>>IT'S MY PLEASURE TO WELCOME
YOU.
I'M THE DIRECTOR OF THE DIVISION
OF ALLERGY AND TRANSPLANTATION
AND I'M VERY MUCH LOOKING
FORWARD TO THIS AFTERNOON'S
SESSION.
WE HAVE TOPICS ON SCIENTIFIC AND
CLINICAL UNDERSTANDING OF THE
ROLE OF HLA AS A DETERMINANT OF
OUTCOMES IS TRULY EVOLVING AND
MUCH THROUGH THE WORK OF THIS
AFTERNOON'S SPEAKERS.
I'M GOING TO LEAVE IT TO NANCY
BRIDGES WHO IS THE
TRANSPLANTATION BRANCH CHIEF FOR
INTRODUCTION OF SPEAKERS AND
COMMENTS ON THE TOPIC IN
GENERAL.
AFTER THESE TALKS WE'LL HAVE
COUNCIL CONSIDERATIONS FOR THE
FIVE FISCAL 2025 CONCEPT
CLEARANCES.
AS USUAL WE NEED YOUR INPUT ON
THOSE AND YOUR RECOMMENDATIONS
IN THAT DIRECTION AND THANK YOU,
NANCY FOR PULLING TOGETHER A
TERRIFIC SESSION AND WE'LL GO
FROM THERE.
OKAY, CAN I HAVE MY FIRST SLIDE,
PLEASE.
>> AND SECOND, THIS MAY SOUND
COUNTER INTUITIVE BUT ANYBODY ON
BY ZOOM PLEASE DO NOT PUT ANY
COMMENTS IN THE CHAT BOX BECAUSE
THAT WILL GENERATE A BACKUP
REQUIREMENT FOR THIS MEETING
WHICH IS NOT WHAT WE WANT.
>> GOOD AFTERNOON.
THIS AFTERNOON'S TOPIC FOR OUR
SPEAKERS IS HLA AND ALOE
TRANSPLANTATION OUR EVOLVING
UNDERSTANDING.
AND PROBABLY EVERYBODY IN THE
ROOM KNOWS THAT HLA IS A TOPIC
THAT CAN BE MADE AS COMPLICATED
AS YOU WOULD WISH TO MAKE IT.
OUR PERSPECTIVE FOR THIS
AFTERN
AFTERNOON'S TALK IS SPECIFICALLY
HOW TRANSPLANTERS THINK OF HLA
AND HOW OUR INFORMAUNDERSTANDIN
HAS EVOLVED OVER TIME.
SO DIFFERENCES IN HLA BETWEEN
DONOR AND RECIPIENT ARE THE
DETERMINATE AND THEY DETERMINE
THE LIKELIHOOD OF GRAPH ACC
ACCEPTANCE AND ANTI-TUMOR
ACTIVITY.
PERFECT MATCHING WOULD BE THE
IDEAL FOR ANY ORGAN TRANSPLANT.
IT ONLY OCCURS AMONG IDENTICAL
BIRTHS EVEN THOSE SAID TO BE HLA
IDENTICAL ARE NOT COMPLETELY
IDENTICAL UNLESS THEY'RE
IDENTICAL TWINS ETCETERA AND FOR
ORGANS AND LIVERS IT'S NOT
POSSIBLE TO WAIT FOR A BETTER
MATCH.
PEOPLE WAITING FOR THOSE ORGAN
DYING AND WE TAKE USUALLY AN
ORGAN PHYSIOLOGICALLY
APPROPRIATE AND DON'T WORRY TOO
MUCH ABOUT HLA MATCHING.
SO OUR VIEW OF HLA HAS REALLY
CHANGED QUITE A BIT FROM THE
1950s WHEN PEOPLE FIRST STARTED
TALKING ABOUT HLA IN ANY
CLINICAL WAY.
THE TYPES WERE DETERMINED S
SEROLOGICALLY LOOKING FOR
ACTIVITY.
SHORTLY AFTER DOING THAT PEOPLE
STARTING RECOGNIZING
CROSS-REACTIVE GROUPS AN
INDICATION THAT MULTIPLE HLA
TYPES HAD SHARED ANTIGENIC SITES
ON THEM.
IT WASN'T ONE ANTIBODY TO ONE
HLA ANTIGEN.
IT WOULD POTENTIALLY REACT TO
MANY DIFFERENT HLA TYPES.
ONCE WE HAD PROTEIN SEQUENCING
AND HIGH RESOLUTION TYPING WE
WERE ABLE TO SEE THE MOLECULAR
BASIS OF REACTIVITY AND TWO
IDEAS GREW.
EPITOPES WERE DEFINED AS
POLYMORPHIC CLUSTERS IN THE
MOLECULE FOR BINDING AND THERE
WAS AN EPLETS TRIGGER'
FUNCTIONAL ANTIBODY RESPONSE.
IT'S BECOME CLEAR THE
IMMUNOGENICITY OF THESE
ANTIGENIC SITES ARE INFLUENCED
BY THE MOLECULAR MILIEU AND NOT
ANTIGENIC SITES ARE CREATED
EQUAL.
THESE IDEAS ARE ALREADY
INFLUENCING HOW WE CLINICAL
TRANSPLANTATION.
AND THAT'S WHAT YOU WILL BE
HEARING ABOUT TODAY.
SOME QUESTIONS ARE MOLECULAR OR
GROUPS OF MISS MATCHES MORE
IMPORTANT THAN OTHERS IN CORP
RATING THIS INTO DECISION MAKING
IMPACTS THE EFFICIENCY OF ORGAN
ALLOCATION, THE EQUITY AND
OUTCOMES OF ORGAN ALLOCATION AND
ORGAN TRANSPLANTATION.
AND CAN KNOWLEDGE OF MOLECULAR
MATCHING OR MISMATCHING BE USED
AFTER TRANSPLANT TO GUIDE
IMMUNOEXPRESSION AND PREDICT THE
DEVELOPMENTMENT OF ANTI-HLAA
ANTIBODIES, REJECTION, GVHD OR
ENGRAFTMENT AND WILL THEY
PREDICT RESPONSE TO TOLEROGENIC
RESPONSES AFTER.
WE HAVE THREE SPEAKERS
ADDRESSING SOME OF THESE TOPICS.
DR. ANNETTE JACKSON OF DUKE
UNIVERSITY FROM CLINICAL
TRANSPLANTATION AND IMMUNOLOGY
AT DUKE AND DIRECTOR OF THE
CLINICAL TRANSPLANTATION
IMMUNOLOGY LIBRARY.
SHE'LL BE TALKING ABOUT THE
IMPORTANCE OF ANTIBODIES IN
TRANSPLANTATION.
DR. EFFIE PETERSDORF IS THE
ENDOWED CHAIR AT THE FRED HUTCH
INSON CANCER CENTER AND TALKING
ABOUT CREATION AND
IMPLEMENTATION OF TOOLS TO
INFORM RISK ASSESSMENT PRE AND
ALLOGENEIC TRANSPLANTATION AND
ROBERT MONT GRI WILL TALK ABOUT
CLINICAL TRIALS OF INTERVENTIONS
TO MITIGATE THE CONSEQUENCES OF
ANTI-HLA ANTIBODIES
DESENSITIZATION, TREATMENT AND
AMR AND PATIENT SELECTION
STRATEGIES.
I THINK BY THE END OF THESE
THREE TALKS YOU'LL HAVE A PRETTY
GOOD IDEA OF THE STATE OF THE
SCIENCE, THE STATE OF CLINICAL
PRACTICE AND WHERE WE NEED TO GO
NEXT.
WITHOUT FURTHER ADO,
DR. JACKSON.
>> THANK YOU FOR THE INVITATION
TO SPEAK TODAY.
SO NANCY TOLD ME THIS WAS GOING
TO BE A DIVERSE AUDIENCE AND I
KNEW I WAS SPEAKING AFTER LUNCH
AND WE HLA PEOPLE CAN GET IN THE
WEEDS AND I TRIED TO KEEP THIS
AT A 30,000 FOOT LEVEL TO TALK
ABOUT THE ROLE OF HLA IN
CLINICAL TRANSPLANTATION.
I WOULD LIKE TO BEGIN BECAUSE
I'LL TALK ABOUT BARRIERS TO
TRANSPLANTATION BUT IN 2021 WE
CELEBRATED ONE MILLION IMPLANTS
AND WE IMPACTED THE PATIENTS,
FAMILIES, SPOUSES, PARENTS AND
FRIENDS.
WE CAN BE PROUD OF THIS.
THERE'S A LOT OF WORK TO BE
DONE.
THERE'S OVER 100,000 PATIENTS ON
THE TRANSPLANT WAITING LIST MANY
WITH END STAGE KIDNEY FAILURE.
AND THIS LIST IS GROWING AS YOU
ARE WELL AWARE WITH A GROWING
PROBLEM OF OBESITY AND DIABETES,
CARDIOVASCULAR DISEASE AND LUNG
DISEASE.
SO IT'S VERY IMPORTANT THAT WE
DISCUSS THE BARRIERS TO
TRANSPLANTATION.
SO ONE OBVIOUS BARRIER IS ORGAN
SHORTAGE DESPITE EFFORTS TO
INCREASE THE DONOR POOL.
THERE'S ABO BLOOD GROUP BARRIERS
THAT MARGINALIZE CERTAIN ETHNIC
POPULATIONS THAT HAVE
PARTICULARLY DIFFERENT BLOOD
GROUP FREQUENCIES AND HLA
ANTIBODIES AS BARRIERS.
FOR THOSE NOT FAMILIAR WITH HLA
IT'S ANALOGOUS TO ABO THE RED
BLOOD ANTIGEN AND IT'S NUCLEATED
CELLS AND WHEN PEOPLE ARE
EXPOSED TO THEM THEY CAN DEVELOP
ANTIBODIES.
HLA IS DIVERSE.
THERE'S CURRENTLY OVER 30,000
GENE VARIANTS ACROSS THE HLA
GENES AS OUR METHODS FOR TYPING
BECAME BETTER AND BETTER EVERY
DAY WE'RE DISCOVERING NEW HLA
TYPES.
IT CONTINUES TO AMAZE US.
SO AS NANCY MENTIONED, MATCHING
HLA MOLECULES IS VERY DIFFICULT
AND NOT VERY PRACTICAL IN
TRANSPLANTATION.
THUS THE DIVERSITY BETWEEN
INDIVIDUALS AND WITHIN US WE
HAVE DIFFERENT HLA MOLECULES.
EACH OF US HAVE HLA 1, ABC AND
CLASS 2 MOLECULES.
EACH PLAYING A DIFFERENT ROLE IN
SAMPLING DIFFERENT COMPARTMENTS.
SO THIS IS A SIDE IMAGE OF AN
HLA MOLECULE.
YOU'LL NOTICE AT THE TOP THERE'S
A POCKET OR CLEFT INTO WHICH YOU
SEE A RED LINEAR STRUCTURE.
THIS IS A SMALL PROTEIN OR
PEPTIDE BEING PRESENTED BY HLA
TO THE ADAPTIVE IMMUNE SYSTEM.
SO T CELLS PROBE THIS ANTIGEN
PRESENTED BY HLA TO DETERMINE
WHETHER IT'S FRIEND OR FOE.
AND THIS DIVERSITY IN HLA GENES
WITHIN OURSELVES AND BETWEEN
OURSELVES ALLOWS A TREMENDOUS
VARIETY OF PEPTIDES AND IT'S A
WAY OF THE HUMAN SPECIES TO STAY
AHEAD OF EVOLVING PATHOGEN.
OUR ROLE IN THE HLA LABORATORY
IS TO LOOK AT GENOTYPING AND
PAIRS AND SURVEY PATIENT SERA
FOR THE PRESENCE OF HLA
ANTIBODIES AT TIME OF BEING
LISTED ON THE ORGAN WAIT LIST
AND POST TRANSPLANT BECAUSE THE
ANTIBODY TO THE DONOR IS
ASSOCIATED WITH REJECTION AND
POOR OUTCOME.
WE HAVE TO DECIDE IF THE HLA
ANTIBODY PRESENT AND IF SO WE
HAVE TO RISK ASSESS.
IS THIS AN ANTIBODY WHERE OUR
SURGERY TEAM CAN DO ACROSS IS
THIS AN INJURIOUS ANTIBODY AND
ALL IN A SPECIFIC CONTEXT
MANNER.
SO THE DEVELOPMENT OF LUMINEX
BEAD PLATFORMS WAS A BOON TO THE
HLA LABORATORY.
AS MENTIONED THERE ARE TENS OF
THOUSANDS OF HLA VARIANTS.
THE LUMINEX ALLOWS US TO TEST A
DROP OF SERUM ACROSS PROTEINS.
THE PLATFORM IS A SET OF BEADS,
100 OR 500 SET IN WHICH EACH
BEAD IS INFUSED WITH TWO
DIFFERENT RATIOS OF RED
FLUORESCENT DIE SO EACH BEAD HAS
ITS UNIQUE FOOTPRINT AND
INCUBATE THESE BEADS WITH A DROP
OF PATIENT SIERRA AND CAN
DETERMINE IF IT MAKES AN
ANTIBODY TO A PARTICULAR
MOLECULE.
THEY'RE PASSED THROUGH AN
INSTRUMENT TO DETERMINE WHAT
BEAD IS PASSING BY COATED WITH
HLA 1, FOR INSTANCE, THE SECOND
LASER DETERMINES IF THERE'S AN
ANTIBODY BOUND TO THE BEAD.
THROUGH THE LARGE BEAD SETS WE
CAN DO A DEEP INTERROGATION OF
WHAT ANTIBODY PATIENTS ARE
FORMING AND WHAT EPITOPES
THEY'RE REACTING TO.
SO THE NEXT SLIDE IS A READ OUT
FROM THESE ASSAYS AND ON THE Y
AXIS IS A FLUORESCENT INTENSITY
WHICH IS SEMI PROPORTIONAL TO
THE AMOUNT OF ANTIBODY IN THE
SERA AND THERE'S BEADS AND THIS
IS A 100 BEAD SET AND THE HLA
MOLECULES CODED ON THE BEAD.
EVEN WOULD TRAINING ALL OF YOU
CAN SEE THIS PATIENT IN FACT
MAKES HIGHER LEVEL MMFI ANTIBODY
MOLECULES WITH LOWER REACTIVITY
TO THE THESE MOLECULES HERE.
AS NANCY ALLUDED TO WHEN WE
ANALYZE HLA ANTIBODY WE'RE
LOOKING AT UNDILUTED SERA WHICH
POSES PROBLEMS AND THERE ARE
SEROLOGICAL TESTS AND TITERS ARE
DILUTED AND WE HAVE THE
BACKGROUND ACTIVITY IN THE SERA.
SO WE USE PATTERN ANALYSIS TO
MAKE SURE WE'RE CALLING REAL
ANTIBODY AND NOT DELVING INTO
BACKGROUND.
THE CIRCLED TOP LINE WITH THE
DR479 AND 1 ARE PART OF THE SAME
CROSS-KRAEKTIVE GROUP.
THEY EVOLVE FROM ONE ANOTHER AND
THEREFORE SHARE IMMUNODOMINANT
EPITOPES.
SO WE CONVEY THE ANTIBODIES TO
BOTH THE PATIENTS AND THE
CLINICIANS THROUGH SOMETHING
CALLED PANEL REACTIVE ANTIBODY.
THIS IS A THROW BACK TO THE DAYS
WHEN WE USED TO DO CELL PANELS
TO DETECT HLA ANTIBODIES.
NOW WE USE OUR BEAD PANELS AND
USE THE ALLELE FREQUENCY IN OUR
DECEASED DONOR POPULATION TO
COUNT THE FREQUENCY IN WHICH
THIS ANTIGEN EXISTS IN THE DONOR
POOL.
IN THE PATIENT ON THE PREVIOUS
SLIDE HAS MULTIPLE DQ AND AL
ALLELES AND DR AND THIS WOULD
HAVE A CPRA OF 89% OUT OF EVERY
100 DECEASED DONOR OFFERS.
IMMEDIATELY THIS PATIENT RULES
OUT 90% OF DONORS.
THIS IS THE SCOPE OF THE
PROBLEM.
30% OF THE SENSITIZED PATIENTS
ARE IN THE HIGHLY SENSITIZED
CATEGORY WITH A CPRA OF GREATER
THAN 80%.
THERE'S BEEN A GROWTH IN THE
NUMBER OF HLA SENSITIZED
PATIENTS IN PART DUE TO OUR
DIAGNOSTICS AND TRANSPLANTATION
OF KIDNEY, HEART AND LUNG AND
DEVICES AND STRATEGIES TO BRIDGE
PATIENTS TO TRANSPLANT SUCH AS
IMPLANTING LEFT VENTRICULAR
ASSIST DEVICES WHERE THEY GET A
LOT OF BLOOD TRANSFUSIONS.
SO AS WITH YOU SPOKEN BRIEFLY
THIS MORNING, HOW DO WE
CIRCUMVENT HLA ANTIBODIES WE CAN
DO A KIDNEY PAIR DONATION WHERE
WE SWAP DONORS BETWEEN
RECIPIENTS.
THE INSTITUTION OF KPD IN THE
U.S. AND I WOULD SAY THE
LEGALIZATION OF KPD WAS REALLY
BROUGHT FOURTH BY THE LEADERSHIP
OF DR. MONTGOMERY TO MAKE IT A
VIABLE MODALITY.
