IN RESOURCE-POOR
AREAS.
HPV-BASED SCREENING, HOWEVER, IS
SUFFICIENT LISTENSTIVE THAT IT
WAS ABLE TO HAVE AN IMPACT ON
MORTALITY WITHIN LESS THAN 10
YEARS.
SO I JUST WANT TO MAKE SURE THAT
WE ALL UNDERSTAND THAT SCREENING
HAS REAL POTENTIAL UTILITY.
I NOW WANT TO TURN TO THE ISSUE
OF PRIMARY HPV VACCINATION.
AND THE LICENSED VACCINES
AGAINST MICROBIAL AGENTS ARE
MAINLY PREVENTIVE, AND THE
INDUCTION OF WHAT ARE CALLED
NEUTRALIZING ANTIBODIES TENDS TO
BE CRITICAL.
NEUTRALIZING ANTIBODIES ARE THE
ANTIBODIES THAT INTERFERE WITH
THE ABILITY OF THE AGENT TO BE
INFECTIOUS FOR THE HOST.
HPVS CONTAIN VIRAL ONCO GENES,
YOU ALREADY HEARD ABOUT E6 AND
E7, E5 IS ANOTHER ONE, AND SINCE
PREVENTIVE VACCINES ARE GIVEN TO
NORMAL POPULATIONS, THE NOTION
WAS THAT YOU PROBABLY WOULD NOT
WANT TO BE GIVING ONCOGENES TO
NORMAL POPULATION, AND SO A
SUBUNIT VACCINE LACKING THESE
ONCOGENES PROBABLY MADE MORE
SENSE IF IT COULD BE SUCCESSFUL,
AND PAPILLOMAVIRUSES ENCODE TWO
PROTEINS THAT INDUCE
NEUTRALIZING ANTIBODIES, WHICH
ARE THE TWO CAPSID PROTEINS, THE
CAPSID IS THE VIRUS PARTICLE,
AND IS COMPOSED OF TWO PROTEINS,
L1 AND L2.
L1 CONTAINS WHAT ARE CALLED THE
IMMUNODOMINANT NEUTRALIZATION
EPITOPES.
WHAT THIS MEANS IS THAT IF YOU
IMMUNIZE WITH THE WITH THE VIRUS
PARTICLE, THE MAIN NEUTRALIZING
ANTIBODIES ARE DIRECTED AGAINST
L1, AND THEY ARE
CONFORMATIONALLY DEPENDENT,
WHICH MEANS THEY ASSUME SOME
KIND OF NATIVE STRUCTURE RATHER
THAN THEIR LINEAR EXTENDED
STRUCTURE, AND THE KEY
HYPOTHESIS WAS THAT L1 COULD
SELF-ASSEMBLE TO MAKE EMPTY
PARTICLES HAVING A CONFORMATION
THAT INDUCES HIGH LEVELS OF
NEUTRALIZING ANTIBODIES, AND
THAT INDEED WAS THE CASE.
THIS IS A PICTURE OF HPV 16
VIRUS-LIKE PARTICLES MADE IN
INSECT CELLS BY INFECTING THEM
WITH A RECOMBINANT BACK LOW
VIRUS THAT EXPRESSES L1.
AND THEY ASSEMBLE SPONTANEOUSLY
INTO THESE PARTICLES, AND THE
PARTICLES HAVE WHAT SEEMS TO BE
THE ARRANGEMENT AND CONFORMATION
OF AUTHENTIC VIRUS PARTICLES
EXCEPT THAT THEY ARE DEVOID OF
THE VIRAL GENOME.
AND THEY'RE ABLE TO INDUCE HIGH
TITERS OF NEUTRALIZING ANTIBODY,
THEY'RE NON-INFECTIOUS AND
NON-ONCOGENIC.
THERE ARE TWO COMMERCIAL HPV
VACCINES.
ONE, GARDASIL MADE BY MERCK, AND
THE OTHER, SERVE RIX, MADE BY
GLAXOSMITHKLINE.
THE GLAXOSMITHKLINE VACCINE IS A
BIVALENT VACCINE, IT USES
VIRUS-LIKE PARTICLES FROM HPV 16
AND 18, AND TOGETHER, THEY
ACCOUNT FOR ABOUT 70% OF
CERVICAL CANCER AND EVEN HIGHER
PERCENTAGE OF THE NON-CERVICAL
CANCERS.
THE MERCK VACCINE, IN ADDITION
TO HAVING PARTICLES FOR HPV 16
AND 18, ALSO HAVE PARTICLES FOR
HPV 6 AND 11.
AND TOGETHER, HPV 6 AND 11
ACCOUNT FOR ABOUT 90% OF GENITAL
WARTS, AND I WANT YOU TO
REMEMBER THAT, BECAUSE I'M GOING
TO SHOW YOU A SLIDE ABOUT THE
IMPACT IN AUSTRALIA ON THE
INCIDENCE OF GENITAL WARTS IN
THE LAST FEW YEARS SINCE THE
INTRODUCTION OF THE VACCINE.
I WOULD POINT OUT THAT BOTH
VACCINES ARE GIVEN IN
INTRAMUSCULAR INJECTIONS OVER
SIX MONTHS.
THE ADJUVANT THAT IS USED BY
GLAXOSMITHKLINE IS A PROPRIETARY
ADJUVANT CALLED ASO4, AND IT'S A
LITTLE BIT MORE IMMUNOGENIC THAN
THE ALUM ADJUVANT THAT IS USED
IN THE MERCK VACCINE, AND I JUST
WANT YOU TO BE AWARE THAT THERE
ARE SOME DIFFERENCES.
IN THE UNITED STATES, AND MOST
PLACES IN THE WORLD, THE MERCK
VACCINE DOMINATES IN TERMS OF
MARKET SHARE.
AND THE REASON FOR THAT IS THAT
THE MERCK VACCINE WAS APPROVED
IN 2006, WHEREAS THE GSK VACCINE
WASN'T APPROVED UNTIL 2009.
SONE OF THE OTHER QUESTIONS
THAT -- WAS ASKING ABOUT IS WHAT
ABOUT SAFETY, OKAY?
I HAVE ANOTHER SLIDE THAT
DISCUSSES THIS FROM A
SOCIOLOGICAL PERSPECTIVE, BUT
THIS IS TO TRY OH TO DISCUSS
THIS FROM A SCIENTIFIC AND
EVIDENCE-BASED PERSPECTIVE.
THE CENTERS FOR DISEASE CONTROL
HAS A PASSIVE REPORTING SYSTEM
CALLED THE VACCINE -- FOR A FEW
YEARS AFTER THE INTRODUCTION OF
THE VACCINE, THERE WERE
THOUSANDS OF REPORTS THAT CAME
IN OF DIFFERENT KINDS OF SIDE
EFFECTS, AND THERE WAS A HIGHLY
PUBLICIZE PAPER THAT WAS
PUBLISHED IN THE JOURNAL OF THE
MEDICAL -- TH THE AMERICAN MEDICAL
ASSOCIATION FOUR OR FIVE YEARS
AGO THAT IDENTIFIED THESE
VARIOUS POTENTIAL SIDE EFFECTS
AS BEING VACCINE-ASSOCIATED.
WHAT THE CDC AND THE FDA DO IS
THAT THEY FOLLOW UP THE --
RESULT WITH WHAT IS KNOWN AS THE
VSD, WHICH IS THE VACCINE SAFETY
DATA --, AND THIS IS A
PROSPECTIVE STUDY FROM SEVERAL
MANAGED CARE ORGANIZATIONS THAT
LOOKS AT WHAT THE SIDE EFFECTS
ARE ASSOCIATED WITH A NUMBER OF
DOSES.
THE PRINCIPLE DIFFERENCE BETWEEN
THE VAIRS AND THE VSV IS THE
SAIRS IS ANECDOTE, THERE IS NO
DENOMINATOR.
