Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online https://clinicalcenter.nih.gov TODAY WE ARE HAVING TWO PRESENTATIONS ON THE TOPIC OF GRAFT-VERSUS-HOST DISEASE. OUR FIRST SPEAKER IS DR. STEVEN PAVLETIC, SENIOR CLINICIAN AND HEAD OF THE GRAFT-VERSUS-HOST DISEASE AND LATE EFFECTS SECTION OF THE IMMUNE DEFICIENCY CELLULAR THERAPY PROGRAM. IN THE CENTER FOR CANCER RESEARCH AT NATIONAL CANCER INSTITUTE. DR. PAVLETIC EARNED HIS MEDICAL DEGREE FROM THE UNIVERSITY OF SCHOOL OF MEDICINE IN CROATIA. HE COMPLETED A CLINICAL FELLOWSHIP IN BONE MARROW TRANSPLANTATION AT UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE AND THE FRED HUTCHINSON CANCER CENTER E IN SEATTLE, WHAT WAXER HE TRAINED IN INTERNAL MEDICINE AND HEMATOLOGY ONCOLOGY AT THE UNIVERSITY OF NEBRASKA MEDICAL CENTER IN OMAHA PRIOR TO HIS APPOINTMENT AS ASSISTANT PROFESSOR MEDICINE AT THE UNIVERSITY OF NEBRASKA COLLEGE OF MEDICINE. DR. PAVLETIC SERVED AS THE DIRECTOR OF THE ALOW GENEIC STEM CELL TRANSPLANTATION PROGRAM AT THE UNIVERSITY OF NEBRASKA MEDICAL CENTER UNTIL HE CAME TO THE NATIONAL INSTITUTES OF HEALTH IN 2002. DR. PAVLETIC'S PROFESSIONAL MEMBERSHIPS INCLUDE AMERICAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION, THE AMERICAN SOCIETY FOR HEMATOLOGY AND AMERICAN SOCIETY FOR CLINICAL ONCOLOGY. HE SERVED ON THE EDITORIAL WORD OF THE JOURNALS BONE MARROW TRANSPLANTATION AND BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2006 HE WAS RECOGNIZED WITH AN NCI DIRECTORS AWARD FOR HIS ACHIEVEMENTS IN DEVELOPING NATIONAL AND INTERNATIONAL CONSENSS GUIDELINES FOR CLINICAL TRIALS IN CHRONIC GRAFT-VERSUS-HOST DISEASE. IN ADDITION, HE LED TWO NIH CONSENSUS CONFERENCES IN 2005 AND 2014 WHICH LAID THE GROUND WORK FOR THE FIRST EVER FDA APPROVED TREATMENTS FOR CHRONIC GBHD. DR. PAVLETIC WILL SPEAK ON LIVING WITH THE CURE PROGRESS AND CHALLENGES IN CHRONIC GRAFT-VERSUS-HOST DISEASE. OUR SECOND SPEAKER IS DR. JACQUELINE MAYS WHO IS AN ASSISTANT CLINICAL INVESTIGATOR AND CHIEF OF THE ORAL MY BIOLOGY UNIT NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH. A POSITION WHICH SHE HAS HELD SINCE 2015. DR. MAYS HOLDS A MASTERS OF HEALTH SCIENCES AND CLINICAL RESEARCH DEGREE FROM DUKE UNIVERSITY SCHOOL OF MEDICINE AND EARNED Ph.D. IN ORAL BIOLOGY AND HER DOCTOR OF DENTAL SURGERY DEGREES FROM THE COLLEGE OF DENTISTRY AT THE OHIO STATE UNIVERSITY. SHE FIRST CAME TO THE NIH IN 2009 PERFORMING POST-DOCTORAL RESEARCH WORK AT THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES