>> GOOD AFTERNOON EMPLOY MY NAME
IS EDCALLAN AT NIAMS AND IT'S MY
GREAT PLEASURE TO WELCOME YOU TO
TODAY'S CLINICAL CENTER
CONTEMPORARY MEDICINE GREAT
TEACHERS GRAND ROUNDS.
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PERMITS.
TODAY WE ARE EXCITED TO ANNOUNCE
DR. YOUN KIM, WORKING AT
STANFORD UNIVERSITY SCHOOL OF
MEDICINE AND DIRECTOR OF
STANFORD'S MULTIDISCIPLINARY CUE
TAINIOUS LYMPHOMA PROGRAM.
DR. KIM RECEIVED HER BACHELOR'S
IN WELSY COLLEGE AND EARNED HER
MEDICAL DEGREE FROM STANFORD
SCHOOL OF MEDICINE AND COMPLETED
AN INTERN HELP AT KAISER
PERMANENT AT SAN FRANCISCO AND
REPORTING RESIDENCY IN
DERMAATOLOGY AT STANFORD.
THE STANFORD MULTIDISCIPLINARY
CUE CUTEAINIOUS LYMPHOMA, NOVEL
DISCOVERY AND SHE AND HER
COLLEAGUES ARE EVALUATING A
NUMBER OF CUTTING EDGE
MODALITIES INCLUDING CELL
THERAPY, VACCINATION, IMMUNE
CHECK POINT BLOCKADE AND ALOE
GENERATED AIC HEMATOPOIETIC STEM
CELL TRANSPLANT.
DR. KIM HAS AUTHORED OVER 200
ARTICLES AND HAS BEEN A
PRINCIPAL OR CO INVESTIGATOR ON
OVER 40 CLINICAL TRIALS.
SHE HAS LED KEY CONSENSUS
PROJECTS IN THE PRACTICE OF
LYMPHOMA, MANAGEMENT AND SHE'S
GLOBAL CO LEADER OF THE
CUTANEOUS LYMPHOMA INTERNATIONAL
CONSORTIUM.
SHE ALSO SERVESOT CUTANEOUS
BOARD, SHE HAS ALSO EARNED THE
JAMES MARK AWARD FOR EXCELLENCE
IN PATIENT CARE AND THE
DISTINGUISHED SERVICE AWARD FROM
THE DEPARTMENT OF DERMATOLOGY,
HER TALK IS ENTITLED INTEGRATING
NEWER THERAPIES IN ADVANCED
SPEAKER CTL.
PLEASE WELCOME OUR SPEAKER
DR. YOUN KIM.
>> THANK YOU SO MUCH DR. CALLAN,
I WILL SHARE MY SCREEN.
TRUSTEES YOU GO SO HOPEFULLY YOU
HAVE MY SLIDES.
THANK YOU.
I WANT TO THANK DR. COWEN FOR
THIS INVITATION AND IT'S A GREAT
PLEASURE AND PRIVILEGE TO
ADDRESS ALL THE MENTORS,
COLLEAGUES AND TRAINEES AT THE
NE H AND I MET THE MRSP MENTEES
THIS MORNING, IT WAS IMPRESSIVE
GROUP OF FUTURE LEADERS AND I'M
SO DPLAD THAT NIH IS SUPPORTING
SUCH TRAINING.
SO TODAY EMBRACE YOUR TIME, I
WILL BE TALKING ABOUT A REALLY
RARE DISEASE GROUP CUTANEOUS
T-CELL LYMPHOMA, SPECIFICALLY
MYCOSIS, FUNNINGOIDS AND SEZARY
SYNDROME.
WE'VE MADE THERAPEUTIC ADVANCES
AND HOW WE CAN HELP OUR
PATIENTS.
MY DISCLOSURES.
AND BRIEFLY THE LEARNING
OBLIGATIONS YECTIVES THIS
MORNING WOULD BE TO HELP YOU
APPRECIATE THE HETEROGENEITY,
CLINICALLY, PATHOLOGICALLY AND
GENETICALLY IN THIS RARE DISEASE
GROUP AND HOW TREATMENTS THAT WE
HAVE, WORK VERY DIFFERENTLY IN
DIFFERENT DISEASE COMPARTMENTS
AND THE SKIN, LYMPHNODE AND
BLOOD AND WE HAVE TO WORK BETTER
AT ALIGNING PEASHTS WITH THE
TREATMENT PROFILE AND HOW WE GO
ABOUT DOING HAD AND HOW WE NEED
TO MAKE MUCH MORE PROGRESS IN
THE FUTURE.
IN ORDERED TO DO THIS, IT IS
VERY VITAL THAT WE WORK AS A
COLLABORATIVE GROUP,
INTERDISCIPLINARY AND IN
CUTANEOUS LYMPHOMA THE DISPLENS
THAT ARE MORE RELEVANT WOULD BE
DERMATOLOGY, MEDICAL ONCOLOGY,
MEDICINE, CELL THERAPY,
RADIATION ONCOLOGY, MORE MAN
SURGICAL ONCOLOGY AND THEN
PATHOLOGY FOR DIAGNOSTICS AND
OUR OTHER PARTNERS.
THIS IS OUR MULTIDISCIPLINARY
GROUP, LEADERS AT STANFORD, NOT
ONLY DID IT SHOW THAT WE HAVE
KEEP PICTURES WHEN WE WERE
YOUNGER, BUT WE DO HAVE LEADERS
THAT ALSO HAVE OUR COLLABORATIVE
PARTERS WITHIN, SO WE HAVE
DERMATOLOGY, RADIO ONCOLOGY,
CELL THISSER ACTIVITIES AND
PROJECTSY TRANSPLANT PART MERAND
IMPORTANTLY MICHAEL KHODADOUST
IS OUR TRANSLATIONAL RESEARCH
LEAD AND MEDICAL ONCOLOGY
PARTNER.
I WILL START WITH A LITTLE
OVERVIEW FOR THOSE WHO DO NOT
KNOW CTCL WELL.
[INDISCERNIBLE] MAKE UP A
MAJORITY OF THE CTCLAND IT'S
STILL IN THE RARE ORPHAN DISEASE
CATEGORY, IT'S UNIQUE IN THAT
THE CLINICAL DISEASE AND HIGHLY
HETEROGENIUS NOT ONLY WITHIN THE
PRIMARY SKIN COMPARTMENT BUT
ACROSS THE EXTRA CUE TAINIOUS
COMPARTMENTS, BEYOND THE
INTERPATIENT DIFFERENCES THERE'S
NOTABLE INTRA PATIENT
VARIABILITY WHERE WITHIN A
PATIENT THERE COULD BE A MIX OF
PATCH LIKE TUMORS AND THERE
COULD BE MIXED RESPONSES OF A
TREATMENT ACROSS ALL THESE TYPE
OF SKIN LESION ANDS COMPART AMS.
AND TO ADD TO THE CHALLENGE IN
THIS RARE DISEASE WITH
HETEROGENEITY, WE OFTEN LACK
ROBUST DATA BECAUSE IT IS A RARE
DISEASE, SO EVIDENCE BASED
DECISION MAKING IS QUITE
CHALLENGING AT TIMES AND WE HAVE
TO PERSONALIZE TO THE MAXIMUM OF
TREATMENT, IT'S VERY HIGHLY
INDIVIDUALIZED.
IN ADDITION TO THE CLINICAL
HETEROGENEITY, PATIENTS OFTEN
HAVE A DIVERSE PROFILE OF
HISTOPATHOLOGY, WITH LESION TO
LESION IMMUNO TYPIC VARIABILITY
WITHIN A PATIENT.
AT THE GENETIC LEVEL WE OBSERVE
NOTABLE HETEROGENEITY ACROSS
PATIENTS AND PATIENT'S GENETIC
DATA OR GENOMIC TESTING HAS NOT
SERVED AS A USEFUL CARE STANDARD
AT THIS TIME, HOWEVER, WITHIN
THE HETEROGENEITY THERE ARE
COMMONALITIES THAT SHARE
MECHANISM ANDS PATHWAYS, FOR
EXAMPLE, IN THE T-CELL SPECIFIC
PATHWAYS LIKE THE TCR,
SIGNALING, AND THUS IN THE
FUTURE WE HOPE WE WOULD HAVE
MORE MOLECULARLY TARGETED
THERAPIES AND GUIDES.
BECAUSE OF THE HETEROGENEOUS ORY
GENERATED AITY LARGELY WHAT
DIRECTS OUR MANAGEMENT AND
CLINICAL FACTORS AND CLINICAL
STAGE.
DISEASE SEVERITY IN THE
COMPARTMENTS, SKIN AND EXTRA
CUTANEOUS DEPARTMENTS AND
PRESENCE OF WHAT WE CALL LARGE
CELL TRANSFORMATION WHERE
DISEASE BECOMES MORE AGGRESSIVE,
WITH LARGE CELL AND MORE HIGH
PROLIFERATIVE INDEX.
THOSE GUIDE OUR MANAGEMENT.
THE CLINICAL RISK STRATIFICATION
APPROACH IS SUPPORTED BY OUR
LARGE COLLABORATIVE PROJECT IN
THE ADVANCED MS AND SS IN THE
CONSORTIUM WHICH OOH DEBTIFYS
LOW, MEDIUM AND HIGH RISK
CATEGORIES OF PASHTS WHERE THE
HIGHER RISK PATIENTS WE ARE MORE
ALIGNED WITH AGGRESSIVE
THERAPIES AND THE LOWER RISK AND
WITHIN THE ADVANCED DISEASE
EMPLOY IN THE EARLY STAGE
DISEASE, SKIN-DIRECTED THERAPIES
PLAY A LARGE ROLE, AND SYSTEMIC
THERAPIES ARE RE7ED MORE FOR
THOSE REFRACTORY FOR SKIN
THERAPIES, OR IN THE ADVANCED
DISEASE.