IT JUST GIVES YOU A CERTAIN
NUMBER OF CASES.
THE VSV IS EVIDENT BECAUSE IT
HAS BOTH A NUMERATOR AND A
DENOMINATOR.
IT TELLS YOU THE FREQUENCY OF
SIDE EFFECTS FOR A CERTAIN
NUMBER OF DOSES, AND IT HAS
COMPARATORS.
THERE'S M NO VACCINE RELATED RISK
TO PRESPECIFIED OUTCOMES IN THIS
STUDY FROM 2011 THAT WAS
RECENTLY UPDATED WITH
1.5 MILLION DOSES PRESENTED AT
THE ADVISORY COMMITTEE ON
IMMUNIZATION PRACTICES LAST
YEAR.
THE RATE OF AN FLAX IS IS
SIMILAR TO THAT OF OTHER VEAK
VACCINES AND THE RATE OF
FAINTING IS SIMILAR TO THAT OF
OTHER ADOLESCENT VACCINES.
HOW ABOUT EFFICACY?
IN BLACK IS THE EFFICACY FOR THE
MERCK VACCINE OND IN ORANGE IS
THE EFFICACY FOR THE GSK
VACCINE.
AND THIS IS IN THE GROUP OF
YOUNG WOMEN WHO WERE 16 TO 23 AT
THE TIME OF VACCINATION WHO
DURING THE VACCINATION PERIOD
WERE VIRUS-NEGATIVE AND/OR
ANTIBODY -- WERE AP ANTIBODY
NEGATIVE.
THIS IS THE GROUP THAT IS
CLOSEST TO THE TARGET GROUP THAT
YOU WANT TO VACCINATE, BECAUSE
YOU WANT TO VACCINATE PEOPLE WHO
ARE NOT YET SEXUALLY ACTIVE, BUT
IN ORDER TO DO THE TRIAL, THE
TRIAL WAS CONDUCTED IN WOMEN WHO
HAD HAD A LIMITED NUMBER OF
*** PARTNERS BUT WERE
SEXUALLY ACTIVE.
AND WHEN LOOKING AT THIS
SUBGROUP OF WOMEN, THE VACCINE
EFFICACY IS OVER 90% AND IS
CLOSE TO 100%.
FOR THE MERCK VACCINE, THERE ARE
NUMEROUS END POINT, CLINICAL
POINTS THAT WERE USED, MODERATE
AND HIGH GRADE CERVICAL
INTRAEPITHELIAL NEOPLASIA, WHICH
IS PRECANCER, ESSENTIALLY,
PRECANCER FOR VULVAR AND VAGINAL
NEOPLASIA AND FOR THE MERCK
VACCINE, ALSO GENITAL WARTS.
AND THE MERCK VACCINE IS
APPROVED BY THE FDA FOR ALL OF
THESE INDICATIONS.
THE GSK VACCINE WAS ANALYZED FOR
A MORE LIMITED NUMBER OF
OUTCOMES JUST FOR CERVICAL
PRECANCER AND AGAIN HAD A
PERFORMANCE THAT WAS VERY
SIMILAR TO THAT OF THE MERCK
VACCINE, BUT IT IS ONLY APPROVED
FOR PREVENTION OF CERVICAL
CANCER, NOT FOR THE OTHERS.
HOWEVER, PART OF MY -- NOT OFF
LABEL USE BUT AT LEAST
MENTIONING, THERE'S EVERY REASON
TO BELIEVE THAT THE GSK VACCINE
WOULD BE JUST AS EFFICACIOUS IN
PREVENTING INFECTION AND DISEASE
AT THE OTHER SITES.
HOWEVER, YOU WOULD NOT EXPECT IT
TO BE AS EFFICACIOUS AGAINST
GENITAL WARTS, AND WITH DATA THE DATA
ACTUALLY SUPPORT THAT BUT I'M
NOT GOING TO PRESENT THAT
BECAUSE THE GSK VACCINE DOESN'T
REALLY -- DOESN'T TARGET HPV
6 AND 11.
SO WHAT ARE THE GOALS OF
VACCINATION?
MOST PEOPLE THINK ABOUT THE
GOALS OF VACCINATION BEING
PRIMARILY TO REDUCE THE RISK OF
INFECTION AND DISEASE IN
VACCINEES.
AND WHILE THAT IS CRITICALLY
IMPORTANT, IN MY OPINION,
ESPECIALLY WHEN IT COMES TO HPV
VACCINATION, THAT'S JUST ONE OF
THE GOALS.
I THINK THAT THERE IS ALSO A
SECOND GOAL, AND THAT IS TO
INDIRECTLY REDUCE THE RISK OF
INFECTION BY REDUCING THE
PREVALENCE OF THE HPV VACCINE
TYPES IN THE GENERAL POPULATION,
WHICH IS KNOWN AS HERD IMMUNITY.
ONE OF THE FEATURES OF THE HPV
VACCINE IS THAT NEITHER VACCINE
IS APPROVED FOR PREVENTION OF OR
OROPHARYNX CANCER.
THE PRINCIPAL REASON FOR THAT IS
THAT IN CONTRAST TO THE
PRECANCERS THAT OCCUR IN THE
*** CANAL, VULVAR OR VAGINAL,
AND AT THE ***, THERE IS NOT
A WELL-RECOGNIZED PRESERVE
CAL -- PRECANCEROUS LEAGUES IN
THE OROPHARYNX.
AND THEREFORE, YOU DON'T HAVE
THAT DISEASE TO FOLLOW TO SEE IF
YOU ACTUALLY PREVENT IT.
SO THE BEST THAT WE CAN DO IS TO
SHOW THAT YOU CAN REDUCE THE
RISK OF HPV INFECTION IN THE
MOUTH, AND THE RELATIONSHIP
BETWEEN HPV INFECTION IN THE
MOUTH AND THE DEVELOPMENT OF
OROPHARYNX CANCER IS MORE
TENUOUS THAN THE RELATIONSHIP
BETWEEN THE PRECANCERS IN THE
GENITAL TRACT AND THE
DEVELOPMENT OF CANCER.
AND SO IT'S NOT APPROVED FOR
THAT.
BUT IN MY OPINION, THERE IS
EVERY REASON TO EXPECT THAT IF
YOU REDUCE THE PREVALENCE OF THE
HPV, YOU WILL REDUCE EXPOSURE
AND IT'S REALLY ALMOST
IMPOSSIBLE TO IMAGINE THE
SCENARIO.
IF YOU REDUCE EXPOSURE, YOU WILL
REDUCE THE INCIDENCE OF THIS
DISEASE.
SO I ACTUALLY THINK THAT BOTH OF
THESE ARE IMPORTANT.
NOW, HERE ARE TWO SLIDES OF
GENITAL WARTS IN AUSTRALIA.
IN AUSTRALIA, AS I'LL SHOW YOU
IN A FEW SLIDES, WAS AN EARLY
ADOPTER COUNTRY AND A RELATIVELY
HIGH RATE OF HPV VACCINATION
AMONG YOUNG WOMEN.
IF YOU LOOK IN BLUE, THIS DOTTED
LINE SHOWS YOU WHEN THE VACCINE
WAS INITIATED IN 2007, AND THE
INCIDENCE OF GENITAL WARTS AMONG
YOUNG WOMEN WHO WERE LESS THAN
21 YEARS OF AGE WENT DOWN
DRAMATICALLY IN THE ENSUING FOUR
YEARS.
IF YOU LOOK IN RED, THIS IS IN
WOMEN 21 TO 30, MANY OF THESE
WOMEN WERE VACCINATED.
WOMEN OVER 30 WERE NOT
VACCINATED, AND YOU CAN SEE THAT
THE INCIDENCE OF GENITAL WARTS
DID NOT GO DOWN IN THOSE
UNVACCINATED WOMEN.
EVEN MORE IMPRESSIVE ARE THE
DATA IN THE MALES.
