WELCOME EVERYONE AND THANK
YOU FOR JOINING.
THIS IS THE OADR SCIENCE TALKS
AND I'M DR. VICKIE SHNG.
I'M THE DIRECTOR OF AUTOIMMUNE
RESEARCH AT THE NIH.
IT'S A PLEASURE TO HAVE YOU WITH
US TODAY.
WE'RE DELIGHTED TO BE JOINED BY
SOME OF THE SMARTEST SCIENTISTS
IN THE FIELD TODAY TO TALK ABOUT
THE INTERSECTION OF AUTOIMMUNITY
AND CANCER.
THIS EVENT WILL BE RECORDED AND
THE RECORDING WILL BE AVAILABLE
IN THE VideoCast ARCHIVE.
IF YOU NEED CAPTIONS, THE
CAPTIONS WILL BE BEST VIEWED
THROUGH VideoCast SO FEEL
FREE TO LOG ON AND LON -- LOG
OFF AND LOG ON TO THE
VideoCast.
YOU CAN GET IT THROUGH ZOOM AS
WELL.
THIS IS AN OPEN SESSION SO
PLEASE BE CONSIDERATE AND
RESPECTFUL WHEN YOU'RE USING THE
Q&A FUNCTION.
IF YOU HAVE ANY TECHNICAL
CHALLENGES, FIRST TRY LEAVING
THE WEBINAR AND REJOIN AND THAT
USUALLY DOES FIX THE PROBLEM.
HERE IS AN OUTLINE FOR TODAY'S
EVENTS.
WE'RE EXCITED TO BE JOIN THE BY
THREE INCREDIBLE SCIENTISTS WHO
WILL EACH PRESENT FOR 30 MINUTES
ON THEIR TOPIC AND THEN WE'LL
HAVE A PANEL QUESTION AND ANSWER
SESSION THAT WILL BE AN OPEN
FORUM.
WE HAVE TWO MODERATORS FOR
TODAY'S EVENT AND I WANT TO
INTRODUCE THEM TO YOU NOW.
WE'LL BE USING THE Q&A FUNCTION
THROUGH ZOOM, SO REMEMBER, IF
YOU FIND YOUR ZOOM TOOLBAR, YOU
CAN GO TO Q&A AND WE WILL HE
ALLOW THE UP-VOTE OPTION FOR
QUESTIONS.
IF THERE IS A BURNING QUESTION,
YOU CAN UP VOTE IT HERE.
THE TWO MODERATORS WILL BE DR.
LILLIAN QUOA WHO IS A PROGRAM
DETECTOR IN THE HEMATOLOGY AND
ETIOLOGY BRANCH IF HE NATIONAL
CANCER INSTITUTE AND DR. HEY
PARK WHO IS A PROGRAM DIRECTOR
FOR AUTO INFLAM DISEASE PROGRAM
AT THE NATIONAL INSTITUTE OF
ARTHRITIS, MUSCULAR SKELETAL AND
SKIN DISEASES.
WITH THAT, I'LL PASS THE MIKE RE
PHONE OVER TO DR. PARK TO
INTRODUCE THE FIRST SPEAKER.
>> THANK YOU DR. SHANMUGAM.
I WILL TURN IT OVER TO DR. SHAH
FROM THE JOHN HOPKINS SCHOOL OF
MEDICINE AND A CODIRECTOR OF THE
MEUN CENTER.
AUTOIMMUNE CENTER.
SHE INVESTIGATES THE CONNECTION
BETWEEN [INDISCERNIBLE] AND
CANCER.
THE FLOOR IS NOW YOURS.
>> THANK YOU, DR. PARK FOR THAT
KIND DESTRUCTION AND FOR THE
OPPORTUNITY TO SPEAK IN THIS
EXCITING SESSION.
SO I WILL BE SPEAKING TODAY
ABOUT THE LINK BETWEEN
SCLERODERMA AND CANCER.
THESE ARE MY DISLOISHERS.
MY GOALS TODAY ARE TO BRIEFLY
REVIEW THE COMPLEX AND BODY
DIRECTIONAL RELATIONSHIP BETWEEN
CANCER AND AUTOIMMUNITY IN
SCHERM DETERMINA.
I'LL REVIEW CLINICAL
IMPLICATIONS FOR SCHERMA AND
CANCER-INDUCED DISEASE.
WHILE MY FOCUS WILL BE ON
SCHERMA DETERMINA, DESCRSH
SCLERODERMA, IT MAY RELATE
TOMORROW OTHER CONDITIONS.
TO PROVIDE A BRIEF PRIMER ON
SCLERODERMA, THIS IS AN
AUTOIMMUNITY SYSTEM EXAGGERATED.
IT'S THE INTERSECTION BETWEEN
THE DIFFERENT MECHANISMS THAT
LEADS TO THE CLINICAL
MANIFESTATIONS FOR OTHER THINGS
LIKE HYPERTENSION, SKIN
THICKENING AND INTERSTCIAL LUNG
LUNG -- INTERSTECIAL DISEASES.
THIS IS CHALLENGING TO PREDICT
FOR AN INDIVIDUAL PATIENT THEIR
LIKELY RISK OF DIFFERENT
COMPLICATIONS OVER TIME.
ONE OF THE THINGS THAT WOULD HE
AS RHEUMATOLOGISTS DO IS PERFORM
A SUBSETTING TO CLASSIFY OUR
PATIENTS AS TOE WHETHER THEY
HAVE THE LIMITED OR DIFFUSE
MANIFESTATIONS OF THE DISEASE.
SHOWN IN THE TOP ARE THE DIFFUSE
SCHERMA DETERMINA.
THE LIMITED IS SHOWN IN THE
BOTTOM PANEL OF IMAGES INCLUDING
DIGITAL LOSS AND HYPERTENSION.
WE KNOW THIS CONSTRUCT DOES NOT
TELL THE WHOLE STORY BECAUSE
PATIENTS WITH DIFFUSE MAY HAVE
OTHER MANIFESTATIONS AND THOSE
WITH LIMITED MAY HAVE SCHERM
DETERMINA LUNG DISEASE.
THE THREE MOST COMMON YA -- THE
AUTOIMMUNITY ANTIBODIES PREDICT
OTHER DISEASE.
THERE ARE OBSERVATIONAL COHORT
STUDIES AND SYSTEMIC REVIEWS IN
GENERAL SUGGEST THERE IS AN
INCREASED RISK OF CANCER IN
PATIENTS WITH SCLERODERMA.
THESE RISK ESTIMATES HAVE RANGED
FROM 1.4 TO 1.8 FOLD RISK OF
CANCER IN PATIENTS WITH SCHERRA
DRMA.
THERE IS A HIGH RISK OF CANCER
BUT A WIDE ARRAY OF TUMOR TYPES
HAVE BEEN REPORTED AS, HIGH RISK
IN THE PATIENT POPULATION.
WHAT IS THE POTENTIAL LINK
BETWEEN CANCER AND SCLERODERMA?
IT IS CONCEIVABLE THAT SOME OF
THE AUTOIMMUNE TREATMENTS MAY
INTERFERE WITH THIS.
IT'S POSSIBLE THERE IS A
DECREASED ABILITY TO CLEAR VIRAL
INFECTIONS IN OUR PATIENTS
RELATED TO THE THERAPIES WE
EMPLOY.
IT IS ALSO POSSIBLE AT THAT
DAMAGE FROM THE DISEASE COULD
PREDISPOSE A PATIENT FROM HAVING
MALIGNANT PROBLEMS IN THE
TISSUES.
WE THINK OF LUNG SCANSER VEL
DEVELOPING INTO INTERSTITIAL
LUNG DISEASE.
IT'S POSSIBLE THAT RAID YEATION
TREATMENTS AND OTHER TREATMENTS
COULD PREDISPOSE PATIENTS TO
DEVELOPING SCLERODERMA AND LIKE
DISEASES.
A PATIENT DEVELOPED CYTO TOXIC
AND ANOTHER THAT DEPOS TESTIMONT
OR DISEASE.
THE DISEASE COULD BE PARA
NEOPLASTIC.
ACKNOWLEDGING THAT THERE ARE
MANY POTENTIAL LINKS BETWEEN
CANCER AND SCLERODERMA.
I'LL FOCUS ON WHETHER A SUBSET
OF OUR PATIENTS WOULD HAVE
PARANEOPLASTIC DISEASE.
OUR INTEREST IN THIS AREA WHEN
WE SAW THIS PATIENT AND OTHERS
LIKE HER.
THIS IS A 43-YEAR-OLD WOMAN WHO
CAME TO OUR CENTER AND DESCRIBED
THAT IN SHE GOT SWELLING OF
OTHER HANDS AND FACE.
WHEN SHE WAS UNDERGOING
TREATMENT FOR THIS, SHE HAD A
LUNG BLAST AND TREATED WITH PRO-
SHE GOT SKIN THICKENING WORSE IN
THE FIELD OF RADIATION BUT
EXTENDING BEYOND THAT AREA.
THIS PATIENT WAS FOUND TO BE
POSITIVE FOR POSITIVE RA 3
ANTIBODIES.
WE WERE IMPRESSED BY THIS
PATIENT AND HAD SEVERAL
HYPOTHESES ON WHY THESE WERE
HAPPENING TOGETHER.
THE QUESTION WAS WHETHER
SCLERODERMA WAS A BI-PRODUCT OF
THIS.
WE WANT TODZ KNOW IF COULD WE
USE THIS AS A TOOL TO INTERIMAIT
IF RELATIONSHIP BETWEEN CANCER
AND SCLERODERMA.
THAT LED TO THIS PILOT STUD CAN
I WHERE WEIGH RECRUITED CANCER
PATIENTS AND WE COULD GET THEIR
TISSUE FROM WHETHER THE
PROCEDURES WERE PERFORMED.
WE WERE INTERESTED IN TIMING AND
THAT'S WHAT I'M SHOWING YOU IS
HOW LONG PATIENTS HAD
SCLERODERMA WHEN THEY WERE
DIAGNOSED WITH CONDITIONSER AND
THE Y AXIS REFLECTS THE
SCLERODERMA ONSET.
WHEN WE LOOKED AT THE SUB
GROUPS, WE IDENTIFIED THAT THE
TYPE 3 ANTIBODIES HAD THE FIRST
SIGNS OF SCLERODERMA OFTEN WITH
CANCER AS THE ONSET AND THIS WAS
DIFFERENT THAN THE ANTIBODY
SUBGROUPS.
WITH WE LOOKED AT THE COHORT, WE
WERE ABLE TO CONFIRM THAT THE
PATIENTS WITH PULL PULMONARY 3A
HIGHER RISK FOR CANCER.
SIMILAR FINDINGS WERE FOUND IN
OTHER SCLERODERMA COHORTS
INTERNATIONALLY.
WE WERE IMPRESSED THAT THIS
SEEMED TO SEGREGATE IN THIS
IMMUNE RESPONSE SUBGROUP AND WE
WERE INTERESTED IN INVESTIGATING
WHETHER OR NOT SCLERODERMA
ANTIGENS WERE, PRESSED IN THESE
PATIENTS.
I SHOW YOU SOME MANIES FROM TWO
SCLERODERMA PATIENTS.
ONE OF WHOM HAD OVARIAN CANCER
AND ONE HAD BREAST CANCER.
YOU CAN SEE WITH THIS BROWN
STAINING THAT THESE PATIENTS HAD
EVEN IN THEIR CANCERS TISSUES.
THESE DATA SUGGESTED TO US THAT
CANCEROUS SPECIFIC AUTOIMMUNE
AND WHETHER THE SCR SCLERODERMA
WAS RELATED.
WE WONDERED IF THIS HIGH IMMUNE
RESPONSE COULD HELP US
UNDERSTAND THE CONNECTION
BETWEEN CANCER AND SCLERODERMA.
WE INCLUDED 16 PATIENTS WITH
CANCER WHO HAD ADEQUATE QUALITY
CANCEROUS TISSUE TO ENABLE
GENETIC SEQUENCING.
THERE WERE EIGHT PATIENTS
POSITIVE FOR ANTITAUPEO
ANTIBODIES.
THE SECOND COLUMN REFLECTS THE
TIME WINDOW FOR RNA 3, THEY
TENDED TO HAVE A SHORT INTERVAL
BETWEEN THE TWO DIAGNOSIS OFTEN
WITH CANCER PRECEDING
SCLERODERMA AND THIS LOOKS
DIFFERENT FROM THE OTHER
ANTIBODIES.
BREAST CANCER WHICH IS THE MOST
COMMON CANCER WAS THE MOST
COMMON CANCER UNDER STUDY AS
WELL.
WHEN THESE PATIENTS CANCEROUS
TISSUTISSUES WERE SCWERNSED, ITS
IDENTIFIED THAT THREE OF THE
PATIENTS WITH THE RNA 3 HAD A
PRESENTATION OF THE CANCER AND
FIVE HAD EVIDENCE OF LOSS OF HET
OORO DIGSITY.