PRIOR TO 2007 IT WAS ACTUALLY
ILLEGAL TO SWAP LIVING DONOR
KIDNEYS BECAUSE IT WAS ILLEGAL
TO BUY OR BARTER FOR ORGANS SO
IT HAS TO BE SHOWN TO BE ETHICAL
AND ABLE TO BE DONE
LOGISTICALLY.
FOR PATIENTS WITHOUT A LIVE
DONOR, THEY'RE GOING TO WAIT ON
THE DECEASED DONOR KIDNEY LIST.
IN 2014 BUT STARTING MANY YEARS
PRIOR, A NEW EFFORT WAS MADE IN
THE DECEASED DONOR KIDNEY
ALLOCATION SYSTEM TO PROVIDE
MORE EQUITY TO THE POPULATION.
PARTICULARLY THE HLA SENSITIZED
PATIENTS WHO WERE TRANSPLANTED
AT VERY LOW RATES AND HAD A VERY
HIGH MORTALITY ON THE WAIT LIST.
AND WE GAVE THEM EXTRA
ALLOCATION POINTS DEPENDING ON
THEIR CPRA.
THE HIGHER THE CPRA THE MORE
POINTS AND BUMPED THEM TO THE
TOP OF THE LIST.
ANOTHER POINT THAT WAS EQUALLY
AS CRITICAL WAS THE IDEA THAT
ORGANS BECAUSE THEY'RE OF SHORT
SUPPLY SHOULD BE CONSIDERED A
NATIONAL RESOURCE SO IF WE
PROCURE AN ORGAN OR KIDNEY AT
DUKE, IT'S NOT DUKE'S KIDNEY TO
GO TO DUKE'S PATIENT BUT SHARED
TO ACHIEVE THE MOST EQUITABLE
AND LIFE-SAVING USE OF THAT
KIDNEY.
REGIONAL AND NATIONAL ORGAN
SHARING WAS MANDATED.
IT WAS LAUNCHED IN 2014 AND THE
HIGHLY SENSITIZED PATIENT THE
BROWN LINE WENT UP DRAMATICALLY
AND THAT YEAR WE GOT A LOT OF
SENSITIZED PATIENTS TRANSPLANTED
AND WE OPENED UP THE DONOR POOL
SO THEY COULD FIND THEIR NEEDLE
IN THE HAYSTACK AND WE
TRANSPLANTED A LOT OF PATIENTS.
HOWEVER, MORE DETAILED ANALYSIS
OF THE DATA HAS SHOWN US THAT
THERE ARE STILL THE MOST HIGHLY
SENSITIZED THE 99.9% THAT ARE
STILL DISADVANTAGED AND NOT
RECEIVING DONOR OFFERS.
THE OTHER LIMITING FACTOR IN
CLINICAL TRANSPLANTATION IS THE
LIMITED ORGAN SURVIVAL TIME.
I LIFTED THIS FIGURE OUT OF A
MEDICAL JOURNAL OF ECONOMICS
REVIEW AND IT SHOWS THE LIFE
SPAN OF TRANSPLANTED ORGANS IN
THE U.S. AND I INSERTED THE
DOTTED RED LINE TO SHOW THE HALF
LIFE OF THESE ORGANS.
FOR KIDNEY, LIVER AND HEART THE
HALF LIFE IS ABOUT 15 YEARS.
MUCH SHORTER FOR LUNG DOWN
TOWARDS LIKE 7 YEARS HALF LIFE.
THIS LOSS OF ORGANS IS DUE TOALO
GRAPH REJECTION AND IT'S A
FOREIGN INVADER.
SO I'M GOING TO RUN THROUGH AND
THIS IS WHERE I'M STILL TAKING
THIS VERY HIGH 30,000 FOOT VIEW
BUT THIS PORTION OF THE TALK I
GIVE TO TRANSPLANT FELLOWS TO
TRY TO MAKE THEM THINK HARDER OF
IMMUNOLOGY IN THE TRANSPLANT
CLINIC.
SO REJECTION BEGINS WITH
ACTIVATION OF HLA SPECIFIC T
CELLS.
MANY MAY KNOW YOUR T CELLS ARE
POSITIVELY SELECTED ON HLA
MOLECULES SO YOU'RE T CELL
REPERTOIRE HAS BEEN SELECTED TO
BIND HLA WELL.
THIS DOES NOT BODE WELL WHEN
YOU'RE TRYING TO HIDE AN HLA
MISS MATCH ORGAN IN A TRANSPLANT
PATIENT.
IT'S ESTIMATED UP TO 10% OF YOUR
T CELL REPERTOIRE WILL RECOGNIZE
AND BE ABLE TO BIND AND BECOME
ACTIVATED TO FOREIGN HLA THROUGH
THE DIRECT PATHWAY BY DIRECTLY
RECOGNIZING OR THROUGH THE
INDIRECT PATHWAY WHEN IT'S
CHOPPED INTO THE LITTLE RED
PEPTIDES LOADED IN THE
RECIPIENT'S HLA.
HLA IS AN INCREDIBLY ABUNDANT
ANTIGEN EXPRESSED AT A HIGH
LEVEL ON ALL NUCLEATED CELLS AND
A BIG BOLUS OF ANTIGEN WHEN WE
PUT IN THE ORGAN AND IT'S
EXTREMELY IMMUNOGENIC.
TRYING TO KEEP A T CELL FROM
BEING ACTIVATED BY FOREIGN HLA
IS ACTUALLY BEYOND REALITY.
SO OUR PATIENT WITHSTAND LIFE
LONG IMMUNOSUPPRESSION AND IT'S
VERY MUCH TARGETED TO SUPPRESS T
CELL ACTIVATION NOT B CELL BUT
JUST T CELL ACTIVATION.
AND IF WE'RE SUCCESSFUL AND SOME
T CELLS BECOME ACTIVATED AND
SLIP THROUGH THEY'LL LOOK FOR
THEIR COGNATE B CELL BECAUSE
THEY'LL ALSO RECOGNIZE FOREIGN
HLA AND BRING IT IN TO THEIR B
CELL RECEPTOR, PROCESS AND WHEN
WE GET THE HLA SPECIFIC T CELL
AND B CELL WE CAN CREATE GER
GERMINAL CENTERS WHICH CREATE
ANTIBODIES AND PLASMA CELLS ARE
A VERY INTERESTING AREA OF
SCIENCE RIGHT NOW.
WE'RE COLLABORATING WITH EMORY
TO REALLY UNDERSTAND PLASMA CELL
SUBSETS AND NICHES.
THEY'RE LONG LIVED ONES THEY WE
TREAT THEM WITH INHIBITOR AND
DEPLETING ANTIBODIES CB38 AND
STILL THESE SURVIVE OR PART OF
THEM SURVIVE.
SO EVOLUTION HAS DONE A GOOD JOB
AT TUCKING AWAY PLASMA CELLS AND
MAKING THEM SURVIVE FOR THE LONG
HAUL BUT ONCE IT OCCURS AND WE
GET PLASMA CELLS IN THE
TRANSPLANT ARENA WE ARE HELD
HOSTAGE AND DON'T HAVE CURRENT
THERAPEUTICS TO FIGHT THE HLA
ANTIBODIES.
SO IF AN IMAGE IS WORTH A
THOUSAND WORDS A VIDEO WOULD BE
WORTH A THOUSAND IMAGES.
IF YOU GO AHEAD AND START THE
VIDEO -- THIS IS REALLY A MOVIE
CREATED BY MARK JENKINS AT
UNIVERSITY OF MINNESOTA AND
SIMULATES THE FIRST 50 HOURS OF
THE IMMUNE RESPONSE.
I USE THIS IN MY TEACHING
LECTURES WITH THE TRANSPLANT
FELLOWS BECAUSE I WANT TO GET A
FEW POINTS ACROSS.
WE START HERE --
>> DOWN HERE IS THE T CELL AND
THESE PURPLE ARE COATED WITH HLA
PRESENTING TO T CELLS WHICH ARE
MONITORING AND PROBING.
THIS IS TO WAKE EVERYBODY UP.
WELL, IT'S SPECTACULAR.
I ENCOURAGE TO LOOK AT THE
VIDEO.
IT'S NOT A TRANSPLANT BUT
INJECTING INTO A LIVE MOUSE AND
IT SHOWS THE GREEN T CELL WOULD
BE PROBING THESE DENDRITIC CELL
AND YOU GET A CALCIUM FLUX IN
THE T CELL.
AS SOON AS THE T CELL GETS
ACTIVATED IT STARTS DIVIDING AND
YOU SEE THE GREEN CELLS APPEAR
IN FRONT OF YOU AND AS SOON AS
THEY'RE ACTIVATED THEY MOVE
TOWARDS THE B CELL BORDER AND
ACTIVATE THE B CELL AND THERE'S
A WHOLE LOT OF SPARKS TO THEM
WHEN WE GET MAJOR FLEX WITHIN
THE B CELL AND REASON I SHOW
THIS TO THE TRANSPLANT FELLOWS
IS BECAUSE IN CLINICAL
TRANSPLANTATION WE THINK OF T
CELL REJECTION IN ONE CAMP AND B
CELL REJECTION IN ANOTHER CAMP
BUT THEY'RE ALL PART OF AN ANY
ADAPTIVE IMMUNE RESPONSE AND IF
A PATIENT HAS REPEATED T CELL
REJECTIONS HE MAY HAVE ALSO
ACTIVATED B CELLS IN THE PROCESS
AND WE SHOULD BE MONITORING FOR
HLA ANTIBODIES PERHAPS MORE
VIGILANTLY AFTER T CELL
REJECTION.
IT'S MY IDEA TO SHOW THEM IF
THEY IMAGINE THIS VIDEO IS THE
FIRST 50 HOURS AFTER A SIMPLE
ANTIGEN INJECTION, IMAGINE THE
FIRST 50 HOURS IN A TRANSPLANT
PATIENT WHEN THEY GO TO THE
BEACH AND FORGET THEIR MEDS AND
GO FOR 48 HOURS WITH LITERALLY
NO MEDICATION HOW WE CAN GET
BREAKTHROUGH OF ALLO IMMUNE
RESPONSE.
WHY DO WE CARE ABOUT HLA
ANTIBODY PRODUCTION?
THEY'RE ACTIVATORS OF COMPLIMENT
WITH THE TRANSPLANTED ALLO
GRAPH.
THIS IS FROM SCIENCE MAGAZINE IN
2014 WHICH SHOWED YOU HAVE TO
GET CLOSE PROXIMITY AND WHY IS
HLA COMPLEMENT A GOOD ACTIVATOR?
IT'S HIGHLY EXPRESSED ON CELL
SURFACES AND A STRONG
IMMUNOGENIC AND THERE ARE
NUMEROUS EPITOPES AND IT'S EASY
TO GET JUXTAPOSE TO THE SUB
CLASS WHICH ARE EXCELLENT
COMPLEMENT ACTIVATORS.
THIS IS A KIDNEY BIOPSY LOOKING
AT THE SPLIT PRODUCT DEPOSITED
ON THE VASCULAR TISSUE.
YOU CAN SEE THIS TYPE OF
COMPLEMENT ACTIVATION WILL
RESULT IN ALLO GRAPH FAILURE AND
LOSS IF WE DON'T INTERVENE WITH
THERAPEUTICS.
THE BIGGEST FEAR WE HAVE IS THE
ROLE OF HLA ANTIBODY AND
INCREASE ANTIBODY MEDIATED
REJECTION.
THIS IS A SILENT INDULLENT
INJURY THAT LIKELY HAPPENS WHEN
THE HLA TITER IS LOW OR DIRECTED
TOWARD ANTIGENS WITH LOWER
EXPRESSION WHEN THINGS ARE CALM
IN THE ALLO GRAPH.
I THINK OF THIS AKIN TO WOUND
HEALING WHERE YOU HAVE ANTIBODY
BINDING AND SMOOTH MUSCLE CELL
PROLIFERATION YOU GET TRANSPLANT
VASCULEOPATHY AND IN THE KIDNEY
WE GET MEMBRANE DUPLICATION
RESULTING IN A NON-FUNCTIONAL
GLOMERULUS AND WHY IT'S NOT
ACHIEVED ITS LONG-TERM GOAL AND
ANTIBODIES TO THE DQ ARE MOST
STRONGLY ASSOCIATED WITH THIS
REJECTION.
SO THE HLA COMMUNITY IS FOCUSSED
ON HOW CAN WE BE BETTER AT DONOR
SELECTION.
AS NANCY MENTIONED WE'RE LOOKING
AT HLA MOLECULAR MATCHING.
THIS IS AN IMAGE FROM A PAPER BY
CHRIS WEAVE AND PETER NICKERSON
LOOKING AT THEM AT TWO ANTIGEN
BUT WE'RE UNDERSTANDING BETTER
THE PARTICULAR MOTIF THAT ARE
PARTICULARLY IMO GENIC.
IN YELLOW ARE EPETS WE CAN
IDENTIFY AS THE EPICENTER OF
ANTIBODY EPITOPES.
WE'RE ABLE TO DEFINE THEM
THROUGH MOLECULAR TYPING OF THE
DONORS AND ABLE TO CHARACTERIZE
ANTIBODIES THROUGH THESE EPLETS
IN OUR ANALYSIS SOFTWARE.
WHILE WE WON'T BE ABLE TO MATCH
HLA IN RECIPIENT PAIRS BUT WHICH
IS MOST IMMUNOGENIC AND AVOID
THOSE MISMATCHES AS A HAPPY
MEDIUM.
I OFTEN GET ASKED WHAT'S THE
WORSE?
I THINK THAT'S THE MOST OFTEN
ASKED QUESTION AND I SAY IT
TOTALLY DEPENDS ON THE GENOTYPE
OF THE RECIPIENT.
IT'S NOT A SIMPLE THING THIS
AMINO ACID IS PARTICULARLY
IMMUNOGENIC.
IT DEPENDS ON THE PATIENT TYPE.
EFFIE AND I ARE POOLING DATA
FROM AROUND THE WORLD TO GET
GREATER DIVERSITY AND
UNDERSTANDING OF THE EPLETS AND
THEIR IMMUNOGENICITY.
TO END, KNOWING I WAS SPEAKING
IN A SESSION WITH EFFIE I HAD TO
SLIP IN A SLIDE ON STEM CELL
TRANSPLANTATION AND THE ROLE OF
ANTIBODIES IN STEM CELL
TRANSPLANTATION AS THE GROWTH IN
THE NUMBER OF HLA MISMATCH
TRANSPLANTS HAPPEN WE ARE
UNDERSTANDING THE ROLE OF HLA
ANTIBODIES.
THIS IS DATA WHEN I WAS AT JOHNS
HOPKINS SHOWING ON THE FAR RIGHT
APPROXIMATELY ALL CANDIDATES
ABOUT 14% HAD DONOR-SPECIFIC HLA
DONOR BODIES TO THEIR INTENDED
STEM CELL DONOR.
THIS WAS HIGHER IN FEMALES AND
HIGHER YET IN MULTI-PAIR
FEMALES.
THE MISS MATCHED STEM CELL
TRANSPLANT GREG AS ARE CELLULAR
THERAPIES AND TREGS ARE BEING
USED AND GROWING EXPEDITIOUSLY
BUT ALLO OFF THE SHELF THERAPIES
ARE ALSO GROWING IN INTEREST NOT
ONLY FOR ONCOLOGY BUT IN
AUTOIMMUNITY AND INFECTIOUS
DISEASE.
AS WE LOOK AT THE HLA DIVERSITY
ESPECIALLY IN OUR NON-WHITE
PATIENTS IT'S IMPORTANT TO
REMEMBER HLA ANTIBODIES DO PLAY
A ROLE IN THE EFFICIENCY AND
EFFICACY OF THESE THERAPIES.
THEY'RE ASSOCIATED WITH REDUCED
STEM CELL ENGRAFTMENT AND
ANTIBODY TESTING IS CENTRAL IN
THE SETTING OF THERAPIES AND I'D
LIKE TO THANK THE RESEARCH GROUP
AT DUKE AND MY HLA LAB.
THANK YOU VERY MUCH.
>> TWO QUESTIONS.
ONE, WHY YOU DON'T USE DILUTED
SERUM AND TWO, IF THERE'S ANY
REASON TO THINK A SHARED EPLET
BETWEEN DONOR AND RECIPIENT CAN
TRIGGER A TOLEROGENIC RESPONSE.
>> A SHARED EPITOPE BETWEEN
RECIPIENT AND DONOR?
THERE'S A LOT OF SHARED EPITOPES
BETWEEN THEM.
HLA EVOLVED FROM GENE
DUPLICATION AND CONVERSION SO
RECIPIENT AND DONOR SHARE AN
ENORMOUS AMOUNT OF AMINO ACID
LINKS.
OUR SYSTEM CAN DETECT --
>> THAT PROBABLY OUTWEIGHS ANY
MATCHING EFFECT.
AND WHY DON'T WE DILUTE, WE DO,
THE LUMINEX ASSAYS MAX OUT
EASILY AND WE DETERMINE THE
TITER OF HLA ANTIBODIES BUT
ANTIBODY DETECTED ARE KNOWN TO
HAVE DETRIMENTAL AFFECTS AT THE
TIME OF TRANSPLANT AND THOSE
DETECTED OVER 5,000 TO 5
CORRELATE TO A POSITIVE
CROSS-MATCH IS A
CONTRAINDICATION TO TRANSPLANT
WITHOUT ADDITIONAL AUGMENTED
IMMUNOEXPRESSION.