BECAUSE DURING THIS TIME PERIOD,
MALES WERE NOT VACCINATED.
THEY RECENTLY HAD INITIATED
VACCINATION OF MALES, BUT THESE
DATA ARE COMPILED BEFORE MALE
VACCINATION WAS INITIATED, AND
THIS IS STRONG EVIDENCE OF HERD
IMMUNITY.
ONCE AGAIN, LOOKING IN BLUE,
THESE ARE THE MEN WHO ARE UNDER
21, YOU CAN APPRECIATE THEIR
INCIDENCE OF GENITAL WARTS WEPT
DOWN DRAMATICALLY, ALTHOUGH NOT
TO THE SAME DEGREE AS THE WOMEN,
AND THE SAME THING IS TRUE FOR
THE MEN WHO WERE 21 TO 30, AND 30 AND NO
STATISTICALLY SIGNIFICANT CHANGE
IN THE MEN WHO ARE OVER 30.
SO I WANT TO SPEND A COUPLE OF
MINUTES ASKING AND TRYING TO
ADDRESS THE QUESTION, WHY IS THE
VACCINE SO EFFECTIVE?
THERE WAS UNDERSTANDABLY GREAT
SKEPTICISM ABOUT THE ABILITY OF
SYSTEMIC IMMUNIZATION WITH A
PROTEIN-BASED VACCINE TO BE ABLE
TO REDUCE INFECTION AND DISEASE
THAT IS CAUSED BY A LOCAL
MUCOSAL INFECTION, BECAUSE THE
PRINCIPAL TARGET WAS CERVICAL
INFECTION, AND CERVICAL
INFECTION IS A LOCAL MUCOSAL
INFECTION.
AND SO WE THINK THAT THERE ARE
SORT OF THREE REASONS.
THE FIRST IS THE REPETITIVE
STRUCTURE OF THE VIRUS-LIKE
PARTICLE I MUTE JEAN IS
IMMUNOGENIC.
THIS IS SOMETHING THAT HAS
BECOME MORE WIDELY RECOGNIZED IN
THE RESEARCH COMMUNITY OVER THE
LAST FEW YEARS, AND ACTUALLY IN
JUNE, THERE'S GOING TO BE THE
SECOND INTERNATIONAL CONFERENCE
ON VIRUS-LIKE PARTICLES AND
NANOPARTICLE VACCINES BECAUSE OF
THEIR IMMUNOJE NECESSITY IN A
SMALL ADVERTISEMENT FOR MY
PARTNER IN CRIME, JOHN SCHILLER,
IS GOING TO BE GIVING THE
KEYNOTE ADDRESS AT THAT MEETING.
A SECOND REASON IS THAT THE
TISSUE ASSOCIATED NEUTRALIZING
ANTIBODIES ARE EXUDATED AT
POTENTIAL SITES OF INFECTION.
WHAT THAT MEANS IS THAT THE
ANTIBODY LEVELS AT THESE SITES
REFLECT THEIR LEVEL IN SERUM
RATHER THAN THEIR LOWER LEVELS
IN THE NON-DISRUPTED GENITAL
TRACT.
AND I'LL SHOW YOU PICTURES ABOUT
THAT IN THE NEXT TWO SLIDES.
AND THEN FINALLY, HPV IS HIGHLY
SUSCEPTIBLE TO NEUTRALIZING
ANTIBODIES.
SO THIS SLIDE SHOWS YOU THAT IN
OUR MOUSE MODEL OF HPV
INFECTION, THE FIRST STEP IN HPV
INFECTION IS ACTUALLY BINDING TO
THE BASEMENT MEMBRANE THAT
SEPARATES THE EPITHELIUM FROM
THE DERMIS.
AND THIS IT REQUIRES TRAUMA,
MICRO TRAUMA IN ORDER FOR THIS
TO BE BINDING.
HPV DOESN'T BIND TO THE APICAL
SURFACE THAT IS THE UPPER SER
FAST OF EPITHELIAL CELLS, EVEN
THE COLUMNAR EPITHELIUM OF THE
CERVICAL CANAL.
BUT IT BINDS VERY AVIDLY TO
THESE AREAS, AND IT INITIATES
LIFE CYCLE WHILE STILL ON THE
BASEMENT MEMBRANE, AND THEN ONLY
LATER TRANSFERS TO THE TARGET
EPITHELIAL CELL.
NOW THIS CARTOON ESSENTIALLY
SHOWS YOU WHAT HAPPENS IN AN
IMMUNIZED INDIVIDUAL.
THERE ARE LOW LEVELS OF
ANTIBODIES IN THE CERVICAL
CANAL, BUT HIGHER LEVELS
REFLECTIVE OF WHAT'S IN THE
SERUM THAT'S IN THE TISSUE.
BUT AT THE POINT OF POTENTIAL
INFECTION, THE BARRIER FUNCTION
OF THE EPITHELIUM IS DISRUPTED
SO YOU GET THE ANTIBODIES GOING
INTO THIS AREA OF POTENTIAL
INFECTION, SO WHEN THE VIRUS
PARTICLE COMES IN, ANTIBODIES
ACTUALLY RECOGNIZE THE PARTICLE,
BIND TO IT AND INTERFERE WITH
THE ABILITY OF THE VIRUS TO BIND
TO THE BASEMENT MEMBRANE.
AND EVEN AT LOW LEVELS, WE SEE
BINDING TO THE BASEMENT MEMBRANE
BUT YOU DON'T GET THE TRANSFER
OF THE VIRUS TO THE TARGET
EPITHELIAL CELL.
SO THERE ARE TWO DIFFERENT
MECHANISMS THERE.
NOW I WANT TO SAY A FEW THINGS
ABOUT, IF YOU WILL, UPTAKE OF
THE HPV VACCINE, AND THERE ARE
MAJOR DIFFERENCES DEPENDING ON
THE COUNTRY WHERE YOU ARE.
AND IN RED ARE SHOWN ONE DOSE
AND IN BLUE ARE SHOWN THREE
DOSES.
IN THE UNITED KINGDOM, WHICH HAS
SCHOOL-BASED VACCINATIONS, YOU
CAN APPRECIATE THAT PROBABLY 90%
ARE FULLY VACCINATED.
IN AUSTRALIA, THE NUMBER THAT
ARE FULLY VA VACCINATED, IT'S A
LITTLE BIT LOWER, BUT STILL A
HIGH NUMBER.
THE UNITED STATES, HOWEVER, WE
ARE SUBSTANTIALLY LOWER SO YOU
CAN EXPECT THAT THE IMPACT FROM
THE VACCINE IS GOING TO BE LESS,
AND JUST SO I DIDN'T WANT PEOPLE
TO THINK THAT WE ARE LAST, THE
UPTAKE IS EVEN LOWER.
SO THE UPTAKE OF THE VACCINE IN
THE UNITED STATES, THERE ARE
SEVERAL REASONS, I'VE OUTLINED A
FEW OF THEM HERE.
ONE IS MEDICAL UNCERTAINTIES AT
THE TIME OF FDA APPROVAL.
SAFETY, DURATION OF PROTECTION,
FOR EXAMPLE, WERE KEY ISSUES.
THESE ISSUES HAVE LARGELY BEEN
ADDRESSED POSITIVELY
SUBSEQUENTLY TO THE EXTENT THAT
THEY CAN BE.
YOU KNOW, SINCE THE VACCINE HAS
BEEN IN USE FOR REALLY ONLY
SEVEN OR EIGHT YEARS, YOU DON'T
HAVE DURATION OF EFFICACY MUCH
BEYOND THAT, BUT THUS FAR IT
SEEMS TO BE -- THE SAFETY DATA.
PROVIDER HESITANCY IS SOMETHING
THAT THE CENTERS FOR DISEASE
CONTROL IDENTIFIED IS A MAJOR
ISSUE, WHICH IS LACK OF STRONG
VACCINE RECOMMENDATION FROM
HEALTHCARE WORKERS IN THE UNITED
STATES.
