>> THANK YOU, CHRISTOPHER.
SO WELCOME, EVERYONE.
THIS IS OUR 16th VIRTUAL MEETING
OF THE ARE FREDERICK NATIONAL
LABORATORY ADVISORY COMMITTEE
AND I WELCOME ALL OF YOU.
I THINK THAT NEXT JULY WE MAYBE
WILL HAVE THE OPPORTUNITY TO
MEET EACH OTHER FACE TO FACE.
I KNOW THIS MEETING WENT BACK
AND FORTH AND I THINK THE
VIRTUAL MEETINGS REALLY CAN DO
WORK PRETTY WELL.
SO WE DECIDED TO CO THIS IN
FEBRUARY SO THANK YOU FOR
ATTENDING.
SO, THERE'S SOME DEVELOPMENTS
SORT OF RELATED TO FNLAC I
WANTED TO SHARE WITH YOU.
THERE'S NO ACTION REQUIRED FOR
THESE.
THESE ARE JUST SORT OF
ANNOUNCEMENTS OF SOME
INFORMATION I THOUGHT WOULD BE
HELPFUL.
WARREN KIBE WILL RETURN TO THE
NCI AS THE FIRST NCI DEPUTY
DIRECTOR FOR DATA SCIENCE AND
STRATEGY.
HE'S A GREAT GUY.
I'VE BEEN ON MANY COMMITTEES
WITH HIM AND NCI FIRST DEPUTY
DIRECTOR FOR DATA SCIENCE AND
STRATEGY.
HE WILL ADVISE DR. RATHMELL AND
OTHER SENIOR LEADERS ON THE
UTILIZATION AND STEWARDSHIP AND
SHARING OF OUR MOST IMPORTANT
TOOLS AND THAT'S DATA.
HE'LL PROVIDE STRATEGIC
DIRECTION, BE RESPONSIBLE FOR
MANAGEMENT AND OVERSIGHT IN ALL
ASPECTS OF DATA SCIENCE FOR THE
INSTITUTE.
WE WELCOME HIM IN THAT ROLE.
AND ONE OF OUR MEMBERS,
DR. BLOSSOM IMANIA IS SERVING ON
THE BOARD OF SCIENTIFIC
COUNSELORS AS OUR EX-OFFICIO
REPRESENTATIVE ON FNLAC.
HER CURRENT STINT ON THE BOARD
OF SCIENTIFIC COUNSELORS HAS
BEEN EXTENDED.
SHE'LL REMAIN AND THANK YOU,
BLOSSOM.
WE HAVE A NEW POTENTIAL MEMBER
MATTHEW VANDERHEIDEN APPOINTED
JULY 14 BY DR. RATHMELL.
HE'S HERE TODAY FOR OUR MEETING
LISTED AS PENDING AND BELIEVE
HE'LL BE WELCOMED IN OPENING
STATEMENTS.
SOME OVER ALL ANNOUNCEMENTS.
I WANT TO REMIND YOU MUST ABSENT
YOURSELF DURING SPECIFIC
DISCUSSIONS WHEN PARTICIPATION
IN THESE DELIBERATION OF A
PRODUCT MANNER WOULD CONSTITUTE
A CONFLICT OR CREATE THE
APPEARANCE OF ONE.
WE ALL KNOW WHEN WE'RE IN
CONFLICT SO PLEASE, IF YOU FEEL
UNEASY OR ARE IN CONFLICT IT'S
INCUMBENT TO ADVISE THE
EXECUTIVE SECRETARY
DR. CHRISTOPHER KING AND ABSENT
FROM ANY PARTICIPATION IN THAT
SPECIFIC DISCUSSION AND
CATEGORIES INCLUDE ALL MEMBERS
OF THIS COMMITTEE WE MUST DEPEND
ON YOU TO VOLUNTARILY ABSENT
YOURSELF IN DISCUSSION MATTERS
THAT COULD CONCEIVABLY IMPACT
THE STATUS OF THOSE HOLDINGS AND
WE TRUST YOUR JUDGMENT.
WE'RE ALL FAMILIAR WITH THESE
SORTS OF CRITERIA ON MANY
COMMITTEES AND BOARDS WE SERVE.
SO, PLEASE, IF IN YOU NEED TO
MAKE YOURSELF AWARE PLEASE DO
SO.
MEMBERS OF THE PUBLIC WHO WISH
TO EXPRESS VIEWS ON ITEMS
DISCUSSED DURING THE MEET MAY DO
SO IN WRITING TO DR. KING THE
EXECUTIVE SECRETARY WITHIN 10
DAYS OF THE MEETING ANY WRITTEN
STATEMENTS WILL RECEIVE
CONSIDERATION.
A QUORUM IS REQUIRED FOR EACH
INSTANCE IN WHICH A VOTE OCCURS
DURING TODAY'S MEETING A MINIMUM
OF EIGHT APPOINTED MEMBERS MUST
BE PRESENT TO VOICE THEIR VOTES.
YOU CANNOT PREDICT THE TIME OR
OCCURRENCE FOR ANY MOTION BUT
YOUR PRESENCE IS A MUST FOR ALL
SEGMENTS OF THIS MEETING SO
PLEASE, STAY TUNED.
DON'T LEAVE YOUR POST, IF YOU
WILL.
AND I ASSUME, CHRIS, WE CONTINUE
TO HAVE A QUORUM?
>> WE DO.
>> THANK YOU.
SO AT THIS TIME HOPEFULLY
EVERYONE HAS HAD A CHANCE TO
LOOK AT THE MINUTES AROUND ARE
THERE ANY ERRORS OR ANY ISSUES
THAT NEED TO BE CORRECTED IN
THOSE MINUTES?
IF NOT, MAY I MAKE A MOTION TO
APPROVE THE MINUTES OF THE MARCH
11, 2024 MEETING?
>> APPROVAL.
>> AND A SECOND?
>> SECOND.
>> THANK YOU, BLOSSOM.
ANY DISCUSSION, ANY
DISAGREEMENT?
ALL IN FAVOR PLEASE RAISE YOUR
HAND OR SAY AYE.
>> AYE.
>> ANY ABSTENTIONS?
ANY DISAGREEMENT?
ANY VOTES NO?
OKAY.
SO WE APPROVE THE MINUTES.
JUST TO HIGHLIGHT OUR FUTURE
MEETING DATES.
I JUST WANT TO CALL YOUR
ATTENTION THAT THE NEXT FNLAC
WILL BE HELD OCTOBER 21st
THROUGH 22nd IN 2024 AND
CURRENTLY PLANNED AS AN
IN-PERSON MEETING.
WE'LL SEE.
HOPEFULLY WE'LL GET A CHANCE TO
NOT ONLY MEET EACH OTHER BUT
TOUR SOME FACILITIES FOR MANY OF
US WOULD BE YOU'VE NEVER BEEN TO
FREDERICK WITH THE MEETING AND
IN OCTOBER AND THE VIRTUAL
MEETING THERE ARE THREE MEETING
DATES, FEBRUARY 26, JULY 13, 14
AND OCTOBER 21, 22 WITH FEBRUARY
BEING VIRTUAL.
I NEED A MOTION TO APPROVE THESE
DATES FOR 2026.
>> SO MOVED.
>> THANK YOU, CAROL.
>> SECOND?
>> SECOND.
>> OKAY.
I DON'T KNOW WHO DID THAT BUT
THANK YOU.
>> RODNEY.
>> THANK YOU, RODNEY.
I COULDN'T SEE YOU.
ANY DISCUSSION?
ALL IN FAVOR?
OPPOSED?
THE.
WE APPROVE THE MEETING FOR NEXT
YEAR SO IT'S MY PLEASURE TO
INTRODUCE DR. KIM RATHMELL WHO
IS GOING TO GIVE THE NCI
DIRECTOR'S REPORT.
>> THANK YOU VERY MUCH.
WELCOME AND I AM LOOKING FORWARD
TO WHEN WE HAVE OUR NEXT, FIRST
FOR ME, IN-PERSON MEETING.
I APPRECIATE ALL THE WORK YOU
DO.
YOU CAN MOVE TO THE NEXT SLIDE.
THAT WILL JUST GIVE SOME OF OUR
OVERVIEW OF WHAT WE'RE GOING TO
TALK ABOUT TODAY.
I'VE BEEN IN THE ROLE NOW ABOUT
SIX MONTHS AND I'VE BEEN
LISTENING AND LEARNING A LOT AND
GATHERING DATA AND WHAT WE CAN
AND CAN'T DO AND WE'LL TALK
ABOUT RECENT NEWS AND UPDATES.
ALWAYS A HOT TOPIC IS BUDGET AND
WE'LL ALSO TALK ABOUT
DEVELOPMENTS WITH THE FREDERICK
NATIONAL LAB.
IT'S BEEN A TOUGH BUDGET YEAR
AND I'LL EMPHASIZE WE'RE NOT
SLOWING DOWN AND LEARNING TO BE
MORE CREATIVE BUT WE'RE EXCITED
ABOUT ALL THE THINGS THAT ARE
HAPPENING.
AND THE OTHER IS THAT Q&A WILL
BE AT THE END.
WE DO WENT TO HEAR FROM YOU AND
GET YOUR THOUGHTS ON HOW WE DO
THIS BEST.
FIRST OFF YOU ALREADY HEARD
DR. VANDER HEIDEN IS FROM M.I.T.
AND WILL SOON BE A PERMANENT
MEMBER AND LOOKING FORWARD TO
YOUR EXPERT COUNSEL WHILE
SERVING ON THE FNLAC SO WELCOME.
MOVING ON TO THE RECENT NEWS AND
UPDATES.
THE FIRST IS RELEVANT FOR MATT
SPECIFICALLY.
THOUGH YOU ALL HAVE AN
ORIENTATION TO THE BOARD THAT
YOU SERVE ON, ONE OF THE THINGS
THAT WE'VE REALIZED IS THIS IS A
BIG ORGANIZATION AND.
THERE'S A LOT OF PIECES AND THAT
BOARD MEMBERS MAY BE MOST
EFFECTIVE IF WE GIVE THEM A BIG
INTRODUCTION TO WHAT HAPPENS
HERE.
SO WE'RE PLANNING A MIXED
ORIENTATION FOR ALL NCI BOARD
MEMBERS AND I HAVE SIX BOARDS.
AS PEOPLE COME ON WE'LL BE
CREATING THIS OPPORTUNITY TO LET
PEOPLE IN ON REALLY HOW THIS
MESSAGE GETS ACROSS THE WHOLE
SPACE SO THE BOARDS CAN WORK
MOST EFFECTIVELY.
SO NEW MEMBERS WILL TAKE
ADVANTAGE OF THAT.
ALL RIGHT, SO PROBABLY THE THING
YOU'RE MOST CURIOUS ABOUT I
CAN'T TELL YOU MUCH ABOUT
BECAUSE IT'S IN THE MIDDLE OF IT
IS THIS IS WHAT GOES UNDER
COMPETITION PERIODICALLY STILL
IN THE NEGOTIATION PHASE.
IT'S AT THE PACE THAT'S BEEN
EXPECTED FOR SOME TIME.
AND THAT'S WHAT I CAN TELL YOU.
IN TERMS OF DATES THAT I CAN LET
YOU KNOW THE ORIGINAL PROPOSALS
WERE DUE IN FEBRUARY 2023.
THERE WAS A PERIOD OF TECHNICAL
PEER REVIEW THAT OCCURRED
SHORTLY AFTER THAT.
NEGOTIATIONS OPENED UP IN JUNE
AND ALL RIGHT.
THE TOPIC THAT COMES UP
FREQUENTLY WE USE LOTS OF
COMPONENTS OF FREDERICK IN LOTS
OF THE WORK WE DO.
I WANTED TO LET YOU KNOW ABOUT
THE DEPUTY SECRETARY FOR HHS AND
I HAD A MEETING WITH HER AND SHE
HAD SEVERAL QUESTIONS AND WERE
TALKING ABOUT WHAT ACTIVITIES
HAPPEN AT THE FREDERICK NATIONAL
LABS AND WE FOCUSSED THE
ENTIRETY OF THE MEETING WITH HER
ON WHAT WE DO IN TERMS OF THE
BENCH TO BEDSIDE AND BACK
APPROACH TO CONQUERING CANCER
AND HAD AN OVERVIEW AT THE
FREDERICK NATIONAL LIBRARY WITH
HER AND SHE ASKED POIGNANT
QUESTIONS AND WAS ENGAGED AND
INTERESTING AND TOOK HER TO THE
MARSHAL LINNAHAN LABORATORY TO
SHOW HER SCIENCE IN ACTION.
IT WAS A PRODUCTIVE VISIT AND I
THINK WHAT WE HAVE TO DO TO HELP
FOLKS IN GOVERNMENT AND KNOW
WHAT WE NEED IN TERMS OF POLICY
AND FUNDING, IN TERMS OF AGENDA
SETTING ABOUT THE WORK THAT WE
DO.
THAT WAS A BIG INITIATIVE IN
HOSTING HER FOR HALF A DAY.
SO WE ALSO CARRY THAT TORCH IN
OTHER PLACES LIKE AUCR AND ASCO
IN TERMS OF MEETINGS WE HAVE A
LARGE FOOTPRINT IN.
IT'S INSPIRING FOR ME TO GO TO
THESE MEETINGS IN THIS NEW
CAPACITY AND SEE THE ENERGY AND
PASSION THAT THERE IS ARRANGE
CANCER RESEARCH IN SO MANY
DIFFERENT ARENAS.
WE HAD TWO OF OUR NCI STAFF
RECOGNIZED FOR SIGNIFICANT
CONTRIBUTIONS AT ACR.
STEVE ROSENBERG RECEIVE THE LIFE
TIME ACHIEVEMENT AWARD FOR
CANCER RESEARCH AND ASCO WON THE
HUMANITARIAN AWARD.
IN ADDITION TO LOTS OF POSTERS
AND PRESENTATIONS AND OTHER
NETWORK
NETWORKING NCI STRIVES TO BE
FRONT AND CENTER AND WE THINK
BROADLY AND A DIFFERENT APPROACH
TO RESEARCH.
WE CALL OUT A NEW ERA.
THIS WAS STILL EARLY IN MY
TENURE AND I USED AN ANALOGY OF
THE TAILOR SWIFT ERAS TO SUGGEST
WE'RE MOVING INTO AN ERA OF.
RESEARCH AND MORE TRANSPARENCY
PARTICULARLY AMONG GROUPS THAT
HAVE NOT HISTORICALLY WE ENGAGE
DIFFERENT STAKEHOLDERS AND
ADVOCATES AND THINK OF
DISTRIBUTED CLINICAL TRIAL
DESIGN BEING FORWARD FROM
DISCOVERY TO CARE MOVING MORE
QUICKLY BECAUSE WE HAVE GOOD
OPPORTUNITIES TO ADVANCE PATIENT
CARE.
THERE WAS A LOT OF ENTHUSIASM
FOR WE CAN DO IT THESE THINGS
FASTER.
JUST TO LET YOU KNOW ABOUT A
COUPLE TRANSITIONS IN OUR
INTRAMURAL PROGRAM.
ONE BIG PART OF THE INTRAMURAL
PROGRAM IS CCR THE CANCER
RESEARCH AND TOMB MISTELI HAS
LED THIS AND BECAUSE IT'S A
LARGE FOOTPRINT OF BASIC AND
CLINICAL RESEARCH WE'RE
OPERATING WITH A CO-DIRECTOR
MODEL.
JAMES GULLEY WAS CO-DIRECTING
WITH GLENN UNTIL HIS RETIREMENT
AND NOW IT'S DR. CAROL THIE LE
AND WHILE LOOK TO FILL THAT
POSITION IN THE NEXT YEAR.
YOU ALREADY HEARD ABOUT
DR. KIBBI.
WE'RE EXCITED FOR THE INAUGURAL
DEPUTY DIRECTOR FOR DATA SCIENCE
AND STRATEGY.
AS YOU HEARD IT WILL BE ABOUT
ALL THINGS DATA.
SO ADVISING ON A.I., DATA
HARMONIZATION AND COMMON DATA
ELEMENTS WILL HAVE A BIG ROLE IN
THINGS WE DO AT FREDERICK
NATIONAL LAB.
AND WE ALSO BROUGHT ON A SENIOR
ADVISER FOR CLINICAL RESEARCH
AND THIS GETS TO THE INITIATIVE
TO TRY TO DEVELOP A CLINICAL
TRIAL FLASHING CAN BE MORE
SIMPLE WITH DR. SHAALAN BEG AND
HE IS WORKING ACROSS THE
CLINICAL RESEARCH SPACE TO HELP
US TO MODERNIZE IN ALL THESE
AREAS.
HE STARTED IN THE LAST FEW WEEKS
GETTING TO KNOW PEOPLE THAT WERE
LOOKING AT ALL AREAS OF CLINICAL
RESEARCH ACTIVITY.
THEN ALSO IT'S NOT ALWAYS JUST
ABOUT NEW INDIVIDUAL LEADERS BUT
DIFFERENT WAYS THAT WE ORGANIZE
THE ORGANIZATION AND BUILDING
LEADERSHIP AND LEADERSHIP
COMMUNICATION.
WE CHANGED THE NAME TO THE
CENTER TO CHANGE CANCER
DISPARITIES TO CANCER HEALTH
EQUITY.
THERE WAS A BIG INITIATIVE TO
BRING TOGETHER A GROUP OF CANCER
EQUITY LEADERS, C.E.L. IS THE
GROUP ON THE LEFT.
THESE ARE ALL LEADERS WHO
DEDICATED THEIR CAREERS TO
ADVANCING EQUITY ACROSS THE
BOARD FROM WORKFORCE TO PATIENT
CARE SO THIS GROUP IS HELPING
ADVISE US HOW WE BRING EQUITY
MORE BROADLY AND THE FIRST IT
BLACK IN CANCER CONFERENCE HELD
BY THE FREDERICK NATIONAL LABS
AND BROUGHT TOGETHER
INVESTIGATORS FROM AROUND THE
COUNTRY TO TALK ABOUT ISSUES
THAT FACE YOUNG PEOPLE GOING
INTO CANCER FIELDS, CANCER
PATIENTS FROM DIFFERENT
COMMUNITIES AND IT WAS REALLY
WELL DONE.
VERY WELL ATTENDED AND DEFINITE
LY A SPECIAL EVENT.
GLAD FREDERICK NATIONAL LAB ED
THIS.
I MENTION THE NAME CHANGE
COMING.
WE'VE BEEN TALKING ABOUT IT SO
MUCH IT'S ALREADY THE PREFERRED
NAME IS THE CENTER FOR CANCER
HEALTH EQUITY, CCHE.
SO THIS IS A GROUP THAT TAKES ON
ALL OF OUR HEALTH EQUITY
INITIATIVES AND LED BY
DR. SPRINGFIELD.
OKAY, LET'S TALK ABOUT BUDGETS.
JUST TO LEVEL SET WHERE THINGS
ARE WITH BUDGET, THE TWO COLUMNS
THE FIRST COLUMN ACTUALLY THE
ONE THERE IN THE MIDDLE IS OUR
OPPORTUNITY EVERY YEAR TO PUT
OUT WHAT WE THINK IT WOULD COST
TO DO THE WORK THAT WE'RE DOING.
SCIENCE GETS MORE EXPENSIVE,
THINGS COST MORE.
THE KINDS OF THINGS THAT WE DO
PARTICULARLY IN RESEARCH BASED
AND IN BASIC SCIENCE JUST ADDS
UP.
YOU CAN SEE IN IN FY23 OUR
ESTIM
ESTIMATE WAS 7.7 AND THEEST PLAT
FOR WILL FY2025 IS 11.46.
THE DELTA IS GETTING BIG.
IN FY23 WE RECEIVED $7.3 BILLION
INCLUDING THE LAST YEAR OF CURES
ACT FUNDING.
AND IN FY24 THE BUDGET WE'RE
OPERATING IN TODAY, WE RECEIVED
AN APPROPRIATION OF $7.22
BILLION.
THAT REFLECTED AN INCREASE IN
OUR BASE OF $120 MILLION, WHICH
DOES WHICH REPRESENTS AN
ACKNOWLEDGEMENT THINGS COST MORE
AND ATTENTION TO THE FACT THEY
DIDN'T WANT THE EXTRAMURAL
FUNDING TO BE HARMED BY THE
CHALLENGING GRANT SITUATION.
NEVERTHELESS, IT WAS A $96
MILLION DECREASE IN EFFECTIVE
DOLLARS.
A DIFFERENT KIND FROM THE YEAR
BEFORE.