ALSO UNIQUE IN CT CELL IS THE
UTILITY OF TOTAL SKIN ELECTRON
BEAM WHERE YOU CAN GIVE
RADIATION TO THE ENTIRE SKIN
SURFACE AND YOU CAN SEE IN THIS
PATIENT, IT COULD BE HIGHLY
EFFICIENT AND DEBULKING THE SKIN
DISEASE AND RADIATION STILL
REMAINS AS THE MOST SINGLE
RELIABLE THERAPY DESPITE ALL THE
MEDICAL THERAPY ADVANCES SO
RADIATION IS A VERY IMPORTANT
COMPONENT.
IN THE ADVANCED DISEASE, THE
LARGE CELL TRANSFORMATION, AS I
ALLUDED TO IS A VERY IMPORTANT
FACTOR BECAUSE IT IS SOSHT WIDE
MORE AGGRESSIVE BEHAVIOR AND
THAT THUS IT WILL LEAD TO US
INTENSIFYING THERAPY EARLIER.
DEC STATUS AND SEVERITY OF THE
EXTRA CUE TINIOUS DEPARTMENTS,
LYMPHNODE, VISCERA, BLOOD, ALL
DICTATE TREATMENT CHOICES, GIVEN
THAT COMBINATION THERAPIES AS
COMBINATION CHEMO THERAPYS THAT
ARE USED IN SYSTEMIC T-CELLS AND
LYMPHOMAS, GIVE SHORT RESPONSE,
SINGLE SYSTEMIC THERAPIES ARE
STILL THE MAIN MODALITY AND THE
ADVANCED DISEASE TO GET MORE
LONG-TERM UTILITY AND MILEAGE
OUT OF OUR THERAPIES AND
COMBINATION THERAPIES ARE USED
MORE TO BRIDGE TOWARDS AN ALALOE
GENERATED AIC TRANSPLANT.
THE UNICK QUALITIES OF PATIENTS
CHALLENGES, NOT ONLY WITH THE
VISUAL ASPECT THAT DEBILITATES
BUT THE ITCHING AND PAIN THAT
OUR PATIENTS SUFFER REQUIRING
INTENSIVE SKIN CARE ISSUES IT'S
VERY DEMANDING ON THE PATIENT
AND THE FAMILY, THUS QUALITY OF
LIFE ELEMENTS MAY LEAD TO
DECISION TO CHANGE TREATMENT
BEFORE AN OBLIGATIONS YECTIVE
DISEASE PROGRESSION, THIS
COMPLICATING OUR DEC PROGRESSION
SURVIVAL TYPE OF DATA.
IT'S IMPORTANT TO INTEGRATE THE
QUALITY OF LIFE TOOLS IN OUR,A
ASSESSESMENT OF MEANINGFUL
THERAPIES, TO OPTIMIZE
SUPPORTIVE CARE TO IMPROVE
QUALITY OF LIFE IS ESSENTIAL.
SO MEANINGFUL, THERAPIES, IN OUR
DISEASE AND CTCL IS COMPOSED OF
A TREATMENT THAT CAN GIVE
DURABLE RESPONSE, SO NOT
COMPLETE RESPONSE THAT LASTS A
MONTH BUT WE WANT A GOOD
RESPONSE THAT'S MORE DURABLE.
AND BECAUSE A DISEASE IS MORE
CHRONIC WE NEED ACCEPTABLE
CUMULATIVE TOXICITY, AND NOT
JUST A SHORT-TERM DLT, THAT ARE
IMPORTANT IN TRIALS BUT
CUMULATIVE THEY CAN TOLERATE
OVER LONG PERIODS OR RETREATMENT
AND IMPROVE LIFE QUALITY.
SO A BALANCE OF ALL 3 FACTORS
CONSTITUTES A SUCCESSFUL
MEASUREMENT OF THERAPY IN CTCL.
THIS IS IMPORTANT BECAUSE
OBVIOUSLY OUR DISEASE IS MORE OF
A CHRONIC THAN PAN KRISTATTIC CA
WHERE OVERALL SURVIVAL MAY BE
THE PRIMARY END POINT.
SO IN TERMS OF LANDSCAPE OF
TREATMENT, WE'VE HAD A LOT OF
PROGRESS OVER THE LAST DECADE,
STARTING FROM THE MOLECULAR
DRIVERS THAT'S BEEN DECODED AND
IN 2015 THERE ARE MANY SERIES OF
PUBLICATION THAT DRIEB THE
MOLECULAR PATHOGENESIS IN CTCL,
STARTING WITH THAT, WE WERE ABLE
TO DO MORE MOLECULARLY OR
BIOMARKER TARGETED THERAPIES.
WE COULD DESCRIBE OUR THERAPIES
IN CTCL IN TARGETING 3 AREAS,
FIRST WOULD BE THE SURFACE
TARGETS AND WE HAVE A LOT OF
PROGRESS IN IDENTIFYING SPECIFIC
SURFACE TARGETS OF THE CTCL
CELLS AND STREAM OF ANTIBODIES,
AND OTHER SURFACE TARGETED
THERAPIES HAVE BEEN DEVELOPED
SINCE.
THAT INCLUDES THE THERAPIES
SOLICITED HERE BUT MUCH MORE
THAN THAT, AND THE GENOMIC
HETEROGENEITY IN OUR DECS
CHALLENGING IN EMERGING ITS OF
TARGETING SPECIFIC PATHWAYS
BECAUSE IT'S HETEROGENIUS BUT WE
HAVE BEEN ABLE TO AS I MENTIONED
IDENTIFY COMMON PATH BAYS
WHETHER IT BE TCR, JACK STAT,
SURVIVAL PATHS THAT ARE COMMON
THAT COULD BE TARGETED NOW WITH
THE BETTER MOLECULAR TOOLS AND
THIS IS VERY IMPORTANT
ESPECIALLY IN THE REFRACTORY
SETTING THAT I WILL DESCRIBE
LATER.
AND OBVIOUSLY IMPROVING THE HOST
IMMUNE SYSTEM TO FIGHT, TO
IMPROVE THE ANTITUMOR ACTIVITY,
INCLUDING CHECK POINT INHIBITORS
HAVE BEEN DEVELOPED AND IS VERY
IMPORTANT TO INTEGRATE INTO OUR
TREATMENT ALGORITHM, OBVIOUSLY
WE NEED TO WORRY ABOUT POTENTIAL
HYPEY PROGRESSION IN T-CELL
LYMPHOMA WITH CHECK POINT
INHIBITORS BUT WITH APPROPRIATE
PATIENT SELECTION AND BIOMARKERS
THAT CAN HELP GUIDE, WE HOPE TO
UTILIZE THESE VERY WELL.
AND IN CTCL, IN MOST CASES NOT A
SINGLE THERAPY IS THE HOME RUN,
BUT WE NEED TO COMBINE
TREATMENTS WITH SKIN DIRECTED OR
SYSTEMIC COMBINATIONS TO
OPTIMIZE TREATMENT.
TO DEMONSTRATE HOW IN REAL LIFE
WE CAN UTILIZE THESE THERAPIES,
BECAUSE IN REAL LIFE CLINICAL
MANAGEMENTS VERY CHALLENGING,
AGAIN BECAUSE OF THE
HETEROGENEITY.
I WILL USE 2 SPECTRUM OF PATIENT
THAT COMMONLY PRESENTED IN OUR
CLIPPIC TO DEMON TRAIT THIS, SO
IN THE LEFT, WE HAVE A PATIENT
WITH MF TUMOR CELL DISEASE THAT
IS A LARGE TRANSFORMATION THAT
CAN RESPENT TO YOU IN THE CLINIC
AND ON THE RIGHT IS LCT, THAT
CAN PRESENT, AND WHEN HAVE YOU
NOT MANAGED A LOT OF PATIENTS
YOU TRY TO LOOK FOR GUIDE LINE
AND YOU GO TO THE NCCN GUIDELINE
AND IN THE GUIDELINE YOU HAVE A
LISTING MENU OF TREATMENT
OPTIONS, AND THAT 1 SINGLE FRONT
LINE REGIMEN THAT YOU CAN START
WITH, THIS KIND OF TELLS YOU
THAT THERE'S NO
ONE-SIZE-FITS-ALL FRONT LINE
CHOICE AND YOU HAVE TO REALLY
PERSONALIZE TO MATCH THE PATIENT
PROFILE IN THIS VERY DIVERSE
DISEASE GROUP.
THAT KIND OF LEADS YOU TO, WELL,
THEN IN WITH ALL THE TREMES THAT
ARE IN THE LISTING FASHION AND
THE PATIENT PROFILE THAT'S VERY
HETEROGENIUS, WHAT HAPPENS YOU
DECIDE IN PICKING THE RIGHT
TREATMENT?