IT'S TEDETECTED AT LOW LEVEL AR
USED WITH LOW SERUM BUT IT'S A
PAIN.
>> HAVE A QUESTION ABOUT THE
PLASMA CELL.
FIRST, DO YOU KNOW IF THERE'S A
DIFFERENCE BETWEEN LONG LIVED
AND SHORT LIVED PLASMA CELL IN
THIS PROCESS?
AND MY SECOND QUESTION IS YOU
MENTIONED CLINICAL TRIALS FOR
DEPLETING CANCER CELLS WOULD IT
BE CONSIDERED TO BE LIFE LONG
WHICH WOULD PROBABLY NOT BE
PRACTICAL BECAUSE A PATIENT
WOULD BE VERY SUSCEPTIBLE TO
INFECTION AND IT'S AT A CRITICAL
TIME IT WOULD BE APPLIED.
>> WHEN WE FIRST START THE
CLINICAL TRIALS I WAS NERVOUS
MAYBE IT WOULD WORK TOO MUCH AND
WE WERE IN THE COVID PANDEMIC
FOR INSTANCE HOWEVER, IT WAS EYE
OPENING HOW RESILIENT THE PLASMA
CELL COMPARTMENT WAS.
WE'RE WORK WITH A BIOLOGIST AT
EMORY AND FINDING HLA ANTIBODIES
RESIDE IN ALL THE PLASMA CELL
SUBSETS LESS MATURE AND MORE
MATURE LONG LIVED AND LOOKING
WITH THE PATHOGEN LUMINEX PANEL
WHETHER PROTECTED AND HLA
IMMUNITY ARE FOUND IN THE SAME
COMPARTMENTS AND FREQUENCY AND
THAT.
WE HAVEN'T DEPLETED TREMENDOUSLY
THE PLASMA CELL DEPARTMENT.
IT'S QUITE RESILIENT.
THAT'S GOOD FOR OUR SPECIES BUT
WE DON'T HAVE TO GET RID OF ALL
THE PLASMA CELLS JUST KNOCK A
HOLE IN IT AND GET THE 99%
PEOPLE TO EVEN 90% AND THAT
WOULD OPEN UP THE FLOODGATES FOR
THEM.
>> THE OTHER ANSWER TO THAT
QUESTION IS WE KNOW THE IMMUNE
SYSTEM HAS TREMENDOUS AMOUNT OF
DUPLICATION AND I THINK WE SAW
IN COVID T CELLS WERE QUITE
IMPORTANT AND WE'RE HITTING T
CELLS HERE AS WELL BUT IT'S
SURPRISING WHEN YOU USE VERY
EFFECTIVE COMPONENT YOU DON'T
CRIPPLE THAT PATIENT.
THEY STILL SEAL TO BE ABLE TO DO
PRETTY WELL.
>> THERE'S PROBABLY NO AREA IN
OUR DIVISION WHERE WE COUNT ON
PRIMATES AND WONDERING YOU CAN
COMMENT ON THE COMPLEXITIES OF
THE RHESUS AND MHC AND HOW WE
CAN ADDRESS SOME OF THOSE
CHALLENGES AS PRECLINICAL MODELS
FOR THE TOPIC YOU ARE TALKING
ABOUT TODAY.
>> SO THE ADAPT CLINICAL TRIAL
TO BLOCK PLASMA CELL
REPOPULATION WAS BASED ON
NON-HUMAN PRIMATE MODEL.
CERTAINLY NON-HUMAN PRIMATE
ALLOWS US TO USE THERAPEUTICS
THAT WE'RE USING IN HUMAN AND
THEY INFORM US VASTLY OVER MOUSE
MODELS.
YET THEIR MHC IS DIFFERENT.
THEY'RE MISSING SOME OF THE
MOLECULES WE HAVE.
AT LEAST UNLIKE MOUSE STRAINS
WHICH ARE CONGENIC AND HAVE LACK
OF DIVERSITY WITHIN THE MHC
REGION.
AT LEAST THE PRIMATES ARE A BIT
MORE OUTBRED.
SO WHEN WE MISMATCH BETWEEN THE
MONKEYS WE'RE GETTING A MORE
DIVERSE ALLO-IMMUNE RESPONSE.
THEY'RE MORE PERTINENT AND
USEFUL BECAUSE WE CAN USE HUMAN
DRUGS IN THEM WE'RE LOOKING INTO
CORRELATIONS WITH HOMOLOGY.
THERE'S HOMOLOGY BETWEEN HOUSE,
HUMAN AND NON-HUMAN PRIMATE
THAT'S HOW IMPORTANT HLA IS TO
THE ADAPTIVE IMMUNE SYSTEM.
IN FACT, IN SOME OF THE XENO
EXPERIMENTS WHERE THEY PUT A PIG
ORGAN INTO A NON-HUMAN PRIMATE
WE RAN THE SERA AND I SAID
THAT'S A VW6 ANTIBODY AND IT'S A
CRITICAL MOTIF.
IT'S PRESENT IN PIG, PRESENT IN
NON-HUMAN PRIMATE AND PRESENT IN
HUMAN.
SO THERE'S CERTAIN MHC PROTEEF
THAT ARE CRITICAL IN OUR
RESPONSE TO PATHOGENS.
WE ARE NOW LOOKING AT THAT TYPE
OF HOMOLOGY BETWEEN NON-HUMAN
PRIMATE AND HUMAN.
WHETHER IT WILL BE USEFUL IN
DETERMINING IMMUNOGENICITY I
THINK WE'RE BETTER OFF MINING
OUR LUMINEX DATA FOR
UNDERSTANDING IMMUNOGENICITY
WITHIN HUMANS.
YOU MENTIONED THE LUMINEX ASSAY
WHICH SOUNDS USEFUL CLINICALLY
AND MENTIONED WHOLE GENOME
SEQUENCING EARLIER DOES THAT ADD
ANYTHING TO THE ANTIBODY BASED
RISK S YOU DO?
>> ABSOLUTELY.
WE DO DEEP SEQUENCING THROUGH
THE HLA GENES TO DEFINE WHAT
EPLETS ARE PRESENT IN THE DONOR
AND LOOK FOR THAT IN THE LUMINEX
ASSAY AND WE HAVE SOFTWARE TO
TELL US THE ANTIBODY HITS ARE
LIKELY DIRECTS AT THESE EPLETS.
UNFORTUNATELY OUR SOFTWARE WE
DON'T KNOW WHAT'S THEORETICAL
AND WHAT IS MEANINGFUL EPLET.
WE'RE WORKING ON TRYING TO DO
MORE MINING OF SERA AND IT'S BIG
DATA.
WE GENERATE 100 DATA POINTS WITH
EVERY SINGLE SERA WE TEST AND WE
TEST 30,000 A YEAR.
IN ONE LAB WE GENERATE A LOT OF
DATA.
WHEN WE COMBINE IT WITH DEEP
SEQUENCING SO THE ALLELE LEVEL
OF THE HLA WE CAN INTERROGATE IT
PRETTY WELL.
WE HAVE THE DATA WE JUST NEED TO
MINE IT.
>> THANK YOU, VERY MUCH, NANCY.
WE'VE HAD A LONG STANDING
INTEREST OF HLA IN BLOOD AND
MARROW TRANSPLANTATION AND I'LL
TAKE A DIFFERENT APPROACH AND
TAKE IT FROM THE GENOMIC
STANDPOINT AND I'LL SHARE WITH
YOU TWO MODELS IN WHICH WE
DEVELOPED TOOLS CURRENTLY BEING
USED BY TRANSPLANT CENTERS
WORLDWIDE.
THE LANDSCAPE UNRYE MARKABLY
OVER THE LAST FOUR --
UNREMARKABLY IN THE BLUE
REPRESENTS MATCH DONORS THE
PREFERRED STEM CELL SOURCES.
AND THAT IS BECAUSE THEY WERE
ASSOCIATED WITH LOW RISK OF
GRAPH REJECTION AND GBHD AND
WITH THE UNRELATED DONOR
REGISTRIES WORLDWIDE YOU SEE THE
ORANGE LINE COME UP HERE WHICH
REPRESENTS UNRELATED DONOR
TRANSPLANTS AND IN 2010 THE
UNRELATED DONOR TRANSPLANT
EXPERIENCE NEARLY ECLIPSED THE
MATCH RELATED TRANSPLANT AND THE
GREEN CURVE WAS MADE POSSIBLE
BECAUSE RESEARCH AND THROUGH
SUPPORTIVE CARE AND PROPHYLAXIS
SO IN 2020 IT ECLIPSED MATCH
RELATED.
NUMBER ONE UNRELATED.
NUMBER TWO [INDISCERNIBLE] AND
THE NEXT SLIDE THE GROWTH OF
UNRELATED DONOR REGISTRIES
SINGULARLY HELPED US ACHIEVE.
THE NEXT SLIDE IS THE WNDA
REGISTERED SUPPORT 1.4 MILLION
REGISTERED UNRELATED DONORS
WORLDWIDE.
A TRUE HUMANITARIAN EFFORT.
THE NEXT SLIDE SHOWS YOU THERE
IS SOMETHING ELSE THAT IS
INCREASING.
THE NUMBER OF HLA ALLELES.
WHEN WE BEGAN THE PROJECT AND WE
STARTED 964 AND ARE TODAY IN THE
MONTH OF JULY, 37,619.
THAT POSES MAJOR ISSUES FOR US
IN TRANSPLANTATION BECAUSE WE
HAVE TO MATCH AS PRECISELY AS WE
POSSIBLY CAN AND TALK FREQUENTLY
ABOUT BLOOD AND MARROW
TRANSPLANTATION.
THE FIRST 02 IS SEROLOGICAL
ANTIGEN SPECIFICITY AND THE
SECOND FIELD SHOWS THE UNIQUE
ALLELE.
YOU'LL HEAR ABOUT NEXT GEN
SEQUENCING WHICH DOES ALLOW US
TO GET TO THE THIRD FIELD AND
THIS NON-CODING REGION
POLYMORPHISMS.
THERE'S PRELIMINARY DATA THAT
SHOW US THERE MIGHT BE BENEFIT
WITH ULTRA HIGH RESOLUTION
TYPING BUT FOR THE TIME BEING
WE'RE STILL AT TWO FIELD.
THE NEXT SLIDE SHOWS YOU WHEN
WE'RE ABLE TO SUCCESSFULLY
IDENTIFY FIVE LOCUS, TEN ALLELE
AND PATIENTS IN THE RED GROUP
ENJOYED SUPERIOR SURVIVAL.
SO WE IN THE IHWG HAVE BEEN
INTERESTING IN UNDERSTANDING
WHEN YOU CAN'T IDENTIFY A MATCH
HOW DO YOU POSSIBLY FIGURE OUT
WHICH MISMATCHES ARE BETTER THAN
OTHERS.
THESE CURVES SHOW THE ADDITIVE
EFFECT OF ONE, TWO, THREE OR
MORE MISMATCHES.
I'LL SHOW DATA OF THE GREEN
CURVE AND SINGLE LOCUS MISS
MATCHES.
BY FAR THE MOST RISKY HLA A AND
B LEADING TO HIGH MORTALITY.
WE WERE VERY INTRIGUED WITH
HLA-B.
AS YOU ALL KNOW IT'S THE MOST
POLYMORPHIC LOCUS IN THE HUMAN
GENOME AND CAUSES MUCH ANGST
WHEN WE TRY TO MATCH SO WE CARRY
OFTEN TWO LOCUS MISS MATCHED
DONORS.
WE WERE INTERESTED IN FOCUSSING
ON HLA-B AND THERE'S TWO MOLE
MODELS TODAY ONE FOR HLA-B AND
WE'RE LEARNING ABOUT NON-CODING
REGION VARIATION AND IN THE LAST
HALF OF THE TALK IN TERMS OF
HLA-DP AND EXPRESSION.
THE NEXT SLIDE GIVES A SENSE OF
THE ORGANIZATION OF HLA-B AND
THE LEADER IS A SHORT AMINO ACID
PEPTIDE ENCODED BY XO1 AND
ESSENTIALLY SHOWS POLYMORPHISM
AT A SINGLE NUCLEOTIDE
POLYMORPHISM THE MINUS 21
POSITION.
THIS SNIP GIVES RISE TO PEPTIDES
AT THE SECOND POSITION.
HLA A AND C ARE INVARIANT AT
THIS PARTICULAR SNIP.
THOUGH THE SNIP RESIDES IT HAS
PROFOUND CONSEQUENCES HOW IT
GETS TO THE SURFACE AND CAN
ENGAGE WITH RECEPTORS.
THE B LOCUS IS THE ONLY ONE THAT
GIVES T LEADERS AND THE TT HOMO
ZYGOTES AND FOR HLA A, B AND C
HAVE LEADERS ASSOCIATED WITH
EXPRESSION.
IN MY LAB WE'RE EXPLORING THE T
CELL BIOLOGY FOR THE LEADER AND
IT'S A STORY FOR ANOTHER DAY.
HLA-B THE MOST POLYMORPHIC GENE
9386 ALLELES.
WE NEEDED TO UNDERSTAND THE
ORGANIZATION OF THESE ALLELES.
IN THE NEXT SLIDE WE LOOKED AT A
THOUSAND NUCLEOTIDES OF CODING
AND DISCOVERED TWO TYPES.
THE FIRST IN BLUE AND THE SECOND
IN RED.
WE ESTIMATE THEY'RE AT LEAST 8
MILLION YEARS OLD ALL THE ALLO
TYPES HERE WE THOUGHT IT WAS A
GREAT OPPORTUNITY TO LEARN AND
WE HYPOTHESIZED IF THE PATIENT
AND DONOR BOTH WERE IN THE T OR
M CLADE THEY'RE CALLED A LEADER
MATCH BECAUSE THEY COME FROM THE
SAME AND LESS MISMATCHES WHERE
ONE CAME FROM THE T AND THE
OTHER CAME FROM THE M.
WE CALL THOSE LEADER MISMATCH.
YOU CAN SEE ONE PIECE OF
INFORMATION WE'RE EXCITED TO SEE
WAS THE NEXT SLIDE THAT ON THE
MATCH TYPE THAT M CLADE WAS
ACTUALLY DRIVING THIS SO IT DID
NOT REQUIRE THE HLA MISMATCHING
TO HAVE AN EFFECT.
IT'S ONE OF THE MODELS WHERE THE
MATCH AND THE MISMATCH HAP
HAPLOTYPES SHOWED THIS OUTCOME
AND THE THIS SHOWS THE STUDY WE
DID 10,000 TRANSPLANTS ALL B
MATCHED SO THE PATIENTS WITH MM
HAS HIGHER FATALITY.
THESE RELATIONSHIPS DO HOLD TRUE
IN MATCH, MISMATCH AND IN THE
FOLLOWING SLIDE WE WERE ABLE TO
CONFIRM THE IMPORTANCE OF THE
LEADER MATCHING WITH HAPLO
IDENTICAL TRANSPLANTATION.
RECEIVING A TRANSPLANT FROM THE
PARENT, CHILD OR SIBLING AND
BARELY MISS MATCH FOR THE OTHER
TYPE.
B MISMATCHES WHO ARE LEADER
MATCH ENJOY SUPERIOR SURVIVAL
COMPARED TO B MISMATCHES THAT
ARE LEADER MISMATCHED IN THE
CURVE.
I'M PARTICULARLY EXCITED BY
THESE DATA BECAUSE UP UNTIL NOW
WE ACTUALLY NEVER HAD ANY
CRITERIA TO BE ABLE TO HELP
CHOOSE BETWEEN A PARENT, A
SIBLING OR A CHILD SO IT'S
REALLY IMPORTANT.
THE NEXT SLIDE SHOWS WHEN YOU
START TO THINK ABOUT TOOLS HOW
WILL YOU GET THE INFORMATION ON
CLADS AND HOW WILL YOU GET THE
INFORMATION IN HAPLO TOGETHER TO
BE ABLE TO INFORM PATIENT RISK
PRIOR TO TRANSPLANT AND HELP
SELECT A BETTER DONOR?
IMAGINE WE HAVE HIGH-RISK TYPING
IN ULTRA HIGH RESOLUTION WE HAVE
TO REDUCE THE TYPE TO A LEADER
MM, TT OR MT IN THE TYPE IN THE
PATIENT AND HAVE TO BE THE SAME
IN THE DONOR.
WHAT THE BIOLOGICAL MODEL HAVE
TOLD US IT'S FAR SUPERIOR TO
SELECT A LEADER MATCH DONOR
OPPOSED TO LEADER MISS MATCHED
DONOR AND YOU'LL SEE IN THE T
CONE PATIENT WHO'S ARE
HETEROZYGOUS HAVE UP TO FOUR
DIFFERENT DONORS BUT THE
PREFERRED DONOR IS THE TOP ONE
WHO IS LEADER MATCHED AND THE
SHARE HAPLO TYPE SHOULD REDUCE
THE RISK.
WE HAD TO THINK ABOUT THE DATA
IN WHICH WE'D BUILD THE
INFERENCE OF SEQUENCE TO THE
ALLELE NAME TO THE GENOTYPE.