THIS IS THE FIRST DECREASE WE'VE
HAD IN QUITE SOME TIME SO IT'S
MADE IT A PARTICULARLY
CHALLENGING YEAR WHEN WE KNOW
THE COST OF DOING THIS WORK IS
QUITE A LOT MORE.
WE'LL FIND OUT FOR FY25 SOME
TIME AFTER OCTOBER 1.
BUT I WILL SAY THE PRESIDENT'S
BUDGET PROPOSAL WAS FOR ALMOST
$9.3 BILLION.
WE WILL WAIT AND SEE.
THIS IS LIKELY TO BE A TOUGH
YEAR.
THE DEBT CEILING IS STILL IN
PLACE AND THAT'S STILL A
REQUIREMENT FOR PLANNING THE
BUDGET OVER ALL FOR ALL OF THE
GOVERNMENT.
WHAT THAT HAS TRANSLATED FOR US,
IT'S EASIEST TO LOOK WHERE THE
EFFECTS ARE IN OUR PAY LINES.
THIS IS FOR EXTRAMURAL PROGRAMS.
WE TEND TO HAVE KEPT THINGS LIKE
THE FREDERICK NATIONAL LAB
ROUGHLY FLAT.
THE PAY LINES IS WHERE WE MAKE
SEM YEAR TO YEAR.
THE AVERAGE FOR ESTABLISHED
INVESTIGATORS WHICH YOU SEE IN
THE DARKER COLORED LINE HAS BEEN
HOVERING AROUND 10, A 10% PAY
LINE.
OF COURSE THE FUNDING RATE IS
HIGHER.
IT COMES FROM SOME SELECT PAY
AND FROM RFAs THAT COME IN AS
WELL.
WE FELT WE STILL NEEDED TO MAKE
A PRIORITY AND KEPT IT AT 17%
FOR INVESTIGATORS.
IT'S A 7% ADVANTAGE FOR BEING AN
EARLY STAGE INVESTIGATOR.
SO, WHEN WE HAVE A TOUGH BUDGET
SITUATION IT'S IMPORTANT TO
PRIORITIZE.
WE HAVE A NATIONAL CANCER PLAN
IT'S A YEAR OLD.
I FOUND IT TO BE VERY HELPFUL.
WHEN I THINK ABOUT HOW TO
PRIORITIZE THE WORK THAT WE DO
AROUND THESE EIGHT GOALS
ARTICULATED FOR THEM
REPRESENTING HEALTH CENTERED
GOALS AND FOR WHAT I CALL
EMPOWERING GOALS BUT YOU CAN SEE
HOW SORT OF A ROAD MAP LIKE THIS
GIVES US SOME OF THE DIRECTION
AND ENERGY FOR WHERE WE'RE GOING
TO PUT OUR RESOURCES BECAUSE WE
DO HAVE THESE GOALS AT THE END
WHICH IS TO IMPROVE HEALTH
OUTCOMES FOR EVERYONE AND TO
REDUCE CANCER MORTALITY BY 50%
BY 2047 SO WE NEED TO MAKE
PROGRESS ACROSS PREVENTION,
EARLY DETECTION, DELIVERING
OPTIMAL CARE, DEVELOPING INFECT
WILL THERAPIES AND ELIMINATING
INEQUITIES.
HUGE PORTIONS OF THE POPULATIONS
TO MAKE BIG IMPROVEMENTS.
MAXIMIZING DATA UTILITY AND
OPTIMIZING THE WORKFORCE AND
ENGAGING EVERY PERSON.
AND WITH THAT IN THE BUDGET
SECTION I THOUGHT I'D SHARE WHAT
I FIND TO BE HELPFUL TO HAVE A
SET OF VALUES THAT I LEAN ON
WHEN I'M WORKING ON MAKING SOME
OF THESE DECISIONS AND FOR ME
THAT'S TALENT DEVELOPMENT SO
THEN NO SURPRISE THAT'S WHY WE
KEPT THE PAY LINE FOR EARLY
STAGE INVESTIGATORS AT 17% AND
ALSO HELD FUNDING FOR TRAINING
PROGRAMS AND KEPT THAT FROM
BEING CUT WHERE EVERYTHING ELSE
SAW A CUT.
THE OTHER VALUES FOR ME ARE
CREATIVITY AND INNOVATION.
THAT COMES IN VERY HANDY WHEN
WE'RE HAVING A TOUGH BUDGET
TIME.
EMPOWERMENT AND ENABLING
EVERYONE TO BE A PART OF THIS
EFFORT AND FISCAL
RESPONSIBILITY.
OKAY.
AND THEN ON TO FUNDS.
SO SOME RESEARCH AND PROGRAM
HIGHLIGHTS.
THERE'S A LOT SO I THOUGHT I'D
JUST SHOW IT AS A SPREAD SHEET.
AND I'M NOT GOING TO GO THROUGH
ALL THESE IN DETAIL.
DIFFERENT PUBLICATIONS AND
INITIATIVES BUT A NEW CRISPR
SCREENING PLATFORM THAT'S
SUCCESSFULLY SHOWN.
PEOPLE BOOST SENSITIVITY.
A NEW WORK IN RAS PARTICULARLY
ON K RAS FOR A VARIANT.
THE SHIFT TRIAL.
WE'RE REALLY EXCITED ABOUT THIS
TRIAL WHICH IS SELF-COLLECTION
OF HPV FOR WOMEN FOR DETECTING
RISK FOR CERVICAL CANCER.
THIS HAS OPENED AND HAS ENROLLED
PATIENTS IN VERY QUICK TIME AND
IS A REALLY EXCITING TRIAL TO
PUT RISK ASSESSMENT LITERALLY
INTO THE HANDS OF PATIENTS AND
MOVE TO A DIFFERENT KIND OF
MENTALITY OF HOW WE ADDRESS RISK
FOR IN THIS CASE CERVICAL
CANCER.
WE'RE ALSO LOOKING AT SOME
REALLY EXCITING WORK ON NEW
INHIBITORS FOR RAS.
I THINK YOU'LL HEAR MORE ABOUT
THAT LATER AND FREDERICK
NATIONAL LAB IS NOT ALL CANCER.
WE'RE THE STEWARDS OF THE
FREDERICK NATIONAL LAB BUT IT'S
A NATIONAL LAB FOR ALL BIO
MEDICAL SCIENCE.
I WANTED TO MAKE SURE YOU WERE
AWARE OF SOME OF THE EXCITING
WORK HAPPENING AROUND WORK
IDENTIFYING ANTIBODIES FOR A
UNIVERSAL FLU VACCINE.
AND IN THE ARENA OF TRANSFORMING
CLINICAL RESEARCH SO THIS SORT
OF COMBINES BY ACR AND ASCO
TALKS AND EVERYONE INCLUDED AND
CAN WE MOVE FORWARD FASTER IS
THE IDEA OF GETTING CLINICAL
TRIALS OUT WHERE THE TRIALS ARE
AND IN THEIR CARE AND PILOTING
VIRTUAL CLINICAL TRIALS AND
FREDERICK NATIONAL LAB IS AN
IMPORTANT PART OF THIS TO BRING
THE STAFFING THAT'S REQUIRED TO
DO CLINICAL WORK OUT INTO SPACES
THROUGH VIRTUAL MEETS AND THIS
IS 2024.
THIS IS WORK WE'RE LEARNING HOW
TO DO THAT AND THE CLINICAL
TRIAL INNOVATION IS STREAMLINING
CLINICAL TRIALS SO THEY CAN BE
OPEN AND ENROLLED MUCH MORE
QUICKLY.
THE MATCH SUCCESSOR LEANS ON THE
STUDY AND IT WAS A PARADIGM FOR
HOW YOU APPROACH A PATIENT'S
THERAPEUTIC DECISION MAKING.
SO MYELOMATCH IS OPEN AND I
THINK ENROLLED THE FIRST
PATIENT.
COMBO AND IMMUNOMATCH ARE BOTH
ON THE WAY.
AND WORKING BROADLY ACROSS THE
CLINICAL RESEARCH SPACE AND A
SHUT OUT THAT WE HAVE A WORKING
GROUP LOOKING AT ENHANCING
CANCER RESEARCH AND QUALITY
CARE.
LOOKING AT HOW DO WE GET
CAPACITY BUILT OUTSIDE OF THE
MAJOR ACADEMIC CENTERS.
BECAUSE THAT'S WHERE MOST
PATIENTS ARE GETTING THEIR CARE.
AND IT FEEDS WELL INTO THIS
WHICH IS THE PART OF THE CANCER
MOONSHOT THE CREATION CANCER
CABINET.
THE CABINET FOR THE FIRST TIME
IS HOSTING A SERIES OF COMMUNITY
CONVERSATIONS.
THESE ARE WEB-BASED
OPPORTUNITIES FOR COMMUNITY TO
ENGAGE WITH EXPERTS.
WE HAVE A TOPIC AND OURS IS
GOING ON -- YOU'LL MISS IT
BECAUSE IT'S NOW AND STARTS IN
HALF AN HOUR.
BUT OUR TOPIC IS IMPROVING
CANCER OUTCOMES: BRINGING
RESEARCH TO RURAL COMMUNITIES
BUT THERE ARE TOPICS THROUGHOUT
THE NEXT TWO WEEKS TO GET TO
BRINGING THE INNOVATION AND
EXCITEMENT AND WORK OUT IN THE
COMMUNITY.
FINALLY A SHOWCASE OF TECHNOLOGY
IN SEPTEMBER AND THE ANNUAL RAS
INITIATIVE SYMPOSIUM THE FIFTH
ONE IS IN OCTOBER AND THE WORK
HAS BLOSSOMED BEAUTIFULLY.
THAT GETS ME TO THE NEW HALLMARK
OF WHAT I'M GOING AT THE BOARD
TALKS MAKING SURE WHAT IT IS I
NEED FROM YOU AS BOARD MEMBERS
AND WHAT I NEED FROM YOU WE CAN
TALK ABOUT IN THE NEXT FIVE
MINUTES OR WHENEVER YOU HAVE AN
IDEA BUT HOW CAN WE ACHIEVE THE
GOALS OF THE NATIONAL CANCER
PLAN AND DO WE HAVE THE RESOURCE
TO BUILD THE CAPACITY FOR THE
NATION'S CANCER INITIATIVE.
THAT'S WHAT WE VIEW THIS FOR AND
YOUR INPUTS ARE VALUABLE AND
MAKES US LEVEL SET AND
SUGGESTIONS HOW TO MOVE FORWARD
FASTER ARE WELCOMED.
THANK YOU VERY MUCH.
I'LL STOP THERE.
>> WE HAVE SOME TIME.
A FEW MINUTES FOR QUESTIONS.
YOU'RE MUTED.
>> THANK YOU SO MUCH, KIM.
CONGRATULATIONS ON BEING IN YOUR
ROLE FOR ALMOST A YEAR.
HOW MANY PEOPLE CAME AND WHO
WERE THE MAIN SPEAKERS AND ARE
YOU GOING TO DO IT AGAIN.
>> SO, I SHOULD KNOW THIS NUMBER
OFF THE TOP OF MY HEAD BECAUSE
WE HAD TO MOVE IT AND KEEP
INCREASING THE SPACE BECAUSE
WAITING LIST WOULD FILL UP EVERY
TIME.
I WANT TO SAY IT WAS 500 OR SO
IF THERE'S ANYONE ONLINE WHO
KNOWS THE NUMBER MORE ACCURATELY
THAN ME.
PLEASE LET ME KNOW.
THAT'S WHAT IT LOOKED LIKE WHEN
I WAS TALKING.
THE AUDIENCE WAS A MIX OF
TRAINEES AND MORE SENIOR
INVESTIGATORS, CLINICAL, BASIC.
ALL DIFFERENT ASPECTS.
THE TALKS WERE ON A RANGE OF
CAREER DEVELOPMENT, SCIENCE
WHERE THERE'S ACTUALLY THE TALK
I REALLY ENJOYED MOST WAS FROM
THE NEW CANCER GRANT CHALLENGES
PROGRAM.
IT'S LOOKING AT ANCESTRY AND
RISK FOR CANCER AND REALLY
POWERFUL TALK.
IT WAS THAT KIND OF TALK AND IT
WAS GOOD AND I HOPE THEY DO IT
AGAIN.
I THINK IT WAS WELL ENOUGH
RECEIVED I WOULD ASSUME SO BUT I
DON'T KNOW THE DETAILS.
>> YES, BLOSSOM.
>> HI, KIM.
THANK YOU FOR THE PRECIPITATION.
YOU MAY NOT BE ABLE TO SPEAK
ABOUT THIS BUT I WAS WONDERING
IF YOU HAD ANY THOUGHTS ON THE
NEW PROPOSAL TO INFORM AND HOW
IT WILL IMPACT NCI?
>> SO, I PROBABLY CAN'T SAY A
LOT BECAUSE I DON'T KNOW MORE
THAN YOU ALL KNOW WHAT'S IN THE
PRESS.
IT'S NICE TO SEE CANCER WASN'T
REORGANIZED.
SO I THINK PEOPLE UNDERSTAND AND
APPRECIATE CANCER IN A DIFFERENT
WAY THAN THEY CAN OTHER DISEASES
AND I THINK THERE'S VALUE IN ALL
THE NIH.
SO WE'RE WATCHING ALL THIS AS
WELL.
>> THANKS.
>> JOHN IS HAVING ISSUES WITH
HIS MICROPHONE.
JOHN.
>> I HAVE THE QUESTION THAT BLUE
-- BLEW OFF MY PAGE.
>> THERE WAS A LIST OF SPEAKERS.
>> THERE WAS A QUESTION FROM
JOHN.
JOHN'S QUESTION WAS -- MY
QUESTION IS HOW DO YOU GET THE
FOCUS ON INNOVATION TO PERCOLATE
DOWN TO THE REVIEWERS OF GRANTS
WHERE REVIEWERS VARY WIDELY ON
HOW MUCH VALUE THEY PLACE --
>> YES, THANKS.
WOW, SOME DAYS I WISH I HAD A
DEGREE IN PSYCHOLOGY.
I THINK WE MAKE IT VERY CLEAR
INNOVATION IS A HUGE PRIORITY.
WE'RE TALKING A LOT ABOUT HOW WE
WRITE OUR REQUESTS SO THAT IT'S
CLEAR WE'RE PRIORITIZING
INNOVATION.
ACTUALLY I'VE BEEN THINKING
ABOUT THIS IN TERMS OF HOW WE
HELP REVIEWERS LEVEL SET WHETHER
IT'S ABOUT PAPERS OR GRANTS AND
WHERE THE APPROPRIATE LEVEL OF
CRITIQUE VERSUS SORT OF OFF THE
MARK.
THAT'S A HARD ONE.
I AGREE.
>> THANK YOU.
SO DR. RATHMELL I WANT TO
CONGRATULATE YOU ON YOUR
ACCOMPLISHMENT TO DATE.
MY QUESTION IS WITH REGARD TO
THE COMMENT ON THE LAST SLIDE
WITH REGARD TO CAPACITY AND
INFRASTRUCTURE.
I WONDERED -- THIS IS NOT A NEW
QUESTION SO EXCUSE ME IF I SOUND
LIKE A BROKEN RECORD BUT WHAT IF
ANYTHING IS HAPPENING WITH
REGARD TO LEVERAGING THE HUGE
AMOUNT OF DATA WITHIN OUR WORLD
AND MAKING THAT AVAILABLE AS A
RESOURCE FOR OUR TRAINING A.I.
ALGORITHMS FOR PROGNOSTIC ASSAYS
FOR IDENTIFYING PATIENTS THAT
WILL BENEFIT FROM SOME OF THESE
THERAPIES AND ALTERNATIVELY ALSO
THE HUGE OPPORTUNITY POTENTIALLY
WITH THESE ALGORITHMS FOR
LOOKING AT NEGATIVE TRIALS AND
POTENTIALLY RESUSCITATING SOME
OF THESE TRIALS.
>> SO, PLEASE FEEL FREE TO KEEP
ASKING THAT QUESTION UNTIL WE
GET IT RIGHT.
I THINK WE'RE INTERESTED IN
MAKING DATA AVAILABLE AND BEING
ABLE TO SHARE IT TO ANSWER THE
QUESTIONS AND DEFINITELY NOT
DUPLICATE WORK AND DEFINITELY --
THIS IS WHERE WE'RE IN A TIGHT
BUDGET LIKE THIS FOR A LONG
PERIOD OF TIME WE CAN'T AFFORD
TO DO THAT.
THIS IS WHERE HAVING DR. KIBBE
ON BOARD WILL BE HELPFUL AND HOW
BEST TO DO THAT AND THAT'S ALL I
CAN SAY ABOUT THAT AT THE
MOMENT.
>> SO WE'RE RUNNING A LITTLE
LATE SO TWO MORE QUESTIONS.
>> I CAN'T THANK YOU ENOUGH FOR
DOING WHAT YOU DO BECAUSE IT'S A
HARD JOB AND WE ALL APPRECIATE
IT IMMENSELY.
ONE THING YOU SAID BOTHERS ME A
BIT HOW TO WE PUT RESOURCES INTO
FREDERICK TO BUILD WHAT WE NEED.
IT OCCURS DO ME WE DON'T HAVE TO
BUILD EVERYTHING AT FREDERICK.
WE CAN TAKE ADVANTAGE OF THE
NATIONAL CANCER CENTERS AND
PERHAPS ISSUE RFPs FOR THE
CANCER CENTERS TO PROVIDE THE
METHODOLOGY THAT MAY ALREADY BE
BUILT WITHIN THEIR VARIOUS
INSTITUTIONS.
AND THAT WOULD NOT ONLY SAVE US
FUNDING BUT IT WOULD PROBABLY
GET US TO THE GOAL FASTER.
>> YEAH, I LOVE THAT AND THAT
ALSO IS SPEAKING TO CREATING
MORE OF A NETWORK AND NOT HAVING
THIS BE A HUB EVERYONE NEEDS TO
COME TO AND I AGREE COMPLETELY.
>> ALSO TO PLAY ON THE LAST
SEVERAL COMMENTS AND REVIEWERS
CRITICIZING GRANTS ESPECIALLY
FOR THE YOUNG ADVOCINVESTIGATOR.
MY EXPERIENCE OF REVIEW
COMMITTEES IS THEY'RE RISK
AVERSE AND DON'T GET THEY'RE
RISK WITH THE YOUNG
INVESTIGATORS AND INNOVATION
MEANS SOMETHING LIKELY DIFFERENT
FROM THEM THAN WHAT IT MEANS TO
ALL OF US OLD DOGS.
I WOULD ENCOURAGE SOME EDUCATION
TO GO INTO THE REVIEW COMMITTEES
BEFORE THEY MEET AND GET THEIR
GRANTS.
BECAUSE THEY NEED TO START
REVIEWING GRANTS WITH A
DIFFERENT EYE.
>> CAROL, OUR LAST QUESTION
BEFORE WE MOVE ON.
>> MORE A COMMENT BUILDING ON
PRIOR COMMENTS.
I THINK FREDERICK NATIONAL LAB
COULD BE A POINT OF NUCLEATION
FOR EFFORTS FOR EXTERNAL GROUPS
AS WELL AS INTERNAL.
TO LISA'S POINT YOU DON'T HAVE
TO BUILD EVERYTHING BUT
FREDERICK HAS A REALLY IMPORTANT
ROLE I THINK IN NUCLEATING
FOCUSSED EFFORTS AND BRINGING IN
INVESTIGATORS FROM ALL PARTS TO
WORK COLLABORATIVELY ON
PROJECTS.
I THINK OF AND I THINK FOR DATA
SCIENCE WARREN'S AN EXCELLENT
LEADER.
HE'S A COMMUNITY BUILDER AND
WILL BE GREAT FOR DOING THAT.
I THINK FOR EFFORT LIKE PDX NET,
FREDERICK HAS PLAYED A REALLY
IMPORTANT NUCLEATING ROLE IN
EFFORTS OF THAT INITIATIVE AND
MORE OF THAT I THINK IS WHAT
FREDERICK COULD DO VERY WELL.
>> GREAT, THANK YOU.
OKAY, THANK YOU, KIM.
>> BEFORE I SIGN OFF BECAUSE
WE'RE ON CAMERA, I WANTED TO
MAKE A CORRECTION ABOUT BLACK IN
CANCER.
APPARENTLY THIS IS THE FIRST IN
NORTH AMERICA.
THIS WAS ONE IN 2022 IN LONDON.
WITH THAT CORRECTION AND
HOPEFULLY WE'LL ALTERNATE BACK
AND FORTH.
>> THANK YOU SO MUCH.