THESE WERE FLOT SEEN IN THE
SCLERODERMA PATIENTS AND NOT
EVEN WITH CANCER PATIENTS IN
GENERAL.
THOSE THAT HAD -- ALL THEY
PATIENTS HAD EVIDENCE OF AUTO
ANTIBODIES THAT DID NOT
DISCRIMINATE BETWEEN THE TYPES.
A PATIENT MAY HAVE A DEVELOPING
CANCER AND ACQUIRE A MUTATION IN
A GENE ENCODING FOR AN AUTO
ANTIGEN IN THEIR TISSUE.
THIS COULD TRIGGER A RESPONSE
SPECIFIC FOR THE AUTOIMMUNE
RESPONSE.
IF THIS SPREADS TO THE AUTO
ANTIGEN THIS COULD TRIGGER
CANCER BUT THIS COULD LAY THE
GROUNDWORK FOR THE DEVELOPMENT
OF AUTOIMMUNITY.
THERE MAY BE SHARED ANTIGEN
EXPRESSION BETWEEN CANCELERS AND
TISSUES TARGETED BY THE IMMUNE
RESPONSE.
THERE IS EVIDENCE IN THE
PARAKNEEO PLASTIC AND WE THINK
ABOUT THIS IN THE CONTEXT OF
MELANOMAA.
THIS WAS A STUDY CONDUCTED BY MY
COLLEAGUE AT JOHNS HOPKINS WHERE
SHE WAS LOOKING AT MI 22 YOU CAN
SEE ON THE RIGHT MI 2 WAS HIGHLY
EXPRESSIONED FROM BREAST AND
LUNG CANCERS BUT ALSO EXPRESSED
IN DETERMINAITE MUSCLE
ESPECIALLY UNDERGOING REPAIR.
SO AS A CLINICIAN AS SEVERAL KEY
QUESTIONS ARISE IN THIS BODY OF
WORK, IF CANCER COULD BE A
TREATMENT FOR THE TREATMENT EVER
SCLERODERMA, HOW SHOULD WE
SCREEN FOR CANCER FOR PATIENTS
WITH NUANCED SCLERODERMA CAN WE
USE THESE AS TOOLS FOR AT-RISK.
AND COULD CANCER THRI THERAPY BE
EFFECTIVE FOR SCLERODERMA
PATIENTS.
WE OFTEN HAVE CASE REPORTS WITH
PATIENTS DIAGNOSED WITH
SCLERODERMA AND CANCER.
IT'S CHALLENGING TO KNOW WHETHER
THE SUPPRESSIVE THERAPIES ARE
INDEPENDENTLY TREATING THE
CONDITIONS OR IS THE TREATING
THE CANCER RESULTING IN A
TREATMENT FOR SCLERODERMA.
THIS IS A 43-YEAR-OLD WOMAN WITH
DIFFUSE SCLERODERMA AND POLY MY
SITEIS.
AROUND THE TIME OF HER DISEASE
ONSET, SHE HAD A DISEUD OWE
PAPILLARY PAN CRITIC NEOPLASM.
WE FOUND THERE WAS INCREASED
EXPRESSION IN THE TUMOR TISSUE.
THE TUMOR WAS SERGE CLI
RECEPTIVE.
THE PATIENT DID NOT RECEIVE
ADDITIONAL CAPSER THERAPY BUT
THERE WAS A DRAMATIC RESOLUTION
OF SKIN THICKENING AND THE
PATIENT WAS TAKEN OFF THE
TREATMENT.
THERE WAS IMPROVEMENT IN THE
RHEUMATIC DISEASE PHENOTYPE.
AS A RHEUMATOLOGIST, I'M LEFT
WITH THIS IMPORTANT QUESTION OF
WHO IS AT RISK FOR CANCER, WHEN
ARE THEY AT RISK AND FOR WHAT
TUMOR TYPES.
WE PERFORMED A STUDY TO LOOK AT
CANCEL CONSIDER INCIDENTS IN OUR
SCLERODERMA POPULATION AND TO
COMPARE THIS TO THE GENERAL
POPULATION USING THE UNITED
STATES REGISTRY AND WOARP
SPECIFICALLY INTERESTED IN
EXAMINING WHETHER CANCER RISK
OVERALL DIFFERS BY THE FILTERS
THAT WE THINK ARE CLINICALLY AND
BIOLOGICAL SIGNIFICANT.
WE NEED TO KNOW THE OUGHT OFER
ANTIBODY SUBSET AND CUTANEOUS
SUBSETS AND TIMING.
WE REVIEWED 2383 PATIENTS WITH
205 CANCERS.
I WANT TO WALK YOU THROUGH SOME
OF THE KEY FINDINGS IN THIS
STUDY.
IN THE TOP GRAPH I'M SHOWING YOU
THE NUMBER OF CANCER CASES WE
OBSERVE OTH OVER TIME IN OUR COT
IN BLUE.
THIS IS THE NUMBER OF CANCER
CASES YOU EXPECT TO SEE WHEN YOU
ADJUST FOR THE DATA SHOWN HERE
IN RED.
IN EACH ONE OF THESE GRAPHS, THE
X AXE ILINGS IS TIMED FROM
SCLERODERMA WHERE TIME ZERO IS
THE ONSET.
I WANT TO SHOW YOU THE RATIO AS
A STANDARDIZED INCIDENT RATIO.
SIR OF 1 IS RISK EQUIVALENT TO
THE BACKGROUND GENERAL
POPULATION.
IN THE BOTTOM GRAPH, I SHOW YOU
CUMULATIVE CANCER IN BLUE WITH A
95% CONFIDENCE AND THE EXPECTED
CUMULATIVE INCIDENTS BASED ON
DATA IN RED.
WHETHER YOU LOOK AT THE JEFER
ALL POPULATION, WE DID NOT SEE
AN INCREASE OF CANCER BUT WHEN
YOU LAYER ON AUTO ANTIBODY AS A
FILTER, YOU CAN SEE DIFFERENT
PATTERNS EMERGE.
WE IELDED THAT THERE WERE MANY
MORE CANCER CASES OBSERVED THAN
EXPECTED AROUND THE TIME OF
SCLERODERMA ONSET.
TRANSLATING TO AN INCREASED
STANDARDIZED RATIO FOR CANCER AT
THE TIME OF DISEASE ONSET AND A
HIGHER CUMULATIVE INCIDENTS OF
CANCER OVER TIME.
IN PRIOR STUDIES WE WERE COMPARE
BEING DETERMINA PATIENTS WITH
THE RESPONSE AND WITHOUT THE
IMMUNE RESPONSE.
WE DID NOT KNOW THE CANCER RISK
IN THE GENERAL POPULATION THAT
WOULD INFORM WHETHER THEY WOULD
BENEFIT FROM CANCER DETECTION
STRATEGIES.
WHEN WE LOOK WITHIN THREE YEARS
WE SEE THAT THE RNA 3 ANTIBODIES
AND A TWOFOLD RISK AND THEY
SEEMED TO DIFFER BASED ON THE
CLINICAL EXPRESSION.
SO THAT'S WITH DIE FUSE HAD
HIGHER RISKS OF BREAST, PROSTATE
AND TONGUE CANCER WHERE AS THOSE
WITH LIMITED SCLERODERMA HAD A
LOWER RISK OF CANCER.
THIS IS FROM A SINGLE CENTER
COSHORT.
THIS REQUIRES REPLICATION IN
EXTERNAL COHORTS, BUT THE DATA
SUGGESTS THAT AUTO ANTIBODY TYPE
AND PHENOTYPE COULD BE USEFUL
TOOLS TO BEMENTER TARGET OUR
CANCER DETECTION STRATEGIES.
I WANTED TO SHOW YOU SOME OF THE
FINDINGS FROM THE OTHER MAJOR
AUTO ANTIBODY SUB GROUPS.
THE THIRD COLUMN HAS ANTIPOLR 3
ANTIBODIES.
WHAT WAS A SURPRISE FOR US WAS
THE SECOND COLUMN HERE OF
PATIENTS WITH ANTICENTER MUIR
ANTIBODIES WHERE THELD A LOWER
CUMULATIVE RISK OF CANCER
OVERTIME.
THIS WAS AN UNEXPECTED FINDING
FOR US.
WHEN WE THINK OF THIS SUBGROUP,
THEY OFTEN HAVE A PROFOUND TEEN
TYPE TO THEIR DISEASE.
WE WONDER IF IN EFFECT THERE IS
AN ANTIANTIJENS EFFECT HERE.
COULD THIS DETERMINE AN EFFECT
IN THEMSELVES?
THEMSELVES COMING BACK TO THE
RNA 3 STORY, IT'S IMPORTANT IT
NOTE IN OUR COHORT ABOUT 20% OF
THESE PATIENTS HAVE A CANCER
DIAGNOSE AND 80% DO NOT.
A KEY QUESTION IS WHO NEEDS
ENHANCED CANCER DETECTION
STRATEGIES AND ARE THERE OTHER
FEATURES THAT CAN BETTER HELPS
SEGREGATE THOSE PATIENTS THAT
THAT WILL HAVE A DETECTABLE
CANCER OR NOT.
IT RAISES AN INTERESTING
QUESTION OF COULD CANCER BE A
DRIVER IN 1-PERCENT OF THE
PATIENTS WITH RNA 3 ANTIBODIES
OR IS IT NOT REACHING A CLINICAL
DETECTION EXCEPT FOR THE 20%
THAT WE OBSERVED?
THIS RAISES THE QUESTION OF
CANCER EDITING.
IF YOU THINK ABOUT IN THE
CONTEXT OF A DEVELOPMENT
MALIGNANCY, THERE MAY BE AN
ANTITUMOR RESPONSE MOUNTED
AGAINST THE CANCER.
YOU CAN ENVISION THREE DIFFERENT
SCENARIOS RILTING FROM THE
INTERSECTION BETWEEN THE
MALIGNANCY AND IMMUNE SYSTEM.
THE FIRST IS THE THAT THE IMMUNE
SYSTEM WOULD BE POALTANT
RESULTING IN ERADICATION OF THE
UNDERLYING CANCER SHOWN HERE IN
THE ELIMINATION PHASE DESCRIBED.
ALTERNATIVELY THE IMMUNE SYSTEM
MAY EXPERT PRESSURE ON A
DEVELOPING MALIGNANCY AND THE
TUMOR MAY UNDERGO EDITING
RESULTING IN A DELICATE DANCE
BETWEEN A DEVELOPING CANCER AND
I IMMUNE SYSTEM THAT KEEPS A
CANCER FROM EMERGING BUT
PREVENTS IT FROM BEING
ERADICATED.
THAT'S REPRESENTED HERE.
THE LAST SCENARIO IS WHERE THE
CANCER IS ABLE TO ESCAPE THE
IMMUNE RESPONSE AND CLINICALLY
EMERGES.
COULD IT BE WE'RE SEEING THE 20%
OF CASES HERE BUT COULD CANCER
BE A DRIVER AMONG THE OTHER RNA
PULLEN RI 3 RESPONSES.
ARE THERE OTHER THINGS THAT CAN
HELP US IDENTIFY THE STUDY.
WE CONDUCTED A STUDY OF 300
PATIENTS HALF OF WHOM HAD CANCER
AND HAVE DID NOT AFTER FIVE
YEARS OF FOLLOW-UP.
IN THE NO-CANCER GROUP, THERE
WERE ADDITIONAL IMMUNE RESPONSES
BRENT AND IN THIS PARTICULAR
STUDY IDENTIFIED, ONE SUCH
IMMUNE RESPONSE IS A RESPONSE TO
IT.
COULD IT BE A CANCER PROTECTIVE
COMBINATION?
IT WAS AROUND THE TIME THAT WE
WERE BEGINNING THESE STUDIES
THAT WE WERE TABLE TO ATTEND A
LECTURE IN A GROUP STUDYING BM H
21, A SMALL MOLECULE HAD
DEMONSTRATED IT HAD ANTITUMOR
ACTIVITY.
THIS WAS INTERESTING TO US.
WHEN WEIGH LOOKED BACK IN THIS
GROUP OF 168 SCER DETERMINA
PATIENTS CAN, WE FOUND THAT 18%
OF THE GROUP WITHOUT CANCER HAD
ANTIBODIES TO THE RNA PLUMBER
ACE ONE.
WE FOUND THERE WERE OTHER
ANTIBODIES PRESENT IN THE
NO-CANCER GROUP INCLUDING THOSE
TARGETING OTHER COMPONENTS OF
THE COMPLEX.
THIS DATA RAISES THE IMPORTANT
QUESTION ON WHETHER A BROADER
IMMUNE RESPONSE, COULD IT HAD A
MORE POTENT CANCER EFFECT.