THERE ALSO WAS PUSHBACK FROM
EFFORTS TO MAKE THE VACCINE
MANDATORY IN 2007, WHICH WAS THE
YEAR AFTER IT WAS APPROVED AND
FOR THOSE OF YOU WHO HAVE LONG
ENOUGH MEMORIES BACK TO THE
REPUBLICAN PRECEDENTIAL -- THE
DATES, YOU KNOW, GOVERNOR PERRY
GOT INTO SOME ISSUES WITH THE
QUESTION OF TRYING TO MAKE THE
VACCINE MANDATORY IN TEXAS.
THEN THERE HAVE BEEN CONCERNS
ABOUT VACCINATIONS PROMOTING
*** DISINHIBITION, WHICH HAS
ALSO HAD AN IMPACT.
I JUST WANT TO SHOW YOU TWO
SLIDES THAT SORT OF CONTRAST OR
COMPARE WHAT THE STORY IS WITH
CERVICAL CANCER INCIDENCE AND
MORTALITY IN THE UNITED STATES
BECAUSE IT REALLY IS QUITE
REGIONAL, AND TO SEE WHAT
HAPPENS WITH VACCINE IMPACT.
THIS IS IN RED OUR HIGH
INCIDENCE, OKAY?
THIS IS NOT THE REPUBLICAN
STATES, OKAY?
AND THESE ARE NOT THE DEMOCRATIC
STATES.
BUT EVEN THE REPUBLICAN STATES
THAT ARE LOCATED HERE WOULD
PROBABLY RATHER BE BLUE, WHEN IT
COMES TO CERVICAL CANCER IPS
DENSINCIDENCE AND MORTALITY.
SO I WANT TO YOU LOOK AT THE
DISTRIBUTION HERE, AND HERE IS
THE VACCINE UPTAKE AS OF 2011.
HERE THE DARKER PURPLES ARE THE
PLACES WITH MORE VACCINATION AND
THE LIGHTER AREAS ARE PLACES
WITH LESS.
AND IN GENERAL, THE AREAS THAT
HAVE THE BIGGEST PROBLEM WITH
CERVICAL CANCER ARE THE AREAS
THAT THE VACCINE HAS BEEN
UNDERUTILIZED.
SO NOW, I WANT TO TALK A LITTLE
BIT, WHAT'S BEING DONE THAT
MIGHT CHANGE THIS OTHER THAN
PEOPLE YELLING AND SCREAMING OR
WHATEVER.
SO THIS IS GOING TO BE LARGELY
SCIENCE-BASED, OKAY?
ONE THING IS, AS WYNN MENTIONED,
WHAT ABOUT THE VECTORS?
WHAT ABOUT MALES?
SORRY.
THAT WAS ME WHO SAID WHAT ABOUT
THE VECTORS.
AND SO MERCK DID SOME LESS
INTENSIVE STUDIES OF MALES, AND
SHOWED THAT THE VACCINE IS ALSO
PROTECTIVE AGAINST MALES, BOTH
AGAINST GENITAL WARTS AS WELL AS
AGAINST *** DYSPLASIA, AND THE
FDA GAVE APPROVAL FOR MALES BOTH
FOR WARTS AND THE PREVENTION OF
*** CANCER, AND THIS LED THE
CDC ADVISORY COMMITTEE ON
IMMUNIZATION PRACTICES IN 2011
TO MAKE THE SAME RECOMMENDATION
FOR BOYS AS FOR GIRLS.
I JUST WANT TO POINT OUT THE
MERCK VACCINE IS APPROVED FOR
BOTH GENDERS, THE GSK VACCINE
ONLY FOR GIRLS, ONCE AGAIN, OFF
LABEL.
THERE IS NO REASON TO BELIEVE
THAT THE GSK VACCINE WOULD BE
LESS EFFECTIVE IN MALES, BUT
EFFICACY HAS NOT BEEN TESTED IN
MALES.
SO THAT'S ONE POTENTIAL WAY OF
TRYING TO INCREASE THE UPTAKE.
SECOND IS WOULD FEWER THAN THREE
DOSES BE PROTECTIVE?
SO THESE DATA ARE TAKEN FROM THE
NATIONAL CANCER INSTITUTE HAS
BEEN CONDUCTING A TRIAL OF THE
GSK VACCINE IN COT COSTA RICA, WHERE
CERVICAL CANCER IS THE MOST
COMMON CANCER IN WOMEN IN COSTA
RICA.
SOME OF THE WOMEN, INSTEAD OF
THGETTING ALL THREE DOSE DOSES, OHM GOT
ONE OR TWO DOSES.
AND WE WERE ABLE TO THEN LOOK AT
THE ATTACK RATE FOR THE WOMEN
WHO GOT ONLY ONE OR TWO DOSE,
AND BEFORE LOOKING AT THE
VACCINATED GROUP, LOOK AT THE
CONTROL GROUP.
THE CONTROL GROUP WITH THREE
DOSES, THE RATE OF ACD16
INFECTION PER HUNDRED WOMEN WAS
APPROXIMATELY 8% HERE, 6% WITH
TWO DOSES AND 8% WITH ONE DOSE,
SO THERE DIDN'T SEEM TO BE ANY
BEHAVIORAL DIFFERENCE, AND
REMEMBER THIS IS A RANDOMIZED
DOUBLE BLINDED TRIAL, SO NEITHER
THE WOMEN NOR THE PEOPLE DOING
THE EXAM KNOW WHO GOT WHICH --
WHETHER THEY WERE IN THE CONTROL
GROUP OR IN THE VACCINATED
GROUP -- THE HPV VACCINATED
GROUP.
YOU CAN APPRECIATE THE RATE OF
PROTECTION, THE VACCINE EFFICACY
FOR TWO IN ON AND ONE DOSES WERE AS
GREAT AS VACCINE EFFICACY FOR
THREE DOSES.
AND I WOULD LIKE TO SAY THAT FOR
TWO VACCINE DOSES, THE FUTURE IS
NOW.
THE FUTURE IS NOW OUTSIDE THE
UNITED STATES.
THE INITIAL REGULATORY APPROVAL
FOR THREE DOSES IN GIRLS WAS
CALLED ON THE BASIS OF WHAT'S
CALLED NON-INFERIORITY BRIDGING.
WHAT THAT MEANS IS THAT THE
YOUNGER ADOLESCENTS WERE
APPROVED NOT BECAUSE OF
EFFICACY, BUT BECAUSE THEIR
IMMUNE RESPONSE TO THREE DOSES
WAS NOT INFERIOR TO THE IMMUNE
RESPONSE OF THE YOUNG WOMEN WHO
WERE IN THE TRIALS WHERE THE
GOOD EFFICACY WAS SHOWN.
BUT THOSE STUDIES SHOWED THAT
THE YOUNG ADOLESCENTS ACTUALLY
MOUNTED A STRONGER IMMUNE
RESPONSE THAN THE OLDER
ADOLESCENTS WHO WERE IN THE
CLINICAL TRIALS.
AND SO THE MOTION OF COULD YOU
GET AWAY WITH TWO DOSES INSTEAD
OF THREE WAS ESSENTIALLY
ADVANCED.
AND TWO DOSES SEPARATED BY SIX
MONTHS PRODUCE AN IMMUNE
RESPONSE SIMILAR TO THOSE IN THE
RESPONSES TO THREE DOSES IN THE
EFFICACY TRIALS.
AND THERE WAS A POSITIVE OPINION
FROM THE EUROPEAN MEDICINES
AGENCY, WHICH IS LIKE THE
EUROPEAN FDA, COMMITTEE FOR
MEDICAL PRODUCTS FOR HUMAN USE,
FOR TWO DOSES FOR BOTH OF THE
VACCINES.