THANK YOU.
>> NOW WE'RE GOING TO TURN TO
DR. KARLOVICH WHO WILL TALK TO
US ABOUT FNLAC SUPPORT FRIENDS
OF CANCER RESEARCH TUMOR
MUTATIONAL BURDEN AND HOMOLOGOUS
RECOMBINATION DEFICIENCY FOR
HARMONIZATION PROJECTS.
IT
>> CAN YOU HEAR ME NOW.
SORRY, I WAS HAVING TROUBLE
UNMUTING MYSELF.
GOOD AFTERNOON, EVERYBODY.
THANK YOU FOR JOINING TODAY.
I'M SHARING MY SLIDES HOPEFULLY
EVERYBODY CAN SEE THOSE.
AND I'LL TALK ABOUT TWO PROJECTS
TODAY.
THE FIRST IS AN EFFORT TO
HARMONIZE TUMOR MUTATIONAL
BURDEN.
THAT PROJECT WAS INITIATED IN
THE FALL OF 2017 AND RAN FOR
THREE YEARS AND ALL THE DATA'S
BEEN PUBLISHED.
THEN I'LL TALK MORE RECENTLY NOW
ABOUT A PROJECT THAT WE'VE BEEN
WORKING ON AND IS JUST WRAPPING
UP TO HARMONIZE CONFLICTS BOUND
MARKER FROM HOMOLOGOUS
RECOMBINATION DEFICIENCY.
I WANT TO MAKE SURE AT THE
BEGINNING I GIVE SPECIAL THANKS
TO LISA McSHANE A STATISTICIAN
AND MICKY WILLIAMS WIHO RETIRED
WHO PLAYED AN IMPORTANT ROLE IN
THE TMB PROJECT.
I THINK EVERYBODY ON THE CALL IS
FAMILIAR WITH TMB.
IT'S THE NUMBER OF SOMATIC
MUTATIONS IN GENOME PER MEGA
BASE.
YOU SEE IT IN NUMEROUS TUMOR
TYPES AND A SURROGATE FOR
NEOANTIGEN LOAD AS ALL ON THE
CALL ARE PROBABLY AWARE AND IS A
PREDICTIVE BIOMEDICAL FOR
RESPONSE TO CHECKPOINT BLOCKADE.
THE PROBLEM AND CHALLENGE IS
THAT METHODS FOR ESTIMATING TMB
VARY WIDELY ACROSS CLINICAL
STUDIES.
TO ADDRESS THIS CHALLENGE,
FRIENDS OF CANCER RESEARCH DID
WHAT THEY DO BEST.
THEY PUT TOGETHER A
PUBLIC-PRIVATE CONSORTIUM
CONSISTING OF FDA, NCI,
FREDERICK NATIONAL LAB AND
DERIVATIVE STAKEHOLDERS TO TRY
TO CONDUCT STUDIES TO GENERATE
EVIDENCE THAT MIGHT DRIVE
ALIGNMENT AROUND HOW WE ASSESS
TMB.
AND THE PROJECT CONSISTED YOU
SEE HERE OF THREE PHASES.
THE FIRST PHASE THERE WAS WILL
INSILICO ANALYSIS OF TCGA DATA
AND IN THE LAST PHASES WE DID
WET LAB WORK ON CELL LINES AND
CLINICAL SAMPLES.
I'LL START WITH DATA FROM THE IN
SILICO FACE FROM LABORATORIES
THAT ARE ALL HOUSEHOLD NAMES.
I'M SURE YOU'RE FAMILIAR WITH
MANY AND I WANTED TO TAKE ABOUT
THEY'RE ASSAYS AND ALL THE LABS
ARE TARGETED ON NEXT GENERATION
SEQUENCING PANELS AND THEY VARY
IN SIZE FROM 324 GENES TO 607.
THEY COVER REGIONS OF THE EXOME
AND THE CANCER RELATED GENES
VARIED FROM 800 KILO BASES TO
1.7 MEGABASES.
THAT'S IMPORTANT BECAUSE YOU
NEED A CERTAIN MINIMUM AMOUNT OF
COVERED TO BE ABLE TO GENERATE
BETWEEN 500 KILOBASES AND A MEGA
THERE IS BASE.
ANOTHER FEATURE THAT'S IMPORTANT
TO CALL OUT AT THE BEGINNING IS
HOW TMB IS ESTIMATED.
EVERY LAB USES NON-SYNONYMOUS
VARIANTS IN THEIR CALCULATION OF
TMB AND THAT MAKES SENSE BECAUSE
NON-SYNONYMOUS VARIANTS GIVE
RISE TO THE -- NEOANTIGENS ONE
OF THE PARTICIPANTS HAS AN FDA
APPROVED TEST FOR TMB IT'S TUMOR
AGNOSTIC.
AND THERE WERE TWO OTHER
PARTICIPANTS.
SORRY MY PRESENTATION IS MOVING.
IT AND THERE'S TWO OTHERS
KETTERING AND PERSONAL GENOME
DIAGNOSTICS.
I WANT TO SAY A LITTLE BIT ABOUT
WHAT WE USED RIGHT UP FRONT.
I MENTIONED THERE WAS AN IN
SILICO PHASE AND WE LOOKED AT
OVER 4,000 SAMPLES AND HAD A WET
LAB PHASE WITH CLINICAL SAMPLES
AND AGREED AT THE BEGINNING ON A
GOLD STANDARD BASED ON WHOLE
EXOME SEQUENCING.
WE WOULD GENERATE A GOLD
STANDARD WHOLE EXOME SEQUENCING
SCORE AND AGREED ON THE METRIC
IN TERMS OF DEPTH AND ALLELE
FREQUENCY AND THRESHOLDS.
WE ALSO AGREED THE DATA WOULD BE
A MATCHED TUMOR AND GERM LINE
WHOLE EXOME SEQUENCE TO
DEFINITIVELY FILTER THE GERM
LINE VARIANTS AND THE OTHER
THING THAT WAS IMPORTANT WE
AGREED UPON WAS WE WOULD ONLY
INCLUDE NON-SYNONYMOUS VARIANTS
IN THE CALCULATION OF THE GOLD
STANDARD WEST TMB.
FOR EVERY SAMPLE EACH
PARTICIPANT CALCULATED THEIR
ONLY PANEL TMB SCORE AND DID A
PAIR WISE COMPARISON FOR EACH
LAB AND COMPARED THE LEFT
STANDARD AND FIT REGRESSION
LINES IF THE PANEL WILL TMB
SCORE MATCHED THE GOLD STANDARD
SCORE THE REGRESSION LINE WOULD
FALL ALONG THIS DOTTED BLACK
LINE HERE.
THAT IS THE IDENTITY LINE.
AS YOU'LL SEE IN SOME CASES
WE'RE VERY CLOSE TO THE IDENTITY
LINE AND IN OTHER CASES WE'RE
ACTUALLY QUITE FAR AWAY FROM
THAT IDENTITY LINE.
AND HERE IS THE IN SILICO AND
ALL TCGA SAMPLES EXCEPT FOR
THOSE THAT HAVE A TMB HIGHER
THAN 40.
AND WE DECIDED TO RESTRICT THE
ANALYSIS TO 40 AND LESS BECAUSE
WE AND THIS REPRESENTS 32 TUMOR
TIMES AND RIGHT OFF THE BAT WHAT
YOU'RE PROBABLY SEEING HERE IS
EIGHT FROM THE 11 LABS HAVE
REGRESSION LINES WITH SLOPES
GREATER THAN 1.
THAT MEANS THEIR PANELS ARE OVER
ESTIMATING TMB.
AND THEN WE THOUGHT, WELL, MAYBE
THAT'S BECAUSE MOST OF THE
SAMPLES HAVE PRETTY LOW TMB DOWN
IN THE ZERO TO 10 RANGE AND
THERE'S A LOT OF SCATTER DOWN
THERE.
LET'S FOCUS ON THE TUMOR TYPES
WITH A NICE DISTRIBUTION OF TMB
BETWEEN 0 AND 40 AND THAT'S
EIGHT TUMOR TIMES ABOUT 800 SAM
MALLS AND LOOKING AT THAT SUBSET
YOU SEE A TIGHTER DISTRIBUTION
BETWEEN THE LABS AND
INTERESTINGLY YOU SEE THE SLOPES
CONSISTENTLY SHIFTING DOWN.
SO THAT DID HELP SOME, I WOULD
SAY.
BUT THERE'S STILL SOME BIASES
HERE.
I'M HAVING TROUBLE ADVANCING THE
SHIEDZ.
-- SLIDES IF WE LOOK AT THE
EIGHT TUMOR TYPE WE SEE
INTERDEPENDENT RELATIONSHIPS.
FOR BLADDER CANCER IT TURNS OUT
ALL 11 LABS SEEM TO BE OVER
ESTIMATING WITH THEIR PANELS TMB
RELATIVE TO WEST BUT BY
COMPARISON IF YOU LOOK AT LUNG
ADENO AND SQUAMOUS AND MELANOMA
THERE IS NOT A TREND TOWARDS
OVER OR UNDERESTIMATE BEING TMB
ON THE PANELS.
IT'S VERY INTERESTING THERE
COULD BE THAT KIND OF CANCER
DEPENDENT RELATIONSHIP.
WILL NOW CAN WE MOVE QUICKLY NOW
INTO THE CLINICAL DATA IN THIS
PART OF THE PROJECT THE
DIFFERENT LABORATORIES WERE SENT
SAMPLES AND SENT 10 CELL LINES
AND NUCLEIC ACID FROM 10 CELL
LINES THAT WAS EXTRACTED AT A
COLLABORATORS LABORATORY AND
THERE WERE ALSO NUCLEIC ACID
FROM 29 CLINICAL SAMPLES THAT
WERE EXTRACTED IN OUR LABORATORY
AT MOCA.
FOR THIS PART OF THE PROJECT,
MOCA PERFORMED WHOLE EXOME
SEQUENCING INTO THE SCORE
ACCORDING TO THE CONSORTIUM GOLD
STANDARD ALGORITHM.
AND THAT DATA WAS IN TURN
COMPARED TO THE PANEL TMB
SCORES.
ADDITIONALLY WE DID IN THIS
PHASE OF THE PROJECT WE USED THE
TCGA DATA TO GENERATE A
CALIBRATOR, IF YOU WILL.
AND WE WERE HOPING THAT
CALIBRATOR MIGHT HELP US
HARMONIZE AND ALIGN THE TMB
SCORES FROM DIFFERENT LABS AND
YOU'LL SEE IN A MOMENT HOW WE
DID THAT.
SO WHAT DID WE SEE?
TURNS OUT THERE WERE 25 OF 29
CLINICAL SAMPLES OF TMB, 40 OR
LESS AROUND WE SAW BIAS ON THE
IN SILICO ANALYSIS AND THERE
WERE NOTABLE EXCEPTIONS HERE.
AND SO WHY MIGHT THAT HAVE BEEN?
WE'RE IN THE CLINICAL PHASE.
WE STARTED LOOKING MORE CLOSELY
AT THIS AND FIRST THING WE DID
WAS WE ASKED THE LABS TO FILTER
PATHOGENIC VARIANTS.
WHY MIGHT WE WANT TO DO THAT?
THESE PANELS ARE BIASSED.
IF YOU THINK ABOUT IT THEY'RE
ALL INTERROGATING CANCER-RELATED
GENES.
SO THEY MAY BE BIASSED TOWARDS
OVER ESTIMATE BEING TMB FOR THAT
REASON.
WHAT IF WE ASKED THE LABS TO
REMOVE KNOWN PATHOGENIC VARIANTS
WE FIND IN THE COSMIC DATABASE.
YOU CAN SEE IN THE BOX AND PLOTS
THE MEDIAN LINE IN THE BOX IS
MOVING DOWN TOWARDS WHERE THE
WEST MEDIAN WAS.
WHEN WE REMOVED THE PATHOGENIC
VARIANT AND THAT SEEMED TO HELP
IMPROVE PANEL TMD ESTIMATES.
MANY LABS INCLUDE SYNONYMOUS
VARIANTS IN THEIR ESTIMATES AND
THOUGHT REMOVING THAT WOULD
ADDITIONALLY HELP.
THAT SEEMED TO HAVE MINIMAL ON
PANEL TMB BUT IT DID NARROW THE
RANGE OF THE BOX SOMEWHAT.
ANOTHER FACTOR THAT COULD HAVE
EFFECTED TMB CLOTH IN SOME CASES
PERHAPS GREATLY IMPACTED IT AND
WE'LL TALK ABOUT THAT AND
REMEMBER I SAID THE WHOLE EXOME
SEQUENCING ASSAY DEFINITIVELY
IDENTIFIED THE VARIANTS AND
FILTERED THEM OUT.
IN THE CLINICAL PHASE WE HAVE
LABORATORIES AND 14 OF THE 16
LABS ONLY DO TUMOR SEQUENCING.
THEY DO NOT SEQUENCE A MATCH
GERM LINE.
HOW DO THEY FILTER GERM LINE
VARIANTS?
THEY COULD GO TO POPULATION
DATABASES WHERE THERE'S TENS OF
THOUSANDS OF NORMAL GERM LINE
SEQUENCES.
AND THE OME WAY TO DO THIS IS TO
FILTER EVERY GERM LINE VARIANT
YOU SEE IN THE DATABASES.
THAT'S THE ORANGE 0% DB.
EVERY VARIANT IS FILTERED AND
THE WHOLE EXOME IS THE SOLID
BLACK LINE.
THE ORANGE IS STARTING TO
APPROACH THE BLACK BUT EVEN THEN
IT'S IMPERFECT.
MOREOVER I WOULD SAY THAT FOR
THOSE INDIVIDUALS WITH AFRICAN
ANCESTRY WHERE THERE'S TYPICALLY
HIGH GENETIC VARIABILITY IT'S
REALLY IMPORTANT TO DO THIS KIND
OF FILTERING OR YOUR CALCUL
CALCULATIONS COULD BE WIDELY
OFF.
I TALKED ABOUT ONE OF THE GOALS
OF THE LAST PART OF THIS PROJECT
WAS TO GENERATE A CALIBRATION
APPROACH TO A WHOLE EXOME
SEQUENCING EQUIVALENT.
THIS IS WHAT WE DID.
IT'S ACTUALLY QUITE SIMPLE.
THE CALIBRATION APPROACH WE USED
WAS LARGELY BASED ON THE TCGA
DATA.
WE SAID EACH LAB LOOKED -- TAKE
YOUR TCGA DATA AND COMPARE IT TO
THE WEST TCGA DATA AND FIT A
REGRESSION LINE.
THAT'S WHAT THIS LINE IS HERE.
THAT IS YOUR CALIBRATION LINE
AND THEN ALL YOU NEED TO DO
REALLY IS FOR ANY OBSERVED Y0
VALUE IN THE PANEL YOU BENCHMARK
IT TO THE REGRESSION LINE, THE
CALIBRATION LINE AND BETWEEN
RATE AN EQUIVALENT X0.
SO THIS IS ROUGHLY 15 MUTATIONS
PER MEGABASE AND IF YOU
BENCHMARK AND OFFER THE
CALIBRATION LINE IT TRANSLATES
TO 12 MUTATIONS PER MEGABASE AND
THERE'S A PREDICTION AT 95%
PREDICTION INTERVAL ON THE HIGH
END 20 AND LOW END 8.
THAT'S HOW IT CAN RECALIBRATE
THE DATA SO IT'S MORE SIMILAR TO
THE GOLD STANDARD WHOLE EXOME
SEQUENCING TMB CALCULATION.
IN PRACTICE HOW WELL DOES THAT
ACTUALLY WORK?
SO WE HAVE THE CLINICAL SAMPLE
SET WE COULD TRY THIS APPROACH
ON.
I KNOW THIS IS A BUSY GRAPH BUT
WHAT YOU'RE SEEING ARE THREE BOX
AND WHISKER PLOTS.
THE BOX AND WHISKER PLOT ON
THEFT IS UNCAL GRIBRATED SAMPLE
DATA AND IN THE MIDDLE IS IT
DATA FROM ALL 16 LABS NOW AND ON
THE WHITE IS DATA FROM THE 10
CELL LINES.
IT'S HARD TO SEE SO I'VE BLOWN
UP ONE SAMPLE TO GIVE A SENSE OF
WHAT WE SAW.
THE OTHER IS EACH SAMPLE HAS A
HORIZONTAL BLACK LIPE AND YOU
WANT EVERYBODY ALIGNED WITH
THAT.
I THINK THE GIST IS WHEN WE
CALIBRATE TO THE TCGA DATA WE
GET A BETTER APPROXIMATION TO
THE WEST VALUE.
YOU CAN SEE THAT HERE IN THE
SAMPLE.
THE BOX AND WHISKER WHICH IS
OVER ESTIMATING TMB WHEN WE
CALIBRATE TCGA IS MORE ALIGNED
WITH IT IN THE BOX IN WHISKER.
INTERESTINGLY WHEN WE CALIBRATE
IT TO THE 10 CELL LINES IT
DIDN'T REALLY HELP.
BOTTOM LINE IS IF ANYTHING IT
ACTUALLY INTRODUCED MORE
VARIANTS IN THE DATA SET PERHAPS
WE ONLY HAD 10 CELL LINES RATHER
THAN 4,000 SAMPLES DUE TO
CALIBRATION.
IN SUMMARY FOR THE PROJECT AS
YOU SAW THE TMB IS VERY
SUBSTANTIALLY BETWEEN
PARTICIPATING LABS.
VARIABILITY WAS PRETTY SIMILAR
AND DOESN'T MATTER AND THE DATA
IS IMPORTANT.
IT SEEMS FOR TARGETED PANELS
FILTERING PATHOGENIC VARIANTS
WILL HELP ADDRESS THE OVER
ESTIMATION WE SEE IN SOME OF
THEM AND ALSO FWERM GERM LINE
FILTERING AND ONLY USING THIS
AND WE TALKED ABOUT CALIBRATION
APPROACHES AND I THINK GOING
FORWARD WHAT WE HAVE SUGGESTED
IS THAT LABS MIGHT CONSIDER IN
THEIR VALIDATION USING TCGA DATA
TO CALIBRATE AND ALIGN THEIR
PANEL TO THE GOLD STANDARD WEST
DATA WE SAW.
SO I'M GOING TO WRAP THIS UP AND
THIS PART OF THE PRESENTATION UP
RIGHT NOW.
I WANT TO ACKNOWLEDGE LISA
McSHANE WHO AGAIN WHO DID THE
STATISTICS WITH THEIR GROUP.
WE HAVE AN R PACKAGE THAT ASSAY
DEVELOPERS CAN USE DEVELOPED IN
LISA'S LABORATORY AND THAT
CALIBRATION PACKAGE WILL DO THE
CALIBRATION I TALKED ABOUT.
THERE ARE INDIVIDUALS FROM OUR
TEAM WHO CONTRIBUTED AS WELL AND
FRIENDS OF CANCER RESEARCH AND A
LARGE CONSORTIUM OF PARTICIPANTS
WHICH I'M SHOWING HERE.
NEXT TIME I WANT TO TALK ABOUT A
MORE RECENT PROJECT THAT WE'VE
BEEN WORKING ON WITH FRIENDS OF
CANCER RESEARCH AND WE'VE
SUBMITTED A MANUSCRIPT TO THE
JOURNAL OF CLINICAL ONCOLOGY AND
I'M GOING TO SHOW SOME OF THOSE
FINDINGS IN A MOMENT.
IT'S AN EFFORT TO HARMONIZE
HOMOLOGOUS RECOMBINATION
DEFICIENCY AND HOMOLOGOUS
RECOMBINATION DEFICIENCY
MEASURES DEFECTS IN DNA REPAIR.
SPECIFICALLY THIS IS EFFECTS IN
DOUBLE-STRANDED DNA BREAK
REPAIR.
THE HALLMARK OF HRD WOULD BE
MUTATIONS AND BRCA 1 AND 2
GENES.
YOU CAN GENERALLY THINK OF HRD
IN TWO CATEGORIES.
THERE'S CAUSES THAT WOULD BE
MUTATIONS IN THE BRCA 1 AND 2
GENES AND OTHER PATHWAY GENES
LIKE POLL B2 FOR EXAMPLE AND
THERE'S EXAMPLES AND
CONSEQUENCES.
THE CONSEQUENCES OF DEFECTS IN
THE HOMOLOGOUS RECOMBINATION
DEFICIENCY IS YOU INTRODUCE
GENOMIC SCARS.