THERE ARE TWO SOFTWARE PACKAGES
I'D LIKE TO INVITE YOU TO THE
LEFT SIDE OF THE SCREEN AND
PLEASE TRY OUT THE PROGRAM THAT
WAS DESIGN BY DR. STEVEN MARSH
AND COLLEAGUES AT THE ANTHONY
NOLAN RESEARCH INSTITUTE IN
LONDON I WAS INVOLVED IN THE
TOOL ON THE RIGHT AND WE'LL SHOW
YOU HOW WE BUILT THE TOOL FROM
THE POPULATION-BASED STUDIES.
WE FELT VERY STRONG IF YOU'RE
GOING TO ROLL OUT A TOOL FOR
CLINICAL PRACTICE YOU HAVE TO
HAVE RIGOR AT MULTIPLE LEVELS.
SO THE THREE MAJOR POINTS OF
RIGOR ARE ON TOP WE DEMANDED WE
HAVE TO KNOW THE BREADTH AND THE
EXTENT OF THE HLA-ALLELES AND
THE TOOL HAS TO BE ABLE TO
HANDLE RARE ALLELES AND THE
INFORMATIVE OF DIVERSE RACE AND
ETHNICITIES TO BE IMPACTFUL FOR
ANY PATIENT WHO NEEDS A TRANS
PLANT.
RECOGNIZING LABORATORIES HAVE
DIFFERENT METHODS AVAILABLE TO
THEM, A TOOL HAS TO BE ABLE TO
HANDLE ANYTHING FROM FIRST FIELD
SEROLOGICAL EQUIVALENT TO NEXT
GEN ULTRA, ULTRA HIGH RESOLUTION
TYPING AND OF COURSE IF YOU'RE
TOOL IS USER FRIENDLY IT'S MORE
APT TO BE USED BY PEOPLE.
SO THE NEXT SLIDE SHOWS YOU HOW
WE BUILT THE TOOL IN THE FIRST
BULLET POINT FOR RIGOR IS HOW DO
WE KNOW THE P2 IS ALWAYS GOING
TO BE IN THE BIND WE EXAMINED
NEXT GEN SEQUENCING IN 1.1
MILLION AMERICAN DONORS FROM THE
BE THE MATCH REGISTRY AND FOUND
OVER 99.9% LEADERS EITHER HAD AN
M OR A T.
WE DID SEE POLYMORPHISM AT P2,
OTHER POLYMORPHISMS WE DID SEE
THEM AT SOME OTHER POSITIONS YOU
CAN SEE FROM THE ACCOUNTS
THEY'RE VANISHINGLY SMALL.
THIS REALLY INCREASED OUR
CONFIDENCE THAT IF YOU HAVE A
NEW ALLELE AND A PATIENT WHO IS
REFERRED FOR TRANSPLANTATION,
YOU CAN ALMOST GUARANTEE THE P2
POSITION WAS GOING TO BE
[INDISCERNIBLE].
NEXT SLIDE SHOWS THE RIGOR FOR
ASKING HOW DO YOU KNOW ALL THE
ALLELES WITHIN THE GIVEN ANTIGEN
FAMILY WILL ALWAYS HAVE THE SAME
LEADER?
WE PUT THIS TO THE TEST.
THE QUESTION IS, THESE SEVEN IS
A MEMBER OF THE M CLADE AND DO
ALL SEVEN HAVE ALL -- ALLELES
AND THEY DID NOT HAVE IT AND THE
B27 A MEMBER OF THE T CLADE WE
HAD THUS FAR FOUND ANY EXAMPLE
OF A B27 THAT'S NOT.
THIS ALSO GIVES ONE CONFIDENCE
THAT EVEN IF YOU ONLY HAVE
FIRST-FIELD TYPING AS YOU HAVE
IN KIDNEY AND SOMETIMES SOLID
ORGAN, YOU CAN LITERALLY TAKE
FIRST-FIELD TYPING AND MAP IT
BACK TO THE PARENT ANTIGEN AND
BE SURE HAVE YOU THE P2 CORRECT.
IN THE NEXT SLIDE WE HAVE THE
ALL-IMPORTANT POPULATION STUDIES
THAT SHOWS US THAT IT'S
IMPORTANT TO KNOW
POPULATION-BASED FREQUENCIES.
IN 8 MILLION OF THE U.S. DONORS
WE COLLAPSED THE TYPING AND YOU
CAN SEE PROFOUND DIFFERENCES IN
THE FREQUENCIES OF THESE LEADER
GENOTYPES.
DONORS WHO SELF-DESCRIBE AS
ASIAN OR PACIFIC ISLANDER ARE
MOST OFTEN GOING TO HAVE THE TT
TYPE AND THIS IS IMPORTANT FOR
SPECIALISTS AND CENTERS TO PLAN
YOUR APPROACH TO DO THE DONOR
SEARCH AND WHAT TO MATCH FOR AND
WHAT ARE THE LIKELY GROUPS TO
FIND THAT MATCH.
NEXT SLIDE SHOWS WE HAVE TO HAVE
THE OUTPUT MET AND USER FRIENDLY
NO MATTER THE SETTING OR
CLINICAL TRAINING.
THE OUTPUT IS FROM HLA ALLELE TO
A LEADER TYPE IN THE PATIENT AND
LEADER TYPE IN THE DONOR.
FOR OUR TOOL THE USER CAN ENTER
IN ANY OF THE NUMBER OF DONORS,
ONE OR 10 DONORS.
WHAT THE TOOL DOES IS MAKES
EIGHT PAIRWISE COMPARISON AND
MATCH OR MISS MATCH AND TELLS
YOU IS THE MATCH HAPLO TYPE AN M
OR T AND THE MOST IMPORTANT
OUTPUT, IT RANKS FOR THE USER.
IT TELLS YOU THIS IS THE MOST
FAVORABLE DONOR BECAUSE THEY'RE
LEADER MATCHED AND SHARE THAT T
THEN IF YOU GO DOWN THE RANK
ORDER IT TELLS THE TRANSPLANT
CENTERS TRY IF POSSIBLE TO AVOID
THAT VERY RISKY DONOR.
Q
WE LAUNCH THE TOOL IN 2021.
WE HAVE ABOUT 1800 UNIQUE USERS.
THIS SHOWS THE DAILY USAGE OF
THE PROGRAM AND EVERY TIME WE
HAVE A BIG SPIKE IT CORRELATES
TO A TRAINING PROGRAM WE DID
WHICH TELLS YOU THE IMPORTANCE
OF EDUCATION AND TRAINING.
SO I'M HOPING THAT WHEN WE PLOT
THIS NEXT AFTER TODAY WE WILL
SEE ANOTHER SPIKE, SEPTEMBER OF
2023 SO PLEASE GO TO THE
BLEADER.NMDP.org.
WE'D LIKE KNOW HOW TO IMPROVE
THE TOOL.
THE USERS COME FROM 55 DIFFERENT
COUNTRIES.
WE COLLABORATE WITH THE WORLD
MARROW DONOR ASSOCIATION AND
PROFESSIONAL SOCIETIES TO HAVE
EDUCATIONAL SESSIONS AND
TRAINING PROVIDERS AT ALL STAGES
OF THEIR TRAINING.
THE NEXT SLIDE I'D LIKE TO TURN
TO THE SECOND EXAMPLE IN THE
LAST FEW MINUTES.
HLA DP.
THIS IS A FASCINATING LOCUS AND
NOT WHAT WE EXPECTED.
WE CAN APPRECIATE POLYMORPHISMS
OUTSIDE THE ANTIGEN RECOGNITION
DOMAIN AND THE LEVEL OF
EXPRESSION IS ONE
CHARACTERISTIC.
WHAT MY LAB DID WAS WE WERE VERY
INTERESTED IN DISCOVERING
DETERMINATES WITHIN THE MHC AND
RAN A SEARCH AND DID A COHORT
ANALYSIS AND VALIDATED TWO SNIPS
OUT OF 1,200 SNIPS.
THE NEXT SLIDE SHOWS THE SNIP OF
INTEREST FOR US WAS AN
ASSOCIATION MARKER ON THE RIGHT
SIDE, THE RS2281389.
IF THE PATIENT GENOTYPE WAS
DIFFERENT THAN THE DONOR THAT
WAS ASSOCIATED WITH HIGH RISK OF
ACUTE MARKER AND THE INDEX
MARKER WAS THE RS9277534 IN RED
WHERE THERE WAS 100% LINK.
THE ASSOCIATION MARKER WAS A
TAG.
IN FACT HAPLO TYPES GO ALL THE
WAY IT EXON 2 THAT YEP CODES THE
ALL PERSON PEPTIDE BINDING
GROUP.
WE HYPOTHESIZED IF THE
ASSOCIATION WAS TELLING US
SOMETHING ABOUT SNIP MISS
MATCHING AND WAS 100% LD WITH
HIGH OR LOW EXPRESSION AND IN
ASSOCIATION WITH THE PEPTIDE
BINDING AND THE FIRST ORDER OF
BUSINESS IS TO PROVE HAVE YOU
DIFFERENTIAL EXPRESSION
ACCORDING TO YOUR PROIMRY ETR
SHOWN ON THE RIGHT SIDE.
THE A ALLELE IS ASSOCIATED WITH
LOWER DP EXPRESSION AS MEASURED
BY QUANTITATIVE DPCR AND LED TO
THE HYPOTHESIS THAT SHOWS WHEN
YOU HAVE A MISMATCH IT'S THE'S
MISS MACHINED DP THAT PROVIDES A
VISIBLE TARGET FOR THE RESPONSE
SHOULD BE HIGHER THAN EXPRESSED
AT LOW LEVELS.
WE FOUND RISK OF GBHD ONE FOLD
HIGHER WHEN I THE DP MISS
MISMATCH IS HIGH.
WE VALIDATED THIS IN A VERY
LARGE POPULATION OF UNRELATED
TRANSPLANTS RELATIVE TO LOW
EXPRESSION.
WE NOW QUANTIFIED A 36% HIGHER
RISK OF GBHD FOR HIGH EXPRESSION
MISMATCHES.
THERE ARE OTHER MODELS AND THIS
SHOWS HOW WE RELATE IT.
PATIENTS INHERENT TOO LOW OR ONE
HIGH HAPLO TYPE.
THE FAVORABLE DONOR IS THE
PERSON MISMATCHED FOR ONLY ONE
DP.
WE WANT TO AVOID DOUBLE DP
MISMATCHES.
PATIEN
PATIENTS WE TRIED TO FORGO THE
MISS MATCH AT THE LOW EXPRESSION
AND THAT SHOULD LOWER AND DRIVE
DOWN THE RATES OF GBHD FOR US.
THERE'S ANOTHER MODEL OF
REACTIVITY ON ABBREVIATED CDE
FOCUSSED ON EXON TWO.
THIS HAS THE MODEL AND IT'S
ASKING HOW IT'S IMPACTING PEP
SIDE REPERTOIRE AND RECOGNITION
OF T CELL.
THIS TCE MODEL WAS DEVELOPED AND
USED ALLO REACTIVE CLONES FROM A
PATIENT WHO FAILED TO ENGRAPH
AND IDENTIFIED THREE GROUPS OF
ALLO TYPES THAT HAVE VERY
DIFFERENT ABILITY TO STIMULATE
AND THE TCE PERMISSIVE IS A
MISMATCH FOR THE PATIENTS AND
DONOR MISMATCHES COME FROM THE
SAME GROUP.
TCE NON-PERMISSIVE MISMATCH IS
WHEN THE MISMATCHES COME FROM
DIFFERENT GROUPS.
THE TCE MODEL HAS BEEN AROUND
LONGER AND BEEN USED BY
TRANSPLANT CENTERS TO SELECT
DP MISMATCHED DONORS.
IN THIS SLIDE SHOWS THE WORK WE
AND OTHERS HAVE DONE IN THE
COMMUNITY TO BE ABLE TO
UNDERSTAND HOW YOU JUXTA POSE
THE EXPRESSION MODEL WITH THE
ISOTOPE MODEL.
WITH LOW EXPRESSION MISMATCHES
ARE VERY UNIFORM AND USUALLY TCE
PERMISSIVE, WE HAVE A LOT OF
HETEROGENEITY AMONG
NON-PERMISSIVE.
THE KEY TO THE MODELS IS EXON
THREE.
IT'S BEEN IGNORED FOR A LONG
TIME.
WE COLLABORATED WITH THE GERMAN
REGISTRY DKMS AND THEY SEQUENCED
32,000 GERMAN DONORS
CONSECUTIVELY RECRUIT AND FOUND
A SEVEN-SNIP HAP HAPLO TYPE IN
100% WITH THE LOW AND HIGH
VARIANTS.
THIS ALLOWED US TO USE EXON
THREE TO THE FULL CAPACITY AND
NOT HAVE TO SPECIFICALLY TARGET
THE UTR REGION.
IT SHOWS THE REQUIREMENT IN
PLACE FOR DEVELOPING A TOOL TO
TRANSLATE THE DP EXPRESSION
MODEL TO THE CLINIC.
AGAIN LIKE THE B READER WE
REQUIRED RIGOR IN THREE
DIFFERENT AREAS AND HAD TO
CATALOG LOW AND HIGH EXPRESSION
DP ALLELES.
THE TOOL HAS TO BE PICK UP ON
THE RARE ALLELE AND OF COURSE IT
HAS TO BE INFORMATIVE FOR
INDIVIDUALS OF ALL RACES AND
ON
ETHNICITIES AND WE HAVE SAMPLE
WERE ONLY TYPE FOR EXON 2 USING
PROBES AND LIMITED PANELS OF
PROBES FOR CERTAIN REGIONS ALL
THE WAY TO LABORATORIES USING
NEXT GEN SEQUENCING AND GET EXON
2 TO UTR.
I'LL SHOW YOU IN THE NEXT SLIDE
I'D LIKE YOU TO SHOW YOU THE
TOOL WE CALL EX-PAT.
IT WAS BUILD ON THROW DIFFERENT
COHORTS.
DATA SET 1 WE USED WHOLE GENOME
SEQUENCING FROM UNRELATED DONORS
IN U.S. REGISTRY, PHASED TWO AND
THREE TO LINK THE HYPERVARIABLE
REGIONS TO THE HAPLO TYPE.
DATA SET 2 DONORS IN CORD BLOOD
UNITS TO GET LINKAGE BETWEEN THE
HAPLO TYPE AND THE MARKER AND
FINALLY COHORT 3 TO SIMULATE NEW
DP SEARCH ALGORITHMS.
THE BOTTOM LINE IS EXON THREE
HOLD THE KEY TO UNDERSTANDING
REACTIVITY IN DP.
AFRICAN AMERICANS HAVE THE MOST
DIVERSE SEQUENCES AND ASIAN
AMERICANS HAVE THE LEAST DIVERSE
SEQUENCES.
WHAT EXON 3 PROVIDES A SITUATION
WHERE YOU CAN HAVE A DP MOLECULE
WITH IDENTICAL PEPTIDE BINDING
GROOVE POLYMORPHISMS BUT
SOMETIMES EXPRESSED HIGH AND
SOMETIMES LOW.
THAT IS A SOURCE OF DISCORDANT
ALLELES WITH THE ISOTOPE AND
MODEL.
THE NEXT SLIDE THOSE EX PAT
ABILITY FOR THE USER TO PUT
EVERYTHING FROM LOW TO HIGH DP
TYPING.
EX-PAT HAS LEARNED AND TRAINED
TO THE EXON THREE POLYMORPHISMS
AND THE OUTPUT WILL DEPEND ON
WHAT THE USER'S GOAL IS.
IF YOU WANT TO USE T CELL
EPITOPE YOU HAVE THE OPTION OF
ONLY DOING T CELL EPITOPE AND IF
YOU WANT TO SEE HOW THE TOOLS
STACK UP YOU CAN DO BOTH.
HERE YOU HAVE AN OUTPUT WHERE
THE FAVORABLE DONOR IS FAVORABLE
FROM BOTH EXPRESSION AND TCE AND
THE UNFAVORABLE DONOR TO AVOID
IS THE ONE ON THE BOTTOM, NUMBER
4, UNFAVORABLE EXPRESSION AND A
TCE NON-PERMISSIVE AND THE
INTERMEDIATE GROUP OF DONORS.
THIS OUTPUT WE FEEL IS INTUITIVE
AND REALLY HELPS SEARCH
COORDINATORS AND TRANSPLANT
PHYSICIAN AND NURSES TO GET A
BETTER HANDLE ON THE DONORS
THEY'D LIKE TO MOVE TO THE NEXT
STEP FOR CONFIRMATORY TYPING AND
SCHEDULING.
THE NEXT SLIDE SHOWS WE JUST
ROLLED OUT EX-PAT LAT OVER A
MONTH AGO.
I'LL INVITE YOU TO THE URL AND
GIVE IT A TRY AND HOW YOU'RE
ABLE TO USE IT.
AND PRELIMINARY USERS IN THE
LAST MONTH TRYING THE TOOL
GIVING US FEEDBACK IS WORE AT AN
EARLY STAGE.
WE CAN LEARN A LOT IN THE
RESEARCH LABORATORY AND DO
POPULATION STUDIES BUT AT THE
END OF THE DAY WHAT TRANSPLANT
PROGRAMS NEED SAY HIGHLY
EFFICIENT ACCURATE WAY TO PICK
THOSE DONORS.