IN DECEMBER, THEY APPROVED THE
GSK VACCINE FOR TWO DOSES IN
YOUNG GIRLS 9 TO 14 YEARS OF
AGE, AND LAST MONTH THE
COMMITTEE RECOMMENDED THE MERCK
VACCINE FOR TWO DOSES IN GIRLS
AND BOYS 9 TO 13.
THE EMA HAS NOT YET APPROVED IT,
BUT APPROVAL IS ANTICIPATED.
BUT I JUST WANT TO REPEAT THAT
IN THE UNITED STATES, THE
RECOMMENDATION IS FOR THREE
DOSES.
MY EXPECTATION IS THAT FIVE
YEARS FROM NOW, WE'LL ALSO BE AT
TWO DOSES, BUT WE'RE NOT THERE,
BUT WE'RE NOT THERE NOW.
THESE ARE THE IMMUNOGENICITY
STUDIES OF THE COSTA RICA TRIAL
WHOSE VACCINE EFFICACY RESULTS I
SHOWED YOU A FEW MINUTES AGO.
AND WHAT I WANT YOU TO SEE IS
NOT JUST THE RESULTS FOR TWO AND
THREE DOSES, IT'S QUITE SIMILAR
BETWEEN TWO AND THREE DOSES, BUT
WITH ONE DOSE, NOTE THAT THE
ANTIBODY LEVELS DON'T GO DOWN
OVER TIME.
THIS IS A TOTALLY UNEXPECTED
RESULT.
PROTEIN BASED SUBUNIT VACCINES
ALMOST ALWAYS, YOU NEED TO BE
BOOSTED.
THE CLASSIC IS THE TESS NA TETANUS TOX
OID.
SO THIS VACCINE IS ANALOGOUS IN
THE SENSE THAT IT IS A
PROTEIN-BASED VACCINE.
WE THINK THAT THE STABLE
ANTIBODY TITERS MAY BE
ATTRIBUTABLE TO TWO FACTORS.
ONE IS THAT THE PARTICLES ARE
HIGHLY IMMUNOGENIC AS I
MENTIONED, AND THE OTHER IS THAT
THE GSK ADJUVANT INCLUDES WHAT'S
CALLED A TLR4 AGONIST, WHICH
ACTIVATES ANOTHER ACTIVATOR OF
THE IMMUNE SYSTEM IN ADDITION TO
ALUM.
AND WE DON'T KNOW WHETHER THERE
ARE IMPLICATIONS FOR OTHER
VACCINES.
POSSIBLY THERE MIGHT BE A
RANDOMIZED CONTROL TRIAL TO
RIGOROUSLY TEST THE EFFICACY OF
ONE DOSE.
SINCE THIS IS CONTRARY TO
EXPECTATION AND THIS WAS NOT A
PRESPECIFIED PRIMARY OUTCOME OF
THE TRIAL, YOU REALLY NEED TO DO
A RIGOROUS RANDOMIZED CONTROL
TRIAL BEFORE YOU WOULD ACCEPT
THAT ONE DOSE WOULD BE USEFUL.
I NOW WANT TO GET TO THE LAST
TOPIC OF THE TALK, WHICH IS
SECOND GENERATION VACCINES.
I HAVE ABOUT FOUR SLIDES.
THE GOAL WOULD BE EITHER TO
MAKE -- PROTECTION LESS
EXPENSIVE.
ONE THING YOU COULD DO IS TO
SIMPLY FIE VACCINE PRODUCTION OR
ADMINISTRATION.
THE MEASLES VACCINE, FOR
EXAMPLE, IT'S AN RNA VIRUS, BUT
THERE'S EXCESS CODING CAPACITY
IN THE VACCINE, AND YOU CAN
ACTUALLY ENCODE L1 FOR HPV 16,
AND EXPRESS L1 IN MEASLES
VACCINE AND AT LEAST IN MICE, IT
INDUCES HIGH LEVELS OF
NEUTRALIZING ANTIBODIES.
AND YOU COULD JUST INCORPORATE
THAT AND YOU COULD THEN GET YOUR
FIRST DOSE, AT LEAST, WITH
MEASLE VACCINE.
CLOSER TO HOME IS THE BROADENING
PROTECTIONS AGAINST MORE HPV
TYPES, BECAUSE I'M GOING TO SHOW
YOU SOME PRELIMINARY DATA FROM A
NEW CANDIDATE OF VACCINES
PRODUCED BY MERCK.
IT COULD PREVENT HIGHER
PROPORTION OF HPV INFECTION AND
INCREASE BORDER PROTECTION,
COULD REDUCE THE -- OF SCREENING
AND YOU MIGHT BE ABLE TO
LENGTHEN THE SCREENING INTERVAL,
AND IT MIGHT LEAD TO INCREASED
VACCINE UPTAKE.
SO THIS DIE GRAMMATICALLY SHOWS
YOU WHAT THE CURRENT VACCINES DO
THAT THEY CAN PREVENT ABOUT 70%
OF CERVICAL CANCER, AND WHAT
MERCK HAS DONE IS TO ADD THE
FIVE MOST COMMON ONCOGENIC HPV
TYPES IN TERMS OF CAUSING
CERVICAL CANCER, AND THIS CAN
PREVENT IN PRINCIPLE CLOSE TO
90% OF SERIOUS CERVICAL
INFECTIONS.
I'D POINT OUT THAT IT'S NOT ALL
OF THEM, BUT IT'S THE VAST
MAJORITY.
AND THEY HAVE RECENTLY PRESENTED
THEIR RESULTS IN ABSTRACT FORM
AT A COUPLE OF RESEARCH
CONFERENCE, AND SO THIS TELLS
YOU THIS D503 ADDS THESE HPV
TYPES, AND THEY DID A CLINICAL
TRIAL THAT THE CONTROL GROUP
ACTUALLY RECEIVED GARDASIL, THE
QAW DRA VALENT VACCINE, AND THE
PRIMARY END POINT WAS MODERATE
CERVICAL INTRAEPITHELIAL
NEOPLASIA, THAT'S MODERATE
DYSPLASIA, AGAINST THE FIVE NEW
HPV TYPES, AND IMMUNOLOGICAL
NON-INFERIORITY AGAINST THE
OTHER FOUR TYPES, AND THE
VACCINE EFFICACY AGAINST THE
FIVE NEW TYPES WAS 96%, AND THE
PROTECTION AGAINST PERSISTENT
INFECTION BY THOSE TYPES WAS
ALSO 96%.
SO THIS WAS ONE CASE IN THE
V503 GROUP VERSUS 27 CASES IN
THE QAW DRA VALENT GROUP.
YOU CAN LOOK ONLINE FOR IF YOU
WANT MORE INFORMATION.
IT HAS NOT YET BEEN PUBLIC.
THIS IS TAKEN FROM A NATURAL
HISTORY STUDY IN DENMARK,
LOOKING AT WOMEN WHO HAVE HAD
THEIR FIRST SCREENING TESTS FOR
CERVICAL CANCER IN THEIR EARLY
20S.
AND THEY'VE HAD ONE POSITIVE
TEST OR IN THE CASE OF THIS
ORANGE LINE, A NEGATIVE TEST,
AND THEY'RE FOLLOWED UP THEN IN
THE SYSTEM FOR THE NEXT 12 YEARS
TO SEE WHAT HAPPENED.
SO THESE ARE WOMEN WHO ARE HPV
16 POSITIVE, AND THEY ARE SITE
LOGICALLY NORMAL.
THEY HAVE A PAP SMEAR AT THIS
TIME PERIOD, AND THEN THEY'RE
FOLLOWED.
WHAT I HOPE YOU CAN APPRECIATE
IS THAT 1 IN 4 OF THEM DEVELOP
HIGH GRADE DYSPLASIA OR INVASIVE
CANCER OVER THE NEXT WELL YEARS.