LOSS OF HETRO ZYGOSITY AND SOME
LABS MEASURE THOSE IN ADDITION
TO MEASURES DEFECTS IN
HOMOLOGOUS RECOMBINATION REPAIR
GENES.
IT'S TURNED OUT TO BE AN
IMPORTANT BIOMARKER.
THE CHALLENGE IS THERE'S
DIFFERENT WAYS TO APPRECIATE AND
TO MEASURE HRD.
IT'S UNCLEAR HOW WE ALL ALIGN.
AND IT'S IMPORTANT TO BRING A
PUBLIC-PRIVATE CONSORTIUM
TOGETHER AND FRY TO ADDRESS IT
HOW THEY DIFFERENT AND HOW WE
MIGHT ALIGN THEM.
OUR LAB PARTICIPATED AND LISA'S
GROUP PARTICIPATE AND WE HAD
FOLKS FROM FDA ON BI-WEEKLY
CALLS AND HAD KEY STAKEHOLDERS
FROM INDUSTRY.
I'M GOING TO FOCUS ON WHAT WE'RE
CALLING PHASE 2 OF THE PROJECT
TODAY WITH YOU.
LIKE WITH THE TMB PROJECT IN THE
IN SILICO ANALYSIS ON TCGA DATA
AND CLINICAL ANALYSIS.
SO LET'S FIRST TALK ABOUT THE
IN SILICO ANALYSIS ON PATIENTS
AND AS EVERYBODY APPRECIATES
THERE'S NO CANCER TIED TO THE
HIGHER PREVALENCE OF HRD AND
IT'S PROOF OF CONCEPT STUDIO AND
HAD ACCESS TO THE TCGA DATA AND
SENT THE RAW DATA FILES AND BRCA
GERM LINE MUTATION FILES TO 11
PARTICIPANTS.
THEY RAN THE DATA FILES THROUGH
THEIR HRD PIPELINE AND NCI AND
THE ENTIRE GROUP REVIEWED THE
FINDINGS.
HERE'S THE SUMMARY OF THE IN
SILICO RESULTS.
ON THE LEFT WE'RE LOOKING AT THE
PERCENT HRD AS CALLED BY THE 11
DIFFERENT IF ASSAY DEVELOPERS.
THE MEDIAN WAS 49%.
49% WERE HRD POSITIVE CASES
AMONG 348 ANALYZED.
YOU CAN SEE THE PERCENT HRD
POSITIVE CASES RANGED WIDELY
FROM A LOW OF 9% TO A HIGH OF
67%.
CERTAINLY HIGHER THAN I WAS
EXPECTING.
IF WE DRILL DOWN DEEPER INTO THE
DATA YOU CAN SEE OVER HERE ON
THE HEAT MAP ON THE RIGHT EACH
ROW IS ASSAY.
EACH COLUMN IS A DIFFERENT
SAMPLE AND YOU CAN SEE ALSO THE
DIFFERENT APPROACHES THE LABS
ARE USING TO CALL HRD.
ALL LABS INTERROGATE BRCA 1 AND
2 AND THEY'RE INTERROGATING
GENOMIC LOSS OF HETEROZYGOSITY
AND ALL MEASURES OF GENOMIC
SCARRING.
WE HAVE A NUMBER OF LABS
INTERROGATING ONE OR MORE AND WE
HAVE A NUMBER OF LABS THAT LOOK
AT HOMOLOGOUS RECOMBINATION
GENES AND REPORT OUT BASED ON
WHETHER THEY SEE MUTATION IN ONE
OF THOSE GENES THEN WE HAVE THE
BRCA MUTATIONS IDENTIFIED BY THE
LABS.
IT'S COMFORTING TO SEE HERE THAT
ALMOST EVERY LAB, NOT EVERY LAB
INTERESTINGLY ENOUGH BUT ALMOST
EVERY LAB WAS PRETTY MUCH IN
AGREEMENT ON WHAT WAS A
DELETERIOUS BRCA MUTATION.
SO I'M GOING TO MOVE ON NOW TO
THE CLINICAL PART OF THE STUDY.
IN THIS PART OF THE STUDY WE
SOURCED 90 ARCHIVAL VARIANT
CANCER SAMPLES FROM THE LAB OF
THE UNIVERSITY OF ALABAMA
BIRMINGHAM.
THE SPECIMENS WERE SENT TO OUR
LAB AT MOCA.
WE DID THE EXTRACTION AND
ALLOCATED THE SAMPLES AND SENT
THEM OUT TO 17 PARTICIPATING
LABS.
WE HAD 17 LABS PARTICIPATING IN
THE CLINICAL ANALYSIS PHASE.
THEY REPORTED THEIR HRD SCORES
BACK TO LISA AND HER TEAM AT THE
NCI AROUND THEN THE ENTIRE GROUP
REVIEWED THE FINDINGS AND I WANT
TO CALL OUT WE DON'T HAVE AGOLD
STANDARD FOR HRD.
THERE'S NOT ONE I THINK IT'S
FAIR TO SAY.
MORE ABOUT THE SAMPLE
CHARACTERISTICS.
THESE SAMPLES ALL CAME FROM
SURGERIES AND REPRESENTED STAGE
3 OR 4 VARIANTS OF CANCER.
IN TERMS OF THE ASSAYS, I
MENTIONED THERE WERE 17
PARTICIPANTS.
THEY ALL HAD BRCA 1 AND 2
MUTATIONS.
IN ADDITION YOU CAN SEE IN TERMS
OF GENOMIC SCARRING, THE MOST
COMMONLY INTERROGATED SCAR WAS
GENOMIC EOH AND WE HAD ALMOST
60% OF LABS LOOK AT MUTATIONS
BEYOND BRCA 1 AND BRCA 2 AND HRD
BASED ON WHETHER THEY SAW
MUTATION IN ANY OF THOSE GENES.
IN TERMS OF THE CLINICAL PHASE
IS SIMILAR TO THE IN SILICO
PHASE MEAN AND MEDIAN WERE 82%
POSITIVITY WITH THE 17
PARTICIPANTS.
AGAIN, A VERY BROAD RANGE FROM A
LOW END OF 23% TO A HIGH END OF
74%.
I MENTIONED THERE WAS NO GOLD
STANDARD AND STARTED COMPARING
LABS TO ONE ANOTHER AND MANY ARE
FAMILIAR WITH THE AGREEMENT AND
DOING PAIR WISE COMPARISONS
BETWEEN ASSAYS THERE IS NO GOLD
STANDARD.
THAT IS SIMPLY THE PERCENTAGE OF
SAMPLES THAT TEST POSITIVE BY
ONE TEST SAY, ASSAY A FOUND TO
BE POSITIVE BY ASSAY B.
AN EXAMPLE TABLE SO FOR EXAMPLE
IF WE WERE COMPARING ASSAY A TO
B, ASSAY A SEES POSITIVE CASES
AND AMONG THEM ASSAY B SAW TWO
OF THEM.
THE POSITIVE PERCENT AGREEMENT
WOULD BE 50%.
WE ALSO FLIPPED THE COMPARISON
AND MADE B THE REFERENCE AND A
66% BPA.
WE HAD 17 ASSAYS AND IF YOU DO
THE CALCULATION IT TURNS OUT TO
BE 136 POSSIBLE PAIRS.
EACH IN TWO DIRECTIONS.
SO WE GOT 272 PAIR WISE
COMPARISONS WE'RE DOING AND ALL
THAT DATA IS SUMMARIZED HERE.
LOOKING AT ALL SAMPLES FIRST.
OVER ON THE LEFT YOU SEE THE
MEDIAN POSITIVE PAIR WISE
AGREEMENT AND POSITIVE PERCENT
AGREEMENT, EXCUSE ME, IS 83% AND
ON THE AGREEMENT REALLY VARIED
QUITE DRAMATICALLY DEPENDING ON
THE PAIR OF ASSAYS THAT WERE
PREPA
PREPARED.
THAT'S POSITIVE PERCENT
AGREEMENT.
WE ALSO LOOKED AT NEGATIVE
PERCENT AGREEMENT USING THE SAME
APPROACH THAT I DESCRIBED FOR
POSITIVE PERCENT AGREEMENT.
AND THEN WE LOOKED SPECIFICALLY
AT BRCA 1 AND BRCA 2 MUTATIONS
AND THERE WERE 23 CASES WHERE AT
LEAST ONE LAB FOUND A BRCA 1 OR
BRCA 2 MUTATION AND I THINK
SOMEWHAT REASSURINGLY THE MEDIAN
WAS 100% SPECIFICALLY FOR BRCA 1
AND 2.
NOW, IF YOU TAKE THE OTHER CASES
THE POSITIVE FELL FROM 83% TO
67%.
THESE ARE ASSAYS USING IS
SCARRING APPROACHES AND IT'S
TELLING US THERE'S NOT AS GOOD
AGREEMENT WITH SCARRING AS WITH
THE BRA CA APPROACHES AND --
BRCA APPROACHES AND THAT'S TO BE
EXPECTED.
WHAT IS ASSOCIATED BETWEEN
AGREEMENTS WITH THE LAB.
THIS HEAT MAP LOOKS AT SOME OF
THOSE AND I'LL CALL THEM OUT
RIGHT NOW.
STARTING WITH BRCA 1 AND 2, IT'S
COMFORTING TO KNOW ALL THE LABS
ARE DOING A GOOD JOB OF CALLING
THOSE MUTATIONS, AS I SAID.
THEN THERE'S RACE.
I DISAPPOINT KNOW -- DON'T KNOW
WE EXPECTED RACE TO FIND AN
INFLUENCE ON THE LAB TO CALL HRD
AND IT DIDN'T.
CCNE1 AMPLIFICATION.
THERE'S A BODY OF LITERATURE
EXCLUSIVE WITH HRD POSITIVITY
AND SEEN IN THE COHORT AS WELL
AND A COUPLE MORE THINGS I WANT
TO POINT OUT.
ASSAY USE.
WE HAD A MIXTURE OF PARTICIPANTS
WITH CLINICAL ASSAYS AS WELL AS
WITH RESEARCHER ASSAYS AND THEY
SEEMED TO DO EQUALLY WELL AND NO
BIG DIFFERENCE IN COMPARING
BETWEEN THE TWO BUT INTERESTING
LY LOOKING AT THE HRD POSITIVE
CASES THAT DID NOT HAVE BRCA
MUTATIONS IS THIS CLUSTER ON THE
LEFT, THERE WAS QUITE A BIT OF
AGREEMENT EXCEPT HERE NEAR THE
TOP.
YOU CAN SEE THERE WERE THREE
ASSAYS THAT WERE KIND OF
OUTLIERS.
NOW, ONE OF THEM, THE TOP ONE,
USES GENOMIC SCARRING APPROACHES
TO CALL BRCA MUTATIONS AND
THEY'RE NOT REALLY AGREEING WITH
MOST THE OTHER LABS.
WE LOOKED AT MUTATIONS AND NOT
GOING TO FIND HRD SAMPLES
POSITIVE AS OTHER LABS USING
GENOMIC SCARRING APPROACHES.
THAT PROBABLY EXPLAINS THE
DISCORDANTS WE'RE SEEING HERE.
I WANTED TO MENTION A FEW MORE
FACTORS WE LOOKED INTO.
ONE IS THE SAMPLE QUALITY.
SO TUMOR PURITY YOU MIGHT THINK
THAT WOULD HAVE AN WHY IMPACT
AND THERE WERE STUD THAT
SUGGESTED IT DOES IF YOU START
TO GET TOO LOW YOU HAVE
DIFFICULTY IDENTIFYING GENOMIC
SCARS SAY DOWN AROUND 30%, 40%.
WE DIDN'T SEE ANY CORRELATION
WITH TUMOR PURITY AND THAT'S
PROBABLY BECAUSE WE REQUIRED FOR
THE STUDY A TUMOR CELLULARITY OF
AT LEAST 70%.
WE WANTED TO CONTROL THE
VARIABLES AND NOT HAVE THEM
INTERFERE WITH THIS ANALYSIS BUT
IN FUTURE STUDIES ONE COULD
INCLUDE SAMPLES WITH NOT ONLY
POORER DNA PURITY AND QUALITY.
IN THIS STUDY WE TRIED TO
CONTROL PRE-ANALYTICAL VARIABLES
AND INCLUDED SAMPLES THAT WERE
VERY GOOD QUALITY BELOW THE DNA
INTEGRITY SCORE OF 2.
AND THE AGE OF THE BLOCK.
WE HAD BLOCKS IN THE STUDY THAT
WERE 10 YEARS OLD OR OLDER AND
DIDN'T SEEM TO MATTER.
SO THE AGE OF THE BLOCK WAS NOT
A FACTOR.
THERE WAS HOWEVER, SOME
CORRELATION WITH THE ASSAY
CUT-OFF LOOKING AT THE ASSAY
MORE CLOSELY.
AS YOU MIGHT EXPECT AND AS THESE
TWO GRAPHS SHOW, AS YOU APPROACH
THE ASSAY CUT-OFF AND THAT'S THE
RED LINE HERE YOU CAN SEE THE
AGREEMENT OF THIS ASSAY WITH
OTHER ASSAYS GO DOWN AND THAT'S
REPRESENTED BY THIS BLUE CURVE
HERE AND THE AGREEMENT IS ON THE
Y AXIS.
SO AGAIN, I DON'T KNOW IT'S
UNEXPECTED.
I THINK THAT WOULD PROBABLY BE
TRUE FOR ANY ASSAY WHEN YOU'RE
LOOKING NEAR THE ASSAY CUT-OFF.
AND THE LAST THING I WANT TO
SHOW IS DATA GENERATED LOOKING
AT CORRELATIONS BETWEEN HRD AND
CLINICAL OUTCOMES.
WE'RE VERY FORTUNATE IN THE
COHORT AND IT WAS ANNOTATED WITH
CLINICAL OUTCOME AND ALL
RECEIVED PLATINUM BASED THERAPY
AND BEFORE I POINT OUT THE
SURVIVAL CURVES I WANT TO POINT
OUT THE WAY WE GROUPED THE
SAMPLES WAS IN TREE CLUSTERS.
WE HAVE HERE THE NOT-HRD CLUSTER
BASED ON MAJORITY RULE.
WHATEVER MOST THE LABS IDENTIFY
AS NON-HRD WE INCLUDED IN THE
CLUSTER.
SIMILARLY YOU HAVE A BRCA
CLUSTER HERE AND THEN WE HAVE AN
HRD-POSITIVE CLUSTER NOT BRCA
AND CALL IT THE SEQUENCES
CLUSTER BUT THAT'S HRD POSITIVE
JUST NOT BRCA.
IF YOU LOOK AT THE OCCURRENCE
FOR SURVIVAL YOU SEE A TREND
TOWARDS THE BRCA CLUSTER HAVING
BETTER SURVIVAL.
BETTER AND AFTER THAT THE
CONSEQUENCES CLUSTER AND THEN
THE NOT-HRD CLUSTER HAVING THE
WORSE OCCURRENCE FOR SURVIVAL.
AND THAT'S CONSISTENT WITH WHAT
HAS BEEN SEEN IN THE PUBLISHED
LITERATURE FOR INHIBITORS AND
THE SEVERITY OF CANCER BRCA
CLUSTER TENDS TO DO BEST AND THE
HRD CLUSTER THAT IS NOT BRCA
NEXT AND THE NOT HRD CLUSTER.
AND SIMILARLY LOOKING AT OVER
ALL SURVIVAL WE HAD A SIMILAR
TREND WHERE BRCA AND CLUSTERS
DID BETTER THAN NON-HRD CLUSTERS
AND THE SURVIVAL CURVES
INTERSECTED HERE AND AT THE END
OF THE DAY IT WAS NOT
SIGNIFICANT AND THE BRCA CLUSTER
HAD A WORSE MEDIAN OVER ALL
SURVIVAL BUT THE TREND WAS IN
THE RIGHT DIRECTION.
SIMILARLY WE LOOKED AT
INDIVIDUAL LABS AND YOU CAN SEE
THEY'RE KIND OF ALL OVER THE
PLACE HERE.
SOME LABS THERE'S NO SEPARATION
OCCURS BUT FOR SOME OF THE
ASSAYS, THERE'S ACTUALLY VERY
GOOD SEPARATION PARTICULARLY FOR
THE OVER ALL SURVIVAL DATA.
SO WHAT DOES THIS ALL TELL US?
I THINK THE LEVEL OF AGREEMENT
BETWEEN DIFFERENT ASSAYS VARY.
I THINK OVER ALL IT WAS A LITTLE
ALARMING IT WAS HIGHER THAN IT
WAS.
I THINK -- I HOPE YOU'RE HAVING
THE SAME REACTION TO IT WE ALL
DID IN THE HRD GROUP.
BUT I THINK SOME OF THAT CAN BE
EXPLAINED BY THE PAIRS OF ASSAYS
BEING COMPARED.
I TRIED TO GET INTO THAT A
LITTLE BIT.
IF YOU COMPARE A LAB'S ASSAY AND
THEY'RE DOING GENOMIC SCARRING
WITH AN ASSAY THAT DOESN'T
INCORPORATE THE SCARS AND MAYBE
JUST LOOKS AT HR REPAIR
MUTATIONS THERE'LL BE MORE
MUTATIONS THAN ONE SCARRING TO
ANOTHER.
THAT'S FAIR.
THAT'S STILL PERHAPS MORE
DISORDERAN ANAN ANAN ANANCE --
YOU'D EXPECT TO SEE AND ABOUT
THE CHARACTERISTICS, WE DIDN'T
SEE ANY CORRELATION WITH THE
SAMPLE CHARACTERISTICS AND
CONCORDANCE BUT THEN AGAIN WE
RESTRICT THE STUDY TO SAMPLES
THAT WERE OF HIGHER QUALITY.
AND THEN FINALLY SOMETHING I
DIDN'T MENTION WAS THAT IT WOULD
HAVE BEEN NICE TO HAVE DONE AN
ANALYSIS STRATIFIED BASED ON
TREATMENT WITH AN INHIBITOR.
COULDN'T DO THAT BECAUSE THE
PATIENTS RETREATED BEFORE THEY
BECAME STANDARD OF CARE IN THE
MAINTENANCE SETTING AND ONLY 15
PATIENTS RECEIVED PART THAT WAS
AN ANALYSIS WE COULD NOT DO.
IN TERMS OF RECOMMENDATIONS FOR
THE FUTURE, WHAT IS THE BEST
APPROACH TO RECORD HRD.
IF WE COULD ALL ALIGN ON THAT,
THAT CONSISTENCY I DON'T KNOW
THAT WE KNOW THAT RIGHT NOW.
AND IT WOULD BE GOOD AS A FOLLOW
UP TO HAVE A COMMITTEE PERHAPS
CONVENE AND DISCUSS THAT.
IN TERMS OF TRYING TO VALIDATE
ASSAYS WE NEED TO RELY ON
EXPECTATIONS FOR HOW WE'RE GOING
TO DO THAT.
THESE ARE COMPLEX BIOMARKERS.
IT'S NOT TRIVIAL THINKING HOW TO
VALIDATE THEM AND THEN WE DON'T
HAVE A GOLD STANDARD.
I MENTIONED THAT SEVERAL TIMES.
SO IT WOULD BE NICE TO HAVE A
BIOLOGICAL GOLD STANDARD
INCLUDING REFERENCE MATERIALS
AND THE IN SILICO DATA COULD BE
USED FOR ASSAY DEVELOPMENT.
SO I JUST WANT TO THANK
EVERYBODY WHO PARTICIPATED IN
THE PARTICULARLY HILARY A
AND-DRANDREWS
AND REBECCA OREN FROM THE
UNIVERSITY OF ALABAMA.
FOLKS IN OUR LAB AND LILLY CHEN
AND LISA CHAPMAN AND I ALSO WANT
TO THANK FOR SUPPORT AND WE'RE
GRATEFUL TO HAVE THE SUPPORT.
THANK YOU.
>> THANK YOU.
QUESTIONS FROM THE GROUP.
ARE
>> HI, I'M FROM WASHINGTON
UNIVERSITY IN ST. LOUIS.
I LEAD AN OVARIAN CANCER GROUP
AND A MEMBER OF OUR GROUP
RECENTLY FUNCTIONED ON
FUNCTIONAL ASSAY FOR HRD USING
RAD 51 FOSI.
I WAS THINKING YOU WERE TALKING
ABOUT THE CAUSES AND
CONSEQUENCES AND SO THE GENOMIC
SCAR IS JUST A SNAPSHOT AND SO
WE'RE WONDERING IF YOU COULD
HAVE A REAL TIME OR FUNCTIONAL
ASSAY WITH ZERO BIOPSY OR
SOMETHING LIKE THAT EITHER FROM
LIQUID BIOPSY OR FROM THE ACTUAL
TISSUE.