TO LOOK IF I IN A MORE
COMPREHENSIVE WAY, WE PARTNERED
WITH THE PITTSBURGH BERG
SCLERODERMA CENTER WHERE WE HAD
OVER 600 CASES AND 600 CONTROLS
THAT WHO DID NOT HAVE CANCER FOR
AT LEAST FIVE YEARS AFTER
FOLLOW-UP.
WE STUDIED 11 DIFFERENT
SPECIFICITSES SHOWN HERE.
IN THIS STUDY, WE WERE ABLE TO
IDENTIFY THAT INDEED RNAPL
PLUMMERACE AND ANTI52 AND THIS
ASSOCIATED WITH A HIGH RISK OF
CANCER AT THE TIME OF
SCLERODERMA ONSET.
IN THIS DA STUDY WE WERE NOT
INTERESTED IN JUST WHETHER AN
INDIVIDUAL SPECIFICITY
ASSOCIATED WITH A HIGHER OR OVER
RISK OF CANCER BUT WHETHER THE
LOWER RISK COULD HELP US
IDENTIFY THOSE THE CANCER RISKS.
WE PERFORMED A WAY TO LOOK AT
THIS BETTER AND BY IDENTIFYING
FIVE SCLERODERMA RESPONSES WE
CAN BETTER RISK STRATIFY OUR
PATIENTS INTO HIGH RISK AND LOW
RISK AS SHOWN HERE.
SO, THUS FAR, WE'VE SHOWN THERE
IS A CLOSE TEMPORAL RELATIONSHIP
BETWEEN CANCER AND SCLERODERMA
ONSET WITH THE SCLERODERMA
PATIENTS WITH RNA PLUMMER'S
THREE.
PLUMMERACE
THREE.
THIS RAISED SOME INTERESTING
QUESTIONS ON WHETHER OR NOT
THESE ARE ANTICANCER IMMUNE
RESPONSES THAT COULD BE AERNASED
THERAPY CLI.
WE THINK ANTITYPE AND PHENOTYPE
COULD BE USEFUL TOOLS TO
IDENTIFY CANCER LAYING THE
FOUNDATION FOR STUDYING TARGETED
CANCER SCREENING STUDIES.
WHILE I'VE BEEN FOCUSED ON
SCLERODERMA, WE THINK A LOT OF
THE KEY PRINCIPLES MAY BE MORE
BROADLY APPLICABLE FOR
AUTOIMMUNE DISEASES.
WE THINK OF DERMATTA.
THIS RISK IS HIGHEST IN
DESCRIRCHGHT AUTO ANTIBODY
SUBSETS.
IN DAMONG PATIENTS WITH HIGH RIK
AUTO ANTIBODIES, IT'S BEEN SHOWN
IN BOTH DISEASES THAT BROADENING
THE IMMUNE RESPONSE ASSOCIATES
WITH AN ATTENUATION OF RISK AND
ITHERE IS ANECDOTAL EVIDENCE THT
THERE MAY BE COLAITION AND DATA
SUGGESTING THAT CANCER SCREENING
COULD BE TARGETED BY AUTO
ANTIBODY TYPE AND CLINICAL
FEATURES OF THE DISEASE.
WE DON'T HAVE MUCH TIME TOLD TO
TALK ABOUT CANCER SCREENING AND
OTHER IMPLICATIONS FOR OUR
PATIENTS.
BUT I DID WANT TO HIGHLIGHT THAT
IT'S IMPORTANT THAT WE REMEMBER
AGE, SEX AND RISK FACTORS IN
THESE PATIENTS AND THERE ARE
SEVERAL STUDIES UNDERWAY LOOKING
AT THE UTILITY OF MEASURES IN
THE HIGH-RISK PATIENTS.
MORE WORK NEEDS TO BE DONE TO
INVESTIGATE CANCER THERAPY AS
SCLERODERMA THERAPY.
OFTEN PATIENTS WITH SCLERODERMA
ARE DENIED ACCESS TO CANCER
IMMUNEO AND RADIATION THERAPY
TREATMENT BECAUSE THERE COULD BE
CAUSES OF FLAIR UPS TO THE
DISEASE BUT THERE IS EVIDENCE
THEY ARE NOT CONTRA INDICATIVE.
WE THINK THAT MULTI-DISCIPLINARY
DECISION MAKING IS CRITICAL TO
HELP OUR PATIENTS MAKE THE BEST
DECISIONS WHEN THEY ARE
CONFRONTING HAVING BOTH
SCLERODERMA AND CANCEL.
AND SO WITH THAT, I WITH WANT TO
THANK YOU AGAIN FOR THIS
OPPORTUNITY TO SPEAK TODAY.
I WANTED TO ACKNOWLEDGE THE WORK
I PRESENTED WAS THE WORK OF
MANY, MANY PEOPLE.
WE'RE GRATEFUL TO OUR FUNDING
SOURCES INCLUDING SUPPORT FROM
THE NIH.
TO THANK YOU VERY MUCH.
>> DR. FOR THAT WONDERFUL TALK.
YOUR QUESTIONS WERE PERTAINING
TO OTHER AUTOIMMUNE DISEASES AND
THAT WILL BE A FRUITFUL
DISCUSSION.
I'M DELIGHTED TO INTRODUCE OUR
SECOND SPEAKER DR. MAUER SEEN
SU.
SHE'S THE MORRISON FAMILY
PROFESSOR IN MIKE
AUTOIMMUNOLOGY.
SHE GRADUATED FROM HARVARD
MEDICAL SCHOOL AND COMPLETED HER
TRAINING AT THE UNIVERSITY OF
CALIFORNIA SAN FRANCISCO.
AS A FELLOW IN THE DEVELOPMENT
PROGRAM FOR PEDIATRICS, SHE
DELINEATED MECHANISMS FOR THE
AUTOIMMUNE DISEASE.
SHE LEADS AN IMMUNOLOGY RESEARCH
PROGRAM FOCUSING ON ANTICANCER
IMMUNITY AND SEX DIFFERENCES IN
IMMUNITY.
SHE SERVES FOR THE UCLA TRAINING
PROGRAM SO SHE'S A TRIPLE
THREAT.
DR. SU, WITH THAT, I'LL PASS THE
MIC OVER TO YOU.
>> THANK YOU SO MUCH.
IT'S A PLEASURE TO BE HERE
TODAY.
THANK YOU FOR THE INVITATION.
SO -- SORRY.
I'M HAVING A LITTLE TROUBLE.
I'M A PEDIATRIC ENDOCRINOLOGIST.
I HELP CHILDREN WITH MEUNITY AND
THAUTOIMMUNITY AND THYROID
DISEASE.
I HAD A PATIENT WITH SYMPTOMS
TYPICAL FOR DIABETES.
SHE HAD HIGH BLOOD SUGARS.
AND POSITIVE FOR KETONES IN HER
BLOOD.
TOGETHER -- THIS IS A PICTURE
CONSISTENT WITH DIABETIC KE
KETOACIDOSIS.
IT'S A STATE THAT WEIGH SEE WITH
TYPE I DIABETES.
IMPORTANTLY FOR THIS PATIENT,
NINE MONTHS PRIOR SHE HAD BEEN
DIAGNOSED WITH CARCINOMAA AND
TREATED WITH THERAPIES.
ADDITIONAL LAB TESTING SHOWED
SHE HAD A LOW C PEPTIDE THAT
INDICATED THAT HER BODY'S
INSULIN PRODUCTION WAS IMPAIRED.
AND SO THIS IF PICTURE WAS
CONSISTENT WITH AUTOIMMUNE OR
TYPE I DIABETES INDUCED BY
ANTICANCER IMMUNOTHERAPY.
WE PUBLISHED THIS CASE AS A CASE
REPORT IN PRECE PEDIATRICS TO AT
DOCTORS THAT PATIENTS RECEIVING
CANCER THERAPIES WERE AT
INCREASED RISKS FOR AUTOIMMUNE
CONDITIONS LIKE DIABETES.
>> TO HSU, WO SU, WOULD YOU REIO
TAKE OVER CONTROL?
>> THAT WOULD BE LOVELY.
>> AND DR. SU, JUST SAY NEXT
WHEN YOU'RE READY.
>> THANK YOU.
ANTIPD-1 AND OTHER INHIBITORS
HAVE REVOLUTIONIZED CANCER
THERAPY.
50% EVER CANCER PATIENTS ARE NOW
ELIGIBLE FOR IMMUNEO CHECKPOINT
INHIBITORS AND THIS WORKS
BECAUSE INCREASED ACTIVATION
INCREASES.
PD-1 IS USUALLY EXPRESSED ON T
CELLS.
WHEN THIS INTERSECTION HAPPENS,
IT SENDS AN INHIBITORY SIGNAL TO
THE T CEL CELLS.
WHEN PD 1 IS GIVEN THE T CELL
CAN BE ACTIVATED, THE BRAKES ARE
REMOVED AND THE T CELL CAN KILL
OFF THE CANCER.
THIS OFFERS A CURE BUT COMES AT
A PRICE.
60% OF PATIENTS DEVELOP
IMMUNE-RELATED ADVERSE EVENTS
THAT ARE AL AUTOIMMUNE CONDITIOS
THAT AFFECT THE CELLS.
ABOUT 50% ARE HOSPITALIZED FOR
THESE SO THEY CAN BE SERIOUS.
ON THE RIGHT HERE IS A SCHEMATIC
OF SOME OF THE DIFFERENT TISH TS
THAT ARE AFFECTED BY IRAEs
RESULTING IN DIABETES.
THHERE WE HAVE A PARADOX IN THE
COURSE EVER ENHANCING IMMUNITY,
AUTOIMMUNEITY CAN BE UNLEASHED.
ONE THING THAT HAS BEEN
DESCRIBED AS AN ANTICANCER
IMMUNITY IS THE PRESENCE OF THE
T CELLS.
THEY'RE CD POSITIVE AND REFLECT
MARKERS.
THESE CELLS ARE STEM-LIKE IN
THAT THEY CAN SELF-RENEW AND ARE
LONG-LIVED AND CAN DIFFER SHAITT
SHAILT INTO OTHER CELL TYPES.
BECAUSE THESE PROGENITORS ARE
LONG-LIVED, WE THINK THEY'RE
MEEMEDIATING THE AUTOIMMUNE
RESPONSE.
THEY SEEM TO BE THE CELLS
TARGETED BY ANTIPD-1 THERAPY.
IN THIS PAPER PUBLISHED IN
IMMUNITY AND OTHER PAUPERS, THE
POSITIVE STEM-LIKE PROGENITORS
SEEM TO BE THE CELLS RESPONDING
TO CHECKPOINT BLOCK 5EUAIDING TE
THERAPY.
THEY SEEM TO PUSH THEIR
CONVERSION INTO THE DETEACTERS S
AND KILL THE CANCER CELLS SO
ANTICANCER IMMUNITY IS ENHANCED.
RECENTLY MULTIPLE GROUPS HAVE
REPORTED THE STEM-LINE
PROGENITORS ARE AN IMPORTANT
PLAYER IN AUTOIMMUNE DIABETES.
THESE POSITIVE CELLS HAVE BEEN
FOUND IN TYPE 1 DIABETES RENEW
AND GIVE RISE TO THE DEFERKTS
FOR BETA -- DEFECTORS RESULTING
IN TYPE 1 DIABETES.
BECAUSE THESE STEM-LIKE
PROGENITORS ARE LONG LIVED, IT'S
FELT THAT THE KR KRONISITY IS DE
TO THE PRESENCE OF THE STEM-LIKE
PROGENITORS.
SIMILAR TO CANCER, ANTIPD-1
SEEMS TO WORK IN THE PROGENITOR
CELLS.
IT WORKS BY DECREASING INTO THE
DEFECTORS AND WE SEE THIS
ACCELERATED FORM OF TYPE 18
DIABETES WITH
CANCER-IMMUNOTHERAPY.
SO, AS I SHOWED YOU PREVIOUSLY,
THERE ARE A NUMBER OF DIFFERENT
TISSUES THAT CAN BE EFFECTED BY
IRAEs.
THESE INCLUDE AUTOIMMUNE
DIABETES AS WELL AS THYROID
DISEASE.
THESE ARE TWO AUTOIMMUNE ENDO
KRIEN-O KRIENOPATH ISTHYS.
A SCIENTIST DID JUST THAT.
SHE PERFORMED THYROID BIOPSIES
ON PISHTS WITH MASH MOATOS
THYROIDIS WITH A THYROID IRAE
AND SUBB SUBJECTED THESE TO THE.
SHE SSHE SAW POSITIVE FERKTS.
WHEN SHE DID PSUEDO TIME
TRAJECTORY OF THE DATA, YOU
COULD SEE A DIFF DIFFERENTIAL.
WHEN WE SEPARATED OUT THE CELLS
BY GROUP, WE COULD SEE THAT
WHETHER OR NOT PATIENTS RECEIVE
THE INPRIPTER CHANGED THEIR
DIFFERENTIATION TRAJECTORY.