SO WE HAVE SPENT TIME IN TRYING
TO GIVE A FRAMEWORK OF
MANAGEMENT, FOR OUR CLINICAL
CARE PROVIDERS, SO, IN OUR
DISEASE, WHEN THERE'S SKIN,
BLOOD, AND VISA AND THAT COULD
BE A DYNAMIC PROCESS SO YOU NEED
TO UPDATE THAT WITH PATES CHANGE
IN THERAPY AND YOU NEED TO
CHARACTERIZE THE COMPARTMENTAL
DISEASE, AND THE BURDEN, AND
THEN YOU HAVE OTHER FACTORS TO
CONSIDER INCLUDING LARGE CELL
TRANSFORMATION THAT I ALLUDED
TO, POTENTIAL ACTIONABLE TARGETS
WHICH ALSO CAN CHANGE OVER TIME
SO THOSE HAVE TO BE
CHARACTERIZED AND IMPOSSIBLE TO
BUILD GREATED AND TO HIGHLIGHT
HOW WE MIGHT UTILIZE THESE KIND
OF INFORMATION, I HAVE THIS
DIAGRAM ON THE RIGHT WHICH IS AN
EXAMPLE OF THE KEY TREATMENTS
THAT WE WILL USE IN CTCL, AND
THE COLOR CODE IS THAT GREEN IS
WHERE THERE'S EVIDENT, CARCKER
GREEN BEING MORE EVIDENT, AND
THE LIGHTER GREEN, AND THE RED
DENOTES, WHERE WE HAVE LESS
EVIDENT OR LACK OF ACTIVITY IN
THAT DISEASE PROFILE.
FOR EXAMPLE, PATIENTS WITH
THICKER SKIN DISEASE WITH
TRIMMER NODULES, THICK SKIN AND
TRANSFORMATION GEOGAFFIC DEC
PROFILE, THE DATA SHOWS THAT
BRENTUXIMAB, WHICH I WILL SPEAK
ABOUT LATER ON, WHEREAS
ROMIDEPSIN, AND WORKS BETTER
WITH SKIN INVOLVEMENT BUT DOES
NOT ALIEP WELL WITH THE
TRANSFORMED THICKER SKIN DISEASE
PATES WHEREAS THE OTHER TREMES
LIKE PRALATEXATE, AND CAN HELP
WITH OTHER SKIN TYPES BUT THE
DAILY BASIS THEA IS MUCH LESS
ROBUST, AND WE MAY NOT USE THEM
UPFRONT IN THAT DISEASE, BUT
THEY ARE GREAT CHOICES TO HAVE.
TO DEMON TRAIT THIS FURTHER WE
WILL USE OUR PATIENT AS AN
EXAMPLE, AND KEEPING THAT
FRAMEWORK IN MIND, WE WILL GO
THROUGH THE PATIENT'S PATH.
SO THIS PEASHT IS AN ERYTH ROUGH
ATOM DERMIC PATIENT WITH, SO
SKIN ELITHE ROUGH ATOM DERMA, NO
LYMPHNODE DISEASE AND NO
VISCERAL DISEASE.
SO WHAT ALIGNS WELL WITH THAT
KIND OF PEASHT PROFILE AGAIN IS
THIS MOBAMAZAB, AND IT WAS A
RANDOMIZED CONTROL TRIAL, HAS
GREAT ACTIVITY IN THE BLOOD
COMPART AM AS YOU CAN SEE,
COMPARED TO OTHER DRUGS, HIGH
AMOUNT, HIGH PERCENTAGE OF
COMPLETE RESPONSES IN THE BLOOD
THAT'S HIGHLY DURABLE SO IF YOU
HAVE A PATIENT LIKE HOURS WITH
HIGH BLOOD DERMA, SELECTING
MOIMRKS AMULIZUMAB WOULD BE A
GOOD CHOICE IN THIS PATIENT.
I WANT TO EXPAND ON HOW
MOGAMULIZUMAB HAS BEEN APPROVED
IN PTCL, AND CTCL AND BECAUSE
NOT ONLY IS IT OVEREXPRESSED IN
THE CELLS, IN JAPAN IT WAS
APPROVE INDEED ATL AND THEN WE
BORROWED IT TO ADVANCE IN CTCL
AS WELL, BECAUSE THE TARGET IS
VERY RELEVANT.
NOT ONLY IS IT HIGHLY EXPRESSED
IN THE TUMOR BUT KRRK CL 4 IS
HIGHLY EXPRESSED IN TREGULATORY
CELLS AND IT HAS A DUAL
EFFECTIVE IMMUNE AUGMENTATION BY
DEPLETING TREGS WHICH MAY HAVE A
NEGATIVE INHIBITORY EFFECT FOR
YOUR IMMUNE SYSTEM AS WELL AS
DIRECTLY TARGETING THE TUMOR
CELLS.
SO AGAIN, WANTED TO USE
MOGAMULIZUMAB AS AN EXAMPLE, AND
HOW WE LEARN ABOUT THE
RESISTANCE MECHANISMS WHICH
WOULD LEAD TO UNDERSTANDING HOW
WE CAN COMBINE OUR SEQUENCE
DRUGS BETTER.
SO AGAIN, MOGAMULIZUMAB WAS
APPROVED, IT WAS APPROVED IN
2018 AND THE TRIAL THAT LED TO
THE APPROVAL WAS CALLED
MAVERICK, WHICH EXCLUDED
ACTUALLY LARGE CELL
TRANSFORMATION.
OF PATIENTS BECAUSE, IN THE
EARLIER PHASE TRIALS,
MOGAMULIZUMAB DID NOT HAVE GOOD
ACTIVITY IN THE AGGRESSIVE LCT,
BUT HAD MORE ACTIVITY IN THE
LEUKEMIC DISEASE, AND THE
PIVOTAL TRIAL DID CONFIRM THAT
IT HAS MORE ACTIVITY IN THE
SENSORY SEN ILLEGALSEN DROAM
WHICH IS A LEUKEMIC PROFILE AND
GREAT ACTIVITY IN THE BLOOD
COMPARTMENT, VERY RAPID RESPONSE
THAT'S VERY DURABLE, IF THEY
DIDN'T HAVE AS GREAT ACTIVITY IN
THE THICKER TUMOR DISEASE, NOR
IN THE LYMPHNODES SO CLEARLY
PROOF THAT LEUKEMIC DISEASE WAS
A BETTER MATCH FOR
MOGAMULIZUMAB.
AND IT TURNS OUT THAT THE
LONG-TERM RESPONDERS THAT
BENEFIT MORE THAN 12 MONTHS,
DURABLE RESPONSE FOR 12 MONTHS,
MOST OF THEM ARE SYNDROME
PATIENTS.
SO AGAIN, IF YOU HAVE A SENSORY
PATIENT, THICKER DISEASE, THAT
WOULD MATCH WITH THIS DRUG.
OF THE SIDE CENTER FOR
EXCELLENCE ON AGINGS OF
MOGAMULIZUMAB, IT'S VERY
IMPORTANT FROM THE TOXICITIES
BECAUSE IT COULD BE A CLUE AS TO
WHETHER IT'S A GOOD MARKER AS
WELL.
SO MAR HAS BEEN SEEN VERY UNIQUE
TO THIS DRUG, AND IT'S
NOVEMBER-IN THE TRIAL IT WAS
ABOUT INCIDENCE WAS ABOUT 25%
BUT IN THE REAL WORLD
EXPERIENCE, THE RASH IS MUCH
MORE PROBLEMATIC, MUCH HIGHER IN
INCIDENCE, AND WE NEEDED TO
LEARN A LITTLE BIT MORE ABOUT
THE RASH BECAUSE IN A CTCL
PATIENT WITH CUTANEOUS DISEASE,
WHEN YOU GET A RASH, IT COULD BE
VERY CHALLENGING, IS IT A RASH?
OR IS IT THE DISEASE
PROGRESSING, GETTING WORSE?
AND YOU CAN SEE ON THE RIGHT,
THE RASH COULD BE VERY
HETEROGENIUS AND PHOTO
SENSITIVE, OR IT COULD BE TUMOR
NODULAR TYPE OF LESIONS BUT IT'S
NOT COMPOSED OF CTCL CELLS BUT
MORE EFTHIMIOSIO SIDIC AND OTHER
REACTIVE INFILTRATE BUT IT LOOKS
LIKE IT COULD BE LYMPHOMA, THUS
WE NEED TO BIOPSY WHEN WE ARE
SUSPECTING IT, KNOWING THE
CLONALITY OF THE DISEASE AND
IMMUNO PHENOTYPE OF THE ORIGINAL
DISEASE HELPS US DISTINGUISH THE
RASH.