SHE SHOWED REALLY NICELY AND
RECENTLY PUBLISHED IN CANCER
RESEARCH RAD 51 FOSI COULD BE A
FUNCTI
FUNCTIONAL MARKER OF HRD AND
WONDER IF THAT CAME UP IN YOUR
DISCUSSIONS.
>> WE DIDN'T AND AT FREDERICK
NATIONAL LAB WE CAN INTERROGATE
RAD 51 FOSI.
I THINK IT WOULD BE INTERESTING
TO COMPARE THAT ASSAY TO SOME OF
THE ONES TALKED ABOUT AND THE
GENOMIC SCARS.
WILL THEY'RE FINE IN THE
TREATMENT NAIVE SETTING.
ONCE PATIENTS HAVE BEEN TREATED
AND DEVELOPED RESISTANCE THE
SCARS DON'T GO AWAY AND THEY'RE
NOT GOOD PREDICTION OF
BIOMARKERS AND YOU MENTIONED RAD
51 FOSI IN REAL TIME MEASURING
THE ABILITY OF CELLS IN REAL
TIME TO PERFORM EFFICIENT DNA
REPAIR IS A BETTER WAY TO GO IN
A PRETREATED POPULATION.
WE DIDN'T DO THAT COMPARISON.
I'D BE CURIOUS TO KNOW IF YOU OR
ANYBODY ELSE HAS DONE THAT AND
HAS DATA I WOULD IMAGINE --
>> WELL, THAT'S THE NEXT STEP
WE'RE LOOKING AT SAMPLES FROM
PATIENTS TREATED WITH CAR
INHIBITORS AND WE'RE REPEATING
THE ASSAY AND THE FIRST IS MARY
MULLEN, M-U-L-L-E-N.
>> THANK YOU FOR THAT.
>> THIS IS TIM CHAN.
VERY NICE PRESENTATION AND
CONGRATULATIONS TO YOU AND YOUR
TEAM FOR DOING THAT VERY
ITERATIVE WORK BUT VERY
IMPORTANT.
SO MY QUESTION HERE IS I'M
CURIOUS OVER THE LAST YEAR OR
TWO ESPECIALLY AS A PUBLICATIONS
HAVE RULED OUT WHETHER YOU HAVE
SEEN ALL THE VARIOUS COMPANIES
WORKING ON TMB AND THE ACTIVITY
AT THE FDA WHETHER THERE HAS
BEEN CONNECTIONS WITH YOU TO
HARMONIZE AMONGST THE VARIOUS
ASSETS FOLKS HAVE IN DIAGNOSTICS
AND WITH THE FDA IN SOME FORM OR
FASHION TO TRY TO PUSH FORWARD A
WORK FLOW FOR HARMONIZATION.
I THINK IN THE LAST 10 YEARS
AFTER THE DISCOVERIES AND SO
FORTH, ONE OF THE CHALLENGES HAS
BEEN THE FIELD AND PUTTING
TOGETHER METHODS EVERYBODY
ACCEPTS RATHER THAN CONTINUED
COMPETING DIAGNOSTICS.
>> YEAH, THANKS FOR THAT, TIM.
THOSE ARE GREAT POINTS.
I'M NOT AWARE OF CONVERSATIONS
THAT HAVE BEEN HAD WITH FDA BY
MEMBERS OF THE FRIENDS
CONSORTIUM ON THE PROJECT.
I MENTIONED THE PROJECT DREW TO
A CLOSE BACK IN 2020, 2021, I
THINK.
I'D BE CURIOUS TO KNOW THE GOLD
STANDARD FDA IS USING WHEN A
SPONSOR COMES WITH AN ASSAY THEY
WANT TO GET APPROVAL FOR.
DO THEY EXPECT THE SUBMITTER TO
HAVE AN ACCURACY STUDY THEY
PERFORMED OR SENSITIVITY STUDY
PERFORMED WITH FOUNDATION
MEDICINE AS THE GOLD STANDARD OR
WOULD IT BE MORE APPROPRIATE TO
THINK ABOUT A CALIBRATOR
APPROACH LIKE I WAS DESCRIBING
TO MAYBE ADJUST TMB VALUES TO A
WEST STANDARD.
THAT WOULD BE MY PREFERENCE
ACTUALLY.
I HONESTLY DON'T KNOW WHERE THIS
HAS GONE.
WE WORK WITH FRIENDS ALL THE
TIME.
I'LL ASK THEM IF THEY'VE HAD
FURTHER CONVERSATIONS WITH FDA
BUT I'M NOT AWARE OF ANY.
>> TERRIFIC, THREW.
-- TERRIFIC, THANK YOU.
>> ANY OTHER QUESTIONS?
OKAY.
THANK YOU, CHRIS.
FOR AN INTRIGUING CONVERSATION
AND WE'RE TAKING A BREAK NOW
UNTIL 2:50.
DOES THAT WORK FOR EVERYBODY?
PLEASE TRY AND BE BACK A LITTLE
BIT EARLY SO WE MAKE SURE TO
START RIGHT ON TIME AND HEAR
FROM DR. McCORMICK ON RAS AFTER THE BREAK.
WELCOME BACK, EVERYBODY.
DR. McCORMICK IS GOING TO TALK
TO US.
PLEASE.
>> WANT TO HEAR ABOUT RAS?
>> YES, WE DO.
>> GREAT.
I'M HAPPY TO GIVE YOU UPDATES ON
OUR PROGRAM.
WHAT I'M GOING TO DO TODAY IS
FOCUS ON TWO ASPECTS OF THE RAS
INITIATIVES THE COMPOUNDS IN THE
CLINIC OR HEADING TO THE CLINIC.
FOR US THESE ARE MAJOR
MILESTONES.
TO BE ABLE TO SAY WE HAVE THESE
IS HUGE AND WE'RE PROUD OF OUR
TEAM AND WANT TO SHARE HOW THE
COMPOUNDS WORK, WHY THEY'RE
DIFFERENT FROM OTHER COMPOUNDS
AHEAD OF US AND WHAT WE EXPECT
IN THE FUTURE.
THE FIRST COUNT IS 8520 THAT
HITS THE G12C OR K RAS PROTEIN
IN THE ACTIVE STATE THEREFORE
DIFFERENT FROM THE OTHER
COMPOUNDS AS I'LL SHOW.
IT'S BEEN IN PHASE I CLINICAL
TRIALS AND TESTED AT FOUR SITES
IN THE U.S. AND TWO IN AUSTRALIA
FOR REASONS I CAN GET BACK TO
LATER AND THE SECOND COMPOUND IS
SOMETHING DIFFERENT.
A COMPOUND DRUG THAT BINDS AND
PREVENTS ALPHA PROTEINS AND THIS
IS A NOVEL WAY OF INHIBITING THE
KINASE ACTIVITY IN CELLS IN
COMBINATION WITH OTHER DRUGS
WITHOUT THE PENALTY OR LIABILITY
OF INDUCING HYPERGLYCEMIA THE
PROBLEM WITH OTHER INHIBITORS.
SO YOU'RE PROBABLY ALL PROBABLY
SICK OF SEEING THE PATHWAY BUT
THIS IS TO REMIND YOU WHY OUR
APPROACH IS DIFFERENT FROM THE
OTHER APPROACHES.
AGAIN YOU ALL KNOW UP CELLS, RAS
PROTEIN CYCLE BETWEEN THE GTP
AND GDP STATE.
BECAUSE PROTEIN C12C AND B AND D
ARE RESISTANT TO GAPS THEY
ACCUMULATE IN THE G BOND STATE
MALIGNANT PROPERTIES.
SO THE CHALLENGE HAS BEEN HOW TO
FIND COMPOUNDS THAT BIND TO
THESE PROTEINS AND BLOCK THE
DOWN STREAM SIGNALLING.
THE NEXT SLIDE HIGHLIGHTS THE
POINT OF INTERVENTION OF THE
APPROVED 12C INHIBITORS AS WELL
AS ANOTHER 10 COMPOUNDS WHICH
ARE SIMILAR IN MANY WAYS TO THE
TWO PIONEERING COMPOUNDS.
THE TWO ON THE SIDE HERE HAVE
ALREADY BEEN APPROVED FOR
THERAPY.
THEY IS SCREENED THE LIBRARY AND
FOUND A NUMBER OF HITS WHEN
SCREENED WITH A GDP FORM OF G12C
BUT NO HIS WITH THE GTP BOUND
FORM.
HE AND OTHERS HAVE CONCLUDED THE
WILL POCKET IS ONLY AVAILABLE
FOR CO-VALENT FINDING IN THE GDP
COMPOUND STATE.
SO THEY'RE THE OFF STATE NOT THE
ON STATE.
THE FEATURE OF TRAPPING IT.
IT SOUND LIKE AN ATTRACTIVE
METHOD FOR SHUTTING DOWN RAS
SIGNALLING.
THE CLINICAL RESPONSES TO THE
COMPOUNDS HAVE NOT BEEN VERY
DURABLE.
IT'S RELATIVELY EASY FOR THE
TUMOR CELL TO ESCAPE FROM THE
TRAP EITHER BY PUMPING MORE
SIGNALS DOWN THE PATHWAY FROM
GROWTH FACTORS TO POWER THROUGH
INTO THE ACTIVE STATE OR SIMPLY
BY MAKING MORE K RAS SO THE DRUG
CAN'T KEEP UP AND TRAP IT IN THE
INACTIVE STATE AND THOSE ARE TWO
MECHANISMS.
THE UPSTREAM SIGNALLING AND OVER
EXPRESSION OF K RAS.
SO OUR APPROACH FROM THE
BEGINNING OF THE INITIATIVE
TARGETING THE ACTIVE FORM OF THE
RAS PROTEIN.
THIS PRECEDED OUR APPROACH TO
G12C AND FELT THE HITTING THE G
POUND FORM WOULD BE MORE
EFFECTIVE NOT REALIZING HOW HARD
IT WOULD BE TO FIND COMPOUND
THAT BIND IN THAT POCKET WHERE
OTHER COMPOUND SQUEEZE IN.
WE SPENT MANY YEARS TARGETING
THE DIFFERENT RAS ALLELES AND
COMBINED OUR EXPERIENCE WITH
OTHERS TARGETING G COMPOUNDS TO
BUILD COMPOUND THAT IS ABLE TO
BIND TO THE GTP BOUND FORM AND
PREVENT DOWN STREAM SIGNALLING.
THIS TOOK YEARS OF ADDITIONAL
BIO CHEMISTRY AND STRUCTURAL
BIOLOGY WITH OUR CREATIVE
PARTNERS AND NATIONAL LAB BUT
EVENTUALLY WE FOUND A COMPOUND
THAT COULD SQUEEZE ITS WAY IN
THE GTP BOUND FORM EFFECTIVELY
AND BIND TO THE GTP AND GDP
BOUND FORM.
JUST TO INTRODUCE 8520 AND THE
TEAM ON THE RIGHT AT FREDERICK
NATIONAL LAB HEADED UP BY A
LARGE NUMBER OF INDIVIDUALS IN
THE RAS INITIATIVE WERE INVOLVED
AND THE PARTNERS AND
COLLABORATORS THAT PROVIDE A
GREAT DEAL OF MACHINE LEARNING
AND A.I. INPUT IN DRUG DESIGN.
THE PROBLEM WITH THE COMPOUND IS
SHOWN THERE.
IT INHIBITS KINASE POCKET
SIGNALLING AND VERY POTENT AND
HAS GREAT DRUG LAB PROPERTIES
AND WE THINK WILL BE WELL
TOLERATED.
WE'LL FIND OUT SOON.
THE BOTTOM LEFT PANEL SHOWS IT'S
POTENT AND IN PROTEOME ANALYSIS
THE ONLY PROTEIN IN THE CELL
THAT IT BINDS TO IS K RAS, G12C.
SO IT'S POTENT AND SPECIFIC AND
DOES HIT THE ACTIVE STATE.
SO THE OFF STATE TRAPPING
COMPOUND AS I MENTIONED HOLD THE
RAS PROTEIN IN THE INACTIVE
STATE.
YOU MIGHT ASK HOW DOES IT BIND
TO THE ACTIVE STATE PREVENT THE
SIGNALLING.
THE KEY TO UNDERSTANDING THIS
COMES FROM STRUCTURAL BIOLOGY
ANALYSIS FROM FREDERICK NATIONAL
LAB WITH A RANGE OF DIFFERENT
ONCOGENIC RAS PROTEINS.
AND THE IMPORTANT PART HERE IS
THAT SOME OF THESE STRUCTURES
LIKE THE ONE ON THE LEFT SHOW
THE SWITCH 1 REGION WHERE RAF
AND OTHER BIND IS OUT IN THE
WIND AWAY FROM THE D DOMAIN THE
BLUE STRETCH AND OTHER CRYSTAL
STRUCTURES IN THE MIDDLE WHERE
SWITCH 1 IS DOWN NOT G DOMAIN.
AND SOLVE THE STRUCTURE OF K RAS
BOUND TO THE EFFECT OF RAF YOU
CAN SEE SWITCH 1 IS IN THE STATE
2 CONFIGURATION AND DOES NOT
BIND TO RAF.
AS IT TURNS OUT IT SQUEEZES IN
THE POCKET AND PUSHES THIS INTO
STATE 1.
IT'S STILL GTP BOUND BUT CAN NO
LONGER ENGAGE EFFECTERS.
WE CAN ALSO ANALYZE IT THIS ON
THE NEXT SLIDE USING 2-D NMR
ANALYSIS SUMMARIZING A PAPER IN
THE BOTTOM OF THE SLIGHT.
A TECHNIQUE DEVISED YEARS AGO TO
MEASURE P31 WITH THE GTP.
YOU CAN TILL THE DIFFERENCE
BETWEEN GTP -- SORRY, STATE 1
AND STATE 2 BY THE RESIDENCE OF
THE GAMMA PHOSPHATE COMPARED TO
THE BOTTOM PANELS IN WHICH
PROTEIN IS TREATED WITH THE
COMPOUND WHY TRAPS IT IN THE
STATE 1 COMPARED TO THE
UNTREATED PROTEIN IN 2.
YOU CAN IMMEDIATELY TELL HOW THE
COMPOUND IS WORKING.
THIS WE CARRIED OVER INTO OUR
OTHER PROGRAMS TARGETING OTHER
ACTIVE ALLELES LEADING TO
COMPOUNDS WE HOPE HEADING TO THE
CLINIC NEXT YEAR BUT I WON'T BE
TALKING ABOUT THOSE TODAY.
THIS TRAPS THE GTP PROTEINS IN
THE STATE 1 MECHANISM FROM
LOCKING THE INACTIVE PROTEINS
WITH THE PREVIOUS COMPOUNDS.
BECAUSE WE'RE ABLE TO BIND
DIRECTLY TO THE GTP FORM WE
ENGAGE TARGET QUICKLY IN CELLS
AND SHUT DOWN RAS SIGNALLING
MORE RAPIDLY THAN WITH CLINICAL
CONCENTRATIONS OF COMPOUNDS AND
TAKE TIME TO CYCLE THROUGH AND
HIT THE RAF PROTEIN AND PREVENT
THE BINDING.
WE EXPECT TO GET MORE RAPID
RESPONSES AND DURABLE RESPONSES
BECAUSE FOR THIS COMPOUND HAVING
UPSTREAM SIGNALLING FEEDING RAS
GTP HELPS BIND THE TARGET RATHER
THAN IN HINDERS IT.
WE HOPE IN THE CLINIC WE'LL SEE
MORE RAPID AND MORE DRAMATIC
INITIAL RESPONSES AND MORE
DURABLE RESPONSES BECAUSE WE
WON'T GET RESISTANCE FROM UP
STREAM SIGNALLING OR EXPRESSION
OF K RAS.
THAT'S THE THEORY.
WE EXPECT MOST THE PATIENTS WILL
BE TREATING WILL HAVE SEEN THE
INHIBITOR AND WILL HAVE
PROGRESSED DUE TO THE TWO
MECHANISMS.
IN THE U.S. MOST THE PATIENTS
WILL BE PATIENTS PRETREATED BUT
IN AUSTRALIA IT'S POSSIBLE TO
FIND TREATMENTS WHO HAVEN'T BEEN
TREATED WITH ANY G12 COMPOUNDS
AND SOME WILL BE G12C NAIVE AND
MAY GET A RATING ON HOW
EFFECTIVELY THE DRUG WORKS ON
PATIENTS WHO HAVEN'T SEEN G12C
PREVIOUSLY IN THE COHORT IF WE
GET ENOUGH PATIENTS IN THE
COHORT.
AND IN TERMS OF ACCRUAL AND
RESPONSES AND PK AND SO ON.
WITH CAN GET WILL RESPONSES IN
THE MODELS.
WE'LL SEE HOW THINGS PAN OUT IN
THE CLINIC.
CLINICAL TRIALS ARE UNDERWAY.
THE OTHER APPROACH, THE IND HAS
BEEN CLEARED AND EXPECT TO START
TREATING IN THE NEXT MONTH OR
TWO.
THIS IS A DIFFERENT APPROACH.
THIS IS BASED ON OUR
UNDERSTANDING OF THINKING ABOUT
HOW RAS PROTEINS ARE ENROLLED IN
KINASE ACTIVATION.
SO ON THE LEFT PANEL I'LL SHOW A
DIAGRAM HOW INSULIN ACTIVATES
THE KINASE AND IS CRITICAL TO
UNDERSTANDING THE PROJECT.
INSULIN RECRUITS THE KINASE TO
THE RS1 THAT RECRUITS THE KINASE
AND INSULIN CAUSES CAUSE TO TAKE
UP GLUCOSE AND IT SHUT DOWN THE
PATHWAY AND THEREFORE PATIENTS
BEING TREATED WITH THOSE DRUGS
CANNOT TAKE UP GLUCOSE AND
SUFFER FROM ALL THE SIDE EFFECTS
OF HYPERGLYCEMIA.
AND OTHER KINASE LIKE PDP AND
EGF ALSO ACTIVATE THE KINASE
WITHOUT AN HELP FROM RAS.
WE KNOW IT'S TRUE AND ACTIVATE
THE PATHWAY WITHOUT ANY HELP
FROM RAS PROTEINS.
MOST OF THAT ACTIVITY IS RAS
INDEPENDENT.
HOWEVER, THE THIRD PANEL SHOWS
SOME CIRCUMSTANCES DURING
DEVELOPMENT IN MICE AT LEAST
DURING THE GENESIS RAS PROTEINS
CAN BE RECRUITED TO TRAP THE
KINASE ALPHA IN THE COMPLEX IN
THE MEMBRANE AND INCREASE SIGNAL
OUTPUT BECAUSE THE SUBSTRATE IS
IN A CLASS.
SO THE PRECISE ROLE IS NOT WELL
UNDERSTAND BUT GENETICS TELL US
SOME RAS PROTEINS ARE INVOLVED
IN ABNORMAL SIGNALLING THROUGH
RTKs.
IN THE FAR RIGHT WE KNOW
ONCOGENETIC RAS PROTEINS CAN
ACTIVATE IT IN THE SIGNALLING.
SO THE PANELS ARE THE ONES WE'LL
BE ADDRESSING WITH THE DRUG THAT
PREVENTS RAS ACTIVATING PF3
KINASE AND HOPE THE NORMAL
SIGNALLING THROUGH RTKs AND
NORMAL SIGNALLING FROM THE
RECEPTOR WILL NOT BE AFFECTED BY
THESE COMPOUNDS.
SO, IT'S WHETHER IT'S AN
EFFECTER.
WE DID A SEARCH AND SOME PEOPLE
SHOW RAS PROTEINS ACTIVATING RAF
AND KINASE AND SOME HAVE THE RAF
PROTEINS ACTIVATING MULTIPLE
PATHWAYS AND IF YOU GO TO
CHATGPT AND ASK WHICH IT
ACTIVATES AND THE ROLE HAS BEEN
HARD TO FIGURE OUT BECAUSE FOR
MULTIPLE FORMS OF RAS AND KINASE
AND THEY INTERACT IN COMPLICATED
WAYS.
I'LL SKIP THE NEXT SLIDE.
THIS IS A KEY SET OF
PUBLICATIONS THAT'S THE BASIS OF
OUR APPROACH.
TO INTERROGATE THE INTERACTION
THEY COMBINE ANY RAS PROTEINS.