THERE'S AN INTERMEDIATE GROUP
COMPOSED OF HPV 18, 31 AND 33,
AND THERE OVER THE NEXT 12
YEARS, IT'S ABOUT 15% OF THEM
DEVELOP A HIGH GRADE DYSPLASIA
OR WORSE.
AND THEN IN BLUE ARE THE --
THERE'S A COCKTAIL OF 13
DIFFERENT HPV TYPES, WHICH IS
ONE OF THE FDA-APPROVED TESTS,
BUT IT'S BEEN FRACTION ATED SO
THAT YOU EXCLUDE THESE FOUR
TYPES, AND YOU CAN SEE THAT THE
RATE OF DEVELOPMENT OF HIGH
GRADE DYSPLASIA OVER THE NEXT 12
YEARS IS VERY LOW, AND YOU KNOW,
A LITTLE BIT HIGHER THAN THAT OF
THE WOMEN WHO ARE NEGATIVE.
I'M SHOWING YOU THIS BECAUSE I
THINK SINCE THESE FOUR TYPES ARE
ALL IN THE NINEVALENT VACCINE,
IF THEY WERE APPROVED BY THE FDA
AND WERE WIDELY USED, IT WOULD
IMPLY THAT THE FAST PROGRESSORS,
THAT IS, THESE FOUR TYPES, COULD
IN PRINCIPLE BE ELIMINATED FROM
THE POPULATION, AND IT MIGHT BE
SAFE TO START CERVICAL CANCER
SCREENING AT A LATER AGE AS LONG
AS THE WOMEN HAVE BEEN
VACCINATED AND THE PREVALENCE OF
THESE HPV TYPES WERE THERE.
SO LET ME SUMMARIZE.
HPV CAUSES SEVERAL DIFFERENT
CANCERS, AS WELL AS GENITAL
WARTS AND OTHER DISEASES.
THE VACCINE CAN PREVENT THE
BENIGN PREMALIGNANT AND
MALIGNANT DISEASES INDUCED BY
THE HPV TYPES TARGETED BY THE
VACCINE.
THE PREVENTION OF THE MALIGNANT
DISEASE IS INFERRED.
THE BASIS FOR THAT INFERENCE IS
EXACTLY THE SAME AS WHAT'S USED
FOR CERVICAL CANCER SCREENING,
SO I WOULD SAY IT'S ON A PRETTY
FIRM BASIS.
SECOND GENERATION VACCINES WITH
ACTIVITY AGAINST THE BROADER
RANGE OF TYPES SHOULD ACHIEVE AN
EVEN GREATER REDUCTION IN
HPV-ASSOCIATED DISEASE, AND THE
HIGH I HUE KNOW GENICITY OF THE
VACCINE IMPLIES IT SHOULD BE
POSSIBLE TO IP DUES LONG TERM
PROTECTION WITH FEWER THAN THREE
DOSES.
THANK YOU VERY MUCH FOR YOUR
LOVE TO HEAR YOUR COMMENTS AND
QUESTIONS.
[APPLAUSE]
>> HI.
THANK YOU FOR YOUR TALK.
I WAS AROUND WHEN YOU INTRODUCED
THIS, I FOLLOWED THE POLITICAL
CHAOS GOING ON WITH THIS.
QUICK QUESTION, AND IT'S MORE
YOUR THOUGHT, IS THE AFFORDABLE
HEALTHCARE ACT GOING TO COVER
IMMUNIZATIONS FOR VARIOUS AGENTS
AND DO YOU HOPE THAT NOW THAT
IT'S GOING TO BE COVERED, AND
THERE'S NOT THE SAME MEDIA
BACKLASH THERE WAS WHEN YOU
FIRST CAME OUT, DO YOU HOPE
THERE WILL BE MORE SUPPORT AND
MORE PEOPLE GETTING VACCINATED?
>> SO THE UNITED STATES HAS A
VERY INTERESTING WAY OF
ORGANIZING VACCINATION.
WE HAVE A FEDERALLY SPONSORED
PROGRAM CALLED THE VACCINE FOR
CHILDREN PROGRAM, THE WHICH
PROVIDES ABOUT 40% OF THE
VACCINE TO CHILDREN UNDER THE
AGE OF 18.
THE HPV VACCINE IS AMONG THE
VACCINES THAT ARE OFFERED
THROUGH THE VACCINE FOR
CHILDREN'S PROGRAMS.
AND SO CHILDREN FROM POOR
FAMILIES THAT ARE
MEDICAID-ELIGIBLE, AND THERE ARE
A NUMBER OF OTHER CRITERIA, ALL
CAN GET THE VACCINE FOR FREE.
IT ACTUALLY COSTS THEM LESS THAN
IT COSTS THE CHILDREN OF PEOPLE
WHO HAVE PRIVATE INSURANCE
BECAUSE THE PRIVATE INSURANCE
DOESN'T ALWAYS PAY FOR THE COST
OF THE VISIT.
THEY PAY FOR THE VACCINE BUT
THEY DON'T ALWAYS PAY FOR THE
COST OF THE VISIT.
IN PRINCIPLE, WITH THE
AFFORDABLE CARE ACT PREVENTION
COSTS ARE SUPPOSED TO BE FULLY
COVERED.
WHETHER THAT'S GOING TO BE A BIG
DIFFERENCE IN THIS INSTANCE, I'M
NOT SURE.
MOST WOMEN GET CERVICAL CANCER
SCREENING, AND WHETHER THE
AFFORDABLE CARE ACT -- YOU KNOW,
WHETHER THE AFFORDABLE CARE ACT
WILL HAVE A BIG IMPACT ON THAT,
I DON'T REALLY KNOW.
IN PRINCIPLE, IT MEANS THAT ANY
WOMAN WHO WANTS TO GET SCREENED
SHOULD NOT NEED TO PAY FOR IT,
BUT I JUST -- IT'S HARD TO KNOW,
THE WOMEN WHO -- A PIE
PROPORTION OF WOMEN WHO DEVELOP
CERVICAL CANCER ARE WOMEN WHO
HAVE NOT BEEN SCREENED, AND
OBVIOUSLY LACK OF ACCESS IS ANG
ISSUE.
ONE WOULD HOACH THAT THER HOPE THAT THERE WOULD
BE LESS -- IT WOULD BE EASIER,
BUT IT REMAINS TO BE SEEN.
>> YOU HAD COMMENTED BEFORE ON
THE -- OF SCREENING, AND WE
HEARD IN MR. CANTRELL'S CASE
THAT MAYBE WHEN THE EARLIEST
DETECTION WAS DUE TO HIS BREATH
AND HIS WIFE COULD SMELL A
DIFFERENCE.
COULD YOU COMMENT ON WHAT
RESEARCH THERE MAY BE FOR USING
ODOR AS A FORM OF DETECTION FOR
HPV?
AND FOR VERY COST-EFFECTIVE
SCREENING?
>> I HAVE NO SPECIFIC
INFORMATION ABOUT THAT.
I CAN'T COMMENT ON IT.
>> I THINK THAT'S A NONSPECIFIC
MANIFESTATION OF HEAD AND NECK
CANCER.
IT'S JUST AS COMMON TO HAVE THAT
IN HPV NEGATIVE AS HPV POSITIVE,
AND IT'S BECAUSE THE BACTERIA
THAT COLONIZE PROBABLY GROW
QUITE WELL.
[INAUDIBLE]
>> I JUST HAVE TWO QUESTIONS.
ONE IS I THINK MAYBE THE RATIO
FOR MEN TO WOMEN IS EVEN HIGHER
TODAY THAN 3:1 THAN IT USED TO
BE.
I WAS JUST WONDERING, IS PRIOR
VAGINAL CERVICAL VACCINE IN ANY
WAY PROTECTIVE, OR IS THAT A
POSSIBLE EXPLANATION TO EXPLAIN
THE DIFFERENCE?
AND MY SECOND QUESTION WAS --
[INAUDIBLE]
>> IT'S ONLINE.