THIS IS SELF-FREQUENCY ON THE Y
AXIS AND IN THE READ ARE THOAS
THAT RECEIVED PREFECTURE AND IN
DEFECTORS.THERE ARE MORE CELLS E
PATIENTS THAN THOSE ARE MASH
HASHIMOTO'S DISEASE.
THIS WAS CORROBORATED WHEN WE
LOOKED AT THE PROPORTION OF
CELLS.
THERE WAS AN INCREASE IN A KOWM
LAITION OF THE THE CELLS IN
PATIENTS WITH THYROIDITIST
IRAEs COMPARED TO THOSE WITH
HASHIMOTOS.
TOGETHER THESE DATA PAINT A
PICTURE DEMONSTRATING THE
IMPORTANCE OF PROGENITOR T
CELLS.
UNLIKE MOST AUTOIMMUNE DISEASES,
ENDOCRINE DISEASES ARE NOT
TREATED WITH IMMUNOTHERAPIES.
TYPE 1 TYPE BEAT 1 DIABETES WASD
AND WE GIVE THERAPY REPLACING
THE MISSING HORMONE.
THERE WAS A NEED TO IDENTIFY THE
TARGETS FOR ENDOCRINE DISEASE SO
WE CAN DEVELOP THERAPEUTIC
MEDICINES FOR THESE CONDITIONS.
WE ASKED WHICH MECHANISMS ARE
CONVERTING THEM TO AUTO
EFFECTERS.
IT CAN POTENTIALLY INTERRUPT THE
DEIF HE CANNERS AND PROTECT FROM
DISEASE.
WE WERE PARTICULARLY INTERESTED
IN ANTIGENETIC MECHANISMS
BECAUSE THE EPIGENETIC
MECHANISMS PLAY A KEY ROLE.
ON THE TOP OF IS A TRAJECTORY ON
THE T CELL AND ENDING WITH
TERMINALLY DIFFERENTIATED
EFFECTERS.
THEY WERE INCREASING THEIR
TRANSCRIPTION OF EFFECTER GENES
WHILE DECREASING THEIR STEM-LIKE
GENES.
THIS CHANGE IN PROFILES IS
ACCOMPANIED BY THE DISTINCT
EPIGENETIC CHANGES.
THE CIRCLES THAT HAVE CHECKERS
IN THEM ARE HI HYSTONES AS
PREFECTURE GENES ARE INCREASING
THEY GAIN THE GREEN HEX HEXAGON.
OPPOSITE OCCURS -- IF YOU GO
BACK FOR A SECOND.
THE STEM-LINE GENES ARE ALTERING
THEIR HYTONE ABILITY AND
SHUTTING DOWN GENE
TRANSCRIPTION.
THIS CHANGE IN HYSTO MARKS IS
NOT RANDOM BUT REGULATED BY UTX.
IT ALTERS CHROMOSOME
ACCESSIBILITY.
WE WERE PARTICULARLY INTERESTED
IN UTX GIVEN A RECENT PAPER
SUGGESTING THAT IT PLAYS A ROLE
IN CONTROLLING CT-8 RESPONSES IN
TUMOR IMMUNITY.
GIVEN THE PARALLELS BETWEEN
ANTICANCER IMMUNITY AND
AUTOIMMUNE, WE FOUND IT WAS
PROMOTING TYPE I DIABETES BY
CHANGING THEM FROM ANTITUMOR TO
STEM-LIKE EFFECTERS.
WE UTILIZED THE UTX MOUSE MODEL.
IT MIMICS DIABETES IN MANY WAYS.
THERE ARE MULTIPLE DIFFERENT
GENES THAT CONTRIBUTE TO
AUTOIMMUNE PREDISPOSITION.
IT'S KNOWN THAT AUTO REACTIVE T
CELLS ARE KILLING THE BETA
CELLS.
ABOUT 8 O% OF FEMALES DEVELOPED
DIABETES SO IT'S A PRO BUST
MODEL.
LIKE THE PAPER THAT ORIGINALLY
DESCRIBED THIS MOUSE WE SAW 80%
INCIDENTS IN OUR COLONY.
AND WHEN WE KNOCKED OUT UTX
SPECIFICALLY IN T CELLS, WE SAW
THAT THE NOD MICE WERE NOW
COMPLETELY PROTECTED.
BY 30 WEEKS, NONE OF THE MICE
HAD DIABETES.
WHEN WE LOOKED IN THE PANCREATIE
MICE THEY HAD THE NO EYELETS AND
THE OTHERS HAD INTACT EYELETS.
THERE WERE A LOT OF EYELETS THAT
HAD MAJORITY OF INFILTRATION
WHERE THE UTXTCD HAD MINIMAL.
WE PERFORMED TESTS ON THE LYMPH
NODES FROM THE WILD TYPE AND THE
UTXTCD MICE.
13 WEEKS WAS THE DISEASE PROCESS
WHICH WAS RIGHT BEFORE THE MICE
DEVELOPED TYPE I DIABETES.
WHEN WE FOCUSED ON THE TCD
CELLS, WE WERE ABLE TO IDENTIFY
A PROGENITOR CLUSTER.
WHEN WE PERFORMED ANOTHER
ANALYSIS THERE WAS A PROJECTION
THAT PROGRESSED THROUGH THE
FACTOR MEDIATORS.
AND WE COULD SEE THAT
TRANSCRIPTION OF STEM-LIKE GENES
WERE HIGHEST IN THE PROGENITOR
POPULATIONS, TCX 1 AND 108 WERE
HIGHEST AT THE BEGINNING OF THE
TRAJECTORY.
AND THE PREFECTURE GENES WERE
HIGHEST IN THE PREFECTURE
POPULATIONS, T.
IT WAS LOW IN PROGENITORS AND
HIGHEST IN THE PREFECTURES.
WE NEXT SEPARATED OUT THE CELLS
THAT WERE DERIVED FROM THE WILD
MICE FROM THOSE MICE MISSING THE
UTX IN THEIR CELLS.
UTX SEEMS TO HAVE AN EFFECT ON
THE DIFFERENTIATION.
WE HAVE UTX AND YT.
THE LEFT PART OF THIS GRAPH, YOU
CAN SEE IS THAT THERE IS
ACCUMULATION OF PROGENITORS IN
THE UTXTCD MICE AND FEWER
EFFECTERS IN THESE MICE COMPARED
TO THE WILD TYPE.
WHEN WE LOOKED AT THE CELL
FREQUENCIES, WE SAW AN INCREASE
IN THE PROGENITOR POPULATION IN
THE UTXTCD MICE AND DECREASE IN
THE PREFECTURE.
WE WANTED TO CONFIRM OUR DALT BY
USING FLOW-CYTOOMETRY.
STEM-LIKE PROGENITORS WERE
IDENTIFIED AS POSITIVE AND
NEGATIVE.
THE PREFECTURE MEELD-ATORS WERE
IDENTIFIED AS DY 108 CD 39
POSITIVES.
WHEN WE LOOKED AT THE MODE,
ACCUMULATION OFORTS PROGENITOR
IN THE UTXCD NICE AND A
DEFICIENCY IN THE MEDIATOR
POPULATIONS.
WE THINK THAT UTX IS WORKING IN
THE SEMI PROGENITORS TO INCREASE
THE CONVERSION OF THE
PROGENITORS TO THE DESTRUCTIVE
MEDIATORS.
AND WHEN WE KNOCK OUT UTX IN THE
T CELLS WE HAVE AN ACCUMULATION
IN THE CELLS AND A DETISHT DEFIN
THE POPULATION.
AS I TOLD YOU BEFORE, UTX
INCREASES CHROMEO GENETIC
TRANSCRIPTION.
HOW DOES UTX POTENTIALLY ALTER
THE ACCESSIBILITY AND GENE
TRANSCRIPTION IN THE
PROGENITORS?
WE HWHEN WE LOOKED AT THE DATA,F
NICE EITHER WILD OR UTXCD, THERE
WAS AN INCREASE IN CHROMEO
ACCESSIBILITY AND A
TRANSCRIPTION OF STEM-LIKE GENES
IN TSPROG CELLS.
IT SEEMED TO BE UPGRADE IN TERMS
OF THERAPY CHROMOSOME
ACCESSIBILITIES.
YOU CAN SEE THAT IN THE DATA WE
SEE INCREASED TRANSCRIPTION AT
THE SAME GENES.
NEXT SLIDE.
AT THE SAME TIME, WE SAW CHANGES
ALSO IN PREFECTURE GENES.
PREFECTURE GENES.
ON THE RIGHT IN THE ATAC-SEQ, WE
CAN SEE DECREASED EXPRESSION IN
THE PREFECTURE GENES IN THE
PREFECTURE MICE.
THEY WERE ALL DECREASED IN THE
UTXCD IN TERMS EVER WILD TYPE IN
TERMS OF CHROMOSOME
ACCESSIBILITY.
ON THE LEFT PANEL WE SAW LESS
TRANSCRIPTION OF THESE GENES.
NEXT SLIDE.
WHAT WE THINK IS GOING ON IS
THAT UTX IS POISING PREFECTURE
GENES IN THESE SEMI PROGENITORS.
PREFECTURE GENES ARE USUALLY
CLOSED IN THE SEMI PROGENITORS
AND UTX IS OPENING THEM UP TO
ALLOW THEM TO BE TRAN SCRIEPED.
IN THE OTHERS IT IS SHUT OFF SO
IT'S NOT IN THE STEM-LIKE STATE.
ALL THE DATA HAS BEEN IN THE
SETTING OF GENETIC DEFICIENCY OF
UTX SO WE ELIMINATED UTX IN THE
T CELLS.
IS IT POSSIBLE TO TRANSLATE THIS
FOR THERAPEUTIC GAIN?
IN 2015, A SMALL MOLECULE
INHIBITOR WAS DESCRIBED THAT
INHIBITS UTX FUNCTION.
AND THIS INHIBITOR HAS BEEN USED
IN VIFO.
VIVO.
WE TREATED THE NLD MICE AND YOU
SEE THAT GSK-J 4 PROJECTED THE
MICE FROM THE DEVELOPMENT.
WHEN WE LOOKED AT THE PANCREATIC
LIMP MODE OF THE MICE WE COULD
SEE TH THE INCREASE OR MEDIATORN
THE MICE SUGGESTING THAT THE
GSKJ4 WAS MIMICKING THE
DEFICIENCY.
WE THINK UTX IS PLAYING AN
IMPORTANT ROLE IN DRIVING THE
SYSTEMIC EFFECTERS.
WHAT ABOUT PD1?
WE UTILIZED THE MICE AGAIN AND
WHEN THEY ARE TREATED WITH
ANTIPD 1 THEY DEVELOP DIABETES
RAPIDLY.
BY TWO WEEKS ALL THE MICE VOLE
DIABETES.
ALL THE MICE DEVELOP DIABETES.
IF THE MICE ARE DEFICIENT FOR
UTX IN THE T CELLS, WE DID NOT
SEE DIABETES AT ALL.
AFTER 30 DAYS, THE MICE WERE
DIABETES FREE.
IT SUGGESTED THAT UTX WAS
REQUIRED FOR ANTIPD 1 INCREWSED
DIABETES.
THE WILD MICE SHOWED
INFILTRATION WAR YAZ THE UTXCD
AFTER THREE DAYS HAD RELATIVELY
PROTECTED EYELET INIF I
TRAITION.
WE ALSO LOOKED IN THE PANCREATIC
IMP NODE OF THE NICE AND SAW A
PATTERN IN THE ANTIPD1 TREATED
MICE IN A CASE OF PROGENITORS IN
THE UTX, AND DECREASE IN THE
MEDIATOR CELL POPULATIONS.
SO WE THINK THAT UT EXPRKS NOT
ONLY IMPORTANT IN DETECTING
DIABETES AND THE PERFORM INDUCED
BY ANTIPD 1 AND WE'RE LOOKING TO
INCREASE CONVERSION.
IF YOU'RE EFFICIENCY IN UTX
DON'T CONVERT.
SO TO SUMMARIZE WHAT I TOLD YOU,
WE THINK THAT UTX IS A
POTENTIALLY DRUGABLE TARGET FOR
INTERRUPTING PROGENITORS TO
EFFECTERS IN BOTH SPONTANEOUS AS
WELL AS ANTIPD 1 DIABETES.
UTX PLAYS AN IMPORTANT ROLE TO
PROMOTE THEIR CONVERSION TO
CYTO-TOXIC EFFECTERS.
WE CAN PROTECT AGAINST DIABETES
AS WELL AS THE POTENTIAL DRUG
SMALL MOLECULE INHIBITOR GSKJ 4
AND PROTECTS FROM TYPE 1
DIABETES.
WITH THAT, I WOULD LIKE TO
ACKNOWLEDGE THE PEOPLE WHO DID
THE WORK.
HOWARD CHEN IS A GRAT WAD
STUDENT AND CLOSE TO GRADUATING.