THE RASH IS HIGHLY MANAGEABLE,
AND IT DEPENDS ON THE SEVERITY
OF THE RASH, WHERE WE USE MILD
TREATMENT, WHERE WE HAVE TO STOP
THE DRUG AND DO MORE, BUT IT
TURNS OUT, YOU MAY ASK, IS THIS
RASH, A GOOD THING OR A BAD
THING FOR THE PATIENTS IT TURNS
OUT THAT THE MORE WITH PATIENT
WHO IS DO BETTER, SO YOU CAN
TELL IN SENSORY PATIENT, WE SELL
MORE OF THE MAR AND IT'S
PROBABLY A REFLECTION THAT
MOGAMULIZUMAB WHICH IS AN IMMUNE
THERAPY AND ACTIVITIES AND
PROJECTS THAT'S DEPENDS ON
ADCC MAY BE IMPEDIMENTSUNE
ACTIVITIES MORE ROBUST IN THOSE
PATIENTS WITH MAR, AND CLEARLY
IN THE STUDY WE DID AT STANFORD,
WITH MOGAMULIZUMAB, WE LOOKED AT
RESPONDERS TO MOGAMULIZUMAB AND
NONRESPONDERS, RED FOR THOSE
WITH MAR POSITIVE AND BLUE DOTS
ARE THOSE WITHOUT MAR, YOU CAN
SEE THAT PATIENTS LO LOCATED AND
ENRICHED IN THE RESPONDERS, KIND
OF SAYING THAT WELL, AGAIN, IT'S
A PASSIVE THING THAT WE SEE WITH
THE RESPONDERS OR IS THAT A
REFLECTION OF GOOD IMMUNE
ACTIVITY IN THAT IS DETERMINED
BUT CLEARLY WHEN YOU HAVE A
PATIENT WITH THIS BAD RASH, NOT
ONLY DOES IT GO WITH MORE
RESPONSE, BUT ALSO, THE DURATION
OF RESPONSE IN OUR TIME TO NEXT
TREATMENT, AND PFS, THE PATIENTS
WITH RED LINE WHICH IS THE MAR
PATIENTS, HAVE MUCH MORE
BENEFIT, SO YOU MAY BE A GOOD
THING, WE CAN REASSURE THE
PATIENTS THAT ALTHOUGH IT'S A
VERY ANNOYING TYPE OF SIDE
EFFECT, THAT IT MAY BE A GOOD
FACTOR, A GOOD RESPONSE MARKER,
HOWEVER THOSE WITHOUT MAR CAN
ALSO HAVE GOOD RESPONSE, SO WE
STILL NEED TO UNDERSTAND MORE
AND MAYBE ONCE WE UNDERSTAND
THAT, WE CAN AUGMENT THOSE
FACTORS TO IMPROVE THE DRUG
ACTIVITY.
AS I MENTIONED THIS DRUG IS
HIGHLY ACTIVE IN LEUKEMIC
DISEASE AND NOT AS ACTIVE IN THE
THICKER DISEASE IN THE SKIN OR
LYMPHNODE OR IN THE TRANSFORM
AGGRESSIVE DISEASE.
SO ONCE THIS--WE WANT TO
LEVERAGE OFF OF ITS POWER, THE
GOOD ACTIVITY AND IN PATIENTS
WITH THICKER DISEASE, WITH
LEUKEMIC INVOLVEMENT, HOW CAN WE
COMBINE TREATMENTS TO OPTIMIZE
AND MAXIMIZE UTILITY OF
MOGAMULIZUMAB, SO THAT LEADS TO
MAXIMIZING EFFICACY WITH
ACCEPTABLE TOXICITIES, FOR
EXAMPLE, WE CAN COMBINE THAT
WITH A TREATMENT THAT REALLY
BEBUNKS THE SKIN DEC WELL WHICH
IS THE RADIATION, SO WE HAVE A
TRIAL AT STANFORD AND A TRIAL
THIS BY THE EUROPEAN COLLEAGUES
THAT WOULD COMBINE THE ACTIVITY
OF THE TOTAL SKIN IN
MOGAMULIZUMAB GETTING AT THE
BEST OF BOTH SIDES OF ACTIVITY
AND COMBOYNING BOYNING--COMBINI.
AND THEN ALSO SUSTAINED THE
DISEASE RESPONSE, AND THEN WE
HAVE OTHER DRUGS THAT CAN BE
COMBINED, WITH MOGAMULIZUMAB,
THAT COULD IMPROVE THE
COMBINATION ACTIVITY, ALSO THAT
WE CAN LOOK AT IMMUNE SYNERGY OF
AUGMENTATION WITH ACTIVITY, AND
THAT INCLUDES COMBINING WITH
ANTICD47, WHICH HAS BEEN SHOWN
TO HAVE HAD GREAT ACTIVITY, AND
WE'RE USING PATIENT CELL LINES
AND THERE'S A CLINICAL TRIAL
THAT WAS DEVELOPED TO COMBINE
THE 2 DRUGS, AND UNFORTUNATELY
WE WERE JUST TOLD THAT UTILITY
AND HEMEAT O LOGIC MALIGNANCY IS
HAS BEEN HALTED SO UNFORTUNATELY
DUE TO SOME SIDE EFFECTS IN THE
AML PATIENTS, BUT IT WAS A
VERY--POTENTIALLY A VERY GOOD
COMBINATION OF SINNER GESTIC
ACTIVITY JUST TO SHOW WE CAN
ENHANCE ACTIVITY BY FINDING OUT
WHICH DRUGS HAVE SYNERGY AND
THERE ARE MANY OTHER TRIALS
INCLUDING TRIAL AT THE NIH THAT
COULD LEVERAGE OFF ACTIVITY OF
MOGAMULIZUMAB AND TO ALSO
COMBINE WITH OTHER AGENTS.
ONE MAY ASK WHAT DO WE KNOW
ABOUT THE TARGET?
SO THE DRUG TARGETS CCR4, SO
DOES IT DO BETTER IN THOSE WITH
HIGHER CCR4 EXPRESSION?
IN CTCL, THE CCL IS CONSISTENTLY
HIGHLY EXPRESSED BECAUSE IT IS A
CHEMO KEEN THAT TRAFFICS THE
LYMPHOCYTES TO THE SKIN THUS
GUYS THE CTCL CELLS TO THE SKIN.
SO THE MEDIAN EXPRESSION IN THE
SKIN OF CCL IS VERY HIGH.
IT'S IN THE 27%.
SO THE PRESENCE IN THE HIGHER
LEVEL, DOES NOT REALLY CORRELATE
AS EXPECTED, BUT THERE ARE SOME
PATIENTS WITH VERY LOW LEVEL OF
EXPRESSION THAT DID NOT LOCALIZE
WITH THE RESPONDERS, SO YOU
WONDER IF VERY NEGATIVE
EXPRESSION OF CCR 4 COULD BE A
PATIENT YOU DON'T WANT TO GIVE
THE DRUG, BUT AGAIN THIS IS TO
BE DETERMINED FURTHER AND BUT
IT'S AN INTERESTING OBSERVATION
YOU MAY ALSO ASK HOW MANY
TARGETS IN THE GENE, AND THERE'S
EVIDENCE IN THE ATL LITERATURE
IF YOU HAVE A GAIN OF FUNCTION
MUTATION IN THE C-TERMINUS,
REGION OF THE CCR 4 GENE THAT,
IT ENHANCES, THE EXPRESSION OF
CCR 4, AND THAT YOU MAY HAVE
MORE AUGMENTATION OF CLINICAL
ACTIVITY, AND CLEARLY MAINTAIN
HERE THAT'S BEEN SHOWN WITH
MOGAMULIZUMAB, PATIENTS DID
BETTER THAN PATIENTS WITHOUT
MOGAMULIZUMAB WHO REQUIRED
TRANSPLANTS.
SOME MOGAMULIZUMAB PATIENTS DID
BETTER EACH WITHOUT TRANSPLANT
BUT IS THIS THE CASE IN CTCL?
SO YOU WONDER, AND IN CTCL, THE
CCR 4 GAIN OF FUNCTION MUTATION
IS MUCH LESS COMMON AND IN SOME
PATIENTS WITH THE MUTATION, WE
SEE DRAMATIC RESPONSES LIKE
THIS.
SO THIS IS A PATIENT WITH THE
KNOWN GAIN OF FUNCTION, WHO DID
REALLY WELL IN THE BLOOD AND
SKIN.
BUT YOU MAY WONDER THAT THE
PATIENTS MAY DO WELL, WITHOUT
THE MUTATION, TOO, SO, HOW
RELEVANT IS THIS GAIN OF
FUNCTION MUTATION IN THE
PATIENT'S BENEFIT, THAT'S STILL
UNCLEAR.
BUT WE DID SEE THAT PATIENTS
WITH GAIN OF FUNCTION MUTATION,
IF THEY HAVE OTHER NEGATIVE
FACTORS LIKE LARGE CELL
TRANSFORMATION, THEY DID NOT
RESPOND EMPLOY SO OBVIOUSLY IF
YOU HAVE OTHER FACTORS THAT
DRIVE THE AGGRESSIVENESS THAT IT
MAY NOT DO WELL.
WE ALSO THEN LOOKED AT WHAT ARE
THE RESISTANCE MECHANISMS FOR
MOGAMULIZUMAB MOGAMULIZUMAB, AND
IT TURNS OUT THAT WHETHER YOU
LOOK AT THE SECONDARY OR PRIMARY
RESISTANCE PATIENTS WHEN THEY
BECOME RESISTANCE, THE TARGET IN
THE SKIN OR IN THE BLOOD, THE
CCR 4 LEVELS DO GO DOWN.
AND WE'VE SEEN THAT IN 3 OF THE
PATIENTS, ALONG WITH THE CCR 4
EXPRESSION DECREASE, THEY DO
HAVE MOLECULAR NEW MUTATIONS IN
THE CCR 4, INCLUDING THE 1 IN
THE BINDING REGION, THIS IS THE
1 THAT PREDICTS GOOD RESPONSE,
AND IN THE RESISTANCE, WE SEE
MUTATION, MUTATION IN THE
BINDING REGION AND THEN 2 IN THE
TRANSMEMBRANE DOMAIN WHERE IT
WAS LINKED TO THE LESION OF THE
CCR4, WILD-TYPE CCR4 SO PATIENTS
DO ACQUIRE GENETIC MUTATIONS IN
THE CCR INCLUDING THE LESIONS
THAT RESULT IN LACK OF
EXPRESSION THAT WE SEE IN THE
PHENOTYPIC EXPRESSION AND THE
PATIENTS DON'T RESPOND BE TO THE
DRUG ANYMORE.