AND KNOCKED THE MUTATIONS INTO
ADULT MICE AND SHOWED THE MICE
ARE HEALTHY AND SURVIVE OKAY
DON'T GET HYPOGLYCEMIA AND BUT
DEFECTIVE IN IT HYPO-GENESIS AND
YOU CAN EFFECT TUMORIGENESIS
WITHOUT ANY OBVIOUS SIDE EFFECTS
ON THE HOST.
WHAT WE WANT IS A DRUG THAT A
GROUP SHOWED YEARS AGO.
SO THIS INTRODUCES A COMPOUND
AND WE HAVE CREATIVE PARTNERS
AND COLLABORATORS AT THE
NATIONAL LAB.
THE ESSENCE OF THIS COMPOUND IS
SUMMARIZED IN THE TABLE HERE.
YOU SEE TARGETED ENGAGEMENT OF
THE KINASE ALPHA AND THREE NANO
MOLAR IN CELLS AND BINDS
SUSTAINED IN THE RAS DOMAIN AND
PROPERTIES AND SOME I'LL SHOW
HERE.
THE WHOLE WORK IS ENABLED BY THE
RAS PROTEINS IN THE KINASE ALPHA
FOR THE FIRST TIME AND YOU SEE
ON THE LEFT IS THE STRUCTURE OF
K RAS BOUND KINASE AND THE BLUE
IS THE WILL RAS BINDING DOMAIN
WHERE THE IT INTERACTS AND THE
COMPOUND BINDS TO KINASE AND
PREVENTS RAS PROTEINS BINDING AT
THAT SITE.
IT CAN WHACK THE INTERACTION.
WE CAN PREVENT THE KINASE ALPHA
BINDING TO PROTEINS SHOWING DOSE
DEPENDENT CURVE ON THE LEFT.
PREVENTING BINDING TO THE 6 NANO
MOLAR IN CELLS AND RECOMBINANT
PROTEINS AND SEE ON THE LEFT
THEY BIND BUT THE COMPOUND
PREVENTS BINDING AND IMPORTANTLY
THE COMPOUND IN THE BOTTOM PANEL
DOES NOT AFFECT THE IT KINASE
ACTIVITY DIRECTLY IN THE TEST
TUBE WHERE THE DRUG APPROVED
MUTANT FOR METASTATIC BREAST
CANCER POTENT.
-- POTENTLY INHIBITS IT AND
PREVENTS THE KINASE ALPHA AND
THAT'S WHERE OUR SELECTIVITY
COMES FROM AND HOPES WHERE OUR
SAFETY COMES FROM.
WE TESTED THIS COMPOUND IN CELLS
AND FORM THREE BUCKETS, P10 AND
CELLS DON'T RESPOND VERY WELL.
THE MUTANT K RAS OR THE KINASE
ALPHA SHOW GOOD RESPONSES BUT
NOT COMPLETE.
AND THE BIG SURPRISE IS THE CELL
LINE WITH NEW AMPLIFICATION ARE
EXTREMELY RESPONSIVE TO THIS
COMPOUND.
THAT WAS A BIG SURPRISE BECAUSE
IN LITERATURE THE ACTIVATION OF
THE KINASE IS RAS INDEPENDENT.
I'LL GET BACK IT THAT IN A
MOMENT.
TOP RIGHT SHOWS TARGETED
ENGAGEMENT ASSAY.
IN ALL THE GENOTYPES WE ENGAGE
THE TARGET EFFICIENTLY AND STILL
BINDING THE KINASE ALPHA
COVALENTLY BUT SHUTTING DOWN THE
INTERACTION DOESN'T HAVE A
COMPLETE EFFECT ON ALPHA IN
DIFFERENT CELL LINES BECAUSE
ALPHA CAN BE ACTIVATED BY
DIFFERENT PATHWAYS.
AND THE BOTTOM PANEL SHOW WHOLE
PANEL CELL LINE WITH MUTATIONS
ALL RESPOND TO SOME DEGREE BUT
THE WINNER HERE IS A NEW PANEL
WE SEE EXTREMELY POTENT EFFECTS
ON KINASE AND ON GROWTH 3-D AND
IN VIVO.
IN THE CASE OF THE K RAS MUTANTS
NOT INTERROGATED FOR THE FIRST
TIME EXACTLY WHAT THE ROLE IS OF
K RAS AND ACTIVATING PF3 KINASE.
THE LEFT PANEL SHOWS IN THE D12C
CELL LINE IF YOU TREAT THEM WITH
AL
ALPELISIB COMES THROUGH ALPHA
AND WHAT IS IN GREEN IS SIMILAR
IN SHUTTING DOWN MOST THE KINASE
ACTIVITY WE CAN CONCLUDE MOST
COMES THROUGH RAS PROTEINS IN
THESE CELLS SAME WITH THE PANEL
ON THE RIGHT BUT THERE'S STILL
RESIDUAL ACTIVITY WE THINK COMES
STRAIGHT FROM THE RECEPTOR
WITHOUT USE RAS.
SO THAT'S RELATIVELY
STRAIGHTFORWARD HELPS UNDERSTAND
HOW RAS PLAYS A ROLE IN
REGULATING THE PATHWAY FOR THE
FIRST TIME IN CELL LINES.
THIS IS THE BIG SURPRISE IN
AMPLIFIED CELL LINES MOST THE
ALPHA ACTIVITY COMES FROM
SOMEWHERE ELSE.
SO JUST LOOKING AT THE RIGHT
PANEL AND WELL KNOWN CELL LINE
AND TREAT THESE WITH ALPELISIB
AND IT WORKS AND THE BREAKUP IN
RED ALSO SHUTS DOWN MOST THE
KINASE ACTIVITY.
HOWEVER, THE INHIBITOR WHICH
INHIBITS HMK AND REM NAS HAS
LITTLE AFFECT.
SOME BUT NOT MAJORITY EFFECT.
SO THERE WAS A LARGE AMOUNT OF
ACTIVITY WHICH IS NOT ACCOUNTED
FOR BY ANY OF THE KNOWN RAS
PROTEINS AND WE EXTENDED THIS
LIST OF UNKNOWNS WHICH ALL THE
GENES PUBLISHED ARE EXPECTED TO
BIND AND ACTIVATE THE KINASE
ALPHA SO IT'S NONE OF THEM.
NOW WE BASICALLY DISCOVERED A
NEW CRITICAL PATHWAY FROM KINASE
WHICH WE PRESUME INVOLVES A
NOVEL RAS PROTEIN WE SOMEHOW
MISSED IN THE PAST AND WHEN WE
UNDERSTAND COULD BE EXTREMELY
INTERESTING IN UNDERSTANDING HOW
TO SHUT DOWN SIGNALLING IN THE
CELLS.
THAT'S AN ACADEMIC ISSUE.
FROM THE PRACTICAL POINT OF VIEW
THE COMPOUND IS POTENT IN THE
GENOTYPE.
THE COMPOUND PLAYS OUT AS WE
HOPE IS NOT JUST KINASE
INHIBITOR BUT DOESN'T PROMOTE
GLYCEMIA AND THE ALPELISIB CAN
INDUCE HYPOGLYCEMIA AND IF YOU
GIVE MICE A GLUCOSE CHALLENGE OR
YOU SEE IN BLUE THE TREATED MICE
AND THE BLACK YOU SEE NO
ACCUMULATION OF GLUCOSE BUT THE
GREEN LINE SHOWS TREATMENT AND
YOU CAN SEE THE SAME ON THE
RIGHT PANEL WITH INSULIN WHICH
ACCUMULATES AS A RESULT OF
HYPERGLYCEMIA AND FAILURE TO
CONTROL THE SIGNALLING PATHWAY.
SO SHUTTING DOWN THE PATHWAY AND
ON THE LEFT PANEL WE DON'T
PROMOTE HYPERGLYCEMIA.
WE THINK IT WILL MAKE THE
COMPOUNDS MORE EASY TO USE IN
THE CLINIC AND KEEPING THE
EFFICACY OR I AM IMPROVING IT
BECAUSE WE CAN DOSE HIGHER
WITHOUT SIDE EFFECTS.
IT OPENS UP THE POSSIBILITY OF
COMBINATION THERAPY.
SO ONE OF OUR FIRST COMBINATIONS
WE'LL TEST IS WITH THE ACTIVE
COMPOUND.
SO ON THE LEFT PANEL WE SHOWED
THE EFFECTS OF B12C ACTIVE
COMPOUND IN GREEN.
PRETTY EFFECTIVE IN THE CELL
LINE MODEL AND THE COMBINATION
IN RED MUCH MORE EFFECTIVE.
MORE IMPORTANTLY IN LUNG CANCER
CELL LINES AND MUTATIONS, THESE
CELLS ARE REFRACTORY IN THE
CLINIC TO G12C INHIBITORS.
WE SEE HERE IN COMBINATION WITH
OUR INHIBITOR ANTITUMOR
RESPONSES IN THE SITUATION.
AND THE RIGHT HAND PANEL IS
ANOTHER NOTORIOUSLY RESISTANT
CELL LINE AND GET RESPONSES IN
COMBINATION WITH INHIBITORS.
THE COMBINATION IS ONE OF THE
FIRST THINGS WELL TEST TO
ENHANCE ACTIVITY OF G12C ON AND
OFF COMPOUNDS IN THE CLINICAL
SETTINGS.
WE CAN GO BEYOND THAT AND IF YOU
FOLLOW DRUG RESISTANCE FOR MANY
YEARS OR FULLY AWARE OF THE FACT
THE KINASE ACTIVITY IS OFTEN
ASSOCIATED WITH DRUG RESISTANCE
IN MANY CONTEXTS INCLUDING CHEMO
AND TARGET AND OTHER THERAPIES
AND MODALITIES.
IN THIS CASE WE DON'T UNDERSTAND
HOW THE KINASE ACTIVATION CO
CONFERS THESE RESISTANT EFFECTS
BUT IT'S A PROBLEM.
AND LIKELY THE ACTIVITY HELPS
DIVIDE THE AGENTS AND IN
COMBINATION WITH THREE DIFFERENT
DRUGS THAT ARE USED ROUTINELY IN
BREAST CANCER.
AND YOU CAN SEE THESE DOSES HAVE
BEEN ADJUSTED FOR PARTIAL EFFECT
IN BLUE AND BREAK ALONE IS IN
GREEN AND THE COMBINATION OF THE
BREAKER PLUS THE TARGETED
THERAPIES GIVES MORE DRAMATIC
RESPONSES.
AND WE SEE THIS ALSO IN
COMBINATION WITH OTHER
CHEMOTHERAPY AN OTHER RESPONSES.
SO IF WE ARE CORRECT AND CAN USE
THE DRUG WITHOUT PROVOKING HY
HYPERGLYCEMIA OR OTHER EFFECTS
WE THINK IT WILL HAVE OTHER
ROLES WHERE PF3 KINASE
ACTIVATION IS A MAJOR PROBLEM
AND CAUSE OF RESISTANCE IN
MR. CASES.
-- MANY CASES.
TO SUMMARIZE IN THE WORLD WE'RE
TARGETING ONCOGENIC RAS AND THE
MYSTERY RAS PROTEIN HERE SHOWN
IN MAGENTA AND OTHERS INVOLVED
IN PATHOGENIC SITUATION USING A
COMPOUND WHERE THE SITUATIONS
ARE NOT NORMAL SIGNALLING.
AND THE LAST SLIDE GIVES CREDIT
TO THE TEAM LED BY FREDERICK
NATIONAL LAB AND A TIGHT
COLLABORATION AND BIG TEAM
EFFORT WITH OUR COLLEAGUES
DEVELOPING OTHER DRUG AND AN
INHIBITOR THAT IS NOW APPROVED
AND THE NATIONAL LAB AND I WANT
TO ACKNOWLEDGE DWIGHT FOR HIS
WISDOM AND GUIDANCE AT FREDERICK
NATIONAL LABS AND THANK YOU ALL
FOR YOUR ATTENTION.
THANK YOU.
>> THANK YOU, GREAT REPORT.
ARE THERE QUESTIONS.
EARL.
>> GREAT PRESENTATIONS.
THANK YOU FOR SUCH NICE WORK AS
ALWAYS.
I HAVE TWO QUESTIONS.
ONE, WHAT IS KNOWN ABOUT THE
MUTATIONS THE OTHER RAS FAMILY
MEMBERS?
ARE THEY CONSERVED IN THE SAME
LOCATION AS THE MUTATION IS AND
IS ANYTHING BEING DONE TO TARGET
THOSE AS WELL?
AND THE SECOND QUESTION IS DO
YOU HAVE ANY PROGRESS ON WHAT'S
BEEN DONE IN TERMS OF GETTING
THE INFORMATION OUT TO THE LAY
PUBLIC?
>> FIRST, WE HAVE A BIG EFFORT
TARGETING K RAS AND PRIMARILY
PANCREATIC CANCER BECAUSE WE'RE
TRYING TO MAKE AN IMPACT IN D12B
AND D12D.
THE NEXT COMPOUND HITS THIS
ALLELES IN THE GTP BOUND STATE
USING THE SAME MECHANISM AS THE
G12C.
WE HAVEN'T FILED THE IND YET BUT
EXPECT TO SOON AND IF THAT ALL
CLEARS THEY SHOULD BE IN THE
CLINIC NEXT YEAR.
THEY SHOULD TAKE CARE OF SOME OF
THE OTHER ALLELES THE MORE
COMMON ONES SO YES THEY'RE
COMING ALONG.
AS FOR DISSEMINATION TO THE LAY
PUBLIC, RIGHT NOW ALL I CAN SAY
IS WE HAVE SEVERAL MAJOR
PUBLICATIONS UNDER REVIEW AND
JOURNALS COMING OUT HOPEFULLY IN
THE NEAR FUTURE AND THAT IS GOLD
STANDARD FOR GETTING THE WORD
OUT TO THE SCIENTIFIC COMMUNITY
AND AS FOR THE LAY PUBLIC I
THINK I'LL DEFER TO MY
COLLEAGUES AT THE NCI OR
FREDERICK FOR THAT COMMENT.
>> YES, MATT.
>> THAT WAS AMAZING WORK AS
ALWAYS.
I HAVE IN THINKING ABOUT THE
FINDING WITH THE HER 2 AND
BREAKER COMPOUND IS INTRIGUING
AND SURPRISING AND MAKES ME
WONDER IF YOU LOOKED AT THIS IN
THE SETTING OF CELLS RESISTANT
TO STRAIGHT UP RAS INHIBITORS
THE REASON I'M ASKING IS BECAUSE
SOMETHING IS ACTIVATING IN THE
HER 2 POSITIVE SETTING AND THE
DATA IS PROBABLY CLEAR IT'S
PROBABLY NOT HER 2 SIGNALLING.
IT'S INTERESTING YOUR
POSTULATING IT'S GOING THROUGH
ANOTHER RAS OR G PROTEIN BUT ONE
MIGHT IMAGINE THE SAME PATHWAY
COULD BE ACTIVE AS A RESISTANT
MECHANISM TO TRADITIONAL
INHIBITERS BECAUSE THOSE AREN'T
TARGETING THAT PATHWAY AND YOU
KNOW ACTIVATING GR2 KINASE CAN
CONFER SOME KIND OF RESISTANCE.
FROM A PRACTICAL STANDPOINT IT
MAYBE THE COMPOUND WILL BE GOOD
IN THE RAS RESISTANT SETTING FOR
THOSE REASON IF THAT MAKES
SENSE.
>> TOTAL SENSE, YEAH.
>> GREAT POINT.
WE DON'T UNDERSTAND AND WE
INCLUDE HE THE COMBINATION DATA
WE DON'T UNDERSTAND AND HOPE IT
CAN BE PICKED UP ON.
AND THAT OPERATES MORE CASUALLY.
>> IT COULD BE AN OPPORTUNITY TO
TRIANGULATE SOME DIFFERENT
SETTINGS AND MAYBE GET A BETTER
SENSE OF WHAT THE MYSTERY TARGET
IS OF THE BREAKER COMPOUND IN
THE SETTING WHERE IT'S NOT RAS
BECAUSE KNOWING THAT MAY OPEN UP
A WHOLE NEW RANGE OF THERAPEUTIC
POSSIBILITIES.
>> GREAT POINT, YEAH.
NOW WE HAVE THE COMPOUNDS THAT
INHIBITS THE RAS PROTEINS WE CAN
ELIMINATE THEM MORE EASILY THAN
DOING KNOCK DOWNS EVEN A YEAR
AGO.
I THINK THE TOOLS ARE BETTER FOR
INTERROGATING THAT.
THANK YOU.
>> THAT'S A COMMENT, QUESTION,
EXCITING WORK.
WHAT IS THE PLAN FOR THE
CLINICAL EVALUATION MUCH THE
BREAKER AS I SOLE AGENT OR IN
COMBINATION?
S
>> WITH THINK IT THE SHOW IN
COLORECTAL AND SMALL CELL LUNG
AND IF THE COMPOUND IS SAFE AND
THERE'S MONOTHERAPY INDICATIONS
WE'LL SWITCH TO THE OBVIOUS ONES
WE JUST REFERRED TO.
WE HAVE A PLAN FOR TACKLING
THOSE.
BREAST CANCER IS ON OUR RADAR
SCREEN AND WE SEE GREAT ENERGY
WITH CDK4 INHIBITERS AND IT'S AN
OBVIOUS PLACE TO GO.
>> THANKS, FRANK.
I THINK WE NEED TO MOVE ON.
APPRECIATE IT.
THANK YOU, McCORMICK.
OUR NEXT PRESENTATION IS BY
DR. SINGER AND PINTO TALKING
ABOUT THE SEROLOGICAL SCIENCES
NETWORK SER NET IN RESPONSE TO
COVID-19.
MANY KNOW THESE WERE SHINING
MOMENTS FOR FNLAC WHERE THEY
CONTRIBUTED SIGNIFICANTLY SO,
PLEASE.
>> DR. SINGER WAS HAVING WEBEX
ISSUES AND WAS GOING TO CALL IN
IF SHE WASN'T ABLE TO AND SHE
MAY BE MUTED.
>> OKAY.
>> DR. SINGER IS MUTED.
CAN YOU UNMUTE HER?
>> I'M CHECKING.
A/V SUPPORT CAN WE UNMUTE?
>> I DON'T THINK WE CAN.
>> YOU'RE GOOD.
THANK YOU.
OKAY.
SORRY.
>> NO PROBLEM.
>> WELL, ANYHOW, THANK YOU FOR
LETTING ME GIVE YOU A VERY BRIEF
UPDATE ON THE SEROLOGICAL
SCIENCES NETWORK OR SERONET
WHICH WAS ESTABLISHED BACK IN
2020 IN RESPONSE TO
CONGRESSIONAL APPROPRIATION OF
ABOUT $300 MILLION TO NCI TO
PROVIDE BOTH SEROLOGICAL SEFT OF
TESTING AND SUPPORT SUPPORT
RESEARCH ON THE OVER ALL
RESPONSE TO SARS COV2.
SERONET WAS ESTABLISHED AFTER
CONGRESSIONAL APPROPRIATION WITH
THE GOALS OF DEVELOPING AND
DEPLOYING BROADLY SEROLOGICAL
SEA
SARS COV2 AND DETERMINE
SEROLOGICAL CORRELATES AND
BARRIERS TO VANING.
-- VACCINATION.
A NETWORK CONSISTS OF A TOTAL OF
FOUR COMPONENTS.
FOUR, 21 RESEARCH GRANTS, 13
WERE UL 1s AND THEY WERE CHARGED
WITH THE BASIC RESEARCH OF
CHARACTERIZING THE IMMUNE
RESPONSE TO SARS COV2 AS WELL AS
IS SEROLOGICAL RESEARCH AND HAD
CAPACITY BUILDING CENTERS TO
GENERATOR MAKE AVAILABLE IS
SEROLOGICAL TESTING NATIONALLY
AND USE BIO SPECIMENS AND FOR
ESTABLISHING STANDARDS AND THEY
WERE ALSO CHARGED WITH
CONDUCTING SURVEILLANCE STUDIES.
THE THIRD COMPONENT WAS ALSO
SEROLOGY LAB THAT WAS CHARGED
WITH HELPING THE FDA TO ASSESS
COMMERCIAL SEROLOGY DEVICES AND
TO DEVELOP SEROLOGY ASSAYS AND
STANDARDS.
AND THEN THE LAST PIECE WAS A
NETWORK COORDINATING CENTER TO
TRY TO MANAGE AND COORDINATE ALL
THE ACTIVITIES OF SERONET.