SO THEY BEGAN PROSPECTIVE DP1
TYPING ACHIEVING 100% TYPING IN
2015 AND SO AS OF TODAY 2.8
MILLION UNRELATED U.S. DONORS
HAVE BEEN FULLY SEQUENCED FOR
DP1 AND THE NEXT SLIDE SHOWS YOU
WHAT A PROFOUND IMPACT THAT
INFORMATION HAS.
WE HAVE BEEN FOR FIVE GENETIC
LOCI FOR A LONG TIME AND WHEN WE
ASSESSED THEM ONLY 20% TO 25%
WERE MATCHED AT THAT LOCUS AND
WITH 2.8 MILLION U.S. DONORS AND
MANY MORE FROM EUROPE ALREADY
HAVING THE DP TYPING IN THE
SYSTEM YOU CAN CONDUCT EFFECTIVE
SEARCHS AND DRIVE UP THE RATE
TREMENDOUSLY.
SO THE BLUE BARS ARE THE SIX
LOCUS MATCHES EXQUISITELY WELL
MATCHED.
WE'RE TRYING VERY HARD TO PICK A
SINGLE DP LOW EXPRESSION IN THE
ORANGE.
WE'RE TRYING TO DRIVE DOWN THE
RATE OF HIGH EXPRESSION
MISMATCHES IN THE GRAY AND YOU
CAN SEE OUR EFFORT PAID OFF EVEN
WITH THE CHALLENGES OF THE
PANDEMIC.
LAST YEAR IN TOTAL 80% OF THE
TRANSPLANTS WERE WELL MATCHED OR
FAVORABLE IN DP MISMATCHES.
THAT'S WHY THIS IS SO IMPORTANT.
YOU LEARN SOMETHING IN THE LAB
AND DO THESE POPULATION STUDIES,
YOU WORK WITH COLLEAGUES TO BE
ABLE TO DEPLOY IT AND THEN THE
FINALLY PRODUCT AND OFFER IT TO
PATIENTS.
I'VE GIVEN YOU TWO TOOLS, AND WE
HAVE A NUMBER IN THE WORKS AND
WE'LL BE MOVING TOWARDS A
COMPLETE MODEL WHERE INSTEAD OF
INDIVIDUAL TOOLS IN DIFFERENT
PLACES WE'D LIKE IT ALL IN ONE
PLACE BECAUSE THE PATIENT
PRESENTS AS ONE PERSON WITH TWO
HAPLO TYPES SO YOU NEED TO PUT
TOGETHER ALL THE TOOLS SO
CLINICIANS CAN CHOOSE FOR EACH
INDIVIDUAL PATIENT
CHARACTERISTIC AND THIS WAY I
THINK WE'RE TRYING TO INCREASE
THE AVAILABILITY OF
TRANSPLANTATION TO ALL PATIENTS
EVEN IF A PATIENT DOES NOT HAVE
A MATCH OUR SINCERE HOPE IS WE
CAN BRING THEM TO A SAFE
CURATIVE TRANSPLANT WITH A
MATCH.
I'D LIKE TO THANK MY COLLEAGUES
WITHIN THE WORKING GROUP
INDIVIDUAL INVESTIGATORS,
TRANSPLANT CENTERS AND DONOR
REGISTRIES AND THE FINAL SLIDE
WOULD LIKE TO THANK THE BIO
INFORMATICS TEAM IN INDIANAPOLIS
WHO PESPEARHEADED THE DEVELOPME
AND ACKNOWLEDGE COLLEAGUES IN
THE BONE MARROW ASSOCIATION AND
PROFESSIONAL SOCIETY.
THEY'VE PLAYED AN AN IMPORTANT
ROLE IN EDUCATION AND PROVIDING
THE FORUMS TO BE ABLE TO HOLD
TEACHING AND EDUCATIONAL
SESSIONS TO REACH THOSE
COLLEAGUES ACROSS THE GLOBE IN
55 COUNTRIES AND WE'RE GRATEFUL
FOR THE FUNDING TO MAKE IT
POSSIBLE.
THANKS VERY MUCH.
>> WE HAVE NEW DATA IN THE LAB
WHERE WE'RE TRYING TO DISSECT
OUT THE GRAPH VERSUS HOST VERSUS
LEUKEMIA EFFECT.
I THINK IT'S GOING CHANGE OUR
PERCEPTION OF WHAT IT IS.
IN INDIVIDUALS WITH GBHD THEY
TEND TO HAVE A LOWER OVER ALL
RATE BUT NOT NECESSARILY SO AND
HAVE NEVER BEEN ABLE TO EXPLAIN
WHY SOME PATIENTS RELAPSE WITH
GBHD AND OTHERS NEVER DEVELOP IT
OR RELAPSE AND PEOPLE WITH
CLASSIC THE CLASSIC AND WE HAVE
SEEN A CLASS.
SO 12 OF 12 MATCHES ABSOLUTELY
HAVE LOWER GBHD LEADING TO
MORTALITY AND THEIR RELAPSE IS
HIGHER SO IT'S A BALANCE.
AT THE END OF THE DAY IT'S ABOUT
SAFETY AND BEING ABLE TO CARRY A
PATIENT THROUGH SAFELY IN THE
FIRST 100 DAYS OF THE TRANSPLANT
SO FOR NOW, WE BELIEVE THERE ARE
BENEFITS FOR MATCHING BECAUSE
THERE'S PROLONGATION OF
IMMUNOEXPRESSION AND VIRAL,
BACTERIAL, FUNGAL INFECTIONS
THESE PATIENTS EXPERIENCE WITH
PROLONGED IMMUNOSUPPRESSION.
IT'S AN ACTIVE AREA.
>> GOOD AFTERNOON.
THANK YOU VERY MUCH FOR THIS
OPPORTUNITY TO BE HERE AND WITH
YOU TODAY.
THIS IS A MESSY TOPIC.
IT INVOLVES A LOT.
ABOUT 30 YEARS OF WORK IN THIS
FIELD I'LL DO MY BEST TO HIT
SOME OF THE HIGH POINTS.
SO THESE ARE MY DISCLOSURES.
YOU'LL SEE A FAIR NUMBER OF
RELEVANT CONFLICTS.
I'VE BEEN IN THIS SPACE FOR A
LONG TIME AND ABOUT 80% OF THE
CLINICAL TRIALS I'LL TALK ABOUT
HAVE BEEN SPONSORED BY
PHARMA-AND THERE'S A NEW DRUG
WHERE THERE'S A LOT OF PATIENTS
AND EXPERIENCE SO THAT IS JUST
HOW IT IS.
SO THIS IS WHAT HYPER REJECTION
LOOKS LIKE.
HYPERACUTE REJECTION IS A
TERMINAL EVENT.
THERE'S NOTHING YOU CAN DO TO
SAVE THIS KIDNEY.
THIS IS CAUSED BY PREFORMED
ANTIBODY TO PROTEINS LIKE HLA
THAT ARE PLENTIFUL IN THEIR
EXPRESSION OR CARBOHYDRATES LIKE
GROUP ANTIGENS OR XENO ANTIGENS
AND HIGH TITER ANTIBODY AND YOU
GET THIS CASCADE OF INJURY THAT
UNFOLDS IN FRONT OF YOUR EYES
OVER A MATTER OF MINUTES,
BELIEVE IT OR NOT.
SO THIS MAN, PAUL TERASAKI GAVE
US A WAY TO LOOK AT THIS AND
BEFORE THAT IT WASN'T UNUSUAL
FOR A KIDNEY TO TURN BACK ON THE
TABLE.
MIX THE SERUM FROM THE RECIPIENT
FROM THE DONOR CELLS AND SO THIS
BASICALLY WAS THE END OF
HYPERACUTE REJECTION BUT IT WAS
THE BEGINS OF A NEW PROBLEM.
THE UNINTENDED CONSEQUENCE WAS
WE NOW WERE ABLE TO DEFINE A
GROUP OF PATIENTS WHO HAD GREAT
DIFFICULTY FINDING A MATCH AND
WERE BASICALLY BEING WAREHOUSED
ON A TRANSPLANT LIST.
SO JUST TO GET A SENSE FOR THE
NATURE AND SCOPE OF THE PROBLEM,
WE KNOW THAT EXPOSURE TO ANOTHER
PERSON'S TISSUE THROUGH A NUMBER
OF WAYS THAT CAN HAPPEN CAN LEAD
TO ANTI-HLA ANTIBODIES.
ABOUT 25% TO 30% OF THE PATIENTS
ON THE TRANSPLANT LIST ARE
HIGHLY SENSITIZED.
THIS IS A BIG PUBLIC HEALTH
PROBLEM WHEN HAVE YOU OVER
100,000 PEOPLE ON THE LIST.
IT WAS THE WORK THAT ANNETTE
THAT ALLOWED US TO BEGIN TO
INNOVATE AND APPROACH THE
PROBLEM.
AS YOU SAW IN BOTH OF THE
PREVIOUS TALKS BACK IN THE '90s
WERE LIKE MEDIEVAL TIMES BECAUSE
WE COULDN'T FOLLOW HLA ANTIBODY.
ALL THESE ALLELES WEREN'T
IDENTIFIED.
SO IN ORDER TO TREAT IT YOU HAVE
TO TRACK IT IN THERAPY.
THIS IS ONE OF THE FIRST
ATTEMPTS TO DO THAT.
THIS IS A WAY OF REMOVING
ANTIBODY BEFORE TRANSPLANT IN
PATIENTS YOU KNOW ARE SENSITIZED
AND IT INVOLVES AN INITIATE WAY
OF REMOVING IGG.
PLASMAPHERESIS REMOVES IT FROM
THE VASCULAR COMPARTMENT AND YOU
HAVE TO WAIT FOR A CERTAIN
PERIOD OF TIME AND THE OPTIMAL
PERIOD IS 48 HOURS UNTIL I
RECALCULIBRATES WITH THE
INTERSTITIUM AND THE ONLY WAY TO
DO THIS IS KNOWING WHEN THE
TRANSPLANT WILL OCCUR WORKING
BACKWARD BUT WITH DECEASED
DONATION IT'S IMPOSSIBLE AND
COULD BE DONE IN THE SETTING OF
A LIVING DONOR.
BASICALLY IT INVOLVED THIS AND
ADDING BACK COOL IGG FOR
PATIENTS AT RISK OF LOW FORM
ANTIBODIES EXPRESSING THE
REBOUND OF THE ANTIBODIES
BECAUSE YOU'RE NOT DOING
ANYTHING ABOUT THE PLASMA CELLS.
THEY'RE SOLUBLE PRODUCTS YOU'RE
REMOVING AND DO THIS WITH
IMMUNOEXPRESSION AND TREATMENTS
AFTERWARD AND YOU COULD GET
PATIENTS TRANSPLANTED WHO HAD
PREFORMED ANTIBODY AT RISK FOR
HYPER ACUTE REJECTION.
NOW, YOU CAN IMAGINE IT'S
DIFFICULT TO DEMONSTRATE
EFFICACY BECAUSE THERE'S NOT A
GOOD PARITY.
YOU'RE NOT GOING TO TAKE A
PATIENT YOU KNOW IS AT RISK FOR
HYPERACUTE REJECTION AND HAVE
THEM AS YOUR PLACEBO GROUP.
SO THIS HAS PLAGUED THIS FIELD.
YOU'LL SEE THIS THROUGHOUT THE
STOREY I TELL.
ON THE PANEL ON THE LEFT IS A
COHORT OF PATIENTS WE
DESENSITIZED AND TRANSPLANTED
ACROSS A POSITIVE CROSS MATCH
OVER A PERIOD OF EIGHT YEARS AT
JOHNS HOPKINS.
IT'S A SINGLE CENTER.
BASICALLY WHAT WE DID WAS AS
EACH OF THE PATIENTS WAS
TRANSPLANTED WE FOUND FIVE
CONTROLS USING AN ITERATIVE
EXPANDED RADIUS MATCHING FROM
THE WAITING LIST SIMILAR TO EACH
OF THE PATIENTS ACROSS 11
VARIABLES KNOWN TO BE IMPORTANT
FOR ALLO GRAPH SURVIVAL SO THESE
WERE MATCH CONTROL.
THE LINE ON THE TOP ARE REAL
PATIENTS WHO WE TREATED AND
TRANSPLANTED.
YOU CAN SEE AS WE WATCH TO SEE
WHAT HAPPENS TO THE PATIENTS
OVER EIGHT YEARS AND THEIR MATCH
CONTROLS, THAT 80% OF THOSE
PATIENTS WERE STILL ALIVE AFTER
EIGHT YEARS.
WHEREAS THE PATIENTS WHO STAYED
ON THE WAITING LIST WAITING FOR
A COMPATIBLE ORGAN HAD A LOWER
SURVIVAL RATE.
IN FACT IF YOU LOOK AT THE TOP
LINE AND NEXT LINE DOWN, IT
REPRESENTS 26% OF THE PATIENTS
ACTUALLY GETTING A TRANSPLANT IN
THE SECOND GROUP BECAUSE MOST
THE PATIENTS NEVER GOT A
TRANSPLANT.
SO IF YOU TAKE THE PATIENTS WHO
REMAINED ON THE LIST AND STAYED
ON DIALYSIS THE WHOLE TIME,
THEIR SURVIVAL RATE AT THE END
OF EIGHT YEARS, A VAST MAJORITY
WAS ONLY 30%.
THAT'S WORSE THAN MOST CANCERS.
WITH WERE ABLE TO DUPLICATE THIS
IN A MULTI-CENTER THE TRIAL SET
UP THE SAME WAY, 22 DIFFERENT
CENTERS TO SHOW IT WASN'T JUST
SOMETHING WE WERE DOING.
NOW, THE OTHER COMPETING
APPROACH WAS PIONEERED BY STAN
JORDAN AT CEDARS AND INVOLVED
GIVING HIGH DOSE IVFG.
MANY IN THE ROOM PROBABLY USE
HIGH DOSE IVIG.
THERE'S SO MANY POTENTIAL
MECHANISMS OF HOW IT WORKS BUT
IT REALLY DIDN'T LOWER PREFORMED
ANTIBODY IN A MEASURABLE WAY AND
RITUXIMAB AND THEY WERE ABLE TO
GET 80% OF THE PATIENTS THEY
TREATED TRANSPLANTED WITH A 95%
SURVIVAL.
THE COMBINATION WORKED BETTER
THAN IVIG ALONE.
NOW, IT'S THE ONLY APPROACH THAT
HAS EVER BEEN TESTED IN A
RANDOMIZED PLACEBO CONTROLLED
TRIAL THE GO2 STUDY FROM WAY
BACK IN THE LATE 1990s, EARLY
2000s AND DOESN'T WORK THAT
WELL.
THE ADDITION OF RITUXIMAB HELPS
AND BRINGS UP THE ISSUE OF END
POINTS AND IS TRANSPLANT RATE A
REASONABLE END POINT?
WE BASICALLY DUPLICATED THE IVIG
ALONE STUDY WITH A GROUP OF
PATIENTS AND IT DID INCREASE THE
TRANSPLANT RATE BUT EVERY ONE OF
THE PATIENTS THAT GOT
TRANSPLANTED WOULD HAVE BEEN
ELIGIBLE FOR THAT ORGAN PRIOR TO
RECEIVING ANY IVIG AND IT WAS
JUST ABOUT CROSS-MATCHING THEM
AGAINST EVERY ORGAN AVAILABLE
AND HAVING THEM READY FOR
TRANSPLANT THAT INCREASED THEIR
TRANSPLANT RATE.
YOU CAN SEE CHOOSING YOUR END
POINT IS A REALLY IMPORTANT
THING AND IT'S KIND OF DIFFICULT
IN THIS SPACE.
SO IN 1998, THIS WOMAN, JOYCE
ROUSH PRESENTED AT HOPKINS AND
SHE WAS THE OG OF AL ALTRUISTIC
DONORS AND WANTED TO GIVE HER
ORGAN AND THERE WERE NO
ALLOCATION STRATEGIES FOR WHAT
TO DO WITH THIS NEW SOURCE OF
ORGANS.
SO WE DECIDED AND I CAN PUT HER
PICTURE UP HERE BECAUSE SHE DID
IT IN A PUBLIC WAY AND WAS
TRYING TO CREATE A REVOLUTION
AND BROUGHT A PUBLICIST WITH HER
AND WE GAVE THE KIDNEY TO A
CHILD BECAUSE THEY'RE MOST
IMPACTED BY TRANSPLANTATION.
THE NEXT DAY WAS IN THE NEWS AND
50 PEOPLE SAID WE WANT TO EXTEND
THE SAME.
AND IN A YEAR AND A HALF WE
TRANSPLANTED ALL THE CHILDREN ON
OUR LIST SO THE QUESTION IS WHAT
DO WE DO WITH THE ORGANS?
THERE WAS A MOMENT WHERE WE
DECIDED TO GIVE THE ALTRUISTIC
OR NON-DIRECTED DONORS TO
SOMEBODY WHO HAD AN INCOMPATIBLE
DONOR AND THAT PERSON WOULD GIVE
TO THE PERSON AT THE TOP OF THE
LIST OF THEIR BLOOD GROUP.
THIS STARTED OF WHAT WE CALLED A
DOMINO DONATION BUT IT WAS JUST
A CHAIN OF TRANSPLANTS.