AND WE TRANSVECTED THE COUPLE OF
PATIENTS, THE VARIANTS INTO
JERKIT CELLS WHICH RESULT INDEED
DECREASE OF CCR EXPRESSION
COMPARED TO WILD-TYPE, SO ORANGE
AND GREEN ARE THE TRANSFECTIVE
1S THAT HAVE A DEE CREASE IN
EXPRESSION XTHIS ALSO LED TO
DECREASING THE ADCC FURCHG,
AGAIN THE OVERWHELMING AND GREEN
MUCH LESS THAN THE WILD-TYPE, SO
CONFIRMING THE FUNCTIONAL
ABNORMALITY IF YOU HAVE THESE
VARIANTS.
SO IN SUMMARY, RESISTANCE TO
THIS APPROVED DRUG, SIGNIFICANT
NUMBER OF PATIENTS HAVE LOSS OF
THE TARGET, SOME OF WHICH COULD
BE LINKED TO GENETIC MUTATION
THAT THEY APPLY UNDER PRESSURE
OF THE DRUG, AND THEN OTHER 1S
WE CAN'T FIND A MUTATION AND
THEP, WE HAVE PATIENTS WHO
RETAIN THE EXPRESSION AND WE
STILL NEED TO FIND OUT WHY THE
RESISTANCE OCCURS IN THAT
SUBSET, BUT IT'S ACTIVITIES AND
PROJECTS EXAMPLE OF HOW WE GET
THE DRUG, WE LEARN ABOUT THE
BIOMARKERS OF RESPONSE AND
RESISTANCE BECAUSE BY DOING
THAT, HOPEFULLY WE CAN IMPROVE
THE ACTIVITY, IS THAT THE TARGET
WE NEED TO INCREASE OR ARE THERE
OTHER PARTNERS WE CAN COMBINE.
SO IN THIS PATIENTS WITH SEZARY
SYNDROME, THE BLOOD TEASE WE
CLEARED WITH MOGAMULIZUMAB, AND
NOW THE PATIENT BECAME MORE LIKE
THE MF PATIENT WITH
[INDISCERNIBLE] DISEASE BUT WITH
THICK PLAQUES AND TUMOROT SKIN.
SO WHEN WE BIOPSIES AT THIS TIME
POINT, THE SKIN BIOPSY DID SHOW
LARGE CELL TRANSFORMATION AND
THE PATIENT UPDATING THE SKIN
SHOWED LYMPHNODE DEC.
SO THEY HAVE A VERY DYNAMIC
COURSE IS IN THE PATIENT WITH
LYMPHNODE DEC WITH LARGE CELL
TRANSFORMATION, THEN WE LOOK AT
WHAT IS THE DATA OUT THERE THAT
WOULD BE A GOOD MATCH AND THE
MOST RIGOROUSLY STUDIED IN LARGE
CELL TRANSFORMATION IS RETUX MAB
WITH GOOD CLINICAL ACTIVITY
WHERE THE TRANSFORMED PATIENTS
HAVE A BETTER ACTIVITY THAN
THOSE IN THE LUNG DEC SO IT'S A
DRUG THAT COULD MATCH, ALIGN
WELL WITH THE MORE AGGRESSIVE
DISEASE, SO IN THIS PATIENT,
WITH THE LARGE CELL
TRANSFORMATION, LYMPHNODE DEC,
IT WAS A VERY GOOD MATCH TO GIVE
BREN TUX MAB, AND I WILL UTILIZE
TO SEE HOW HARD THE TARGET
IS,OOSE A VERY WELL KNOWN TARGET
IN HUMAN O LOGIC DEC AND
LYMPHOMA.
IT TARGETS C30 LINKED WITH THE
DRUG WHICH IS A [INDISCERNIBLE]
INHIBITOR, IT GOES INSIDE THE
CELL, RELEASES THE DRUG AND ALSO
KILLS SOME OF THE CELLS THAT ARE
CD30 NEGATIVE, IN THE PROXIMITY
AS WELL.
SO WE MAY ASK, SO WHAT IS THE
DATA OUT THERE WITH THE TARGET
EXPRESSION.
AND AT STANFORD AND COLLEAGUES
AT MD ANDERSON, WE'VE STUDIED
THE RETUX MAB THAT WAS IMPROVED
IN HODGE CONDITIONS AND ALCL BUT
EXPORTED IN OUR DEC.
BUT IT TURNS OUT IF YOU HAVE
VERY HIGH CD30 EXPRESSION, THIS
IS CD30 EXPRESSION, YELLOW IS
THE NONRESPONDERS, BLUE ARE THE
RESPONDING PATIENTS AND THIS
Y-AXIS IS HOW MUCH REDUCTION YOU
HAVE IN THE SKIN DISEASE.
MINUS 100 BEING COMPLETELY
CLEAR.
SO THESE ARE THE GREAT
RESPONDERS DOWN HERE AND THE
CD30 LEVEL, IF YOU HAVE VERY
HIGH EXPRESSION, RELIABLY THEY
MAY HAVE GOOD RESPONSES AND DEEP
RESPONSES BUT WHAT IS
INTERESTING IS THAT IN THE LOW
EXPRESSERS, 0-5%, YOU ALSO HAVE
A MIX, A VERY GOOD RESPONSES AS
WELL AS NONRESPONSE.
SO IN THE HIGH EXPRESSION, IT'S
GOOD TO CHOOSE THIS DRUG BECAUSE
IT'S RELIABLE, BUT IT DIDN'T
EXCLUDE YOU FROM CHOOSING THE
DRUG IN THE REFRACTORY SETTING,
EVEN WHEN YOU'RE
IMMUNOHISTOCHEMISTRY CANNOT
DETECT CD30.
SO YOU MAY ASK, WELL, WHY IS THE
TARGET NOT THERE, AND IT STILL
CAN WORK.
SO HERE'S A PATIENT WITH WIDE
SPREAD, TRANSFORMATION AND THIS
IS THE LESION THAT WE BIOPSIED
WHICH SHOWS 0% CD30 BY
IMMUNOHISTOCHEMISTRY WITH OUR
EYES AND YOU GIVE BREN TUX MAB
AND YOU CAN SEE THAT CLEARLY THE
LESION HAS REGRESSED.
SO TIMES THE TARGET EXPRESSION,
DETECTION MAY BE A MATTER OF
WHAT METHOD YOU USE, SO IF YOU
USE A MORE SENSITIVE TOOL SUCH
AS MULTISPECTRAL IMAGING, THEN
YOU CAN SEE THAT THIS IS GREEN
LINE THRESHOLD VISIBILITY WITH
THE EYE WITH
IMMUNOHISTOCHEMISTRY BUT THE
MOLECULES EXIST IN CD30 WAY
BELOW THE DETECTION THRESHOLD,
SO MOLECULES ARE THERE IN MAYBE
A MATTER OF IT'S NOT NEGATIVE,
BUT WHAT YOU CAN DETECT WITH THE
EYE, SO THE DRUG IS VERY
POWERFUL, WORKED WITH VERY LOW
AMOUNT OF MOLECULES.
SO AGAIN, THEN THE DRUG SHOULD
BE WHEN YOU BIOPSY A PATIENT
WITH DIFFERENT DISEASE, THE
MOLECULE MAY BE VERY VARIABLE IN
EXPRESSION DIFFERENT PARTS OF
THE BODY.
SO THE PIVOTAL TRIAL SHOWS THAT
YOU HAVE VERY DIFFERENT LEVELS
OF EXPRESSION, EACH PATIENT IS
[INDISCERNIBLE].
YOU CAN SEE THE HIGH VARIETY OF
EXPRESSION IF YOU BIOPSY
MULTIPLE LESIONS WITHIN THE
PATIENT, AND BLUE BEING
RESPONDER, RED BEING
NONRESPONDERS, CAN YOU SEE THAT
IT DOESN'T REALLY HAVE A GOOD
PREDICTION OF THE EXPRESSION
LEVEL WITH THE RESPONSE PROFILE.
THUS WE DO NOT USE CD30 TO
ULTIMATELY GUIDE TREATMENT
SELECTION BECAUSE ESPECIALLY IN
THE REFRACTORY SETTING.
ANOTHER WAY TO SHOW THE
HETEROGENEITY IS THAT WITHIN THE
SAME PATIENT, CAN YOU USE A MUCH
MORE SPATIALLY SUPERIOR
TECHNIQUES LIKE CO DECKS AND
THEN LOOKING AT THE PATCH WORK
WITHIN A PATIENT, CAN YOU SEE
THAT THE TUMOR PROFILE, THE
TISSUE MICROENVIRONMENT PROVIDES
VERY HETEROGENIUS WITHIN THE
PATIENT AGAIN DEMON TRAITING THE
HETEROGENEITY WITHIN A LESION,
CAN YOU SEE THAT DEPENDING ON
WHICH CORE YOU BIOPSY, THAT
COULD BE STRIKING HETEROGENEITY
IN THE LESION PROFILE.
THUS THE CAUTIONARY WORD IN THE
CTCL IS THAT YOU NEED TO TAKE
MULTIPLE SAMPLES BECAUSE IT'S
VERY HETEROGENIUS CLINICALLY,
AND IN THE BIOMARKER GUIDED
MANAGEMENT.
SO NOW I WILL TALK ABOUT A
LITTLE BIT OF CELL THERAPIES, IN
ADVANCE DISEASE WHERE WE WANT TO
CURE PATIENTS, WE DO NEDRA TO
UTILIZE TREATMENTS THAT CAN BE
MORE INTENSIVE AND B-CELL
LYMPHOMAS, OBVIOUSLY CAR-Ts
HAVE BEEN GREATLY BENEFICIAL AND
IN CTCL, IT'S BEEN MORE
DIFFICULT.