WE WOULD LIKE TO ACKNOWLEDGE AND
GRATEFUL FOR THE SUPPORT OF THE
OADR AND UCLA ALLOWED US TO DO
MANY OF THE STUDIES THAT YOU SAW
TODAY.
AND MANNISH BEUT AND WILLY HUGO
ARE PART OF THIS TEAM.
>> THANK YOU DR. SU FOR THAT
UNSITEFUL PRESENTATION.
I WILL NOW INTRODUCE DR.
ANDERSON, SENIOR SCIENTIST AT
THE BRIGHAM HOSPITAL AND CORPS
FACULTY MEMBER.
HER LABORATORY FOCUSES ON
UNDERSTANDING THE PATHWAYS AND
MECHANISMS THAT REGULATE THE
T-CELL WE SPHONS IF CHRONIC
DISEASES PARTICULARLY IN CANCER.
IT'S A PLEASURE TO HAVE YOU WITH
US TODAY.
THE SCREEN IS YOURS DR.
ANDERSON.
>> THANK YOU.
WONDERFUL.
THANK YOU DR. KUO FOR THAT NICE
DESTRUCTION AND THANK YOU TO THE
OADR AND DR. SHANMUGAM FOR THE
INVITATION TO PRESENT AT THIS
INTERESTING FORUM.
I'M NOT HAVING LUCK AT ADVANCING
MY SLIDES EITHER.
>> DRL SHANMUGAM: IF YOU HAND IT
OVER TO ME, I'LL WE TAKE CARE OF
IT.
>> THANK YOU VERY MUCH.
GO TO THE NEXT SLIDE, PLEASE.
WE'VE BEEN TALKING TODAY ABOUT
THE LINKS BETWEEN AUTOIMMUNITY
AND CANCER.
INDEED, CANCER CAN BE THOUGHT OF
A DEEZ WHERE THE IMMUNE REACTION
IS SLOW WHERE AS IN AUTOIMMUNITY
YOU HAVE AN ACTIVE RESPONSE
AGAINST ANTIGENS.
AS YOU HEARD FROM THE PREVIOUS
TALKS, THIS RELATIONSHIP BETWEEN
THESE TWO DISEASES IS NOT
UNI-DIRECTIONAL.
WE CAN SEE HOW SCLERODERMA CAN
PREVENT BREAST CANCER AND IBD IS
WELL-KNOWN IT TO BE A RISK
FACTOR FOR THE DEVELOPMENT OF
COLORECTAL CANCER.
ICIs CAN PROMOTE THE
DEVELOPMENT OF IMMUNE-RELATED
ADVERSE EVENTS OR IRAEs IN
PATIENTS THAT HAVE TUMOURS AND
ARE BEING TREATED WITH THESE
IMMUNOTHERAPY AGENTS.
THESE LINKS AT THE LEVEL OF SORT
OF THE O ORGANISM AND PROPERTIES
DO EXIST IN ORDER TO UNDERSTAND
THE LINKS BETWEEN THESE TWO
DISEASES IT'S IMPORTANT TO GO TO
THE CELLS AND MOLECULAR
MECHANISMS.
SO MY TYPE OF FOCUS ON STEM-LIKE
T CELLS.
YOU HEARD ABOUT THESE FROM THE
PREVIOUS TALK.
I'LL GET MORE IN-DEPTH INTO WHAT
THEY ARE AND ABOUT THEIR BIOLOGY
IN BOTH THE CONTEXT OF
AUTOIMMUNE INFLAMMATION AND
CANCER.
THE STEM-LIKE T CELLS HAVE THE
CAPACITY TO SELF-RENEW.
THEY ARE THE CELLS THAT FEED THE
PREFECTURE RESPONSE.
YOU HEARD ABOUT CD 8 IN THE LAST
TALK AND I'LL TALK ABOUT CD-4.
THESE ARE CENTRAL PLAYERS IN
CANCER AND AUTO IMMUNITY.
ONE OF THE MAJOR TRAN
DESCRITRANSCRIPTIONFACTOR IS TC.
ON THE RIGHT SIDE IS A CARTOON
WE WROTE.
TCF-1 IS HAVE A RAN DESCRIPTION
FACTOR AND MEMBER OF THE
SIGNALING PATHWAY.
IT HAS FOUR DIFFERENT MODES OF
ACTIVITY.
IT CAN EITHER ACT AS A
TRANSCRIPTIONAL ACTIVATOR OR
SUPPRESSER DEPENDING ON WHETHER
IT'S ASSOCIATED WITH TCT OR
SIGNALING FACTOR.
IT COULD HAVE PIONEERING
FUNCTIONS.
IT'S KNOWN TO MODIFY HI HYT TON.
IT'S BEEN DESCRIBED TO ACT AS A
TRANS REPRESSER AND IT CAN
COMBINE WITH OTHERS AND
INTERFERE WITH THE ACTIVITY OF
THOSE TRANSCRIPTION FACTORS.
I'LL GET BACK TO THAT PARTICULAR
MECHANISM LATER IN MY TALK.
WE'RE FOCUSED ON TH-17 CELLS.
THESE ARE MAJOR DRIVERS OF
AUTOIMMUNE IN MAJOR DISEASES.
THEY'RE TWO TYPES OF TH-17 CELLS
HEN IN THE MIDDLE OF BLUE, TH-17
CELLS THAT ARE STEM-LIKE.
THEY PRODUCE ISLE 17, ISLE 22
AND ISLE 10.
THEY CAN BE IDENTIFIED BY SLAMF
6 ON THEIR CELL SURFACE AND HAVE
IMPORTANT TISSUE FUNCTIONING
PARTICULARLY IN THE GUT WHERE
THEY MAINTAIN BARRIER FUNCTION.
THESE CAN BE DIFFERENT SHAIPTED
BY ISLE 23 WHICH I'VE HE
DEPICTED IN RED TO BECOME THE
INFLAMMATORY CELLS.
THEY CAN BE INDUCED IN A CULTURE
WITH ISLE 21, 6 AND 23.
THESE CELLS CAN BE FOUND IN
VITRO BY EXPRESSION.
WHEN THEY'RE DIRECTED TO
SELF-TISSUES THEY ARE A MAIN
DRIVER.
I'M SHOWING YOU THE GENETIC MAP
OF MULTI MULTIPLE SCLEROSIS.
I DEPICTED HERE STEP THREE AND
STEP FOUR.
THESE ARE SIGNAL TRANSDUCERS
DOWNSTREAM OF ISLE 23 THAT
CONFLICTS HOMEOSTATIC TO THE
INFLAMMATORY TH-17 CELLS.
WHAT WE GOT INTO IN IS WHEN WE
SAW THE TCF 7 WHICH IS THE GENE,
IT WAS ALSO FOUND TO BE HAVE
SNIPS ASSOCIATED WITH MS RISK.
SO WE DECIDED WE NEEDED TO LOOK
AT THIS IN MORE DEPTH.
WE LOOKS AT TCF 1 EXPRESSION AND
MOHOMIO STATIC CELLS OR THOSE
SHOWN IN RED.
THE TCF-1 HAS A HIGHER
EXPRESSION RATHER THAN THE TH-17
CELLS.
IN PANEL B, WE FOUND IF WE
CULTURED THE CELLS AND WENT TO
ISLE 3, WE SAW DECREASED
EXPRESSION OF TCF-1 INDICATING
THAT ISLE 23 ONE OF THE THINGS
THAT IT DID TO CONVERT THE CELLS
THAT DRIVE AUTOIMMUNE YIPT WAS
TO DECREASE THE AUTO EXPRESSION.
WE LOOKED AT MICE WITH THE MODEL
FOR MS.
WE COULD SEE THERE WERE LOWER
LEVELS OF TCF-1 SHOWN IN GRAY.
WHEN WE DID THIS WITH THE MICE
WITH THE INABILITY TO SENSE ISLE
23, THEY RETAINED HIGHER LEVELS
OF TCF 1 EXPRESSION INDICATING
THAT I'LL 23 PROMOTES THE
DEVELOPMENT OF INFLAMMATORY
TH-17 CELL BUSINESS TURNING DOWN
TCF 1.
WE GAIN AND LOSS OF FUNCTION
APPROACHES.
WE USED A T-CELL RECEPTOR MICE
RECOGNIZING AN ANTIGEN AND WE
WERE ABLE TO CROSS THESE MICE TO
MICE THAT HAVE CONDITIONAL
DISLEETIODELETION.
TCF-1 IS CRITICAL DURING
DEVELOPMENT SO WE NEEDED TO
BYPASS ISSUES STEMMING FROM
ABNORMAL T CELL DEVELOPMENT.
WE WERE ABLE TO USE THESE DISTAL
MICE TO STUDY TCF 1.
WE STUDIED A MOUSE THAT
OVEREXPRESSES TCF 1 UNDER THE CD
2 PROMOTER.
WE WERE ABLE TO USE THE MICE TO
ADOPT TRANSFER EXPERIMENTS.
WE COULD GENERATE OUR STEM-LIKE
OR HOMEOSTATIC CELLS OR
INFLAMMATORY CELLS SHOWN IN RED.
ON THE RIGHT IS THE FACT THAT
THE DIFFERENTIATION INTO THE
DIFFERENT TYPES OF CH-17
CELLS -- TH 17 CELLS WERE
DIFFERENT IN THE MICE.
WHEN WE HL TURNING THE CELLS
INTO WILD TYPE MICE, THEY
INCREASED THE CELLS.
WHEN WE LOOKED AT PANEL C AT THE
CYTOKINE PRODUCTION OF TS T
CELLS ISOLATED FROM THE CENTRAL
SYSTEM THEY HAD INCREASED
AMOUNTS OF TCF 1 CKO.
SHOWN IN PANEL A IS THE
OVER-EXPRESSION OF TCF 1 AND
WE'RE NOT GETTING SUPER
PHYSIOLOGICAL, IT'S WITHIN THE
RANGE OF NORMAL CELLS BUT
THEY'RE UNABLE TO TURN DOWN
THEIR EXPRESSION OF TCF 1.
WHEN WE TRANSFERRED NIECE INTO
WILD TYPE RECIPIENTS, THE TCF 1
MICE HAD MARKEDLY LOWER DISEASE
DEVELOPMENT.
THIS WAS COMMENSURATE WITH FEWER
2 D 2 CELLS.
THESE CELLS HAD LOWER EXPRESSION
EXPRESSION.
THESE CELLS HAD LOWER EXPRESSION
0OF ISLE 17-A.
TOGETHER IT INDICATED THAT
MODULATION OF TCF 1 COULD
ENHANCE DISEASE OR ABROGATE
DISEASE.
IN ISLE C, IT DECREASES TCF 1.
WE REASONED THAT TRUE, IS IT
POSSIBLE THAT TCF 1 DEFICIENT
CELLS NO LONGER REQUIRE ISLE 23
TO BE THE DISEASE DRIVING CELLS.
WE LOOKED AT CELLS AND
TRANSFERRED THEM INTO PD-1 MACE
THAT COULD NOT PRODUCE THE
DISEASE.
WE FOUND THEY HAD HIGHER NUMBERS
OAF POSITIVE CELLS INFILTRATING
THE CLS.
THE WILD CELLS WERE MORE LIKE
TH-1 CELLS AND WHEN WE LOOKED AT
THE CYTOKINES WE FOUND THEY WERE
PRODUCING MORE IL 17 A.
THE TRULY DIFFERENTIVE
EXPERIMENT IS WHAT WE DID IN
PANEL D.
WE CROSSED OUR TCF KNOCKOUT MICE
TO ID 23 RECENTER MICE AND WE
CAN SEE THAT THE WILD-TYPE CELLS
IN IMLAK NICELY INDUCED DISEASE.
THE DEFICIENT CELLS WERE UNABLE
TO PRODUCE THE DISEASE.
THE LOSS OF CDF-1 WAS ABLE TO
ESSENTIALLY RESCUE THE INABILITY
OF THESE IL RESERPT KNOCK OUT
CELLS TO PRODUCE THE DISEASE.
THE MAJOR MECHANISM IN WHICH IL
23 WAS THE AUTO IMMUNE CELLS WAS
THROUGH THE LOSS OF TCF-1.
WE DECIDED T -- I'M SHOWING YOU
HERE THE RNASQ DATA.
WE INTRODUCED TH 17 FROM WILD
TYPE AND TRANSFERRED THEM INTO
MICE AND SAW THAT THEY
ACCUMULATED THE DISEASE.
WE DID THE RNASK FOR THESE
CELLS.
THERE WERE A LOT OF GENES
ASSOCIATED WITH INFLAMMATORY
PHENOTYPES.
SHOWN IN B IS WHERE WE DID A
TEST TO CONFIRM WHAT OUR
OBSERVATIONS WERE TELLING US WAS
TRUE.
WE LOOKED AT THE GENES ON THE
RIGHT WHICH ARE THE GENES
EXPRESSIONED IN THE TCF KNOCKOUT
JERS US THE GENES ON THE LEFT
EXPRESSED IN THE WILD TYPE CELLS
AND SCORED SIGNATURES.