>> I KNOW, BUT -- NOTICED ANY --
[INAUDIBLE]
>> SO THE ANSWER TO THE FIRST
QUESTION IS THAT WE DID STUDIES
ACTUALLY BACK IN THE 90s THAT
DEMONSTRATED THAT MALES HAD A
MUCH LOWER RATE OF BEING
ANTIBODY-POSITIVE THAN FEMALES,
AND WE SUSPECT THAT IT IS THE
CAUSE OF THE GENITAL INFECTION
IN THE WOMEN, SOMEHOW LEADS
TO -- THEY'RE MORE LIKELY TO
DEVELOP ANTIBODIES WHICH WE TAKE
TO BE AN INDEX OF IMMUNITY.
AND SO I THINK IT'S CERTAINLY
POSSIBLE THAT IMMUNITY IS
SOMEWHAT PROTECTIVE, AND THAT
WOMEN ARE MORE PROTECTED THAN
MEN ARE.
BUT THIS IS SPECULATION.
>> YOUR SECOND QUESTION REALLY
IS ONE OF HPV TYPE -- PLACEMENT,
AND THUS FAR, THERE IS NO
EVIDENCE THAT THERE HAS BEEN HPV
TYPE REPLACEMENT AND MY MEDICAL
EPIDEMIOLOGIC COLLEAGUES, THEIR
NOAX IS
THAT THESE VIRUSES TEND
TO BEHAVE RELATIVELY
INDEPENDENTLY ONE FROM THE
OTHER, BUT CLEARLY BOTH
COMPANIES ARE FOLLOWING UP
POPULATIONS IN SCANNED 2345EU6
YA FOR A MINIMUM OF 15 YEARS AND
WILL BE LOOKING AT THAT
QUESTION, AND IN COSTA RICA,
WE'RE ALSO DOING A LONG-TERM
FOLLOW-UP LOOKING AT THAT ISSUE
AS WELL.
>> ASSUMING THERE'S NO DECREASE
IN ANTIBODY TITERS OR IMMUNITY,
DO YOU THINK A POSSIBLE SOLUTION
TO THE SOCIAL BACKLASH COULD BE
OFFERING THE VACCINE MAYBE AT A
YUFNYOUNG AGE, AT 3 OR 4?
>> THIS IS CERTAINLY A -- THIS
IS A POTENTIALLY VIABLE
POSSIBILITY, BUT THERE ARE
CURRENTLY TWO PROBLEMS.
THE FIRST IS THAT IT WOULD TAKE
THAT MUCH LONGER BEFORE YOU
WOULD SEE AN IMPACT FROM THE
VACCINE, AND FROM A
COST-EFFECTIVENESS POINT OF
VIEW, THAT MIGHT BE A REDUCTION,
OKAY?
THE SECOND IS THAT WE HAVEN'T
FOLLOWED PATIENTS WHO HAVE BEEN
VACCINATED FOR LONG ENOUGH TO
KNOW WHETHER IT WOULD LAST LONG
ENOUGH.
WHAT I THINK ONE COULD MAYBE
MORE SAFELY ENVISION IS MAYBE
THE FIRST DOSE, IF YOU WERE
GOING TO BE DOING TWO DOSES, YOU
MIGHT GIVE THE FIRST DOSE AT
THAT AGE AND THEN A BOOSTER DOSE
AS AN ADOLESCENT, BUT AGAIN,
WOULD YOU GET INTO THE -- YOU
KNOW, GET INTO THE SAME SOCIAL
PROBLEM.
>> YOU'VE BEEN VERY PATIENT.
>> TWO QUICK QUESTIONS.
>> IT'S YOUR PUNISHMENT FOR
SITTING IN THE BACK.
>> WHAT DO YOU KNOW ABOUT THE
EFFICACY IN WOMEN WHO ARE
EXPOSED TO HPV 16 OR 18 PRIOR TO
GETTING THE VACCINE?
I DON'T KNOW WHETHER THERE'S A
WAY TO KNOW THAT.
>> SO IN COSTA RICA, MY
COLLEAGUES LOOKED AT THE NATURAL
HISTORY OF THE WOMEN WHO WERE
VACCINATED EITHER WITH THE VFK
VACCINE OR WITH THE CONTROL
WHICH ACTUALLY WAS HEPATITIS A
VACCINE AND LOOKED AT THE WOMEN
WHO HAD PREVALENT INFECTION AT
THE TIME OF VACCINATION.
AND THERE IS NO DIFFERENCE IN
THE RATE AT WHICH THEY CLEAR,
OKAY?
SO THERE'S NO STRONG SUGGESTION
THAT THERE IS A CHANGE IN THE
NATURAL HISTORY OF PEOPLE WHO
ARE PREVALENTLY -- WHO ARE
PREVALENTLY INFECTED, OKAY, AND
MERCK HAS SAID THE SAME THING,
ALTHOUGH I HAVEN'T SEEN IT
PUBLISHED IN THE SAME DETAIL AS
WITH THE GFK VACCINE.
>> MEN, OLDER MEN RECEIVING THE
VACCINE, SAY BETWEEN THE AGES OF
20 AND 30?
>> SO THE ISSUE OF -- THE
VACCINE, THE MERCK VACCINE IS
APPROVED FOR MALES UP THROUGH
AGE 26, I GUESS.
25 OR 26.
SO ABOVE THAT AGE WOULD BE OFF
LABEL.
THERE ARE PEOPLE WHO RECOMMEND
AN OFF LABEL USE BECAUSE WHEN
YOU LOOK AT THE PROFILE OF THE
APPARENT AGE OF ACQUISITION OF
ORAL HPV INFECTION, IT LOOKS AS
THOUGH MANY MEN ARE REQUIRING REQUIRING
ORAL HPV WHEN THEY ARE IN THEIR
20S OR EVEN IN THEIR 30s, SO
ON THAT BASIS, IT HAS BEEN
SUGGESTED.
>> SO IF NEWBORNS ARE BORN OF A
MOTHER THAT HAS -- INFECTION,
NEWBORNS DON'T HAVE ANTIBODIES,
DO THEY?
IF THEY DO, WHY DON'T NEWBORNS
GET THE DISEASE?
>> SO THE FIRST POINT IS THAT
IGG ANTIBODIES DO GO ACROSS THE
PLACENTA AND AND A PROPORTION OF
THE WOMEN HAVE IGG ANTIBODIES.
THE SECOND IS THAT THE INCIDENCE
OF GENITAL HPV INFECTION IN
PREGNANT WOMEN IS VERY HIGH,
BECAUSE IT ACTUALLY TENDS TO GO
UP BECAUSE OF THE RELATIVE
IMMUNE SUPPRESSION OF PREGNANCY,
PROBABLY YOU GET REACT VAITION, VAITION,
AND AFTER DELIVERY, THE
PERCENTAGE OF HPV POSITIVITY
ACTUALLY GOES DOWN.
BUT THERE IS POTENTIALLY SERIOUS
INFECTION KNOWN AS LARYNGEAL
PAPILLOMATOSIS OR RECURRENT
RESPIRATORY PAPILLOMATOSIS THAT
OCCURS IN CHILDREN, AND A
REASONABLE PROPORTION OF THOSE
CHILDREN ARE BELIEVED TO ACQUIRE
THE INFECTION DURING DELIVERY
THROUGH THE BIRTH CANAL.
ONE POTENTIAL UTILITY OF THE
VACCINE IS THAT IT SHOULD, AT
LEAST FOR THE MERCK VACCINE, IT
SHOULD VIRTUALLY ELIMINATE THIS
DISEASE.
THE PROBLEM IS THAT IT'S NOT SO
MUCH OF A PUBLIC HEALTH PROBLEM
BECAUSE THERE WERE MAYBE A
THOUSAND CASES IN THE UNITED
STATES PER YEAR, AND SO IT'S
DIFFICULT TO STRONGLY ADVOCATE
FOR THAT, IN ADDITION, IT WOULD
BE AN OFF-LABEL USE OF THE
VACCINE TO VACCINATE FOR THAT
REASON.