AND WE HAVE IN CELL THERAPIES,
WE HAVE OUR DONOR STEM CELL
WHICH DOESN'T TARGET A SPECIFIED
DEFINED TARGET BUT IN CAR-T, YOU
CAN TARGET A DEFINED MORE
SPECIFIC TARGET AND THE REASON
IN T-CELL, THE FOCUS HAS BEEN
SLOW, IS THAT CAR-Ts ARE A
LYMPHOMA, SO DEPENDING ON WHICH
TARGET YOU SELECT, YOU MAY BE
THE T-CELLS MAY BE KILLING EACH
OTHER, TO TRY TO ATTACK A T-CELL
MARKER, IN A T-CELL LYMPHOMA SO
YOU DON'T WANT TO WORRY ABOUT
THE FRACTURE SIDE OF THE T-CELLS
ILLEGALS CANNING EACH OTHER, SO
NOW WITH THE IMMUNE EDITING,
CRSPR, AND OTHER EDITING
TECHNIQUES, THE CAR-Ts ARE
BETTER MODIFIED SO YOU CAN
REMOVE THOSE TARGETING SYSTEMYS
WITHIN THE CAR-T.
BUT TARGET THE MALIGNANCY AND
SOME OF THOSE ADVANCEMENTS HAVE
BEEN IN THE CD7, TRBC1, CD30 AND
OTHERS.
AND SO NOW I THINK YOU WOULD SEE
MORE ADVANCES IN THE CAR-T
THERAPY AND T-CELL LYMPHOMA.
THE MORE COMMONLY UTILIZED CELL
THERAPY IS THE STEM CELL
TREATMENT, AND WE ASK THEM, WHAT
ARE--WHO DO WE TRANSPLANT, WELL,
IN THE ADVANCED DISEASE, YOU SEE
THE RISK PROFILE THAT I
MENTIONED AND WE WOULD NOW
TRANSPLANT BECAUSE OF THE
COMPLICATIONS OF THE TRANSPLANT
SIZE, IN THE PEASHT WHO IS HAD
LOW RISK BUT DEFINITELY IN THE
HIGH RISK AND IN THE ISHT
MEDIATE RISK PATIENTS WE
CONSIDER A TRANSPLANT SOONER OR
WHEN YOUR TREATMENTS BECOME VERY
REFRACTORY, YOU WOULD CONSIDER
THAT BECAUSE YOU WOULD THEN RUN
OUT OF TREATMENTS AND THEN YOU
MAY NOT BE ABLE TO CLEAR THE
PATIENT TO GET THEM INTO
TRANSPLANT.
SO THE TRANSPLANT DATA AT OUR
CENTER, USING TOTAL LYMPHOID
GLOBUE LYNN AS A CONDIGGING, WE
SHOWED GOOD OVERALL RESPONSE AND
OVERALL SURVIVAL RATES OF ABOUT
60%, AND THIS IS MUCH BETTER
THAN A NATURAL COURSE OF SIMILAR
PATIENT, WHERE THE HIGH RISK
PATIENTS MAY BE 30%, SO IT MAY
BE BETTER WITH THE OVERALL
SURVIVAL, AND THOSE PATIENTS
WITH NEGATIVE MOLECULAR DISEASE
ARE OBVIOUSLY PSYCHED THEY'RE
MORE CURED, SO THEY DO BETTER
AND IF YOU LOOK AT ACROSS ALL
THE CENTERS A KEY STEM CELL,
TRANSPLANT DATA, THE STANFORD
CONDITIONING BECAUSE IT'S A
MILDER NONAPLATIVE REGIMEN, IT
DOES ALLOW OLDER PATIENTS TO BE
TRANSPLANTED AND THIS IS
RELEVANT BECAUSE THE MEDIAN AGE
OF THE CTCL PATIENT IS OLDER SO
WE DO WANT TO TRY TO OFFER THE
TRANSPLANT TO THE OLDER
POPULATION BUT A LOT OF PATIENTS
ARE NOT TRANSPLANT ELIGIBLE, OR
THEY DON'T HAVE MATCHES, THAT'S
WHY WE NEED TO IMPROVE OTHER
CELL THERAPIES AS WELL, BUT WE
HAVE SIMILAR DATA REGARDLESS OF
THE TRANSPLANT PROTOCOL, BUT OUR
METHOD DOES ALLOW OLDER PATIENT
POPULATION FOR TRANSPLANT.
SO IN THIS PATIENT, WITH SENSORY
STARTED WITH HYBRID LEUKEMIC
DISEASE WHICH WE WERE ABLE TO
CLEAR WITH MOGAMULIZUMAB, HE
TURNED MORE INTO AN MF PROFILE,
LYMPHNODE DISEASE, WE ALIGNED
THE TREATMENT THAT WORKED WELL
IN THAT PROFILE AND THEN
EEIVETTUALLY BECAUSE HE'S HIGH
RISK WITH EMILY NODE DISEASE, WE
GOT HIM TO ALOE TRANSPLANT, HE
SUCCESSFULLY KNOWN THROUGH OUR
TRANSPLANT PROGRAM, WE'RE ABOUT
A YEAR OUT NOW AND WITHOUT GBH
AND HAVING PROLONG CURATIVE,
HOPEFULLY CURATIVE REMISSION.
DESPITE THE HETEROGENEITY OF THE
CLINICAL DIVERSE PROFILE,
INTERESTING THAT THEIR TCR
DOMINANT TCR SEQUENCE IS
IDENTICAL WHICH GIVES A CLUE
THAT MAYBE THE TCR IS A GOOD
TARGET REGARDLESS OF PATIENT
TRANSITIONING INTO THIS DYNAMIC
PROFILE, WE DO HAVE A CONSTANT
VARIABLE WHICH IS THE TCR THAT'S
REARK RANGED IN THE T-CELL
LYMPHOMA AND MAYBE COULD BE A
TARGET FOR EITHER ANTIBODY CELL
THERAPIES, ANY OF THESE
VACCINATIONS AND AT STANFORD
WE'RE WORKING ON VACCINATION
TECHNIQUE TARGETING TCR.
SO WHAT'S NEXT IN CTCL?
WE HAVE A LOT'VE THERAPY AND
-THERAPIES AND WE NEED TO
LEARN MORE ABOUT BIOMARKERS AND
HOW TO UTILIZE THEM IN PRACTICE
IN ORDER TO DO DATA TRIALS.
SO HIGHLY ENCOURAGE UTILIZING
BIOMARKERS IN YOUR TRIAL, IF YOU
HAVE BIOMARKER DRIVEN TRIALS IF
POSSIBLE, WE HAVE FORTUNATELY A
MULTITUDE OF COOL TOOLS TO HELP
PROFILE THE TUMOR, THE
MICROENVIRONMENT, TISSUE AND
BLOOD COMPARTMENTS, AND DON'T
HAVE TIME TO GO INTO ALL OF THEM
BUT WANTED TO HIGHLIGHT ONCE
AGAIN, NOW, A LOT OF CENTERS AND
GIVEN COMMERCIAL ENTERPRISES
THAT OFFER MOLECULAR PROFILING
OF THE CANCER.
WE DO UTILIZE THIS IN OUR
REFRACTORY SETTING, JUST AS AN
EXAMPLE, IN THE JACK STAT
SIGNALING THAT'S VERY RELEVANT
IN CTCL, AND IT IS NOT VERY
COMMON TO HAVE PATHOGENIC
VARIANTS BUT WE DO SEE THAT
PATIENTS TUMOR ACQUIRING
MUTATIONS WITHIN IT WHEN THEIR
DISEASE BECOMES MORE
AGGRESSIVEENTIOUS SPECIALLY WITH
LARGE CELL TRANSFORMATION, SO IT
IS VERY RELEVANT IN OUR DISEASE
AND MAKING THEM ACCELERATE AND
MAKING THEM MORE AGGRESSIVE.
WE DO SEE SOME RARE JACK 2
VARIANTS INCLUDING FUSION
MOLECULES DEMON TRAITING
EXAMPLE, BUT THERE'S BEEN A
TRIAL IN T-CELL LYMPHOMA,
HOWEVER THE TRIAL SHOWED ONLY
14%, RESPONSE FOR AND HOWEVER,
IT WAS NOT ENRICHED FOR THE
GENETIC VARIANTS, SO IT WASN'T
ALIGNED THAT IF YOU HAVE JACK 2
MUTATION OR FUSION, YOU SHOULD
USE MOGAMULIZUMAB, SO IT WASN'T
ALIGNED THAT WAY.
SO IN OUR PATIENT TO DEMONSTRATE
WE THIS ALIGN BETTER PERHAPS IN
THE FUTURE IS THAT TO USE THE
PATIENT WHO WE HAD OFFLABEL,
THIS WOULD BE OFFLABEL USE
OTHERS PATIENT WITH 2 B, WITH
LCT, WITH MULTIPLE LINES OF
THERAPY AND RADIATIONS, IT
DOESN'T RESPOND TO RADIATION
WELL, BUT WE FOUND IT HAD AIAC 2
P[INDISCERNIBLE] MUTATION, WE
FOUND THIS WAS MORE OF A FOUNDER
MUTATION AND DOWN STREAM
ACCELERATING VARIANT, SINCE SHE
FAILED MULTIPLE STANDARD
THERAPIES WE DIDN'T USE
RUXOLITINIB, AND IN A FEW MONTHS
THIS IS THE 5 MONTH DATA SHE HAD
VERY DRAMATIC SHRINKAGE OF HER
TUMOR WHERE THE PRIOR THERAPIES
WERE NOT, WAS NOT ABLE TO SHRINK
IT EVEN RADIATION, SO CAN YOU
SEE THE DRAMATIC CHANGE.