WE STARTED DOING THIS NOW NOT
JUST WITHIN OUR OWN INSTITUTION
BUT BETWEEN INSTITUTIONS AND
ALLOWED IT TO DEVELOP OVER A
PERIOD OF TIME TO CRET LONGER
CHAINS, KIDNEYS WOULD BE FLOWN
FROM ONE CENTER TO THE OTHER AND
YOU DIDN'T HAVE TO SHIP THE
DONOR, YOU COULD SHIP THE
KIDNEY.
THIS HAD A HUGE IMPACT BUT
NOTFUL IT BECAME A NATIONAL.
WHEN WE WERE DOING IT THE IMPACT
WAS PRETTY SMALL BUT PEOPLE WILL
GET TRANS PLANTED THROUGH
KIDNEY-PAIR DONATION WHO WOULD
NOT HAVE OTHERWISE BEEN
TRANSPLANTED.
OVERNIGHT 2014 THE NEW KIDNEY
ALLOCATION SYSTEM IS NOW IN
CLINICAL PRACTICE.
AND AS MENTIONED ON THE LEFT OF
THE SCREEN YOU CAN SEE
ALLOCATION POINTS WERE GIVEN TO
PATIENTS AT THE HIGH END OF THE
CPR STARTING AT 98% CPRA THEY
GOT AN EXPONENTIAL NUMBER OF
POINTS.
PATIENTS WHO WERE 99.5 AND ABOVE
WERE CALLED 100%.
THEY WERE ROUND UP.
THOSE WHO GET 200 POINTS, ONE OF
THE BIGGEST PROSECUTORS IN THE
PAST IS THEY WERE ONLY EXPOSED
TO LOCAL OR REGIONAL ORGANS.
THE LIKELIHOOD OF FIND MATCH IF
YOU'RE HIGHLY SENSE TYPE OFFED
IS MUCH GREATER IF YOU CAN SEE
EVERY ORGAN THAT COMES OUT IN
THE COUNTRY.
THAT'S WHAT THE 200 POINTS DID.
YOU CAN SEE IN THE PAPER THERE'S
AN INFLEXION POINT IF YOU TAKE
THE CPRA OUT TO FOUR DIGITS AND
AT ABOUT 99.7 THE LIKELIHOOD OF
A MATCH STARTS TO DROP OFF.
AT 99.9 YOU'RE REALLY NOT
IMPROVING THE LIKELIHOOD OF THEM
FINDING A NACH.
-- MATCH, NOW, THE DATA ON THE
NEXT SLIDE I'LL SHOW AFTER THE
BOLUS PERIOD DURING THE
STABILITY PERIOD THIS IS WHAT
THE FATE OF HIGHLY SENSITIZED
PATIENTS ARE NOW IN THE
POST/PAST ERA.
STARTING ON THE LEFT SIDE, THE
FIRST TWO BARS THE TRANSPLANT
RATE IS GOOD BUT AS YOU MOVE OUT
MORE SENSITIZATION NOW AT 99.9
THAT PATIENT IS MORE LIKELY TO
DIE GET D LISTED THAN TO GET
TRANSPLANTED AND ON AVERAGE
THEY'LL RECEIVE .1 OFFERS A
YEAR.
IT WILL TAKE THEM 10 YEARS TO
GET AN OFFER.
NOW, IT'S NOT JUST THAT GROUP
THOUGH.
SOME INTERESTING THINGS FELL OUT
AS WELL.
FIRST, WE USED TO BE ABLE TO
WITH DESENSITIZATION TRANSPLANT
A LOT OF PATIENTS WITH A LIVING
DONOR.
LIVING DONORS ON AVERAGE LAST
TWICE AS LONG AS DECEASED OWNER
KIDNEYS.
NOW 1.1 PAIR WOULD GET A LIVING
DONNER BECAUSE ALL THE GROUPS
DECIDED WE'LL PUT THESE PATIENTS
ON OUR LIST.
THEY'VE GOT THIS ADVANTAGE,
THEY'LL GET TRANSPLANTED.
THAT'S NOT EXACTLY WHAT
HAPPENED.
NOW, 50% OF THE PATIENTS IN THE
GROUP HAVE GREATER THAN FIVE
YEARS OF WAITING TIME AND THE
MORTALITY RATE FOR A PATIENT ON
THE LIST FOR FIVE YEARS IS 50%.
ANYONE WITH A CPA OF 98% WE SAW
NO IMPROVEMENT IN THE WAIT LIST
MORTALITY AND THE 99.9% WHICH IS
THE NEW BENCHMARK OF THE
APPROPRIATE PATIENT TO HAVE IN
STUDIES THAT LOOK AT
DESENSITIZATION IT'S ALMOST
3,000 PATIENTS.
UNFORTUNATELY THE FDA HAS USED
THAT AS THEIR LIT MUSS TEST FOR
THE PATIENT'S THEY'LL CONSIDER
WHEN ISSUING AN IND BUT THERE'S
A LOT OF OTHER S THAT ARE
DISADVANTAGED.
THIS IS THE STATE OF LAY.
IF YOU'RE LUCKY ENOUGH TO HAVE A
LIVING DONOR YOU CAN GO WITH
LOW-DOSE IVIG OR DONATION SCHEME
AND GET TRANSPLANTED THAT WAY
BUT NOT EVERYBODY IN THE PAIR
DONATION GETS TRANSPLANTED IF
YOU HAVE A HIGH CPRA YOU'RE IN A
LARGER POOL.
IF YOU DON'T HAVE A LIVE DONOR,
THAN YOU CAN GET IT UP OR WAIT
ON THE LIST WITH THE ALLOCATION
PRIORITY.
BECAUSE MORE PATIENTS HIGHLY
SENSITIZED WERE GETTING
TRANSPLANTED THE FIELD BECAME
COMPLACENT ABOUT DESENSITIZED.
IT WAS A YOU'LL SEE IN THE
STUDIES I SHOW YOU THIS HAPPENED
THEY'VE BEEN CONCEIVED IN THE
PRE/PAST ERA AND SUDDENLY
DESENSITIZATION WAS A HUGE
PROBLEM.
THIS IS A GROUP OF AGENTS.
WHEN DESENSITIZATION WAS LESS
POPULAR AND EQUIPOISE WAS HARDER
TO DEMONSTRATE WITH THE NEW
ALLOCATION SYSTEM WE STARTED TO
LOOK FOR OTHER ALTERNATIVES FOR
AGENTS THAT WOULD BE MORE POTENT
AND RELIABLE AND REDUCE THE
INCIDENTS OF AMR.
AMR IN THE STRATEGIES THAT HAVE
SHOWN YOU WAS AS HIGH AS 40%
AFTER DESENSITIZATION.
THERE BECAME A LOT OF INTEREST
IN TRYING TO REDUCE AMR.
I'LL TELL YOU ABOUT A COUPLE.
WE MENTIONED THE PROTEOSOMAL
INHIBITORS THAT TARGET PLASMA
SELLS AND RITUXIMAB IS AN IL6
AGENT AND ANTI-CD38 WAS
MENTIONED.
A DRUG WHICH IS A VERY
INTERESTING DRUG WITH
STIMULATION BLOCKING WE
MENTIONED AND BLISS.
NOW, WE HAD COMPLEMENT
INHIBITORS AND TOLD YOU ABOUT
THE CDC CROSS MATCH IS HOW YOU
KILL THE CELLS SO COMPLEMENT IS
IMPORTANT.
THERE'S TONS OF COMPLEMENT
INHIBITORS IN THE PIPELINE FOR
OTHER DISEASES MOST LY NONE HAV
BEEN APPROVED FOR
TRANSPLANTATION SO THEY'VE BEEN
USED OFF LABEL.
SO ECULIZUMAB MADE IT THROUGH
AND IT WAS BASED ON DATA FROM
THE MAYO CLINIC SHOWING THE RATE
OF ANTIBODY REJECTION AFTER
DESENSITIZATION WITH LOW DOSE
IVIG IF YOU GAVE THIS DRUG FROM
THE TIME OF THE TRANSPLANT
WITHOUT MORE PLASMAPHERESIS AND
IT WILL REMOVE THE DRUG AND IT'S
THE MOST EXPENSIVE DRUG IN THE
WORLD AND THEY WERE RANDOMIZED
TO GOING ON RITUXIMAB AND THE
PRIMARY END POINT WAS AMR OR
LOSS OF THE PATIENT IN THE STUDY
AND YOU CAN SEE THE P VALUE.
BUT THIS STUDY WAS FLAWED.
THE FIRST FLAW AND IT COMES TO
THE ISSUE OF HOW THESE STUDIES
ARE DESIGN BY PHARMAIN
COLLABORATION WITH EXPERTS BUT
THEY DIDN'T -- FIRST, WE DON'T
EVEN THINK OF AMR OF HAVING
GREAT.
IT'S PATHOLOGIST DEFINITION.
WE THINK OF AMR AS BINARY.
EITHER YOU HAVE IT OR DON'T.
THEY DIDN'T INCLUDE GRADE 1 AF
MR AND THE CENTRAL PATHOLOGISTS
DIDN'T HAVE CRITICAL DATA. MR
AND THE CENTRAL PATHOLOGISTS
DIDN'T HAVE CRITICAL DATA.MR
AND THE CENTRAL PATHOLOGISTS
DIDN'T HAVE CRITICAL DATA.
WHEN WE WENT BACK AND RELO LOLO
AT THE DATA AND WE SAW THIS WAS
A NEGATIVE TRIAL.
SO IT'S OVER.
ALL THE WORK EVERYBODY HAD DONE
WAS A NEGATIVE TRIAL.
SO IF YOU JUST PUT BACK THE
DEFINITION YOU HAVE A POSITIVE
TRIAL AND IF YOU GAVE THE
CENTRAL PATHOLOGIST THE CLINICAL
DATA IT EVEN BECAME MORE
POSITIVE WITH THE P VALUE.
UNFORTUNATELY IN THE MEANTIME,
THE MAYO GROUP DEMONSTRATED
WHILE IT WAS GOOD AT REDUCING
AMR FROM 43% TO 7% WHEN THEY
FOLLOWED THE PHASE 2 PATIENTS
OUT FURTHER THERE WAS NO
DIFFERENCE IN THE CHRONIC
LESION.
THE DRUG BASICALLY IS STILL
BEING USED OFF LABEL BUT IT WAS
A NEGATIVE TRIAL IN EVERYONE'S
MIND.
NOW, IMLIFIDASE WAS A MOLECULE
ISOLATED AND IT'S AN EFFECTIVE
BACTERIA IT CLEAVES HUMAN IGG AT
THE CONSENSUS.
THE SINGLE CLEAVE IS NO LONGER
EFFECTIVE.
IT BASICALLY INHIBITS FC
MEDIATED ACTIVITY AND ADCC
PHAGOCYTOSIS AND IT CLEAVES ALL
FORMS OF IGG BOUND B CELL
RECEPTORS AND IT'S DISTRIBUTED
WITHIN ALL THE COMPARTMENTS AND
BODIES WITHIN HOURS.
YOU NO LONGER HAVE THE PROBLEM
OF ACCESS TO THE VASCULAR SPACE.
YOU CAN GET RID OF ALL THE IGG
IN THE BODY SO YOU CAN HAVE A
KIDNEY COME IN WITH A POSITIVE
CROSS MATCH HOURS LATER HIM TO
THE TRANSPLANT ROOM.
IT DOESN'T DO ANYTHING TO THE
PLASMA CELLS SO WHEN THE DRUG
WEARS OFF THE ANTIBODIES START
TO COME BACK IN SOME CASES NOT
ALL.
THE SECOND THING IS HUMANS ARE
RESPONDED TO THESE NASTY LITTLE
BACTERIA BY HAVING A PRIMED
IMMUNE SYSTEM.
IT'S VERY IMMUNOGENIC.
YOU CAN ONLY GIVE THE ENZYME TWO
TIMES AND EVERYBODY HAS
NEUTRALIZING ANTIBODIES.
WE DID THIS WITH AN NATIONAL
GROUP WE TOOK LIVE DONORS AND
THE CROSS MATCH TURNED NEGATIVE
IN NEARLY EVERY INCIDENCE.
AND IT CLEAVES HUMAN AND RABBIT
ANTIBODY AND MOST THE
THERAPEUTIC ANTIBODIES DEPLETE T
CELLS YOU HAVE TO GET ATGAM FROM
AN HOURS OR WAIT SEVERAL DAYS
UNTIL THE DRUG DISAPPEARS AND
YOU GET RITUXIMAB AND WITH THIS
PROTOCOL WE FOUND ALMOST ANYBODY
COULD BE DESENSITIZED BUT THE
RATE OF AMR WAS NO DIFFERENT
THAN IT WAS WITH PLASMAPHERESIS
AS YOU WOULD EXPECT BECAUSE MOST
PATIENTS WILL REBOUND.
YOU TAKE PATIENTS ON THE
DECEASED OWNER LIST WHO ARE
99.9% DESENSITIZED AND GET THEIR
ANTIBODIES DOWN TO AS CLOSE AT
99.5% AS THEY CAN TO START TO
GET OFFERS AND THEN YOU GET AN
OFFER FROM FOR THE PATIENT AND
BRING THEM IN AND GO OFF THEIR
VIRTUAL CROSS MATCH, IF IT'S
POSITIVE THEY GET RANDOMIZED TO
EITHER STANDARD OF CARE, WHICH
IS EITHER PLASMAPHERESIS OR IGIG
AND THE CLOCK IS TICKING.
MOST THE PATIENTS WITH A
POSITIVE CROSS-MATCH WON'T GET A
TRANSPLANT IN THE STANDARD OF
CARE ON.
THIS IS ACCRUING PRETTY WELL AND
THE END POINT IS AT THE END OF
ONE YEAR.
NOW, BASED WORK ANNETTE ALREADY
TOLD YOU WE NOW HAVE ANOTHER
TRIAL CALLED THE REBOUND TRIAL
OF PHASE 2 TRIAL BASED ON IF YOU
GIVE A PROTEOSOMAL INHIBITER YOU
WILL KILL CANCER CELLS BUT DON'T
LOWER THE ANTIBODY BUT THERE ARE
NOW PLASMA BLASTS REFILLING THE
NICHES AS YOU KILL THE PLASMA
CELLS THROUGH THE PERIPHERAL
LYMPHOID TISSUE AND SIGH THE
WHOLE THING HAPPENING BEFORE
YOUR EYES.
IF YOU GIVE THE INHIBITOR THEN
YOU DEPLETE AT BOTH ENDS.
WE PUT TWO PATIENTS THROUGH THIS
AND NEITHER HAD A SIGNIFICANT
REBOUND.
WE DID BONE MARROW BIOPSIES AND
DEMONSTRATE THE MECHANISM IS
WHAT WE THOUGHT IT WAS.
UNFORTUNATELY THIS IS THE THING
ABOUT PHARMA.
THE COMPANY DOING THE PHASE 3
TRIAL AT THE SAME TIME IT'S A
TERRIBLE TIME FOR INVESTMENT IN
PHARMA AND THEY HAVE TO TURN IT
INTO AN INVESTIGATOR-INITIATED
TRIAL.
WE BELIEVE IN THIS SO I THINK
THAT'S THE FUTURE AND IT'S THE
SAME PEOPLE WHEN WE START THE
STUDY AT THE END AND THE COMPANY
HAS CHANGED THREE TIMES AND
DIFFERENT OWNERSHIP SO THIS
INVOLVES THE UBER WAY TO GO
ABOUT THIS USING CAR T CELLS AND
LEVERAGES THE SAME DATA YOU HAVE
TO BLOCK THE SUPPLY OF NEW
PLASMA CELLS BY USING CART 19
AND THE PLASMA CELLS WITH A CART
AGAINST BCMA.
THERE'S A DOSE FINDING PHASE AND
WE'RE USING THIS
CYCLOPHOSPHAMIDE SO IT'S A 3X3
CANCER METHODOLOGY AND WE'LL
DOSE ESCALATE, IF YOU WILL.
THIS IS A PHASE 1 TRIAL BUT THE
SECOND END POINT IS A DROP OF 3%
IF YOU REMEMBER THE GRAPH WILL
GET YOU MORE.
AMR EITHER FROM PRE FORMED
ANTIBODY INCOMPLETELY REMOVED BY
DESENSITIZATION OR DE NOVO
ANTIBODY WHICH AGAIN IS A
FAILURE IN THE T CELL THERAPY
AND RESPONSIBLE FOR PROBABLY 50%
OF GRAFT ASSISTS.
NOW, THE CURRENT PARADIGM FOR A
LOT OF TRIALS MENTIONED AND THE
COUPLE I'M GOING TO MENTION NOW
FOR AMR IS YOU HAVE A GROUP LIKE
HOURS INTERESTED IN THE SPACE
WHO FINDS AN EXISTING DRUG IN
THE AUTOIMMUNE ORPHAN OR
ONCOLOGY SPACE OR A NEW COMPOUND
AND IT LOOKS INTERESTING FROM A
MECHANISTIC STANDPOINT AND LOOKS
LIKE IT MAY HELP WITH AMR
DESENSITIZATION AND DO A PHASE 1
AND 2 TRIAL AND IT'S POWERED TO
SHOW EFFICACY AND THEN PHARMA
COMES IN AND USES A SIMILAR
METHODOLOGY FOR YOUR PROTOCOL
AND THREW AN ADVISORY BOARD AND
LAUNCH THE TRIAL.
THE FLAWS FROM THAT PILOT TRIAL
ARE CARRIED FORWARD AND NEW ONES
ARE INTRODUCED BY A PHARMA
GROUP.