SO, ONE NOTEWORTHY ASPECT THAT
SETS IT ASIDE FROM OTHER EFFORTS
TO STUDY SARS COV2 INFECTION WAS
ITS FOCUS ON SPECIAL POPULATIONS
INCLUDING CANCER PATIENTS AND
IMMUNOCOMPROMISED PATIENTS,
PATIENTS WITH A VARIETY OF
IMMUNE MEDIATED INFLAMMATORY
DISEASES.
AS WE STOOD SERONET UP WE
ADOPTED A NUMBER OF PRINCIPLES
TO WORK ACROSS THE NETWORK.
ONE WAS IN ORDER TO MAKE AS MUCH
AS INFORMATION AVAILABLE AS
QUICKLY AS POSSIBLE ALL SERONET
PUBLICATIONS HAD TO APPEAR IN AN
OPEN ACCESS FORMAT.
ALL THE DATA UNDERLYING THE
RESEARCH HAS TO BE SHARED
IMMEDIATELY FOR PUBLICATION AND
FINALLY WITHIN SERONET A NETWORK
WIDE AGREEMENT TO SHARE
INFORMATION PREPUBLICATION AND
COLLABORATE EXTENSIVELY.
BECAUSE SERONET WAS STOOD UP IN
2020 IN THE HEIGHT OF THE
PANDEMIC, WE ANTICIPATED THE
PANDEMIC WOULD CHANGE OVER TIME
AND WE WOULD WANT TO RE-ASSESS
THE PROGRESS OF THE GRANTS AND
THE CDCs CENTERS AFTER A PERIOD
OF TIME TO MAKE SURE THEY WERE
FOCUSSING ON THE RELEVANT
PROBLEMS THAT WE HEARD AFTER TWO
YEARS OF FUNDING.
SO BUILT INTO OUR PROGRAM WAS
THE RE-ASSESSMENT AFTER TWO
YEARS OF THE PROGRAM
SPECIFICALLY OF THE CAPACITY
BUILDING CENTERS AND OF THE
GRANTS.
THE REVIEW WAS CONDUCTED BY A
PANEL OF EXPERTS AND INTERNAL
PANEL OF EXPERTS FROM BOTH NCI
AND THE INSTITUTE, SCIENTISTS
WHO WERE EXPERT BUT NOT DIRECTLY
INVOLVED WITH THE PROGRAM.
SO THE CAPACITY BUILDING CENTER
ASSESSMENT WAS BASED ON
SEROLOGICAL TESTING WAS NOT
CONSIDERED A PRIORITY AND IN
HIGH DEMAND AT THE TIME.
IT WAS ASSESSED THE CDC'S
CONDUCTED IMPORTANT BUT PERHAPS
NOT UNIQUE RESEARCH AND FINALLY
THE BIO SPECIMENS BEING
COLLECTED HAD PROVIDED THE TOTAL
NUMBER OF BIO SPECIMENS THAT
WERE NEEDED FOR THE SEROLOGY LAB
AND WE FOUND THERE WAS A LIMITED
INTEREST IN SERONET
INVESTIGATORS IN FURTHER
COLLECTION OF BIO SPECIMENS.
SO THE RECOMMENDATION FROM THE
REVIEW PANEL WAS WE MAINTAIN ONE
OF THE CDCs TO BE POISED TO
RESPOND THERE WAS A RESURGENCE
IN THE PANDEMIC AND ALSO TO
CONTINUE SOME OF THE RESEARCH
EFFORTS AND THE LONGITUDINAL
COHORTS.
OF THE 21 GRANTS, ALL BUT ONE
WERE APPROVED FOR CONTINUATION.
ONE ON THE EXTENSION.
OF THE GRANTS THAT WERE APPROVED
FOR CONTINUATION, WE ALLOWED
THEM FLEXIBILITY TO ADJUST THEIR
SCIENTIFIC AIMS WITHIN THE SCOPE
OF THE GRANT TO ALLOW THEM TO
INCORPORATE THE CHANGES THAT HAD
OCCURRED IN THE PANDEMIC OVER
TIME.
SO FOR INSTANCE THE RAPID
AVAILABILITY OF VACCINES WAS
NECESSITATING TO LOOK AT THE
RESPONSE TO VACCINATION.
AND TO LOOK AT THE EFFECT ON
LONGITUDINAL COHORTS.
THE APPARENT OF VIRAL VARIANTS
WAS ALLOWED TO BE INCORPORATED
IN THEIR STUDIES AND HOW THOSE
EFFECTED THE IMMUNE RESPONSE AND
FINALLY WITH THE APPEARANCE OF
LONG COACHED, THAT WORK WAS ALSO
ALLOWED TO BE INCORPORATED IN
THE GRANTS.
SO I THINK IF YOU LOOK OVERALL,
SERONET WAS HIGHLY SUCCESSFUL
SCIENTIFICALLY.
LOOKING AT THREE BROAD
CATEGORIES OVER THE NEXT THREE
SLIDES AND A NUMBER OF THE
INVESTIGATORS WERE LOOKING AT
THE IMMUNE RESPONSE TO SARS COV2
AND ITS VARIANTS IN THE GENERAL
POPULATION AS WELL AS THE
RESPONSE THE IMMUNE RESPONSE TO
VACCINATION AND HOW THE RESPONSE
TO VACCINE AND VIRUSES
DELIVERED.
OTHER INVESTIGATORS WERE LOOKING
AT THE VACCINE RESPONSES AND
COMMUNICATIONS WITH CANCER TO
SEE HOW CANCER PATIENTS THOSE
WHO EITHER HADN'T BEEN OR HAD
BEEN UNDER THERAPY WOULD RESPOND
AND RESPONSES WERE OBSERVED IN
CANCER PATIENTS BUT
INTERESTINGLY, THIS WAS REALLY
THE FIRST STUDY THAT HAD EVER
BEEN DONE IN RESPONSE TO ANY
VACCINE.
THAT'S WITH PATIENTS WITH
CANCER.
WHAT WE LEARNED HERE WILL BE
APPLICABLE BEYOND WHAT WE JUST
LEARNED ABOUT SARS COV2.
THE FINAL WAS LOOKING AT THE
VACCINE RESPONSES IN OTHER
REPRESENTATIONS IN
IMMUNOCOMPROMISEDD INFLAMMATION
MAY EFFECT THE RESPONSE TO THE
VACCINE.
FROM THIS QUICK OVERVIEW OF THE
SCIENCE IN SERONET IT'S BEEN A
HIGHLY SUCCESSFUL PROGRAM BUT
TRYING TO LOOK AT IT MORE
OBJECTIVE WE CAN ASK WHAT IMPACT
HAS THIS PROGRAM HAD ON THE
BROADER COMMUNITY AND THAT'S
SHOWN IN THE NEXT SLIDE WHEN WE
LOOK AT THE SERONET PUBLISHED
ARTICLES AND WHEN WE WORK WITH
THE TOP 1% OF ARTICLES THAT ARE
CITED, THAT SERONET RANKS ABOVE
THE OTHER COMPARATIVE GROUPS IN
THE FREQUENCY OF APPEARING IN
THE TOP 1%.
AND I'D LIKE TO THANK ALL THE
PEOPLE WHO HAVE BEEN INVOLVED
ESPECIALLY SAM AND JUDY AND
OTHERS FOR THEIR INCREDIBLE
EFFORT AND OTHERS WERE CRYSTAL
AND TACTIC AND THE REST OF THE
NCI STAFF WERE INVOLVED.
I THINK RATHER THAN THE
QUESTIONS RIGHT NOW WE GO TO THE
NEXT SLIDE I'D LIKE TO HAND THE
PRESENTATION TO DR. PINTO WHO
WILL TELL YOU ABOUT THE AMAZING
EFFORTS OF THE FNL SEROLOGY
CENTER.
>> THANK YOU.
IT'S A PLEASURE TO BE WITH YOU
ALL TODAY.
THANK YOU SO MUCH FOR THE
INVITATION TO PRESENT ON SOME OF
OUR WORK IN SERONET TO SUPPORT
THE NCI RESPONSE TO THE COVID-19
PANDEMIC.
WE'RE UNDER THE SCIENCE AND
TECHNOLOGY GROUP AT FNL
INCLUDING THE SEROLOGY
LABORATORY AND IMMUNOPREVENTION
LABORATORY AND TWO INITIATIVES.
THE SARS COV2 SEROLOGICAL
NETWORK AND THE SEROLOGY LAB AND
THE COORDINATING CENTER
DR. SINGER WAS REFERRED TO AND A
CENTER FOR EXCELLENCE FOR
SEROLOGY DEVELOPMENT AND
EMERGENCY REPAIPREPAREDNESS.
THE MISSION OF THE GROUP IS TO
STUDY IMMUNE RESPONSES TO HUMAN
PAPILLOMA VIRUS AND SARS COV2
INFECTION AND VACCINES AS WELL
AS OTHER CANCER PREVENTION
STRATEGIES IN THE CONTEXT OF
CLINICAL AND PRECLINICAL
STUDIES.
ALWAYS WITH THE GOAL OF
TRANSLATING LABORATORY SCIENCE
INTO PUBLIC HEALTH BENEFIT.
WE HAVE BEEN WORKING FOR THE
PAST TWO DECADES ON IMMUNOLOGY
AND SEROLOGY.
AND OUR WORK INCLUDES SUPPORT
FOR NCI VACCINE TRIALS AND
LAUNCH EPILOGICAL STUDIES AND WE
COLLABORATE EXTENSIVELY WITH THE
EXTRAMURAL COMMUNITY AND WE ARE
LEADING THE HPV STANDARD
INITIATIVE SERVING AS THE
CENTRAL REFERENCE LAB WITH
SEVERAL PARTNERS ACROSS THE
GLOBE THE BILL AND MELINDA GATES
FOUNDATION AND THE NATIONAL
INSTITUTES FOR BIOLOGICAL
STANDARDS AND CONTROL IN THE
U.K., VARIOUS INSTITUTES AND
WHL.
WE'RE A WHL REFERENCE LABORATORY
AND DURING THE EPIDEMIC WE SE
SERSER
SERVED AS AN FDA TESTING
LABORA
LABORATORY FOR THE COMMUNITY.
OUR LABORATORY PLAYED A CRITICAL
ROLE IN UNDERSTANDING HOW HPV
VACCINES WORK.
WE WERE ONE OF THE FIRST FEW
LABS TO DEMONSTRATE LONG-TERM
ANTIBODY RESPONSES FOR A SINGLE
DOSE OF HPV VACCINE SUGGESTING
THIS SINGLE DOSE MAY BE AS
EFFECTIVE AS THE RECOMMENDED AND
APPROVED TWO AND THREE-DOSE
SCHEDULES.
AND WITH INCREASING NUMBER OF
TRIALS FOR NOVEL HPV VACCINE
REGIMENT RECOMMENDATIONS AND
VACCINES, WE RELIED ON SEROLOGY
AS END POINT IN BRIDGING TRIALS
TO INFORM REGULATORY DECISIONS.
WE FELT THERE WAS AN URGENT NEED
AS THERE WAS NO STANDARDIZED
ASSAYS OR PROCEDURES.
TO ADDRESS THIS WELL RECOGNIZED
STANDARDIZATION GAP, WE
ESTABLISHED THE HPV SEROLOGY
STANDARDIZATION INITIATIVE IB
202127 -- IN 2017 AND SPONSORED
BY THE NCI AND GATES FOUNDATION.
REALLY THE MISSION OF THIS
INITIATIVE IS TO WORK IN
PARTNERSHIP WITH THE
INTERNATIONAL HPV COMMUNITY TO
PROMOTE FURTHER STANDARDIZATION
AND ORGANIZATION AND PROFICIENCY
TO ESTABLISH FACTS IN
IMMUNOGENICITY IN CLINICAL
TRIAL.
WE DO THIS THROUGH THE
DEVELOPMENT OF QUALIFIED ASSAY
STANDARDS, CRITICAL RE-AGENTS
AND THE EMPHASIS TO LOOK AT
ANTIBODY RESPONSES THROUGH THE
DEVELOPMENT OF MULTIPLEX HIGH
THROUGHPUT ASSAYS THAT WE MAKE
ALL AVAILABLE TO THE SCIENTIFIC
COMMUNITY AT OUR WEBSITE LISTED
BELOW.
WITH HAVE CAPABILITY FOR
CLINICAL TRIALS AND HOPE BY
DOING THIS BIG THE SCIENTIFIC
COMMUNITY WE ARE ABLE TO THEN TO
COMPARE RESULTS FROM DIFFERENT
VACCINES IN A MANNER NOT
POSSIBLE BEFORE AND CELEBRATED
IMPLEMENTATION OF NEW VACCINES
AND RECOMMENDATIONS.
AND AS MENTIONED EARLIER WE'RE
DOING THIS IN COLLABORATION WITH
A LARGE NUMBER OF PARTNERS AND
NCI AND GATES FOUNDATION AND CDC
AND PUBLIC HEALTH ENGLAND AND
THE NATIONAL INSTITUTES OF
BIOLOGICAL STANDARDS AND CONTROL
AS WELL AS A STRONG
COLLABORATION WITH MANY ACADEMIC
LABORATORIES AND OTHER
REGULATORY BODIES.
AND USING THE STANDARDIZED AND
VALIDATED ASSAYS, WE HAVE BEEN
CONDUCTING IMMUNOGENICITY
TESTING IN A LARGE NUMBER OF HPV
VACCINE TRIALS.
HERE IS A LIST OF SOME OF THE
ONE-DOSE TRIALS WE ARE
SUPPORTING.
WE HAVE CONDUCTED MORE THAN
100,000 TESTS ON ALL THE TRIALS.
YOU CAN SEE THESE TRIALS ARE
OCCURRING IN DIFFERENT PARTS OF
THE WORLD AND ALSO COVERING
DIFFERENT AGE GROUPS AND BOTH IN
GIRLS, WOMEN AND BOYS.
SO USING TECHNOLOGIES WE'VE BEEN
ABLE TO COMPARE DATA IN CLINICAL
TRIALS WHICH HAVE BEEN USED IN
PART FOR THE RECENT ENDORSEMENT
OF ONE DOSE OF HPV VACCINE BY
W.H.O.
WE BELIEVE THE STANDARDIZATION
IS THE KEY TO EVOLVE THE FIELD
TO FIGHT EFFECTIVELY AGAINST
CANCER AND POSSIBLY ELIMINATING
IT.
WITH ALL THE PARTNERSHIPS AND WE
WERE VERY WELL POSITIONED TO
RESPOND TO THE COVID PANDEMIC IN
MARCH 2020 WHEN WE WERE
APPROACHED BY THE NCI LEADERSHIP
AND WHY LOWY AND DR. SHARPLESS
TO DEVELOP SEROLOGY ASSAYS AND
ALSO DEVELOP STANDARDS FOR
SEROLOGY IN A MANNER THAT IS
SIMILAR TO WHAT WE WERE DOING
FOR THE HPV BECAUSE WE HAD BEEN
WORKING CLOSELY WITH W.H.O. FOR
THE INTERNATIONAL STANDARDS FOR
HPV.
SOON AFTER THAT FDA ASKED NCI
AND US TO HELP EVALUATE THE
QUALITY OF THE EMERGING
COMMERCIAL SEROLOGY DEVICES.
THEY WERE SUBMITTED TO FDA FOR
EMERGENCY USE AUTHORIZATION.
I HAVE TO SAY IT WAS AN AMAZING
EFFORT AND IT WAS EXCITING WAS
VERY LARGE AND INVOLVED SO MANY
HHS AGENCIES AND SO MANY
ACADEMIC LABORATORIES.
IT WAS A TREMENDOUS
COLLABORATION AND SOON AFTER
THAT AS DR. SINGER WAS
MENTIONING THERE WAS FUNDING
FROM HHS TO SUPPORT THE SARS
COV2 SEROLOGY INITIATIVES.
SO NOW I'D LIKE TO REVIEW SOME
OF OUR CONTRIBUTIONS AND
MILESTONES AT THE SEROLOGY LAB
RESPONSE TO THE COVID-19
PANDEMIC AND I HAVE TO REALLY
THANK DOCTORS CAMP AND RAUSCH
FOR THEIR LEADERSHIP IN THE
AREA.
WE HAVE A KEY ROLE IN THE
EVALUATION PROGRAM ESTABLISHED
BY FDA FOR SARS COV2 SEROLOGY
TEST AND VALIDATION PANELS WITH
WELL CHARACTERIZED PANELS TESTED
AGAINST MORE THAN 115 COMMERCIAL
TESTS.
AND SOME RECEIVED UA.
ONE THIRD RECEIVE UA AND IN SOME
CASES IT WAS REVOKED AND HAD A
KEY ROLE IN REDUCTION OF THE
SEROLOGY STANDARDS MORE THAN 185
REQUESTS IN THE UNITED STATES
AND GLOBALLY.
AND WE IMPLEMENTS A NUMBER OF
IMMUNOLOGICAL ASSAYS AND
VALIDATED A NUMBER OF THOSE
ASSAYS AND WE HAVE ESTABLISHED
AN 18 PLEX THAT INCLUDES ALL THE
VARIANTS AND ALSO THE COMMON
CORONAVIRUS AND WE'RE NOW IN THE
QUALIFICATION PHASE OF THE
ASSAYS WORKING CLOSELY WITH DUKE
UNIVERSITY.
SO USING THIS VALIDATED
TECHNOLOGIES WE DEVELOPED WE
INVESTIGATED IMMUNE RESPONSE TO
THE APPROVED VACCINES AND WE
TESTED MORE THAN 80,000 SAMPLE.
WE PLAYED A KEY ROLE IN
ESTABLISHING SERONET AND
MARCHING -- MANAGING THE DATA
CENTER AND THE MANAGEMENT OF THE
CAPACITY-BUILDING CENTERS WHICH
A COLLECTION OF A NUMBER OF
SPECIMENS FOR PRODUCTION OF
REFERENCE MATERIALS BUT ALSO
LONGITUDINAL STUDIES AND THE
MANAGEMENT OF HOW THAT PLAYED AS
WELL AS THE DATA OCCUR --
CURATION DR. SINGER MENTIONED.
I ALSO WANT TO SPEND A COUPLE
MINUTES TALKING ABOUT THE
CLINICAL ENGINES OF THE SEROLOGY
TASK FORCE WE ESTABLISHED IN
FEBRUARY 2021.
THESE ARE THE PUBLICATIONS
RESULTING FROM THE WORK AND I
WOULD LIKE TO NOTE THIS
PUBLICATION FROM OUR COLLEAGUES
AT FDA HIGHLIGHTING THE EFFORT
MARK THE FIRST TIME IT
RECOMMENDED THIS TYPE OF
APPROACH FOR FUTURE PANDEMICS
I'D LIKE TO SPEND A MINUTE
TALKING ABOUT THE SPECIMENS BY
THE CAPACITY BUILDING CENTERS.
AND WHAT IS INTERESTING ABOUT
THIS IS THAT WE HAVE REALLY BOTH
SERUM AND PERIPHERAL BLOOD IN
OUR CELLS CRYO PRESERVED FROM
HEALTHY INDIVIDUALS AS WELL AS
INDIVIDUALS WITH CANCER, AUTO
IMMUNITY AND SOME TRANSPLANT
RECIPIENTS AND HIV.
AND USING THE SAME SAMPLE
PROCESSING AND ALSO THE SAME
DATA ELEMENTS.
THE PARTICIPANT ENROLLMENTS
STARTED IN 2021 AND WENT UNTIL
EARLY 2024.
AND THE SAMPLES HAVE BEEN USED
BY THE SEROLOGY LAB FOR A NUMBER
OF STUDIES ONGOING AS WELL AS TO
SERONET MEMBERS AND WANT TO
EMPHASIZE THE REACH, COLLECTION,
TIME POINTS WE HAVE HERE AFTER
VACCINATION OR INFECTION AND WE
HAD MANY VACCINES AND ALSO
BREAKTHROUGH INFECTIONS THAT
REALLY WE HAVE TO START/RESTART
THE TIME LINE AS NEW EVENTS WERE
OCCURRING.
I WANT TO EMPHASIZE THIS WAS
DONE REALLY THE POWER OF
COLLABORATION AND THE IMPRESSIVE
TIME LINE OF ACHIEVEMENTS WITH
THE NCI AND THE LABS AND THE
MATERIALS ARRIVED IN THE
LABORATORY AT THE END OF MARCH
AND USING OUR PLUG AND PLAY
TECHNOLOGIES WE WERE ABLE TO
HAVE THE ASSAYS IMPLEMENTS
WITHIN ONE TO TWO WEEKS AFTER
THE PROTEIN GENERATION WHICH WAS
AN AMAZING ASSET WE HAVE HERE
AND ALLOWED IT TO MOVE FAST AND
GRANTS FROM THE NCI AND
CONTRACTS AWARDED VERY SOON
AFTER THE RFAs WERE PUBLISHED
AND FUNDING WAS RECEIVED.