OF COURSE IT'S PERFECTLY FINE TO
VACCINATE WOMEN WHO ARE NOT PREG
NAN, WHO ARE OF CHILD BEARING
AGE, THAT'S PERFECTLY
LEGITIMATE, BUT IT'S NOT AN
FDA-APPROVED USE.
>> -- [INAUDIBLE] THEY SHOWED
ACTUALLY THAT THERE'S THOSE TWO
PEAKS ACTUALLY OF ORAL
INFECTION, AND -- ONE IS
ACTUALLY MORE LIKE IN THEIR
40s, RIGHT?
AND I JUST WONDER, IF YOU DON'T
GET A STRONG IMMUNE RESPONSE
FROM *** EXPOSURE TO
CANCER -- [INAUDIBLE]
>> THIS IS A LITTLE BIT OF AN
INSIDE BEAS BALL KIND OF BASEBALL KIND OF
DISCUSSION, BUT -- AND HER
COLLEAGUES HAD A PAPER LOOKING
AT SINGLE TIME POINT PREVALENCE
PUBLISHED IN THE JOURNAL OF THE
AMERICAN MEDICAL ASSOCIATION
ABOUT TWYEARS AGO, AND WHAT
WAS SHOWN WAS THIS BIPHASIC
CURVE SO THAT MEN WHO ARE IN
THEIR WIT 50s HAD A HIGHER
PREVALENCE THAN MEN WHO WERE IN
THEIR 40s.
I THINK THAT IT REMAINS TO BE
SEEN WHETHER THIS IS
ATTRIBUTABLE -- THERE WERE
SEVERAL POTENTIAL EXPLANATIONS.
ONE IS IT'S SIMPLY A COHORT
EFFECT.
IF YOU HAD BEEN ABLE TO SAMPLE
THOSE MEN IN THEIR 50s, YOU
SAMPLED THEM IN THEIR 40s,
THEY WOULD HAVE BEEN HIGH THEN
TOO.
ANOTHER POSSIBILITY IS THAT IT'S
ACTUALLY REACT VAITION OF A
FORMER INFECTION WHERE YOU HAVE
HAD CLINICAL RESOLUTION BUT YOU
WERE STILL VIROLOGICALLY
POSITIVE, SO YOU NOW HAVE A
REACT VAITION.
THEN THE THIRD POSSIBILITY IS A
NEW EXPOSURE.
SIMILAR KIND OF BIPHASIC
PREVALENCES HAVE BEEN SEEN IN
SOME COUNTRIES IN WOMEN AT THE
*** AND YOU GO THROUGH THE
SAME KIND OF ISSUES AND IT
REALLY HASN'T BEEN RESOLVED.
>> I HAVE A QUICK QUESTION ON
HPV TESTING, A LOT OF THE
STATISTICS ARE BASED ON TESTING
POSITIVE OR NEGATIVE FOR HPV,
AND WHAT DO YOU THINK IS THE
TRUE POSITIVE AND TRUE
NEGATIVE -- FALSE POSITIVE AND
FALSE NEGATIVE TESTING FOR HPV,
BOTH GENITAL AS WELL AS ORAL?
WHAT DO WE KNOW ABOUT FALSE
POSITIVE AND FALSE NEGATIVE
TESTING?
>> SO IT MAY BE A QUICK
QUESTION, I'M NOT SURE IT'S A
QUICK ANSWER.
I THINK FIRST LET'S DEAL WITH
GENITAL INFECTION.
OKAY?
WHEN -- FALSE POSITIVE, SHE
DOESN'T MEAN YOU WERE HPV
POSITIVE BUT YOU'RE NOT
INFECTED.
SHE MEANS YOU'RE HPV POSITIVE
BUT YOU DON'T HAVE PRECANCER.
OKAY?
LET'S JUST UNDERSTAND, THE TEST
IS VERY SPECIFIC IN TERMS OF
DETECTING HPV.
THERE WERE VERY FEW FALSE
POSITIVES IN THE SENSE THAT
YOU'RE POSITIVE FOR THE TEST BUT
YOU'RE NOT REALLY INFECTED.
BUT THERE ARE MANY PEOPLE WHO
ARE INFECTED BUT DON'T REQUIRE
TREATMENT BECAUSE AS I
MENTIONED, THE NATURAL HISTORY
FOR MOST INFECTIONS IS THEY JUST
GO AWAY.
YOU DON'T NEED TO BE TREATED.
SO THIS BRINGS UP THE ISSUE OF
FALSE POSITIVE IN THAT SENSE,
AND A LOT OF PEOPLE ARE WORKING
ON WHAT ARE CALLED ANCILLARY
TESTS, SO ONE OF THE FAVORITE
ANCILLARY TESTS IS P16, WHICH
DR. VON WAES MENTIONED IS
POSITIVE IN A VERY HIGH
PROPORTION OF HPV-POSITIVE
CANCER BUT ALSO IN A HIGH
PROPORTION OF HPV POSITIVE
PRECANCERS.
SO THAT'S ONE POSSIBLE TEST.
ANOTHER TEST THAT IS BEING
EXAMINED IS METHYLATION.
THERE IS METHYLATION OF SPECIFIC
PARTS OF THE HPV GENOME WHICH
SEEMS TO BE PREDICTIVE OF
WHETHER OR NOT YOU ARE GOING TO
HAVE -- WHETHER OR NOT YOU HAVE
PREMALIGNANT DISEASE.
SO THOSE ARE THE KINDS OF THINGS
IN TERMS OF FALSE POSITIVE,
WHAT'S BEING DONE WITH IT.
FALSE NEGATIVE.
THE HPV-BASED TESTING IS
REMARKABLY GOOD AT ELIMINATING
FALSE NEGATIVES, AS LONG AS YOU
HAVE A VALID TEST, THAT IS SOME
KIND OF DNA TEST, THE DNA IS
REALLY THERE IN A TEST.
THERE'S ALMOST NOTHING THAT
HAPPENS IN THE NEXT 10 YEARS.
YOUR CHANCES OF BECOMING -- YOUR
CHANCES OF DEVELOPING HIGH GRADE
CERVICAL DYSPLASIA ARE VERY LOW.
THIS IS ONE OF THE REASONS WHY
WITH CO-TESTING, THE
RECOMMENDATIONS NOW OF THE U.S.
PREVENTIVE SERVICES TASK FORCE
IS EVERY FIVE YEARS, IF YOU HAVE
CYTOLOGY PLUS HPV TESTING.
WHEREAS CYTOLOGY ALONE IS EVERY
THREE YEARS.
SO THAT TAKES CARE OF BELOW THE
WAIST.
NOW, IN THE MOUTH, THE
PREVALENCE OF INFECTION IS MUCH,
MUCH LOWER, AND I THINK THERE'S
JUST NOT BEEN THAT MUCH
EXPERIENCE.
AND I THINK THE PREDICTIVE VALUE
IS JUST NOT THAT GREAT.
SO IN THAT SENSE, THERE WOULD BE
A LOT OF FALSE POSITIVES.
ONE THING THAT I DIDN'T MENTION
IS THAT THERE WAS A RECENT STUDY
WITH DATA IN EUROPE USING HPV
6 ANTIBODIES AS A SERUM TEST,
AND IT'S DEEMED TO BE HIGHLY
PREDICTIVE OF PEOPLE WHO WERE
DESTINED TO DEVELOP WHAT ARE
PRESUMED TO BE HPV-POSITIVE
OROPHARYNX CANCER, BUT MORE
RESEARCH NEEDS TO BE DONE TO TRY
TO LOOK AT THOSE CORRELATIONS
BECAUSE A LOT OF THEM ARE
INFERENTIAL RATHER THAN STRONGLY
EVIDENCE-BASED.
THANK YOU.