INFLAMMATORY AND THOSE THAT
OVERLAPPED WITH THE TCF SLACKOUT
CELLS.
WHEN YOU SLOOK LOOK AT THE SLAMS
THEY OVERLAPPED WITH THE GENES
IN THE WILD TYPE CELLS.
PLEASE GO BACK TWO SLIDES.
SHOWN IN PANEL C IS THE DATA
LOOKING AT THE OPEN CHROMOSOME
GENES AND KNOCKOUT T CELLS.
WHAT WE FOUND IS THAT THE OPEN
CHROMATIN OVERLAPPED WITH THE
CHROMATIN CELLS WITH AUTO
IMMUNITY.
THEY SHARED 88% 6 THEIR
CHROMATIN IDENTITY.
JUST THE LOSS OF TCF THEMSELVES
IT WAS LIKE THE CELLS THAT WERE
INFLAMMATORY.
ONE OF THE THINGS I POINTED OUT
EARLIER IS THAT MAR GA WHEN WE D
AT BINDER SITES ENRICHED NEITHER
THE WILD TYPE CELLS OR KNOCKOUT
CELLS, THE KNOCKOUT CELLS HAD
THE TCF 1.
WHEN YOU SEE THAT RORGAM WA WAS
THE MOST BINDING SITE OF THE TCF
1 DEFICIENT CELLS.
I HAD SHOWN YOU EARLIER THAT TCF
1 THAT COULD ACT AS A TRANCE
REPRESSER.
WE THOUGHT MAYBE IT WAS ACTING
AS A REPRESSER.
WE TESTED WHETHER THEY COULD
BIND TO EACH OTHER.
IT'S -- THE LEFT PANEL IS NOT
SHOWING CLEARLY BUT THE RIGHT
PANEL HAS ALL THE THE DATA YOU
CAN SEE THAT WE COULD -- IF YOU
TREAT THE CELL WITH DNA, YOU SEE
THAT THE PRECIPITATION IS NOW
LOST.
NEXT SLIDE.
IN THE END, WE AGAIN, THIS IS
NOT DISPLAYING ENTIRELY
PROPERLY, WHAT WE DID IS
INDICATED OUR EPIGENETIC DATA
AND BUILT A REGULATORY NETWORK
BASICALLY TO VISUALIZE HOW TCF 1
WAS DETERMINING AND MAINTAINING
HOMEOSTATIC OR STEM-LIKE STATE
OF TH 17 CELLS.
SHOWN IN THE MIDDLE ARE TRANCE
DESCRIPTION FACTORS.
BLUE ARE THE TRANSCRIPTION
FACTORS EXPRESSED IN THE
HOMEOSTATIC STATE AND THE RED IS
INFLAMMATORY STATE.
WE TARGETED GENES EXPRESSED IN
THE RNC STAT AND LOOKED AT THE
WHAT THE GENES ARE AND FACILITY
BAMLIES AROUND THE TARGET GENES
AND PROCESSES THAT THEY
REGULATE.
ASPECTED YOU'D SEE THAT THE BLUE
TRANSCRIPTION FACTORS CONNECT
WITH THE HOMEOSTATIC CELLS AND
THE RED TRANSCRIPTION FACTORS
YOU SEE THINGS INVOLVED IN
MIGRATION, ADHESION THINGS
ASSOCIATESSED WITH MORE DAMAGING
FEENO TYPES.
TCF 1 MAINTAINS TH 17 CELLS BY
BINDING TO RORGT AND BY ORGANIZE
IT STRAIGHTING A REGULAR NETWORK
WITH A HOST OF TRAN DESCRIPTION
FACTORS.
HOMEOSTATIC TH 17 CELLS BECOME
INFLAMMATORY TH 17 CELLS UPON IL
23 DOWN REGULATION OF TCF 1.
NOW I'M GOING TO GIFT GEARS AND
TALK TO YOU ABOUT SOME OF OUR
WORK ON STEM-LIKE CD 8 CELLS.
AS DR. SU PREVIOUSLY MENTIONED,
THESE CELLS WERE DISCOVERED BY
OUR LAB AND OTHER LABS IN HUMANS
AND MOUSE MODELS.
THE STEM-LIKE T CELLS ARE
IMPORTANT IN MAINTAINING
RESPONSE TO THE BLOCKADE AND
THEY EXPRESS TCF 1.
OUR DATA SHOWN HERE A FEW YEARS
AGO WE WERE ALREADY INTERESTED
IN TCF 1.
IF YOU IMPLANTS CLONE TUMOURS
THAT EXPRESS LOW LEVELS, IF YOU
DO THIS IN WILD TYPE WITH
KNOCKOUT MICE, WE SAW THAT IF
YOU COMPARE THE BLUE TO THE RED,
THE WILD TYPE MICE RESPOND CELL
AND CONTROL TUMOR GROWTH.
IF YOU COMPARE THE LIGHT BLUE TO
THE PINK YOU SEE THE TCF 1 MICE
HAVE A MUCH MORE LIMITED
RESPONSE.
ON THE RIGHTS PANEL I SHOW YOU
WHERE WE INJECTED TUMOURS
INTERTUMOR ALLEY WITH A TR-9
WHICH HAS REGRESSION BUT IN THE
KNOCKOUT MICE MANY OF THEM
FAILED TO RESPOND.
AS SHOWN WITH THE RED ARROW, YOU
SAW THAT SOME OF THE KNOCKOUT
MICE WERE STILL ABLE TO RESPOND
AS WILD TYPES.
WE WANTED TO UNDERSTAND WHAT IS
TCF 1 IN CD 8 CELLS AND IS THE
REQUIREMENT FOR TCF ABSOLUTE?
WE DECIDED TO MODEL THIS.
WE TOOK ADVANTAGE OF TUMOR
MODELS THAT ARE EITHER POORLY OR
HIGHLY IMMUNEO JEN RICK DEPICTED
IN THE BLUE AND GREEN WE USED
THE SAME -- MODELS THAT
EXPRESSED THE SAME MODEL TUMOR
ANTIGEN.
WE IMPLANTED THESE TUMOURS INTO
WILD AND KNOCKOUT MICE AND DID
OUR IMMUNOTHERAPY.
AS YOU CAN SEE HERE WE SAW THAT
THESE MICE IN THE ABSENCE OF TCF
1 DID NOT RESPOND.
YOU CAN SEE THAT THE KNOCKOUT
MICE DIDN'T RESPOND TO THE
IMMUNOTHERAPY WHEREAS THE WILD
MICE DID.
HOWEVER, WHEN WE DID THIS WITH
MC 28 OVA, HERE WE SAW THAT TCF
1 WAS NOT NEED THE AT ALL.
BOTH KNOCKOUT AND WILD MICE
RESPONDED EQUALLY AS WELL.
WE LOOKED -- DECIDED TO START
WITH THE TUMOR DRAINING LIMP
NODE QUR THE TUMOR ANTIGENS ARE
PRIMED.
WE TRANSFERRED WILD TYPE OR THE
T CELLS AND GAVE A SINGLE DOSE
OF IMMUNE OR THERAPY TO THE
MICE.
WE CONFIRMED THAT THEY HAD
ESTABLISHED TIMERS AND GAVE THEM
IMMUNOTHERAPY.
WE LOOKED AT CELL DIVISION AND
WE SAW THAT AT IMAIS LINE, THE
ICE TICEO TYPE, THE T CELLS HAD
DIFFICULTY IN RELIVER RATING AND
DIVIDING.
WHEN WE GAVE THEM THE SINGLE
CHECKPOINT THERAPY, THE SMALL
DEFECT WAS COMPLETELY RESCUED
AND WERE ABLE TO DIVIDE EQUALLY
AS WELL AS WILD TYPE CELLS.
WHEN WE DID THE SAME EXPERIMENT
IN THE CONTEXT OF B-16 OVA TUMOR
WHERE WE KNOW THAT THE KNOCKOUT
MICE COULD NOT RESPOND WELL TO
IMMUNOTHERAPY, THERE WAS A
DEFECT IN THE MC 38-OVA, WE
COULD NOT REACH SAME LEVEL AS
WHAT WE SAW IN THE WILD TYPE
ANIMALS.
WE ARE ESSENTIALLY UNABLE TO
RESCUE THE PR PRO LIVE RAIVE EFT
OF THE CELLS.
TC F 1 WAS IMPORTANT TO THE
PRIME OR ANTIGENIC ABILITY.
WE NEXT WANTED TO ADDRESS HOW
THIS TRANSLATES TO THE TUMOR
ENVIRONMENT.
HOW DO THESE DIFFERENCES
TRANSLATE TO TUMOR TISSUE?
WE DID BASICALLY OUR SAME
EXPERIMENT.
WE TREATED WILD TYPE KNOCKOUT
MICE WITH EITHER B-16 OR MC-OVA
THERAPY AND PERFORMED RNA
SEQUENCING.
WE IDENTIFIED 8 DIFFERENT
CULTURES OF CELLS.
THE U-MAP SHOWS CLUSTERS ARE
STHOAN AT THE BOTTOM.
ON THE RIGHT-HAND SIDE I SHOW
YOU HERE THE PSUEDO TIME
TRAJECTORY.
NOTABLY THE LARGE BLACK SCHTICK
ARROWS I DREW THERE FOR YOU
INDICATE THAT THE TUMOR -- T-C
DIFFERENTIATION IS DIFFERENT.
IN THE MC-28 OR VA WHERE THEY
DIFFERENTIATE TOWARDS THE T
CELLS IN CLUSTER 8.
WE NEXT LOOKED AT HOW THE
CLUSTERS AND WILD TYPE CHANGE
UPON IMMUNOTHERAPY AND WHAT WE
FOUND IS THAT THIS TRANSITORY
PREFECTURE CLUSTER IN THE MC 38
TUMORS TRANSLATES INTO WILD TYPE
AND THE KNOCK YOWPT MICE.
WE KNOW THEY BOTH RESPOND WELL.
THAT INDICATED TO US THAT IT WAS
THE ABILITY OF THE TRANCE
EFFECTERS DRIVING THE RESPONSE
IN THE ANIMALS.
HOIFER, WHEN WE LOOKED AT B 16
OVA TUMORS, THEY COULDN'T MAKE
THE CELLS WELL, BUT THE WILD
MICE RESPONSIBLE AND THE
KNOCKOUT NICE DO NOT RESPOND
WELL.
ONE OF THE MAJOR POPULATIONS
THAT THE MICE RETAIN IS THE
DYSFUNCTIONAL T CELL POPULATION.
WE ZEROED IN ON THAT POPULATION
TO FIND OUT THE DIFFERENCE.
WE DID DIFFERENTIAL SCREEN
EXPRESS AND FOUND THAT IN THE --
GENE EXPRESS AND FOUND THAT IN
THE ABSENCE OF TCF-1 THE CELLS
FAILED.
AND WHEN WE LOOKED AT THE
EXPRESSION, WE FOUND UPON
IMMUNOTHERAPY, THE TCF WERE LESS
ABLE TO SURVIVE.
WHEN LEE LOOKED CLOSELY A AT THO
AT THE GENES, A LOT OF GENES
WERE GENES REPORTED IN A PAPER
AS BEING REPRESENTATIVE OR
INDICATIVE OF DESTABILIZED OREN
STABLE DYSFUNCTIONAL T-CELLS.
WJUST TO SHOW WHAT THE CLINICAL
DEVELOP RANS ORELEVANCE OF OUR ,
WE LOOKED AT THE GENES EFFICIENT
IN OUR TCF 1 KNOCKOUT T CELLS
AND SCORED THOSE IN THE
PRETREATMENT LESIONS EVER
MELANOMA PATIENTS.
THIS IS PUBLISHED DATA FROM THE
LAB.
WE SAW THAT THE PATIENTS OR
BIOPSY SAMPLES FAIL RESPONSE HAD
HIGHER EXPRESSION OF THE
STABILIZED DYSFUNCTIONAL T-CELL
DESCRIPTION.
IN SUMMARY, WHAT I'VE SHOWN YOU
IS THAT TCF 1 IS FOREIGN FOR
MAINTAINING FITNESS IN THE CD 8
CELLS.
WHAT WE DEMONSTRATE LOOKING AT
THE BC-OVA SETTING.
IT ENSURES 89 MAINTENANCE OR
GENERATION OF DYSFUNCTIONAL
T-CELLS THAT CAN TURN AND BETTER
ABLE TO SURVIVE AND PROVIDE
STABILITY TO THE DISFUNKAL
CELLS.
IT ENSURES THE GENERATION OF
DYSFUNCTIONAL CELLS FIT TO
SURVIVE TOX.
I WOULD LIKE IS TO BRING THE TWO
STORIES I GAVE YOU TOGETHER.