IT WAS AN AMAZING EXAMPLE OF THE
COLLABORATION.
I WOULD LIKE TO EMPHASIZE ALSO
ANOTHER ACHIEVEMENT AND REALLY A
PLEASURE THAT HAS BEEN WORKING
WITH ALL THE COLLEAGUES FROM SO
MANY ORGANIZATIONS ON THE
CLINICAL AND TRANSLATIONAL
SEROLOGY TASK FORCE CO-CHAIRED
WITH DR. SARGO AT MOUNT SINAI
AND WE'RE STILL MEETING AND WE
ORGANIZED MORE THAN 64 MEETINGS
AND ONE WORKSHOP AS WELL AND WE
HA
HAVE THE SERONEWS WE PUBLISH.
THE COURSE OF THE TASK FORCE WAS
BRINGING TOGETHER AND ENGAGING
VARIOUS GOVERNMENT ORGANIZATIONS
SO ALL THE COLLABORATORS WE WERE
WORKING WITH FROM CDC, FDA, THE
ACADEMIC GROUPS, INDUSTRY
PARTNERS BECAUSE WE WORKED WITH
SEVERAL INDUSTRY PARTNERS ALSO
DURING THE PANDEMIC TO PROVIDE
TOOLS AND INFORMATION RELATED TO
SEROLOGY TESTING AND DEVELOPMENT
AND HELP DECISION MAKERS MANAGE
THE CURRENT AND FUTURE STATUS OF
THE PANDEMIC.
YOU CAN SEE HERE THE LINK TO THE
VARIOUS SERONEWS WE PUBLISHED.
I WANT TO EMPHASIZE TWO OF THE
OUTCOMES OF THE CLINICAL AND
TRANSLATIONAL TASK FORCE AND
WE'RE PROUD OF THIS WORK WORKING
AGAIN CLOSELY TOGETHER AND
ILLUSTRATING THE POWER OF
CONVENING.
ONE WAS THE REAL WORLD DATA
INFRASTRUCTURE THAT WAS
DEVELOPED TO EVALUATE THE IMPACT
OF INFECTION AND VACCINE
EFFECTIVENESS IN HEALTHY
INDIVIDUALS AND
IMMUNOCOMPROMISIZED INDIVIDUALS
WITH AN EMPHASIS ON CANCER
PATIENT AND THE WORK IS BEING
LED BY DR. BEN BURKE AND
NORTHWELL AND I WANT TO THEM
THEM FOR THAT.
THIS IS AN AMAZING
INFRASTRUCTURE FILLING AN
AMAZING GAP WE LAD AND THE
CENTER OF EXCELLENCE FOR SAMPLE
ACQUISITION WICK BIO SPECIMENS
THAT WILL BE WELL CHARACTERIZED
AND ANNOTATED AND HIGH QUALITY
SEROLOGY AND OTHER IMMUNOLOGICAL
TESTING WHERE WE ARE INTERESTED
IN STANDARDIZING T CELL ASSAYS
NOW AND WORKING CLOSELY WITH
DR. AHMED TO ACHIEVE AND BRING
THEM TO THE SAME LEVEL WE HAVE
WITH SEROLOGY THAT CAN BE USED
TO INFORM REGULATORY DECISIONS
AND FOR PUBLIC HEALTH BENEFIT.
SO JUST A COUPLE OF SLIDES ON
THE CENTER OF EXCELLENCE TO
CONTROL FUTURE AND CURRENT
OUTBREAKS AND ADDRESSING GAPS IN
STANDARDIZATION IN FAST
DEVELOPMENT AND DEVELOPMENT OF
ASSAYS THAT CAN BE USED TO
PROVIDE ACCURATE INFORMATION TO
VACCINATION TO SERVE THE PUBLIC
HEALTH NEEDS OF HEALTHY
INDIVIDUALS AND OF COURSE VERY
INTERESTED WITH POPULATIONS IN
PARTICULAR IN PEOPLE WITH
CANCER.
AND THE APPROACH IS REALLY
PROGRESS.
IT'S THE WAY WE HAVE TO DO
THINGS IS WORK TOGETHER AS WE
WORKED FROM THE BEGINNING OF THE
PANDEMIC AND ALSO WITHIN
CLINICAL CENTERS WITH THE
CAPABILITIES TO PROVIDE LARGE
BLOOD COLLECTIONS AS WELL AS
TESTING CENTERS THAT CAN DO HIGH
THROUGHPUT TESTING IN AN
EFFICIENT MANNER AND DOING THAT
THROUGH ESTABLISHMENT OF
CONTRACTS AND OF COURSE HUGE
COLLABORATION ACROSS OUR
DIRECTORATES.
THIS IS EMPHASIZING BIG PROBLEMS
AND BOTTLENECKS AT THIS
BEGINNING OF THE PANDEMIC AND
LACK OF SAMPLES AND LACK OF
STANDARDS AND GUIDELINES AND
THAT CREATED SOME PROBLEMS IN
UNDERSTANDING WHAT IS THE IMMUNE
RESPONSE IN INFECTION TO THE
VACCINE AND WE'RE BUILDING A
STRONG NETWORK OF PARTNERS WITH
THE EXPERTISE AND CAPABILITIES
AS WELL AS DEVELOP A
STANDARDIZED DATA MANAGEMENT
INFRASTRUCTURE AND MAKING THE
TOOLS WE PRODUCE AVAILABLE TO
SCIENTIFIC COMMUNITY OUR GOAL IS
TO DO THAT THROUGH A PORTAL THAT
IS CURRENTLY UNDER DEVELOPMENT.
IN TERMS OF LONG-TERM PLANS WE
THINK WE NEED TO SUSTAIN THIS
TYPE OF CAPABILITIES AND WE NEED
TO LEVERAGE THE ESTABLISHED
INFRASTRUCTURE AND EXPERTISE FOR
PUBLIC-PRIVATE PARTNERSHIPS AND
THIS IS RELATED A LITTLE BIT TO
WHAT WE HEARD DISCUSSING ABOUT
THE NUCLEATED ROLE OF THE
FREDERICK NATIONAL LAB FOR
MULTIPLE USES FOR COVID-19 AS WE
AND SEE WITH RESULTS FROM CDC
AND W.H.O., THE INFECTIONS ARE
GOING UP.
THIS COVID-19 IS REALLY ONE OF
THE TOP CAUSES OF DEATH IN
CANCER PATIENTS SO WE NEED TO DO
A LOT OF RESEARCH WITH COVID-19
BECAUSE IT'S HERE AND HERE TO
STAY FOR A WHILE AND CAN AFFECT
VULNERABLE POPULATIONS SUCH AS
PEOPLE LIVING WITH CANCER
UTILIZING AGAIN THE PLUG AND
PLAY TECHNOLOGIES WE HAVE AND
ALL THE INFRASTRUCTURE AND WE'RE
INTERESTED IN CANCER VACCINE
IMMUNOLOGY AND STANDARDS
DEVELOPMENT AND THE THIS COULD
BE ANOTHER MODEL FOR APPLICATION
BEYOND COVID-19.
I WANT TO THANK EVERYONE THAT
MADE THIS POSSIBLE.
IT WAS REALLY AN AMAZING
COLLABORATION.
I HAVE TO GIVE A SPECIAL THANKS
TO DR. LOWEY SINCE HE WAS WITH
US SINCE THE FIRST DAY --
DR. LOWY AND ALL THE COLLEAGUES
AT NCI.
AND JIM CHERRY WAS INSTRUMENTAL
AT THE BEGINNING AND EVERYONE AT
THE FREDERICK NATIONAL LAB AND
THE LABORATORY WORKED TIRELESSLY
DURING THE PANDEMIC AND IT WAS A
JOY TO WORK WITH THE FDA AND CDC
AND W.H.O. AND MY COLLEAGUES AND
THE BILL AND MELINDA GATES
FOUNDATION AND THANK YOU FOR
LISTENING AROUND HAPPY TO ANSWER
QUESTIONS.
>> THANK YOU.
TWO OUTSTANDING PRESENTATIONS.
WE HAVE A MINUTE OR TWO FOR
QUESTIONS.
ALLISON.
>> CAN YOU HEAR ME?
>> YES.
>> I UNMUTED MYSELF.
OUTSTANDING.
THIS IS JUST AWESOME.
DR. RATHMELL AT THE BEGINNING
WAS SAYING WHAT CAN WE DO FOR
THE FUTURE OF IF FNL.
THIS EFFORT SERONET'S EFFORT IS
A POSTER CHILD OF THAT FUTURE.
YOU'RE INTERACTING WITH OTHER
AGENCIES TO HELP THEM DO THEIR
JOB.
YOU'RE LEADING OUR UNDERSTANDING
OF THESE ON VULNERABLE
POPULATIONS.
I THINK IT'S JUST AN A COMMENT
OF SAYING THIS TYPE OF RESOURCE
REPRESENTS WHAT A NATIONAL LAB
SHOULD BE PUTTING FORWARD.
ALL THE PARTNERSHIPS, PUBLIC,
PRIVATE, OTHER ORGANIZATIONS OR
CONGRATULATIONS ON A JOB WELL
DONE.
ARE THIS EM PEOPLE IN YOUR
GROUP PUBLISHING TO DISSEMINATE
THE RESEARCH BECAUSE THERE'S A
DARK OF PUBLICATIONS IN THIS
AREA TO HELP PEOPLE MOVE TOWARDS
THIS STANDARDIZATION IN TERMS OF
COLLECTION PROCESSING, ETCETERA.
>> WE ARE EXTREMELY EXCITED
ABOUT THE WORK WE ARE DOING IN
THIS AREA AND YOUR IDEAS IS
GREAT.
WE HAVE BEEN TRYING TO PUBLISH
METHOD DEVELOPMENT PAPERS.
WE ALSO PUT IN OUR WEBSITE ALL
THE SOPs AND VALIDATION
GUIDELI
GUIDELINES WITH REGULATORY
STANDARDS AND THE BIO SPECIMEN
JOURNALS ARE WONDERFUL.
THANK YOU VERY MUCH.
WE'LL CONSIDER.
>> DR. ROBERTSON.
>>
>> GREAT PRESENTATION AND
IMPRESSIVE WORK.
I HAVE A QUESTION ON WHAT YOU
MAY HAVE UNDERSTOOD BASED ON
WHAT'S OUT NOW IN THE CONTEXT OF
LONG COVID AND AND INCIDENTS OF
CANCER.
DO THEY HAVE MORE INCIDENTS OF
LONG COVID?
I THINK SOME STUDIES HAVE SHOWN
THAT BUT I'M CONCERNED WE NEED
TO START LOOKING AT OTHER
POTENTIAL CANCERS THAT ARE HPV
RELATED CANCERS AND EPSTEIN-BARR
VIRUS THAT THRIVE MALIGNANCIES.
THESE TYPES OF CANCERS MIGHT
HAVE A GREATER INCREASE
INCIDENTS IN PATIENTS THAT HAVE
LONG COVID.
DO WE HAVE ANY DATA OR
INFORMATION AS TO WHAT MIGHT BE
HAPPENING IN THESE POPULATIONS?
>> A NUMBER OF INVESTIGATORS ARE
BEGINNING TO LOOK AT THIS
QUESTION AND LOOK AT THE
CORRELATION BETWEEN LONG COVID
AND CANCER.
I KNOW THERE'S BEEN A NUMBER OF
ARTICLES IN TERMS OF A
DEFINITIVE STATEMENT AND IN
TERMS OF HPV AND VIRUSES I DON'T
KNOW WE HAVE ENOUGH DATA TO BE
DEFINITIVE BUT IT'S AN IMPORTANT
AREA PEOPLE ARE LOOKING AT
ESPECIALLY THE RELATIONSHIP
BETWEEN THE VIRUS ITSELF AND
CANCER.
>> I AGREE WITH DR. SINGER.
DEFINITELY THERE ARE SEVERAL
PAPERS IN THIS AREA.
THERE'S INDICATION THAT
INCIDENTS OF LONG COVID IS
HIGHER IN IMMUNOCOMPROMISED
INDIVIDUALS BUT WE NEED MORE
DATA.
I THINK ONE OF THE GOALS OF THE
REAL WORLD INFRASTRUCTURE THAT
IS BEING LED AND MORE THAN $5
MILLION PATIENTS INCLUDED IN
THAT DATABASE I THINK 1.3
MILLION CANCER PATIENTS IT WILL
BE EXCELLENT TO LOOK AT THE
CANCER PATIENTS AND LOOK AT THE
INFRASTRUCTURE.
THIS IS WHY IT'S IMPORTANT TO
LOOK AT INFRASTRUCTURE TO ANSWER
QUICKLY THESE TYPES OF
QUESTIONS.
>> IT'S AFTER 4:00 PUT WE HAVE
ONE MORE QUESTION.
>> THANK YOU.
I WAS GOING TO ASK ABOUT LONG
COVID BUT MORE SPECIFICALLY CAN
YOU SPEAK TO WHAT, IF ANY,
COLLABORATIONS ARE ONGOING WITH
THE RECOVER INITIATIVE
SPECIFICALLY FOCUSSED ON LONG
COVID AND I GUESS I'LL GO BACK
TO THE QUESTION PREVIOUSLY ASKED
ABOUT DATA AND WHAT ARE THE
ACTIVITIES ON TRYING TO MAKE
THIS DATA AVAILABLE AND USED BY
THE RESEARCH COMMUNITY.
>> IN TERMS OF RECOVER, WE DON'T
HAVE A FORMAL COLLABORATION WITH
RECOVER THOUGH OUR NCI STAFF IS
IN COMMUNICATION WITH THE
RECOVER STAFF IN SHARING
INFORMATION.
IN TERMS OF THE DATA SHARING
THAT'S A REQUIREMENT OF SERONET
ALL THE DATA BE MADE PUBLICALLY
AVAILABLE IMMEDIATELY UPON
PUBLICATION.
THE COORDINATING CENTER REALLY
IS RESPONSIBLE FOR THAT.
THEY'VE BEEN DOING A GREAT JOB.
DO YOU WANT TO COMMENT?
>> ALL THE DATA, 413
PUBLICATIONS FROM SERONET IS
DEPOSITED IN IMPORT SO WE HAVE A
COLLABORATION WITH NIAID FOR
THAT CURATION AND SPEND HERE WE
MADE THE DATA AVAILABLE TO ALL
SERONET INVESTIGATORS.
WITHIN OUR CENTER FOR SEROLOGY
AND ACADEMIC PREPAREDNESS WE'RE
DEVELOPING A COMPREHENSIVE DATA
RESOURCE AND WE ARE MAKING A
DATE PLANNING TO MAKE IT
AVAILABLE TO THE OUTSIDE.
>> RODNEY HAS HIS HAND UP.
SORRY, HOPEFULLY IT'S A QUICK
QUESTION BECAUSE IT'S AFTER
4:00.
YOU'RE MUTED.
>> THANK YOU.
KIND OF LATE BUT I THINK THIS IS
EXACTLY WHAT WE HAVE BEEN ABLE
TO ORGANIZE PUBLIC-PRIVATE
PARTNERSHIPS TO EXPAND ON THE
DETAIL OF SEROLOGY.
FOR A LONG TIME PEOPLE THOUGHT
ABOUT THE RESPONSE AND DO YOU
MEASURE IT AND CROSS OVER AND
THIS IS IMPORTANT.
AND THEN HAVING A TOOL NOW
AVAILABLE FOR TREATMENT AND
DEVELOPMENT.
THE QUESTION I HAVE IS ALL THE
DATA THAT YOU COLLECTED ARE
MULTI-FACETED RESPONSE AND OTHER
THINGS SO HOW DO YOU THINK THIS
REPOSITORY WILL BE USED AND
ACCESSED BY INVESTIGATORS USING
THE POOL OF SAMPLES TO ANALYZE
CLINICAL DATA, BIG DATA, THE
DATA THAT EXISTS AND TRYING TO
UNDERSTAND AND TAKE ARE LEADS TO
NEXT GEN OF VACCINE DEVELOPMENT
POTENTIALLY FOR CANCER VACCINE
AND WHAT ARE THE STRATEGIES
BECAUSE WE ALREADY EXPANDED A
LOT.
AT LEAST WHAT ARE THE TOOL SETS
CDC MAY NOT HAVE BUT YOU HAVE
ORGANIZED?
SO LESSONS LEARNED CAN BE
APPLIED TO MULTIPLE DISEASES AND
SOME INCLUDE PEOPLE WITH LUPUS
HAVE IMMUNE RESPONSES THAT MAY
NOT RESPOND TO COVID FOR EXAMPLE
AND THAT COULD BE A FUNDAMENTAL
UNDERSTANDING THAT I THINK WE'RE
IN A POSITION TO HELP.
>> SO, IN TERMS OF THE BIO
SPECIMENS THAT WERE ORIGINALLY
COLLECTED BOTH FOR THE SEROLOGY
LAB AND IT FOR THE SERONET
INVESTIGATORS BUT NOW THAT WE'RE
COMING TO THE END OF SERONET
WE'LL BE MAKING THE BIO
SPECIMENS STANDARDS AVAILABLE TO
THE GENERAL COMMUNITY.
PEOPLE INTERESTED IN THAT SHOULD
LET US KNOW ALICIA DO YOU WANT
TO RESPOND TO THE REST OF THE
QUESTION.
>> I THINK IT'S A GOLD MINE OF
SPECIMENS AND OUR GOAL AS
DR. SINGER WAS SAYING IS MAKING
IT AVAILABLE TO THE OUTSIDE.
WE HAVE BEEN IN COMMUNICATIONS
CREATING A COMMUNICATION PLAN TO
MAKE THAT HAPPEN IN THE UPCOMING
FEW MONTHS SO THAT'S REALLY
WONDERFUL AND THEN IN TERMS OF
EVEN UTILIZING FOR OTHER
TECHNOLOGIES AND REALLY FOR
ADVANCING SCIENCE AND HYPOTHESIS
GENERATING, WE HAVE A STUDY WE
JUST DID USING THE TECHNOLOGY
FOR PROTEOMICS TO SIGH IF WE CAN
COME UP WITH SOME MARKERS
PREDICTIVE OF FAILURE OR SUCCESS
TO VACCINATION AND WE ARE
ANALYZING AND SUBMITTING THE
MANUSCRIPT NOW BUT THERE WILL BE
OPPORTUNITIES FOR USING PDMCs
FOR GENERATION OF MONOCLONAL
ANTIBODIES AND THERE COULD BE
UTILIZATION OF DIFFERENT
TECHNOLOGIES.
I THINK THIS WILL BE WONDERFUL
TO UTILIZE.
AGAIN, WE HAVE SPECIMENS FROM
PHASES THAT WE'LL NEVER HAVE
AGAIN.
EARLY ON IN THE PANDEMIC
INFECTED INDIVIDUALS AND
INDIVIDUALS WITH DIFFERENT
VACCINES THAT WERE APPROVED AND
DIFFERENT TIMES OF THE MONOAND
BIVALENT.
IT'S WHAT WE PLAN TO LEVERAGE.
>> I WAS THINKING AN ORGANIZED
WAY TO MANAGE AND HELP
FACILITATE THAT OPPOSED TO ONE
OFF.
THAT WOULD BE HELPFUL.
>> THAT'S AN EXCELLENT
SUGGESTION.
I THINK SOMETHING WE'LL TALK
ABOUT HOW DO WE HAVE A
COORDINATED EFFORT BEYOND
SERONET.
>> THANK YOU.
>> THANKS VERY MUCH.
I'M SORRY AS CHAIR I ALWAYS TRY
TO BE PROMPT AND IT'S ALMOST 10
MINUTES AFTER 4:00 BUT I THINK
IT WAS WORTH IT BECAUSE THESE
WERE INTRIGUING PRESENTATIONS
GENERATED A LOT OF INTEREST.
EVERY TIME WE HEAR ABOUT THIS IT
GENERATES INTEREST.
THANK YOU VERY MUCH.
REALLY OUTSTANDING.
I THINK WE'RE AT THE END OF OUR
AGENDA.
CAN I HAVE A MOTION TO ADJOURN?
>> SECOND?
ALL IN FAVOR.
THANK YOU VERY MUCH EVERYBODY.
THANK YOU ALL FOR JOINING US AND
FOR THE WONDERFUL CONVERSATION
AND HOPEFULLY WE'LL ALL SEE EACH
OTHER AT OUR NEXT MEETING.
>> THANK YOU.