ON INFLUENZA VIRAL PROTEIN EXPRESSION. AND THE ANTIVIRAL MUCOSAL IMMUNE RESPONSE IN 2011 SHE WAS APPOINTED AS A CLINICAL RESEARCH FELLOW AT NIDCR WHERE SHE STUDIED CHRONIC GRAFT-VERSUS-HOST DISEASE IN THE ORAL CAVITY WHICH YOU WILL HEAR MORE ABOUT SHORTLY. DR. MAYS CURRENT RESEARCH PROGRAM AT NIDCR AIMS TO ELUCIDATE THE UNDERLYING IMMUNE PROCESS OF CHRONIC GRAFT-VERSUS-HOST DISEASE IN THE ORAL CAVITY, WITH A FOCUS ON THE SALIVARY GLANDS, IN ORDER TO IMPROVE MONITORING AND THERAPEUTICS FOR PATIENTS WITH THIS DISORDER. DR. MAYS WILL SPEAK ON SITE MATTERS ORAL MUCOSAL IMMUNITY IN CONTEXT OF CHRONIC GRAFT-VERSUS-HOST DISEASE. SO NOW LET'S BEGIN BY WELCOMING DR. PAVLETIC. [APPLAUSE] >> THANK YOU, BOB. GOOD AFTERNOON. THANK YOU ALL FOR BEING HERE THE FOR THIS CLINICAL CENTER GRAND ROUNDS, THE TOPIC IS CHRONIC GRAFT-VERSUS-HOST DISEASE. IN MY PRESENTATION I WILL TELL YOU SOMETHING BRIEFLY ABOUT THE SIGNIFICANCE OF CHRONIC GRAFT-VERSUS-HOST DISEASE THEN GO OVER SOME THINGS THAT WE DID HERE OVER YEARS, NIH CHRONIC GBHD STUDY GROUP, THEN I WILL COVER SOME ASPECT OF CLINICAL TRIALS DEVELOPMENT OF THIS DISEASE AND FINISH WITH A FEW DETAILS ABOUT SOME STUDIES GRAFT-VERSUS-HOST DISEASE TAKING PLACE HERE AT THE CLINICAL CENTER AS WELL AS NATIONALLY. THE REASON WE ARE TALKING ABOUT CHRONIC GRAFT-VERSUS-HOST DISEASE TODAY IS BECAUSE ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION BECAME ONE BEST PROVEN FORMS OF IMMUNOTHERAPY OF CANCER OVER LAST FOUR DECADES. HERE IS A 1990 YOU CAN SEE WHEN DON THOMAS WHO RECEIVED NOBEL PRIZE IN -- FOR CLINICAL DEVELOPMENT OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION AND THE BLUE CURVE HERE IS SHOWING THE RATES OF TRANSPLANTS PER YEAR IN THE U.S. OVER DECADES AND YOU CAN SEE HOW THIS SURGE OF UNRELATED TRANSPLANTS IS MOST WIDELY USED SOURCE OF HEMATOPOIETIC STEM CELLS WENT UP DUE TO EXPANSION OF TECHNOLOGY AND GROWING REGISTRY AND SAFETY OF TRANSPLANTS. IN 2003 WE FORMED THE NIH CHRONIC GBHD STUDY GROUP AND YOU CAN SEE HOW FURTHER THE NUMBERS AND FREQUENCIES OF UTILIZATION OF ALLOGENEIC TRANSPLANTS SUBSEQUENTLY WENT UP AND CREATED ALL THIS LATE EFFECTS AND LONG TERM SURVIVORS THAT WE ARE INTERESTED IN DEALING WITH AND STUDYING. SO CHRONIC GRAFT-VERSUS-HOST DISEASE IS MAINLY A DISEASE, A NEW DISEASE IN MEDICINE THAT'S CREATED BY OUR ALLOGENEIC TRANSPLANTATION CELLULAR THERAPY FOR PATIENTS WITH OTHERWISE INCURABLE CANCERS. IT'S ONE OF THE MOST COMPLEX AND ACTUALLY VERY APPEALING