I TALKED TO YOU ABOUT TCF 1,
THERE ARE IMPLICATIONS WHAT I
SHOWED YOU FOR BOTH AUTOIMMUNE
AND CANCER.
THE SINGLE POLYMORPHISMS HAVE
BEEN ASSOCIATED WITH NOT JUST
WITH MS BUT WITH MULTIPLE
AUTOIMMUNE DISEASES.
NOW THE FUNCTION OF MOST OF
THESE SINGLE NU NUKE.
-- THEY MAY AFFECT
THE FUNCTION.
MAYBE THEY EFFECT THE COMBINED
AND PARTNER WITH OTHER
TRANSCRIPTION FACTORS SO
AFFECTING THE ABILITY TO
RESPOND.
THESE MAY PREDISPOSE TO
AUTOIMMUNITY BY PROMOTING OUT OF
THE STEM-LIKE STATE TO THE
INFLAMMATORY STATE.
THEY COULD ALSO AFFECT THE
STABILITY OF THE STEM-LIKE
POPULATION AND AFFECT THEIR
ABILITY TO SUSTAIN IMMUNEO THIMP
RESPONSE.
IN THE CONTEXT OF IMMUNE ORE
THERAPY, THEY MAY ALSO --
IMMUNOTHERAPY, THEY MAY ACT TO
PREDISOAZ OR NOT TOE
IMMUNE-RELATED ADVERSE EVENTS.
IF WE DEVISE STRATEGIES TO BOOST
THE EXPRESS OF TCF 1, WE IN A BE
ABLE TO CONVERT THE CELLS FOR
THE BENEFIT OF PATIENTS WITH
AUTOIMMUNE DISEASE AND CANCER.
WITH THAT, I WILL END AND THANK
ALL THE PEOPLE IN THE LAB WHO
DID THE WORK.
I WOULD LIKE TO HIGHLIGHT THE
FEW PEOPLE WHO SPEARHEADED THE
INVESTIGATION STORY.
THERE WERE MANY WHO CONTRIBUTED
TO THIS STUDY OF UNDERSTANDING
THE POISING OF CELLS FOR OPTIMAL
RESPONSES TO LOW T-CELL
STIMULATION.
I WOULD LIKE TO ACKNOWLEDGE MY
SUPPORT FROM NCI, MS SOCIETY AND
ALL OF YOU FOR YOUR ATTENTION.
THANK YOU.
>> I WANT TO STHARCHG, DR.
ANDERSON FOR THAT WONDERFUL TALK
AND THANK ALL OF OUR SPEAKERS.
AS PEOPLE ARE GETTING THEIR
VIDEOS BACK ON, AND MICS READY,
I JUST WANTED TO REMINE PEOPLE,
YOU CAN PUMENT YOUR QUESTIONS IN
THE Q&A.
YOU CAN UP LOAD THE PEOPLE'S
QUESTIONS USING THE THUMBS UP
BUTTON AND I THIS IS A MIKE IS
GOING TO CHANGE US OVER SO
PEOPLE CAN SEE THE SPEAKERS ANDO
AND WITH THAT, I'M GOING IT PASS
THE NI MICROPHONE OVER TO DR. PK
TO GET US STARTED WITH THE FIRST
QUESTION.
>> SURE.
THANK YOU.
SO I WOULD THRIEK ASK THE
PRESENTER THE FOLLOWING
QUESTION: HOW DO YOU SEE THE
RESEARCH EVOLVING OVER THE NEXT
THREE TO FIVE YEARS.
>> I THINK THERE ARE SEVERAL
INTERESTING QUESTIONS AND AFTERD
AVENUES TO PER SIGH.
FIRST CAN WE IDENTIFY THE
PATIENTS AND STUDIES STRATEGIES
IN THESE PATIENTS.
I THINK ONE REALLY QUESTION IS
WHETHER CANCER COULD BE A DRIVER
FOR THE DEVELOPMENT OF
AUTOIMMUNITY IN ALL OF OUR
PATIENTS AND ARE THERE MORE
SENSITIVE CANCER DETECTION
STRATEGIES WHETHER THEY'RE
LIQUID BIOPSIES IS THAT WE CAN
DETEDETECT INS THEY PATIENTS IF
THERE ARE THINGS THAT DRIVE THE
AUTOIMMUNE DISEASE.
THERE ARE IMPLICATIONS AS TO
WHETHER OR NOT WE SHOULD THINK
OFFER CANCER IMMUNE PRO TIKS AS
FAR AS AUTOIMMUNITY.
THOSE ARE EXCITING DEVELOPMENTS
FOR THE NEXT THREE TO FIVE
YEARS.
CAN YOU MAKE ANY COMMENTS DR.
SU?
I AGREE WITH DR. SHAH.
I WANT TO FIND OUT WHO WILL
DEVELOP THE IRAEs.
THE PATIENT I PRESENTED IN THE
BEGINNING OF THE TALK, SHE DID
NOTE HAVE THE ANTIBODIES.
HER FORM OF TYPE 1 DIABETES WAS
DIFFERENT IN A LOT OF WAYS FROM
SUSTAIN YUS DIABETES FOR EXAMPLE
THE AUTOIMMUNE PROFILE IS NOT
THE SAME.
THIS IS THE SAME WITH OTHER
STHAS DO NOT HAVE THE AUTO
ANTIBODY PROFILE.
THE DISEASE COURSES FASTER AS
WELL.
IT SEEMS TO BE ACCELERATED AND
THE PATIENTS PRESENT WITH A
PRETTY SEVERE ADVANCED FORM OF
TYPE I DIABETES.
MORE SO THAN WITH SPEAN YUS TYPI
DIABETES.
HOW DO WE KNOW?
DO WE KNEE TO LOOK AT THE
TC-REPERTOIRE.
ARE THERE HLA LINKS WE DON'T
DMOA ABOUT?
THOSE ARE QUESTIONS THAT ARE
EXPLORED.
DOES GENDER PLAY A ROLE?
THAT'S A CONTROVERSIAL AREA AS
WITH.
>> THANK YOU.
DR. ANDERSON, DO YOU WANT TO ADD
MORE COMMENT?
>> YES.
ABSOLUTELY.
I HAVE A COUPLE OF THINGS I
WOULD LIKE TO NOTE.
THERE IS A LOT OF DEBATE IN THE
FIELD ESPECIALLY ON THE CANCER
SIDE WHETHER THE IMMUNE-RELATED
ADVERSE EVENTS ARE AUTO
IMMUNITY.
BECAUSE THEY ARE REVERSIBLE.
SO YOU KNOW, WHETHER THAT WILL
CHANGE WITH CONTINUOUS -- WE
LOOK AT DEESCALATION OF
PATIENTS.
THAT'S AN OPEN QUESTION AND
WOULD HE NEED MORE CLINICALLY
TRANSLATABLE RESEARCH.
PATIENT-BASED RESEARCH TO UNDER
THAT BETTER.
WE NEED MORE MODELS TO STLDY
SOME OF THESE KKSES BETWEEN --
SO WE CAN UNDER THE AT A
MECHANISTIC LEVEL.
WE CAN DO A LOT WITH PATIENT
SAMPLES BUT IT'S BELTER BETTER T
IN MODELS.
WE NEED TO STUDY SOME OF THE
CONNECTIONS AT THE LEVEL OF
STISH EU FLS CELLS AND MOLECULAR
ISSUES.
I THINK HAVING TRAINED IN THE
AUTO IMMUNITY FIELD AND NOW
DOING A LOT OF CANCER WORK IN MY
LAB, I HAVE THE PERSPECTIVE OF
WHAT EACH FIELD HAS BEEN DOING
AND UNFORTUNATELY, WE'RE STILL
VERY SILOED.
THERE ARE A LOT OF INFORMATION
THAT IS NOT BEING SHARED AND
LEVERAGED.
ONE EXAMPLE IS THE -- ALLUDED TO
IN MY TALK IS THE GWA STUDIES
DONE EXTENSIVELY.
WE KNOW WHAT THOSE SNIPS ARE AND
WE CAN THINK ABOUT CREATING SNIP
PANELS THAT WILL SCREEN THOSE
PATIENTS GOING INTO THERAPY AND
SEE WHICH ONES ARE MORE
SUSCEPTIBLE TO DEVELOPING
AUTOIMMUNE TOKSITIES ET CETERA.
WE'RE NOT LEVERAGING ANY OF THAT
INFORMATION RIGHT NOW.
I THINK MORE CROSS OVER
INVESTIGATION AND THERE IS MAYBE
AN OPPORTUNITY HERE I KNOW NIH
HAD DONE SOMETHING A FEW
YEARSING ATO TRY IS TO BRING
INVESTIGATORS TOGETHER.
BUT THIS WAS SOMETHING I THINK
NID AND NCI COULD PERHAPS
PARTNER ON TO PUSH THIS FIELD
FORWARD.
THAT'S WHAT I HAVE TO SAY.
>> THANK YOU ALL FOR THOSE
THOUGHTS.
YOU TALKED ABOUT CROSSOVER AND
CROSS DISCIPLINE AIRY TRAINING.
WHAT RESEARCH NEEDS TO ADVANCE
FOR THIS COLLECTIVE RESEARCH?
>> I'LL START.
YOU KNOW, I DO THINK THAT ONE OF
THE CHALLENGES FOR A LOT OF
THESE AUTOIMMUNE DISEASES IS IS
THAT THESE ARE RARE MANFICATIONS
OR MAYOR EVENTS.
PARTNERING ACROSS CENTERS TO
AGGREGATE LARGE NUMBERS OF
PATIENTS EXPERIENCING THESE
EVENTS IS CRITICAL TO HAVE
FURTHER THIS TYPE OF STANDARDY
LOOKING AT THE CONNECTION
BETWEEN CANCER AND AUTO AUTO
IMMUNITY.
WHETHER WE TAKE PATIENTS WITH
TRADITIONAL AUTO IMMUNITY
DISEASES OR PATIENTS WITH
ADVERSE EVENTS ACROSS MULTIPLE
SITES, AND THE MULTIPLE
DISCIPLINARY COOPERATION, I
THINK ALL OF THAT IS REQUIRED
TO-US ELUCIDATE THIS AND
UNDERSTAND MORE.
>> I THINK AGGRAVATED EVENTS ARE
RARE.
AT UCLA WE SEE QUITE THE TAME
CASES.
I THINK BEING ABLE TO PARTNER
WITH MULTIPLE SITES TO STANDARDY
THIS CONDITION IS VERY IMPORTANT
AND SO BEING PART OF THIS ACE
NETWORK HAS BEEN EYE-OPENING FOR
ME TO SEE HOW WE CAN WORK
TOGETHER WITH OTHER ACEs
ACROSS THE COUNTRY.
I THINK COLLABORATION IS GOING
TO BE THE KEY TO THAT AND
GETTING INTO THE MECHANISMS
UNDERLYING THESE DISEASES.
>> WHAT I'M HEARING IS WE NEED
MORE CO CONSORTIA TO COME TOGETR
BOTH ON THE CASE SAMPLE SIDE AND
WE NEED SOME BIG DATA GENOMICS
INVESTIGATIONS AS WELL TO KNOW
WHAT IS GOING DOWN.
>> GREAT TIPS FOR US AS WE THINK
OF ADVANCING THE FIELDS.
I WANTED TO TACKLE SOME OF THE
QUESTIONS THROUGH THE CHAT.
I'M GOING TO MERGE A FEW
QUESTIONS TO ALLOW US TO COVER
MORE GROUND.
FIRSTLY, AND THIS IS OBVIOUSLY
IMPORTANT TO OUR OFFICE, WE SIT
WITHIN THE OFFICE EVER RESEARCH
ON WOMEN'S HEALTH.
WE KNOW MOST AUTOIMMUNE DISEASES
ARE MORE COMMON IN WOMEN AND
THERE ARE PEOPLE IN CLAT
WONDERING AND I WONDER, WHAT DO
YOU SEE WHEN YOU LOOK AT THE
PATIENTS THAT DEVELOP EITHER
CANCER ASSOCIATED WITH
AUTOIMMUNE OR THE FLIP THAT
HAVE, CANCER ALONG WITH
TEMPERING TEMPERING WITH AUTOIMH
WOMEN AND CAN YOU THINK OF WHAT
IS GOING ON?
>> I THINK ABOUT CANCER INDUCED
AUTOIMMUNITY IN TERMS OF
TRADITIONAL RHEUMATIC DISEASES,
WE DEFINITELY IN OUR REUM TOE
LSTUDIES WESEE A SEX BIAS BUT WK
BETWEEN CANCER AND AUTOIMMUNITY
IN BOTH MEN AND WOMEN.
WE SEE THOSE ACROSS THE TYPES
INCLUDING THOSE ENRICHED IN
MACHINE LIKE PROSTATE CANCER AND
WOMEN WHICH IS BREAST CASTER. C.