SO WE HOPE THAT UTILIZING SUCH
STRATEGY COULD HELP IN THE
FUTURE AND DESIGNING TRIALS AS
WELL.
ANOTHER EXAMPLE OF OF ACTIONABLE
NG S PROFILE WOULD BE A TEMPORAL
[INDISCERNIBLE] TRIAL BUT AGAIN
THE RESPONSE WAS ABOUT 30%,
WHICH IS THE STANDARD RESPONSE
RATE FOR ALL THE CTCL TRIALS IF
YOU DON'T ENRICH BUT SOME OF THE
PATIENTS WITH LCT HAVE PDL 1
STRUCTURAL VARIANT ANDS IN THOSE
PATE WHEN IS WE SEE THAT, WHEN
WE TARGET WITH PEMBRO, IT IS
MUCH HIGHER THAN 30%EM
SOPHISTICATED HAVE DRAMATIC
RESPONSES AND THAT ARE DURABLE.
AND THIS IS COB CYST EPT WITH
DATA USING MOGAMULIZUMAB AS
WELL, SO AGAIN, MAYBE WHEN WE
ENRICH OUR POPULATION OF
PATIENTS WHO CAN BENEFIT WE CAN
HAVE A BETTER RESULT, ESPECIALLY
IN THE RARE DISEASE, IT MAKES
MORE SENSE, AND AGAIN IN ORDER
TO WORK TOGETHER, AND WHEN WE
DISCOVER FINDINGS IN A CENTER,
WE WANT TO BE READY TO VALIDATE
OR DEMONSTRATE THE CRUCIATE
LIGAMENTTILITY OF THAT DISCOVERY
IN THE END SIZE SO IT CAN HAVE
GREATER IMPACT, BE MORE MEANING
EMPLOY.
SO WE BUILT THIS WITH OUR UK
COLLEAGUE, INTERNATIONAL
CONSORTIUM, NOW IT'S MORE THAN
70 CENTERS WHERE WE GATHER
PROSPECTIVE DATA TOGETHER, WE
BUILT A BIOBANK WITH THAT
PATIENT AND WITH LARGE CELL
TRANSFORMATION AND PROGRESSION
EVENTS AND WITH TREATMENT
RESPONSE.
WE HAVE A DIGITIZED PATHOLOGY
DATA BANK WHERE PATHOLOGY
LEADERS COULD UTILIZE THE PATH
SLIDES FOR PROJECTS, SO THIS HAS
BEEN BUILT, AND WE HOPE THAT
DISCOVERIES IN SINGLE CENTERS
COULD BE TESTED IN MUCH LARGER
SAMPLE SIZE TO BRING MORE
MEANINGFUL IMPACT AND WE WILL BE
READY TO DO SO MORE IN THE
FUTURE.
SO IT MAKES SENSE IN A RARE
DISEASE TO BUILD IN SUCH
PLATFORMS, SO IN SUMMARY,
DEMONSTRATE THAD IT IS HIGHLY
HETEROGENERATED YIEWS, WE HAVE
TO SPECIALIZE BECAUSE OF THE
TREATMENT VS DIFFERENTIAL
ACTIVITY NOT ONLY ACROSS SKIN
DEC, TYPINGS BUT ACROSS
COMPARTMENTS, WE HAVE TO ALWAYS
UPDATE THE DEPARTMENT ACTIVITY
BECAUSE OF THAT TO MATCH
ACCORDINGLY IN PATIENTS WITH
VERY HIGH RISK DISEASE,
OBVIOUSLY CURRENTLY WE SHOULD
CONSIDER TRANSPLANT BUT WE NEED
BETTER THERAPIES BUT LOWER
PATIENTS ARE NOT TRANSPLANT
ELIGIBLE, SO WE WOULD LOAMACYIC
--LIKE TO
HAVE MORE THERAPIES OR CELL
SPECIFIC TYPES.
AGAIN CAUTIONOT TISSUE OF
BIOMARKERS IN CTCL BECAUSE OF
THE HETEROGENEITY SO WE HAVE A
LOT OF INTRA PATIENT INTRA
LESIONAL, INTRA TOMB OARAL
HETEROGENEITY.
SO CAUTION OF THE BIOMARKERS AND
OBVIOUSLY WE NEED TO DO MUCH
BETTER IN THIS RARE DEC WITH
TREATMENTS THAT CAN BETTER MATCH
WITH THE PATIENTS SO IN THE
FUTURE WHEN WE DESIGN CLINICAL
TRIALS WE WANT TO ENRICH THOSE
WHO CAN BENEFIT, RATHER THAN
JUST GIVE 1 DRUG TO ALL PATIENTS
AND THEN COME UP WITH THE 30%
RESPONSE RATE.
SO WE WANT TO DO BETTER IN THAT
AREA.
SO I WANT TO THANK ALL OF MY
PARTNERS AT STANFORD, ESPECIALLY
MICHAEL [INDISCERNIBLE] WHO IS
OUR TRANSLATIONAL LEAD, WITHOUT
HIS GROUP, IT WOULD BE HARD TO
MAKE SENSE OF ANY CLINICAL
FINDINGS, AND/OR BRING DISCOVERY
TO OUR PATIENTS IN A SENSE OF
ALL FASHION, AND ALSO OUR HUGE
CLINICAL TEAM THAT WE CANNOT DO
WITHOUT ON A DAILY BASIS.
AND HERE WE ALSO DO HAVE FUNDS
AND THAT'S ALL WITH MY TALK
TODAY AND REALLY APPRECIATE YOUR
ATTENTION THIS MORNING.
>> THANK YOU VERY MUCH DR. KIM.
THAT WAS WONDERFUL AND
APPRECIATE SORT OF THE BROAD
PERSPECTIVE AS WELL AS SOME OF
THE DETAILS ABOUT THE MOLECULAR
PROFILING, I GUESS, MY FIRST
QUESTION SORT OF BIG PICTURE IS
JUST GIVEN THE AMOUNT OF
VARIABILITY AND RESPONSE TO
TREATMENTS AND AND THE VARIOUS
WAYS PEOPLE PRESENT AND
OBVIOUSLY THE PROGNOSIS THAT'S
DIFFERENT, I LIKE THE CONCEPT OF
CONPART AMS, BLOOD AND SKIN EVEN
WITHIN THE SKIN COMPARTMENT
WHERE YOU HAVE PATCH DISEASE
VERSUS TUMOR DISEASE, THOSE
PATIENTS ARE GOING TO HAVE A
DRAMATICALLY DIFFERENT
PROGNOSIS, YET WE STILL CALL ALL
THESE PATES CUTANEOUS T-CELL
LYMPHOMA SO ARE DOING A
DISSERVICE BY CONSIDERING THIS
ALL 1 DISEASE?
IS THE FUTURE JUST ANYTHING TO
BE GOOD ENOUGH MOLECULAR
PROFILING THAT THESE WILL BE
DIFFERENTIATED IN A MORE
MEANINGFUL WAY?
>> VERY GOOD QUESTION.
BECAUSE I ONLY SEE THESE, 70% OF
MY PATIENTS ARE T-CELL AND WE DO
HAVE OBVIOUSLY B-CELL, AND OTHER
CUTANEOUS CELLS, MFNS IS THE
MOST COMMON, SO WE HAVE THE CD30
PHOSPHATE, AND THE CYTOTOXIC
T-CELL LYMPHOMAS, A LOT OF
DIFFERENT TYPES, BUT WITHIN MF
AND SEZARY, IT'S SO
HETEROGENIUS, SO, I ONLY STUDY
THIS DEC, AND IT'S CONSOUPING MY
CAREER AND MY LYMPHOMA
COLLEAGUES ARE GOING, LIKE, YOU
ONLY DO THAT, WHY CAN'T YOU DO
MORE, THE THING IS LIKE YOU
SAID, EACH PATIENT IS SO
HETEROGENIUS, IT'S LIKE TREATING
MULTIPLE DIFFERENT DISEASES AND
LEARNING ABOUT IT.
SO IN TERMS OF IS IT ALL 1
DISEASE, I THINK IT DEPENDS ON
HOW YOU DEFINE IT, OBVIOUSLY WE
DEFINE CURRENTLY THE MF BECAUSE
THEY HAVE A SIMILAR SHARED
CLINICAL PRESENTATION WITH THE
PATCH BACK TUMOR AND THEY HAVE A
MIX OF IT.
THEY ARE ALL CONNECTED, PATIENTS
ARE PATCH LIKE TUMORS AND
SOMETIMES VICE VERSA, AND IN THE
SPECTRUM OF THEIR PATH, YOU CAN
CLEAR THE TUMOR AND TUMORS THEN
THEY'RE WITH PATCHES ONLY, THEN
YOU HAVE TO USE THE TREATMENTS
THAT WORK WITH THE PATCHES, SO
IT'S VERY DYNAMIC, PLASTIC,
PLACENTASISSITY, SO THEY'RE
INTERRELATED SO WE DON'T WANT TO
LIKE SEPARATE IT, I'M USUALLY A
LUMPER SO I DON'T WANT TO LIKE
SEPARATE THEM ALL OUT, BUT THE
LEUKEMIC DISEASE, AGAIN,
OBVIOUSLY IT MAKES YOU WANT TO
BE IN THE BLOOD MORE THAN THE
SKIN, WE HAVE TO UNDERSTAND
THESE BETTER BUT THEN IF YOU SAW
MY PATIENT, IN THE SAME PATIENT
IT'S DYNAMIC SO THERE WERE LUNG
CANCER LUNG
CANCER--LEUKEMIC AND THEN THEY
LOOKED LIKE SKIN CANCER
PATIENTS.