WHAT WE KNOW IS IF YOU HAVE AN
ANTIBODY THAT ACTIVATES
COMPLEMENT AGAINST HLA YOUR
OUTCOMES ARE GOING TO BE MUCH
WORSE.
THE TREATMENT OF AMR BECAME A
TOPIC FOR INVESTIGATION.
WE TOOK PATIENTS AT RISK FOR AMR
AND HAD PREFORMED ANTIBODY AND
DEVELOP ACUTE AMR40% AFTER THE
TRANSPLANT AND WE GAVE THEM
PLASMAPHERESIS AND AN INHIBITOR.
IT WAS VERY GOOD AT RESOLVING
THE AMR AND THIS WAS A PLACEBO
CONTROLLED TRIAL.
SO WE MAKE ENDOGENOUS C1
INHIBITOR IN THE BLOOD.
SO THE PATIENTS HAD MORE C1
BECAUSE WE WERE GIVING IT
EXOGENOUS AND THEY HAD
TRANSPLANT GLOMERULOPATHY AND WE
SAID OKAY, THAT WILL BE OUR
PRIMARY OUTCOME.
SO THEY WENT TO A PHASE 3 TRIAL
AND AT THE SAME TIME WE WERE
DOING THIS THE BOTTOM FELL OUT
OF DESENSITIZATION.
THERE WERE A LOT WHO WERE
GETTING TRANSPLANTED WITH THE
ANTIBODY.
THIS WAS THE PHASE 3 TRIAL WHICH
MIRRORED WHAT WE HAD DONE.
UNFORTUNATELY IT SUFFERED FROM
AN ENROLLMENT PROBLEM.
BASICALLY THIS WAS A STRATEGY --
THIS TRIAL, THIS IS THE PHASE 2
THE END POINT WAS CHANGE IN EFR
AND THE PHASE 2 TRIAL WAS DONE
BY THE FRENCH GROUP AND
CONSORTIUM.
THIS WAS FOR CHRONIC
UNRESPONSIVE ANTIBODY MEDIATED
REJECTION USING ANOTHER C1
INHIBITOR.
THE PHASE 3 TRIAL MYIRRORED THA
AND IT'S A LONG PERIOD AND THE
PATIENTS GET AN INITIAL ATTEMPT
OF TREATING THE AMR AND IF IT
PERSISTS THEY GET RANDOMIZED TO
HIGH DOSE IVIG PLUS C1 PLUS
PLACEBO OVER A LONG PERIOD OF
TIME AND FOUR YEARS OF
FOLLOW-UP.
WORRIED ABOUT THE TRIAL.
IT'S ENROLLING REASONABLY WELL
NOT GREAT.
THEY'RE HAVING TO BRING THEM IN
EVERY MONTH.
SAME STORY WITH THE IL6 AGENTS.
THIS WAS THE STAN JORDAN PHASE
1, PHASE 2 TRIAL.
THIS IS THE PHASE 3 TRIAL WHICH
THERE'S NO TREATMENT FOR CHRONIC
ACTIVE AMR.
ONCE YOU DEVELOP IT YOUR TIME OF
HAVING THAT TRANSPLANT IS
GREATLY CURTAILED.
THERE'S NO FOR IT.
WE WERE FORTUNATE TO HAVE THAT
WITH THE PLACEBO VERSUS THE IL6
BLOCKING AGENT.
THIS IS STILL ENROLLING
OBVIOUSLY COVID HAD A BIG IMPACT
ONLY BOTH TRIALS.
ANYWAY, THAT'S AN ATTEMPT TO
SUMMARIZE 30 YEARS OF MOSTLY
MESSY CLINICAL TRIALS IN THE
SPACE.
I THINK THERE'S INTERESTING
POSSIBILITIES AHEAD OF US BUT I
SAID THAT 20 YEARS AGO.
THESE ARE REALLY DIFFICULT
TRIALS TO DO THESE THINGS.
SORRY, WE RAN A LITTLE BIT OVER.
I DON'T KNOW IF WE HAVE TIME FOR
QUESTIONS BUT I'LL BE AROUND.
>>
>>'M WONDERING IF THERE'S BEEN
ENOUGH UPTAKE THERE TO GET A
LITTLE BIT MORE AND IF YOU
WANTED TO SPECULATE DIFFERENCE
IN ALLOCATION AND TAKES CARE OF
THE PROBLEM WITH THE DIFFERENT
ALLOCATION SYSTEM IN EUROPE.
DIFFERENT ENVIRONMENT.
>> THEIRS IS CALLED THE
ACCEPTABLE MISMATCH ALLOCATION
SYSTEM.
IT BASICALLY DOES WHAT WE DO
WITH TAS GETTING TO THE SAME END
POINT.
I THINK THEY'RE STRUGGLING QUITE
A BIT.
IN THE PHASE 2 TRIAL THE FDA
INSISTED ON PLACEBO CONTROLLED
PHASE 3 TRIAL.
I WOULD SAY THE UPTAKE HASN'T
BEEN GREAT.
THERE'S A HANDFUL OF CENTERS
WITH A HISTORY LIKE THE PARIS
CONSORTIUM OF DOING
DESENSITIZATION AND IT'S EASIER
FOR THEM TO UNDERSTAND WHICH
PATIENTS ARE GOOD HAND DATES FOR
THE DRUG.
-- GOOD CANDIDATES AND IT'S SO
POTENT YOU CAN GET IN TROUBLE.
IF YOU TAKE SOMEBODY IN WITH
HIGH LEVELS OR AGAINST THEIR
DONOR, WHEN THE REBOUND OCCURS
IT'S GOING TO BE ONE OR TWO OF
THOSE AND THE RUMORS AND
ENTHROUGHSIASM.
YOU HAVE TO UNDERSTAND IT TO
AVOID THIS SITUATION.
>> A QUICK QUESTION AND FEEL
FREE NOT TO ANSWER IF YOU DON'T
WANT BUT WHAT DO YOU THINK WE AT
THE NIH COULD DO TO ALLEVIATE
WHAT YOU BROUGHT UP WITH THE
MESSY CLINICAL TRIALS?
>>T'S A GREAT QUESTION.
QUIN OF THE PROBLEMS WITH THE
FDA I SEE MAYBE CHANGING IS THAT
WE NOW HAVE A BUNCH OF DRUGS AND
INTERVENTIONS EACH BY THEMSELVES
DOESN'T DO THE WHOLE JOB.
BUT I'M CERTAIN IN COMBINATION
WITH EACH OTHER IT WOULD BE A
DIFFERENT PICTURE.
THAT'S SOMETHING UP UNTIL
RECENTLY THE FDA HAS NOT BEEN
COMFORTABLE WITH COMBINING TWO
EXPERIMENTAL OR THREE
EXPERIMENTAL DRUG TOGETHER.
AGAIN, WE DON'T HAVE A LABEL FOR
ANYTHING.NOT EVEN, PLASMA FOR
PHERESIS HAS BEEN RECOGNIZED BUT
IT'S NOT LABELLED SO.
SO I THINK THAT ONE THING THAT
COULD REALLY HELP IS TO ALLOW US
THAT FREEDOM TO COMBINE ONCE THE
SAFETY OF EACH DRUG HAS BEEN
PRETTY CLEARLY SHOWN TO COMBINE
THE MODALITIES TODAY.
[OFF-MIC]
>>T IS BUT IT'S NEVER BEEN
THOUGHT OF THAT WAY.
[OFF-MIC]
TO THE OTHER PROBLEM IS YOU
DON'T HAVE THE CONSTITUENCY AS
IN CANCER OR AIDS.
WE DON'T HAVE A BUNCH OF PISSED
OFF PEOPLE.
WE HAVE A FEW PEOPLE WHO GOT A
TRANSPLANT AND FEEL SUPER LUCKY.
THEY FEEL THEY CAN'T SAY
ANYTHING BECAUSE SOMEBODY ELSE
HAD TO DIE IN ORDER FOR THAT TO
HAPPEN.
WE DON'T HAVE A GOOD PATIENT
ADVOCACY SO IT'S EASIER TO
IGNORE IT AND IT'S COMMISSION
VERSUS OMISSION.
>> THERE'S INDUSTRY PARTNERSHIP
AND THE CLINICAL IS WAY MORE
INTERESTING.
>> WE'RE SUPER EXCITED ABOUT
CTOC.
THAT IS GOING TO BE DRAMATIC ONE
WAY OR THE OTHER.
WE ARE A LITTLE BIT BEHIND TIME
BUT WELL WORTH SPENDING TIME ON
THESE TERRIFIC TALKS.
YOU'LL START OFF WITH THE
CONCEPT CLEARANCE.
I'LL ASK TO YOU INTRODUCE
YOURSELF AND SAME FOR YOUR
COLLEAGUES.
>> OKAY.
>>'M A PROGRAM OFFICER IN THE
BASIC IMMUNOLOGY BRANCH, KENTNER
SINGLETON AND YOU'LL GET A TWO
FOR HERE.
I'LL BE PRESENTING TWO FY25
INITIATIVE CONCEPTS WHERE THE
GOAL IS TO SUPPORT RESEARCH TO
ADVANCE OUR UNDERSTANDING OF THE
SYSTEM.
AND THE W.H.O. ESTIMATED 75% OF
EMERGING DISEASES COME FROM
ZOONOTIC PATHOGENS BUT THE
MAJORITY ARE COMING FROM BATS
AND MICE.
WHAT WE KNOW ARE THAT BATS CAN
SERVE AS RESERVOIR HOSTS FOR A
NUMBER OF HUMAN PATHOGENS
INCLUDING CORONAVIRUS AND RABIES
AND FOR MANY VIRUSES THEY CAN
ELICIT IN HUMANS A STORM OF
CYTOKINES THAT RESULTS IN
INFORMATION AND TISSUE DAMAGE
AND ULTIMATELY PATHOLOGY AND
POTENTIALLY DEATH IN HUMANS.
HOWEVER, BATS APPEAR TO BE WELL
ADAPTED TO THE RESULTING
INFORMATION.
THESE APPEAR TO BE WELL ADAPTED
AT PREVENTING OR RESOLVING THE
INFORMATION WHILE STILL
CONTROLLING THE PATHOGEN.
SO WE KNOW INFORMATION ABOUT THE
SYSTEM AND THEY SHARE COMPONENT
WITH HUMANS.
THEY HAVE T CELL RECEPTORS AND
MCH CLASS 1 AND 2 AND HAVE
ANTIBODIES AND THEY HAVE BEEN
FORMALIZED AND THEY CAN
RECOGNIZE AND BIND TO PATHOGENS.
THEY ALSO HAVE THE SAME FAMILY
OF CYTOKINES.
THERE ARE SOME DIFFERENCES BATS
HAVE SO BATS CAN CLEAR VIRAL
INFECTIONS HOWEVER, DIFFERENT
BAT SPECIES CAN TAKE DIFFERENT
APPROACH IN CONTROLLING AND
CLEARING THE INFECTIONS.
SOME BATS HAVE ALPHA GENES BUT
CAN EXPRESS THEIR mRNA THING
CAN UPREGULATE THE IMMUNE
RESPONSE AND DOWNREGULATE BACK
DOWN.
OTHER BATS DON'T EXPRESS mRNA
BUT HAVE EXPANDED INTERFERON
OMEGA.
THAT HAS 22 INTERFERON OMEGAS IN
CONTRAST TO HUMANS WITH MICE AND
ONE COMMON THING THAT'S COME UP
OVER AND OVER AGAIN THE LIMITED
BAT RESEARCH THAT'S OCCURRED IS
BATS HAVE EVOLVES TO AVOID
INFLAMMATION.
NOM KNOWLEDGE GAPS AROUND
RESEARCH AND THERE'S LITTLE
KNOWN ABOUT THE IMMUNE RESPONSE
TO THE PATHOGENS AND WHY THEY'RE
NOT PRESENTING WITH DISEASE.
WRL OF ONE ISSUE IS THEY'RE
LIMITING AND IF YOU CAN'T DO THE
PHENOTYPING IT CAN LIMIT YOUR
STUDIES SIMILARLY IF YOU DON'T
HAVE THE CYTOKINES IT CAN LIMIT
THE STUDIES YOU CAN END UP WITH
AND ONE OF THE OPPORTUNITIES
FROM HERE IS UNDERSTANDING THE
MAJOR S BUT IT'S TWEAKED AND
THEY HAVE DIFFERENCES IN THE
REGULATORY CIRCUITS TO PROVIDE
INSIGHTS ON THERAPEUTIC
APPROACHES WE CAN TAKE FOR
TREATING PEOPLE THAT HAVE BEEN
AFFECTED WITH THE PATHOGENS.
THESE ARE THE PROPOSED
INITIATIVES.
THE FIRST IS THE RESEARCH
COMPONENT.
THE RESEARCH COMPONENT MAY BE ON
THE MECHANISM AND UNDERSTAND THE
PROTECTIVE IMMUNE MECHANISM FOR
THE POTENTIAL OF HARBORING
ZOONOTIC PATHOGENS AND PROPOSE
AN RO1 STYLE MECHANISM AND THE
PROJECT FOR FIVE YEARS.
IN PARALLEL WE PROPOSE TO
ANOTHER INITIATIVE TO SUPPORT
REAGENT DEVELOPMENT.
THIS IS TO SUPPORT THE
DEVELOPMENT OF ANTIBODIES,
CYTOKINES TO SUPPORT THE
IMMUNOLOGICAL STUDIES CONDUCTED
NOT ONLY BY THE R01 GRANTS AND
COMMUNITY AS A WHOLE.
THE CRITICAL COMPONENT IS THE
VALIDATION OF REAGENTS ACROSS
BAT SPECIES AND THEY'LL DO THAT
ON THEIR OWN AND IN PARTNERSHIP
WITH THE RO1 USING THE U24
MECHANISM.
IT'S A COOPERATIVE AGREEMENT AND
SUBSTANTIAL PROGRAMMATIC
INVOLVEMENT WITH THE GRANTEE FOR
DEVELOPMENT OF THE AGENTS AND TO
WORK WITH THEM ALONG WITH THE
BAT COMMUNITY TO DIRECT THEM ON
WHAT ARE NEEDED TO MOVE THE
RESEARCH FORWARD.
WITH THE RO1s WE EXPECT IT'D BE
A FIVE-YEAR GRANT AWARD.
WE SEE THESE TWO MECHANISMS
WORKING TOGETHER.
WE'D HAVE AN ANNUAL MEETING TO
BRING EVERYONE TOGETHER TO
DISCUSS IN PERSON.
THIS IS SOMETHING THAT'S WORKED
WELL FOR US IN OTHER INITIATIVES
AND LAY A FOUNDATION FOR THE
FIELD FROM WHICH IT CAN GROW
AFTER THE INITIATIVES ARE
COMPLETE.
WITH THAT I'M HAPPY TO ANSWER
ANY QUESTIONS.
>> GOOD AFTERNOON.
I'M MARILYN AND I'M A PROGRAM
OFFICER.
IT WAS ESTABLISHED IN 2004 AND
WE TAKE OUR RESEARCH AND MY
FOCUS FOR THIS INITIATIVE IS
GOING TO BE ON THE MISSION
SPACE.
WE HAVE THREE SPECIFIC ENTRIES.
ONE IS TRIAGE AND DISASTER AND
FOR THOSE CONCERNED THAT MAY BE
EXPOSED TO RADIATION AND THOSE
ACTUALLY EXPOSED AND FIRST
RESPONDERS ARE TRIAGED AND THIS
WILL HELP THE MEDICAL COMMUNITY
TO COME UP WITH STRATEGIES TO
TREAT THEM AND ADVISE THEM HOW
TO COME UP WITH THE FOLLOW-UP
STRATEGY.
ANOTHER ASPECT TO OUR PORTFOLIO
IS THE PREDICTIVE ASPECT AND TO
SAY WHAT IS THE OUTCOME OF THE
EXPOSURE TAKING INTO ACCOUNT THE
SENSITIVITY AND THE AIM AND
PERHAPS DIETARY STATUS AND ALL
FACTOR INTO THE OUTCOME
EXPOSURE.
AND WE USE A PLETHORA OF GRANT
MECHANISMS.
OUR RESEARCH SUPPORT WE HAVE A
HUGE FOCUS AND WE REGISTER WITH
THE AGENCY BECAUSE WE NEED THIS
COLLABORATION TO ADVANCE OUR
DEVICES AND IN ADDITION TO THAT
WE HAVE DEEP CONNECTIONS WITH
SISTER AGENCIES AS WELL AS
COMPANIES AND ACADEMIA THAT
ACTUALLY DO THE RESEARCH.
I CAN'T EMPHASIZE ENOUGH WHY THE
INTERACTIONS ARE IMPORTANT
BECAUSE TO DATE WE DON'T HAVE A
SINGLE DEVICE THAT'S BEEN FDA
CLEARED FOR USE FOR HUMANS WITH
CLEAR INCIDENT.
THIS PARTICULAR U01 WE
ANTICIPATE IF PEOPLE COME TO US
IF THEY COME TO US WITH WE WON'T
SEE IT BECOME READY TO GET A
CONTRACTOR A MORE ADVANCED
FUNDING MECHANISM.
THIS IS A QUICK SNAPSHOT OF THE
PORTFOLIO.