I DON'T THINK WE TEND TO SEE
THAT SAME SEX BIAS IN TERMS OF
THE PEOPLE PRESENTED WITH
RHEUMATIC PHENOTYPES INCLUDING
INFLAMMATORY ARTHRITIS.
I THINK WHEN DR. ANDERSON SAID
ARE THESE TRUE AUTOIMMUNE
DISEASES?
THERE ARE DIFFERENCES BETWEEN
THE TRADITIONAL AND DISEASES.
I'LL PASS TO DR. SU.
>> THE RATIO OF MALES TO FEMALED
AFFECTED IS 5 TO 1 SO VERY
BIASED.
IT'S FEMALE BIASED BUT MUCH LESS
SO.
IT SEEMS TO NOT BE AS DRAMATIC
AS WITH SPONTANEOUS THYROID
DISEASE.
WHAT IS UNDERLYING THAT IS THE
QUESTION THAT WE'RE INTERESTED
IN.
I THINK IT'S A WINDOW INTO
UNDERSTANDING WHAT IS CAUSING
THIS SPONTANEOUS DISEASE.
UTX IS ACTUALLY ON THE X
CHROMOSOME AND THAT IS WHAT IS
INTERESTING.
IT'S OVEREXPRESSIONED IN FEMALES
RATHER THAN MALES SO WE THINK
THAT MAY BE UNDERLYING THE SEX
DIFFERENCES WE SEE IN OTHER
IMMUNE CONDITIONS LIKE AN TROA X
DEPENDENTS.
THIS IS IMPORTANT TO ADDRESS.
DIABETES AND THYROID DISEASE
RELATED TO EXEC POINT INHIBITOR
IS THOUGHT TO BE A CHRONIC
CONDITION.
WINDOW DON'T THINK IT'S
REVERSIBLE EVEN WITH THE
DISCONTINUATION OF THE
CHECKPOINT INTRIBUTERS.
ONE -- INHIBITORS.
ONE OF THE THINGS WE'RE
INTERESTED IN IS WHETHER THE
LONG LIFE CELLS ARE INTERPRETING
THIS.
I'LL STOP THERE.
>> I MOON I THINK YOUR POINT
ABOUT THE STEM-LIKE T CELLS IS
WELL-TAKEN BUT I ONE DR IF IT'S
ABOUT THE TRIGGERS THAT MAKE
THOSE CELLS DIFFERENTIATE AND
HOW THEY DIFFERENTIATE.
THEY'RE NOT DESTINED TO BE BAD
CELLS.
WE NEED TO KNOW MORE ABOUT
CONTEXT AND WHAT MAKES THEM
BECOME ONE OR THE OTHER.
REGARDING THE SEX BIAS, IT'S
CURIOUS THAT FROM THE CANCER
PERSPECTIVE, CANCER IS MORE
ADDRESSIVE IN MEN.
BUT MEN OR MALES TEND TO RESPOND
BETTER TO IMMUNOTHERAPY.
THERE IS ACTUALLY SOME DATA TO
PLAIN EXPLAIN WHY AND IT HAS TOO
WITH THE AN TROA JEN RECEPTOR.
WHEN IT FUNCTIONS, IT FUNCTION
AS A TRANSCRIPTION FACTOR AND.
THERE WERE QUIEPT A FEW PAIPS
THAT ARE CAME IN THE LITERATURE
FROM MULTIPLE LABS THAT WERE ALL
HITTING AT THIS QUESTION OF --
HINTING AT THE QUESTION OF
MALE/FEMALE BIAS IN RESPONSE TO
IMMUIMMUNOTHERAPY.
I THINK IT'S A LOT MORE
COMPLICATED THAN WE APPRECIATE.
I THINK WE NEED TO DO A LOT MORE
RESEARCH.
IT MAY NOT ALWAYS -- DEPENDING
ON THE TISH EWE AND CANCER TYPE
AND, THERE MAY BE OTHER
VARIABLES WE NEED TO THINK
ABOUT.
>> THAT'S GREAT BECAUSE IT LEADS
ME INTO MY NEXT QUESTION FOR THE
THREE OF YOU WHICH IS A FAIRLY
BROAD QUESTION.
I'M GOING TO ASK YOU TO
SPECULATE A LITTLE BIT AND
TELLING YOU WHAT YOU THINK THE
FIELD NEEDS IN ORDER TO AERNAS
SOME OF -- HARNESS SOMENT OF
THIS TECHNOLOGY.
THAT PERTAINS TO THE ISSUE OF IF
WE WANT TO BE ABLE TO USE THESE
ME ELECTRIC LAR DIAGNOSTIC
TECHNIQUES, THEY IDENTIFY BEST
TREATMENT FOR SPECIFIC
INDIVIDUALS BOTH IN CANCER IN
AUTOIMMUNITY.
WHAT DO WE NEED TO DO TO ADVANCE
THAT SCIENCE BOTH FROM A
STRUCTURAL POINT OF VIEW,
INFRASTRUCTURE POINT OF VIEW AND
WHAT IS NEEDED TO ADVANCE THIS
FIELD.
DR. SHAH.
>> I THINK A LOT OF THIS DOES
TIE INTO HAVING MULTI-CENTER
CONSORTIA THAT CAN AGGRAVATE
LARGE VOLUMES OF PATIENTS
EXPERIENCING THESE CRITICAL
EVENTS IN TISSUES TARGETED BY
THE IMMUNE RESPONSE AND BU
BIOSPECIMENS AND IT'S CRITICAL
TO ENABLE THE REST OF THIS WORK
TO HAPPEN.
I THINK ONE FEATURE OF ALL OF
THIS IS THE HETEROGENEITY.
THE DEMOGRAPHICS OF YOUR
PATIENTS, THE CLINICAL
MANIFESTATIONS AND SUBSETS OF
PATIENTS, THERE IS MET MET HET E
JHETEROGENEITY.
YOU NEED TO LOOK AT THE
SUBGROUPS THAT BEE HAICH
DIFFERENTLY TO TEASE SOME OF THE
THINGS APART.
I THINK THE COLLABORATION ACROSS
GROUPS AND BUILDING THE
INFRASTRUCTURE IS CRITICAL.
I WILL SEE IN RHEUMATOLOGY, WE
HAVE A NATIONWIDE SCORE SHOM
WITH PATIENTS WITH AUTOIMMUNE
ADVERSE EVENTS BECAUSE IT WILL
TAKE MULTIPLE PEOPLE
COLLABORATING TOGETHER TO CRACK
THIS OPEN.
I THINK IT'S AN IMPORTANT
OPPORTUNITY.
>> I THINK WE WERE HAVING DINNER
THE OTHER DAY AND THINKING ABOUT
WHAT WE WISH FOR IF WE COULD TO
CRACK OPEN THESE QUESTIONS
TECHNOLOGICALLY.
AND I THINK WHAT'S BEEN REALLY
EYE-OPENING FOR ME ARE THE
SINGLE-CELL TECHNOLOGIES THAT
HAVE BECOME AVAILABLE.
IT'S BEEN REALLY POWERFUL TO BE
ABLE TO LOOK AT T-CELL RESPECTER
CHROMEALITY.
AS THE COSTS COME DOWN, HOW CAN
WE USE TS SINGLE-CELL
TECHNOLOGIES TO CHARACTERIZE
THESE ADVERSE POPULATIONS AND TO
PERHAPS FIND MARKERS FOR
PREDICTING THE ONSET OF IRAEs
WITH CHECKPOINT INHIBITOR
THERAPIES.
IT'S BEEN AMAZING HOW QUICKLY
SINGLE CELL TECHNOLOGIES HAVE
CHANGED AND IECH I'VE ENJOYED G
THEM TO UNDERSTAND WHAT HAS BEEN
GOING ON IN TISSUES OF INTEREST.
LOOKING FORWARD TO WHERE THAT IS
GOING.
>> SO I WOULD LIKE TO BUILD ON
WHAT DR. SU JUST SAID.
AND WHAT I THINK WE NEED TO DO
IS BUILD ON EFFORTS SUCH AS LIKE
THE HUMAN CELL ATLAS WHICH WAS A
LARGE EFFORT TO JUST PROFILE
NORMAL CELLS AND TISSUES.
NOW THAT WE HAVE THAT
INFORMATION, WE CAN BUILD BUILDN
THAT AND PROFILE CELLS IN
ABNORMAL TISSUES WERE THEY'RE
CONVENTIONAL RA OR CHECKPOINT
INDUCED RUE MADDIC INVESTIGATION
OR WHETHER IT'S CLASSICAL SORE
PSORIASIS OR CHECKPOINT
DETERMDERMATITIS.
WE NEED TO ALSO THINK ABOUT THE
GENETICS OF THE INDIVIDUAL.
WOVE A LOT OF INFORMATION
AVAILABLE TO US THAT WE COULD
REALLY LEVERAGE TO SEE IS THERE
A PATTERN WHERE INDIVIDUALS THAT
HAVE CERTAIN SINGLE NUKE LA TYPO
TYPES.
>> I APPRECIATE EVERYBODY'S TIME
JOINING US TOAD.
I'M GOING TO START TO WRAP UP
BECAUSE WE ONLY HAVE A COUPLE
MINUTES LEFT.
AS MIKE PULLS UP THE SLIDES, I
WANTED TO GIVE A FEW PLUGS FOR
THINGS GOING ON IN THE LIFE OF
THE AUTOIMMUNE RESEARCH.
ONE IS OUR REGULAR QUARTERLY
UPDATES ON THE OFFICE ACTIVITIES
CALLED UPDATES ON OADR.
IT'S OPEN TO ANYONE.
EVENT PAGE FOR THE UP COMING
EVENT ON JANUARY 31ST CAN BE
ACTIVATED THROUGH THE QR CODES.
THIS WILL BEING HELD FROM NOON
TO 12:45 ON THE 31ST OF JANUARY.
TYPICALLY I WILL GIVE I BRIEF
UPDATE ON OFFICE AND WHAT WE'VE
BEEN DOING SINCE THE LAST UPDATE
TO THE COMMUNITY AND THEN THERE
IS A FORUM THAT ALLOWS US TO LET
COMMUNITY MEMBERS UNMUTE AND
TELL US WHAT IS GOING ON IN THE
LIFE OF THEIR ADVOCACY GROUP OR
AREA OF INTEREST THEY WANT TO
SHARE WITH THE COMMUNITY.
WE ALWAYS HAVE A NICE DIALOGUE
AT THAT EVENT AND I WANT TO MAKE
SURE THAT THE UP COMING DATES ON
YOUR RADAR -- UP COME TOKING
DATES ARE ON YOUR RADAR.
THE NEXT EVENT PUT INTO YOUR
CALENDARS FOR 2025 IS THE NEXT
SCIENCE TALKS EVENT WHICH WILL
BE ON MARCH 4TH FROM NOON TO
2:00 P.M.
AND WE'LL BE LOOKING AT CELL
THERAPIES AND KIND OF DIE
SEGGING THE POTENTIAL OF THESE
THERAPIES FOR BOTH TREATING
AUTOIMMUNE DISEASES AND WHAT IS
NEEDED TO ADVANCE THE SCIENCE OF
THESE TREATMENTS FOR AUTOIMMUNE
DISEASE.
I HOPE YOU CAN JOIN US AND WE
LOOK FORWARD TO A GRIT SESSION.
FINALLY, THE SCIENCE TALK
SESSION WILL BE PART OF A LARGER
CADRE EVER ACTIVI OF ACTIVITY FS
THIS MONTH.
IF YOU CAN WATCH YOUR CALENDARS
FOR POTENTIAL EVENTS COMING UP
IN MARCH 2025, WE HAVE A FULL
DOCKET OF ACTIVITIES PLANNED.
PLEASE SIGN UP FOR THE
E-MAILS.
THE QR CODE FOR THIS SLIDE IS TO
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SERVE.
YOU DO HAVE TO SCROLL DOWN ON
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PACIFIC TO OUR OFFICE.
THAT WAY, YOU'LL GET THE SIGN
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WE'RE ALWAYS HAPPY TO SEE AS
MANY MEMBERS AS CAN JOIN THOSE
SESSIONS.
SO WITH THAT, I REALLY WANT TO
GIVE A HUGE ROUND OF APPLAUSE TO
OUR SPEAKERS TODAY.
THANK YOU SO MUCH TO ALL OF YOU
FOR SHARING YOUR SCIENCE,
SHARING YOUR VISION FOR THIS
FIELD.
I WANT TO THANK YOU TO THE
MODERATORS AND HELPING US PUT
THIS EVENT TOGETHER AND
MODERATING THE QUESTIONS.
AND THEN WE'RE ALWAYS HAPPY TO
HEAR FROM THE COMMUNITY, SO YOU
WOULD LIKE TO CONNECT WITH US,
OUR WEBSITE IS ON THIS SLIDE AND
WE'RE HAPPY TO FIELD QUESTIONS
FROM THE GROUP.
THANK YOU SO MUCH FOR LISTENING.
HAVE A GREAT AFTERNOON.