SO I WANT TO CALL IT LIKE A
SPECTRUM OF DISEASE, BUT MAYBE
THE MOLECULAR PLATFORMS IN THE
FUTURE?
I WOULD LOVE TO GET TO A POINT,
IT'S LIKE CLL, AND YOU HAVE THIS
MUTATION YOU TREATED THIS WAY
AND WE NEED TO GET THERE BUT
IT'S NOT GOING TO BE THAT EASY
BECAUSE AGAIN, WE DON'T HAVE
VERY COMMON RECURRENT GENETIC,
YOU KNOW ABNORMALITIES IN A LOT
OF THESE PATIENTS, BUT I WOULD
LIKE TO GROUP THEM, BUT IT'S
VERY JUST DIVERSE HETEROGENIUS.
>> I WAS INTERESTED IN THE JACK
STORY AND JACK INHIBITORS ARE
WIDE SPREAD USE HERE FOR MANY,
MANY THINGS AS CAN YOU IMAGINE
AND IF YOU HAD ANY EXPERIENCE
WITH LYMPHOMAS DEVELOPING ON
JACK INHIBITOR THERAPY AND YOUR
THOUGHTS ON HOW THAT FITS.
>> ANOTHER VERY GOOD POINT WITH
THE EXPLOSION AND THE ATOPIC
DERM PSORIASIS, AND BIOLOGICS
AND IT'S A DIFFERENT THING WHEN
YOU HAVE OUR PATIENT THAT
PATIENT, THAT PATIENT HAD A VERY
SPECIFIC TUMOR MUTATION, CANCER
MUTATION, THAT WE THINK IS LIKE
A DRIVING, DRIVER OF THAT
CANCER, BUT LET'S SAY YOU DON'T
KNOW THAT AND THAT'S WHY I DON'T
LIKE USING THESE JACK INHIBITORS
OR ANY OF THAT, ESPECIALLY WHEN
YOU DON'T KNOW WHAT DRIVER OF
THE CANCER IS, BUT IN THE ATOPIC
DERMA PSORIASIS, LET'S SAY YOU
USE IT AND THE PATIENT NEVER
EVEN HAD DERMA TITIS.
SO WHAT I THINK IS THAT YOU
THINK THE PATIENT HAS ETOPPIC
DERM, BUT THEY LOOK, CTCL LOOKS
LIKE ATOPIC DERM, SO YOU DIDN'T
DO A DEEP DIVE INTO THE
DIAGNOSIS, CLONALITY AND MAYBE
COULD FIND THE CLONE BUT THEY
WERE EVOLVING LYMPHOMA, SO NOW
YOU'RE LIKE NOT GETTING TO THE
FUNDAMENTAL DRIVER MUTATION OF
THE CANCER PATIENT THAT YOU
THINK, IT'S DERMATITIS BUT IT'S
LIKE EVOLVING CANCER BUT YOU'RE
JUST IMMUNE SUPPRESSING THEM IN
THAT CASE, I THINK YOU'RE
GETTING INTO SOME TROUBLE.
SO NOW WITH THE JACK INHIBITORS
AND ATOPIC DERM, AS HAPPENED IN
THE [INDISCERNIBLE] TRIALS WHERE
PEOPLE WERE NOT DIAGNOSTICALLY
VERY DISCIPLINARY FIN TIFF, I
THINK YOU WILL GET INTO SOME
CASES WHERE IT WAS NEVER ATOPIC
DERMA TITIS TO BEGIN WITH AND
THEN YOU WILL SEE MORE OF THE
UPMASKING.
WHEREAS IN SOME CASES JUST THE
CHRONIC SKIN DISEASE LIKE
WOUNDING, YOU KNOW CAUSES
GENETIC EVENTS.
SO WITH TIME YOU DID START WITH
A DERMATITIS, AND THEN WITH TIME
THEY EVOLVED AND HAD MUTATIONS
AND THEN, YOU KEEP HITTING THEM
WITH AN IMMUNE SUPPRESSIVE AGENT
AND IT WASN'T THE DRIVER OF THAT
CANCER, THEN YOU'RE GOING TO GET
INTO PROBLEMS, SO I THINK WE'RE
GOING TO--TIME WILL TELL BUT I
DO THINK WE NEED TO HAVE SOME
CAUTIONARY WORD OUT THERE THAT
MAKE SURE YOU HAVE A CORRECT
DIAGNOSIS, AND BE ENTHUSIASTS OF
THE BIOLAGIC USERS.
>> THANK YOU.
>> WE DO HAVE A QUESTION THAT
CAME IN VIA THE VIDEOCAST
WEBSITE, THERE ARE A NUMBER OF
QUESTIONS BUT THE FIRST WAS
REGARDING YOUR EXAMPLE OF PEMBRO
WITH RAIDERIATION, YOUR THOUGHTS
ON WHETHER OR NOT THERE'S A
SYNERGY WITH SPECIFIC TARGETED
THERAPIES AND RADIATION?
>> YES, AND WE'RE VERY INTO
RADIO IMMUNOTHERAPY, THAT
SYNERGY BECAUSE OBVIOUSLY IT'S
RADIATION IS A VERY IMPORTANT
DEBULKING TREATMENT, IT CAN
UNMASK ANTIGENS, WE LOVE IT AND
COMBINING WITH IMMUNE THERAPY
WOULD BE GREAT.
WE DO THINK THERE'S SYNERGY WITH
PEMBRO, WITH RADIATIONS WE WOULD
LIKE TO COMBINE, TOTAL SKIN IS
GREAT BUT EVEN LOCAL RADIATION,
DO WE HAVE SCIENTIFIC DATA?
WE'RE NOT THERE BUT CLINICAL
SYNERGY WE'RE SEEING.
SO CLINICAL SYNERGY--EACH IF YOU
HAVE SCIENTIFIC DATA THEY MAY
NEVER HAVE CLINICAL SYNERGY,
VICE VERSA, BUT WE DO SEE THAT,
AND THE IT WORKING.
WE HAVE A PATIENT WHO IS WITH
SEZARY, AND WHO IS ON THE PEMBRO
TRIAL, BUT IT'S CLEAR, BUT SOME
STARTED COMING AND SOME BLOOD
STARTED TO MOLECULARLY RISING SO
WE DECIDED TOADA THE TOTAL
ELECTRON SCREENING SO ONCEEE
SHOULD THAT WE SHE HAD
REMISSION, WE GAVE VERY LOW
DOSE, BUT USING VERY LOW DOSE
FOR THE SKIN, WE HAD IMMUNE O
GENICMENTATION IN THAT PATIENT
CLINICALLY AND THEN, SHE HAD
LIKE SUSTAINED SUSTAINED CR, SO
IT'S IMPORTANT TO COMBINE THOSE
AND DO MORE EVALUATIONS.
>> ONE OF THE OTHER QUESTIONS
THE PERSON HAD WAS IF YOU HAD
ANY THOUGHTS ABOUT CD70 AS A
THERAPEUTIC TARGET.
>> ALTHOUGH CD70 HAS BEEN HIGHLY
EXPRESS INDEED A LOT OF CANCERS,
NORMAL CELLS, TOO, BUT IN T-CELL
LYMPHOMA IT'S HIGHLY EXPRESSED
AND SO, THERE'S CD70 TARGETED AS
A NAB O BODY OR CAR-T, I'M SURE,
MANY OF YOU MAY KNOW ABOUT CRSPR
THAT HAS DONE SOME GREAT EDITING
WORK OF THE GENE EDITING OF THE
CAR-T, TO MAKE IT EFFECTIVE
AGAINST T-CELL LYMPHOMA,
REDUCING THE FRACTURE SITE AND
HAVE MORE LASTING CAR-Ts, SO
CD70 IS A TARGET BECAUSE OF
THAT.
BECAUSE IT'S EXPRESSED, VERY
MUCH IN T-CELL LYMPHOMA AND CTCL
AS WELL.
>> AND MY LAST QUESTION, I'M
CURIOUS YOUR OPINION WITH CHECK
POINT THERAPY AND SIDE EEIVETS,
IS IT WHAT WE SEE WITH MELANOMA
AND OTHER MALIGNANCIES?
>> YES, I DON'T THINK THERE'S
ANY SIGNIFICANT DIFFERENCE, BUT,
YOU KNOW WE DON'T--WE HAVE NOT
SEEN TOO MUCH AND WE DON'T WORRY
TOO MUCH ABOUT LONG-TERM
[INDISCERNIBLE] BECAUSE I WISH
THINGS WORKED THAT WELL IN ALL
PARENTS FOR A DURABLE PERIOD OF
TIME BUT IT DOESN'T, SO, BUT I
THINK THERE'S NO DIFFERENCE IN
THE SIDE CENTER FOR EXCELLENCE
ON AGING PROFILE.
--SIDE EFFECT PROFILE.
>> THANK YOU AGAIN FOR A
WONDERFUL TALK, A COMPLEX TOPIC
AND IN THE INTEREST OF TIME I
THINK WE WILL END THERE AND
THANK YOU SO MUCH FOR YOUR TIME
>> THANK YOU DR. COWEN FOR THE
INVITATION AND HOPEFULLY IT WAS
BENEFICIAL FOR THE LARGER
AUDIENCE.
>> THOWCH.
>> THANK YOU.