WE'VE HAD SEVERAL VERY EARLY
SUPPORT FOR OUR RESEARCHERS AND
CONTRACTS AND FINAL GOAL OF
COURSE IS FDA APPROVAL WITHIN
THE LIFE OF THESE CONTRACTS AND
GRANTS WE DO ASK OUR P.I.s TO
HAVE A CONVERSATION WITH THE FDA
BECAUSE THEY CAN GIVE REALLY
GOOD FEEDBACK ON WHAT THE
DEVELOPMENT LOOKS LIKE AND HOW
TO MAKE IT HAPPEN.
IN ADDITION TO THAT WE ARE
REALLY HAPPY TO SAY WE'VE HAD
SEVEN PROJECTS THAT THE
TRANSITION FROM OUR EARLY
RESEARCH PORTFOLIO TO BARTER
CONTRACTS FOR DEVELOPMENT.
AS I SAID, WE STILL HAVE NOT HAD
SUCCESS.
IN ADDITION TO PROVIDING FUNDING
TO THE AGENCY AS WELL AS BORDER
WE ALSO PROVIDE RESOURCES TO OUR
GRANTEES BECAUSE THEY START WITH
IN VITRO ASSAYS AND STARTED WITH
STUDIES IN MICE BUT THE
TRANSLATION ASPECT GIVEN THE
GLOBAL THAT'S BEEN A HUGE DEAL
AND THEY'VE NOT HAD ACCESS TO
THE PRIMATES.
SO WE CONDUCT STUDIES IN
PRIMATES AND MAKE THE BIO
SAMPLES AVAILABLE TO THE
COMMUNITY AND WE WERE ABLE TO
CONDUCT STUDIES WITH 10 PRIMATE
AND PROVIDE THEM TO 12 MONKEYS
WHICH I THINK WAS A BIG DEAL.
CURRENTLY THE UL 1 CORBS SHUM WE
AWARDED SEVEN AWARDS IN TOTAL
AND YOU CAN SEE THERE ARE
MULTIPLE APPROACH TO ADDRESSING
THE DIFFERENT ASPECTS OF THE
MULTI-OMICS.
AND METABOLOMICS TO PREDICT IF
YOU'LL HAVE LATE EFFECTS TWO
MONTHS OR TWO YEARS DOWN THE
LINE OR 20 YEARS DOWN THE LINE.
PROTEOMICS OR A QUICK YES OR NO
ANSWER AT ONSET AND
TRANSCRIPTOMICS MORE FOCUSSED ON
IMMUNE CHANGES BECAUSE WE KNOW
RADIATION CAUSES ALL SORTS OF
DYSFUNCTION.
AND YOU CAN DO A QUICK
PAPER-BASED ASSAY.
THAT BRINGS US TO WHAT THE UO1
CONSORTIUM AND THE GOAL REMAINS
THE SAME A RAPID DIAGNOSTIC KIT
AND DOSE ASSAYS AND IT'S A TRUE
PARTNERSHIP WITH P.I.s.
THE DURATION WILL BE FOUR OR
FIVE YEARS.
WE ANTICIPATE BEING ABLE TO WARD
SIX TO EIGHT AWARDS.
WITH THAT I'LL BE HAPPY TO
ADDRESS YOUR QUESTIONS.WARD SIX.
WITH THAT I'LL BE HAPPY TO
ADDRESS YOUR QUESTIONS.
>>'M THE WITH IN THE ALLERGIC
MECHANISMS SECTION IN THE
BIOLOGY BRANCH.
AND I'M GOING TO DISCUSS AN
INITIATIVE ON DRUG ALLERGY.
I WANT TO SAY FROM THE START
THAT WHEN I'M TALKING DRUG
ALLERGY IN THIS SENSE I'M
TALKING ABOUT IMMUNE DRIVEN
IDIOSYNCRATIC FORMS OF DRUG
REACTION.
SO NOT JUST MEDIATED BUT
DEFINITELY NOT TOXIC REACTIONS.
SO ALLERGY IS A COMMON
DIAGNOSIS.
IT'S A BIG CAUSE OF VISITS TO
THE E.R. IF YOU'RE IN THE
HOSPITAL AND HAVE AN ALLERGY
DIAGNOSIS YOU'LL BE OFTEN GIVEN
LESS THAN TOP LINE DRUG OR
INDICATED DRUGS AND HAVE A
PROBLEM WITH CDIF AND INCREASES
THE CHANCE OF VRE AND SM8 AND
INFECTIONS.
OUR PROBLEM IS THAT WE DON'T
FUND MANY GRANTS IN THE AREA AT
ALL.
IN THE PAST 14 YEARS I THINK
WE'VE HAD 10.
THREE WERE K AS AND Fs SO EARLY
STAGE.
AND THERE'S BEEN ABOUT THAT MANY
ACROSS THE NIH IN THAT PERIOD.
MOST COMES HERE BUT IT'S NOT
VERY MUCH PERIOD.
SO THE PROPOSAL IS TO ENHANCE
UNDERSTANDINGS OF THE MECHANISMS
AND MANAGEMENT OF DRUG ALLERGY
WITH AN INITIAL FOCUS ON
ANTIBIOTICS AND VACCINES AND
WHEN WE SAY ANTIBIOTICS WE
INCLUDE OTHER ANTIMICROBIALS
BECAUSE WE'RE TRYING TO JUMP
START THE FIELD WHERE WE WERE
WITH FOOD ALLERGY 15 YEARS OR SO
AGO.
WE STARTED RIDGE R21s.
WE HAVE A VERY ROBUST FOOD
PORTFOLIO NOW AND HOPING TO MOVE
DRUG ALLERGY IN THAT DIRECTION.
AND THE ALLERGY IS COMMON IN THE
HOSPITAL CHART.
33% OF THE CASE LINKED TO
SYLPHONOMIDES AND YOU HAVE
REACTION TO ALL THE OTHERS AS
WELL PRETTY MUCH ALL OF THEM.
WE DON'T REALLY UNDERSTAND WHAT
THE TRUE PREVALENCE IS.
WE DON'T REALLY UNDERSTAND WHY
THEY HAPPEN AND WHAT WE TELL
PEOPLE TO DO IS EXPERT OPINION
NOT DATA DRIVEN.
AND WE HAVE INCREASED SIDE
EFFECTS AND CONTRIBUTE TO
ANTIBIOTIC RESISTANCE WHICH WE
KNOW IS A HUGE PROBLEM ALL BY
ITSELF.
WE KNOW LESS ABOUT VACCINE
ALLERGY.
THE MOST COMMON HYPERSENSITIVITY
REACTION INCLUDING TOUCH AND HE
H1N1 AND mRNA VACCINES.
THERE'S A SMALL PROPORTION DUE
TO GELATIN AND EGG AND THEY SEEM
TO BE NON-SPECIFIC BUT THERE'S
REALLY NOT MUCH KNOWN ABOUT
THIS.
THERE'S CONSEQUENCES IF A PERSON
GETS LABELLED THAT AND MAY GET
MORE UNNEEDED VACCINES AND MAY
ACCOUNT FOR VACCINE HESITANCY
WHEN WORD GETS OUT THIS PERSON
HAD THIS OR THAT WITHOUT
BACKGROUND TO SAY HOW COMMON IS
THIS OR ANYTHING ELSE?
OR IMPROVE THE UNDERSTANDING OF
ALLERGY THAT ARE DIAGNOSTICS AND
INFORMATION OF MECHANISMS.
WE WANT TO GROW THE RESEARCH IN
THE FIELD AND RESEARCHERS.
IDEALLY JUNIOR RESEARCHER AND
HAVE EXPERIENCE IN THE FIELD
WE'LL TAKE THEM TOO AND
PROPOSING THE UG3 AND UH3 AND
IT'S A COOPERATIVE AGREEMENT AND
WE'LL HAVE PROJECT SCIENTISTS
WORK WITH THE INVESTIGATORS.
WE'RE ALSO PLANNING ON ANNUAL
MEETINGS TO ENCOURAGE MIXING OF
IDEAS AND UNDERSTANDING HAVING
TAKEN FROM ONE DRUG TO ANOTHER
POTENTIALLY.
THE FIRST TWO YEARS YOU PROPOSE
MILESTONES AND IF YOU MEET THE
MILESTONES YOU CAN MOVE INTO
ANOTHER THREE YEARS.
SO WE'RE MOVING FORWARD THE BEST
OF THE PROPOSALS WE GET NOT
NECESSARILY ALL OF THEM.
IF THEY WERE ALL GRET THAT WOULD
BE GREAT.
SO WE'RE ANTICIPATING FOUR OR
FIVE AWARDS.
AS I SAID IT'S A SMALL FIELD.
HOPEFULLY WE'LL GET IT MOVING.
I'D BE HAPPY TO TAKE QUESTIONS.
>>T'S A GOOD ANALOGY WHEN YOU
SAID THIS IS HOW YOU GOT THE
FOOD COVERED IN THE THEME AND AS
THE RFA GETS WRITTEN IT'S GOOD
TO ACKNOWLEDGE THAT IN THE RFA
THERE'S DESCRIPTIVE INFORMATION
NEEDED AND WHY A LOT OF GRANTS
HAVEN'T BEEN FUNDED IN THE PAST
IN THIS AREA BECAUSE THE AREA IS
BEHIND AND PEOPLE PROPOSE
DESCRIPTIVE THINGS THAT KIND OF
GET DOWNGRADED FOR THAT REASON
BUT THAT'S SORT OF FOUNDATIONAL
INFORMATION IS REALLY NEEDED.
>> RIGHT.
AND WE ARE REQUIRING MECHANISMS
IN THE UH3 BUT NOT PRELIMINARY
DATA OR IT BE MECHANISTIC IN THE
FIRST TWO YEARS.
IT COULD IN FACT INCLUDE
GATHERING THIS KIND OF DATA AND
FINDING THE RIGHT PARTICIPANTS.
THERE'S NO CLINICAL TRIAL THERE.
ANY OTHER COMMENTS?
>> ALLERGIC REACTIONS ARE WELLED
IN THE MEDICAL RECORDS IS THAT
NOT TRUE?
>> THEY'RE DOCUMENTED.
THE WELL I WOULD DISAGREE WITH.
>> WAS WONDERING IF YOU COULD
DO A LOT OF DATA GATHERING.
>> THINK THERE ARE PEOPLE
WORKING ON DHR RESEARCH AND
TRYING TO FIGURE OUT WHAT IS
DOCUMENTED AND WHAT IT ACTUALLY
MEANS AND THEN THEY COULD FOR
INSTANCE TAKE THOSE IN THE
MECHANISMS.
THESE PEOPLE ALL SAY THEY HAVE
HAD STEVEN JOHNSON TO X.
WHAT CAN WE FIND OUT ABOUT THOSE
PEOPLE.
IF YOU'RE GOING TO DO GENOMICS
HLA IS LINKED TO DRUG
SENSITIVITY.
IF YOU'RE DOING GENOMICS --
>> THINK IT'S OVER DOCUMENTED.
>>T IS.
THIS IS ABSOLUTELY CLEAR IF YOU
TEST PEOPLE FOR JUST PENICILLIN
ONLY 10% OF THOSE ACTUALLY ARE
PENICILLIN ALLERGIC BUT THAT'S
THE ONLY DRUG WE CAN TEST.
THANK YOU.
>> YOU THUD BE ONLINE.
>>'M HERE.
>> THANKS.
>>'M ARI JOFFE AND I'LL BE
PRESENTING WHAT IS THE FINAL
INITIATIVE CONCEPT OF THIS
SESSION.
THIS IS TITLED UNDERSTANDING
MECHANISMS OF TRAINED IMMUNITY.
TO BRIEFLY INTRODUCE THIS THINK
OF IT AS INNATE IMMUNITY BEING
EXPOSED TO PATHOGENS AND IT'S
DIFFERENT FROM TRADITIONAL
ADAPTIVE COMMUNITY THINKING OF T
CELLS AND B CELLS.
ONE WAY IT'S DIFFERENT IS IT'S
NOT SPECIFIC AND SPECIFIC TO ONE
ANTIGEN AND IT'S REALLY MORE OF
A WAY IN WHICH CELLS ARE PRIMED
AND RESPOND TO SUBSEQUENT
CHALLENGES.
THERE'S A LOT MECHANISMS AND
THERE'S EPIGENETIC ALTERATIONS
IN THE IMMUNE CELLS AND
METABOLIC REWIRING AND YOU HAVE
A MACROPHAGE WHICH UNDER GOES
STIMULATION AND BECOMES ACTIVATE
AND WHEN IT GOES BACK TO ITS
RESTING STATE IT'S DISTINCT FROM
THE NAIVE STATE AND MAY HAVE A
DIFFERENT EPIGENETIC LANDSCAPE
AND WILL RESPOND DIFFERENTLY
UPON A SUBSEQUENT STIMULATION.
BACK IN 2021 THERE WAS A
NON-SPECIFIC EFFECTS OF VACCINES
AND SOME TAKEAWAYS WERE THAT
TRAINED IMMUNITY OFFERED A
LIKELY EXPLANATION OF
NON-SPECIFIC VACCINE EFFECTS BUT
ALSO THERE'S A LOT TO BE LEARNED
HERE SO WE NEED A BASIC
UNDERSTANDING OF TRAINED
IMMUNITY BEFORE THE CONCEPT CAN
BE MORE BROADLY APPLIED AND
EFFICIENTLY APPLIED TO VACCINES
AND THERAPIES.
FURTHER SCIENTIFIC GAPS
IDENTIFIED ARE WE NEED
IDENTIFICATION OF BIO MARKERS
ASSOCIATED WITH THE CELL
TRAINING AND WE NEED TO KNOW
MORE ABOUT THE DURATION AND
PLASTICITY AND FUNCTIONAL
SIGNIFICANCE OF THE SIGNATURES
AND FINALLY A LOT MECHANISTIC
UTILITIES NEED TO BE UNCOVERED
INCLUDING HOW CELLS ARE TRAINED
IN THE FIRST PLACE AND ONCE
THEY'RE TRAINED HOW THE INNATE
MEMORY FUNCTIONS DURING
SUBSEQUENT CHALLENGES.
WITH APPLICATIONS WE HAVE
RECEIVED IN THE PAST.
THERE'S INCREASING INTEREST IN
THIS FIELD WHICH IS RELATIVELY
NEW.
YOU CAN SEE IT IN THE RO1
APPLICATIONS THAT MENTION THE
TERM TRAINED IMMUNITY.
YOU CAN SEE THE DEFINITE
INCREASE IN THESE APPLICATIONS
THOUGH THEY'RE NOT NECESSARILY
AN INCREASE IN THE AMOUNT
FUNDED.
WHEN YOU DIG INTO THE
APPLICATION OF THE ACTIVELY
FUNDED GRANTS THERE'S ONLY FIVE
EXPLORING FUNDAMENTAL ASPECTS OF
TRAINED IMMUNITY.
AND SOME OF THE POTENTIAL
BARRIERS FOR FUNDING HERE ARE
THE IDENTIFICATION OF NOVEL
BIOMARKERS WHICH IS NEEDED HERE
IS REALLY DESCRIPTIVE IN NATURE
AND AS DISCUSSED IN THE LAST
PRESENTATION THE PROJECTS DON'T
NECESSARILY FARE WELL AND
THERE'S TRAINED IMMUNITY AND I'D
ARGUE WE'RE TOO EARLY IN THE
FIELD TO SAY WHETHER THIS IS
VALID OR NOT.
THE PROPOSED INITIATIVE FOR
FISCAL YEAR 2025 IS
UNDERSTANDING MECHANISMS AND
OUTCOMES OF TRAINED IMMUNITY.
THIS WOULD BE PAR, PROGRAM
ANNOUNCEMENT WITH SPECIAL REVIEW
CONSIDERATIONS AND THE OBJECTIVE
WOULD BE TO SOLICIT PROJECTS
THAT AIM TO DEFINE BIOMARKERS
AND TRAINED IMMUNITY PROJECTS
BEING SUBMITTED TO THIS AND THEN
WE MAKE AN ALLOWANCE FOR
DESCRIPTIVE STUDIES.
THE MECHANISM RO1 AND R21 AND
FIVE YEARS FOR THE RO1 AND TWO
YEARS FOR THE R21.
I'M HAPPY TO TAKE ANY QUESTIONS
IF THERE ARE ANY.
ASK
>>T SEEMS THERE ARE NOT.
>> OKAY.
THANK YOU.
>> ALL RIGHT, BEFORE WE GO AHEAD
TO THE ON BLOCK RECOMMENDATION I
NEED TO BRING TO COUNCIL'S
ATTENTION TWO NOTICES OF SPECIAL
INTEREST IN THE ELECTRONIC
COUNCIL BOOK.
THE SECOND IS RNA DELIVERY
TECHNOLOGY TO ALLOW SPECIFIC
TISSUE HONING BECAUSE THESE ARE
NOTICES OF SPECIAL INTEREST OR
NOSIS AND WE'LL NOT KEEP YOU
LONGER FOR DISCUSSION OF THOSE.
AT THES POINT I'M GOING ASK FOR
UNBLOCK RECOMMENDATION IN THE
SECOND FOR THE CONCEPT CLEARANCE
US YOU HEARD.
SECOND FROM A COUNCIL MEMBER.
OKAY, THAT WRAPS US UP FOR
TODAY.
THANK YOU TO ALL OF OUR STAFF
AND SPEAKERS THIS AFTERNOON.
THIS IS A VERY ENJOYABLE SESSION
AND LOTS OF GOOD SCIENCE.