TO STUDY MODEL FOR LATE EFFECTS OF CANCER THERAPY. THIS IS A PATIENT WITH THE MOST SEVERE FORM OF CHRONIC GRAFT-VERSUS-HOST DISEASE WITH DIFFUSE SKIN INVOLVEMENT, VISIBILITY, YOU CAN SEE THAT, FORTUNATELY THESE CASES ARE RARE. HOWEVER HERE AT THE CLINICAL CENTER WE SEE MORE OFTEN THIS SIMILAR MANIFESTATIONS IN THEIR PARTICULAR STUDY. SO IT'S A SYSTEMIC ALLO IMMUNE AUTOIMMUNE DISORDER, INVOLVING WHOLE IMMUNE SYSTEM BASICALLY LIEU THE ACUTE AND CHRONIC GRAFT-VERSUS-HOST EFFECTS. MAIN INVOLVED ORGANS ARE SKIN, DIFFERENT DEPTHS OF INVOLVEMENT, SUPERFICIAL AND DEEP GOING DEEP TO FASCIA. EYES WITH OCULAR MUCOSA AND LACRIMAL GLAND INVOLVEMENT, ORAL CAVITY WITH ORAL MUCOSA AND SALIVARY GLAND E INVOLVEMENT, OTHER ORGANS LIKE LUNGS AND THE LIVER AND SO ON, INCLUDING THIS FUNCTION OF THE IMMUNE SYSTEM, SO IS IT'S A LIFE THREATENING DISORDER AND EFFECTS 30% OF ALLOGENEIC TRANSPLANT RECIPIENTS. THE MAIN CAUSE OF DEATH, IMMEDIATE CAUSE OF DEATH IN THESE PATIENTS ARE INFECTIONS. IT'S COMPLEX. IT'S INFECTIOUS BECAUSE IMMUNE DEFICIENCY CREATED BY ALLOGENEIC TRANSPLANTATION AS WELL AS HEAVY IMMUNOSUPPRESSIVE TREATMENT THESE PATIENTS ARE RECEIVING. THIS PAPER IS SHOWING THE TIME LINE OF EVOLUTION OF ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE. SO IT'S MAINLY A DISEASE THAT STARTS AT DAY ZERO THE MOMENT INFUSED DONOR HEMATOPOIETIC STEM CELLS, WE INFUSE DONOR TO THE RECIPIENT AND HE CAN SUE HOE THIS IS THE IDEAL -- YOU CAN SEE HOW THIS IDEAL COURSE DOING THIS, WE WILL CURE PATIENTS FROM OTHERWISE MOST OF THE TIME INCURABLE CANCER. THIS IS STATUS OF FUNCTIONAL, KNOWN GBHD CLINICALLY DISABLING AND GRAFT VERSUS LEUKEMIA EFFECT WHICH IS WHY WE ARE DOING ALLOGENEIC TRANSPLANTS, MINOR HISTOCOMPATIBILITY AND TARGET CELLS OF THE MALIGNANCY. THE OTHER CASE SCENARIO YOU DON'T HAVE GBHD AND DON'T HAVE BIOLOGICAL GRAFT VERSUS TUMOR EFFECTS, MALIGNANCY RELAPSE IS A HUGE PROBLEM SO WE A WONDERFUL TOLERANCE OF THE NEW DONOR IMMUNE SYSTEM AND REALLY THERAPEUTIC EFFECT NON-EXISTENT OR MINIMAL. THIS IS THE PATH OF ACUTE AND CHRONIC GBHD, ACUTE TISSUE DAMAGE FROM DONOR T-CELLS TO CHRONIC INFLAMMATION AND SCARRING. THIS IS THE PATH THAT WE ARE TRYING TO AVOID AND MOVE THIS ARROW UP IN THE RANGE WHERE THIS CLINICAL MANIFESTATION COULD BE TOLERABLE TO OUR PATIENTS. WE DEVELOPED A SCORING SYSTEM NIH CRITERIA, THIS IS TO SHOW HERE THAT PATIENTS WITH SEVERE FORMS OF CHRONICS GBHD HAVE IMPAIRED SURVIVAL AND INCREASE NON-RELAPSE MORTALITY, IT'S 25% OF PATIENTS THAT FIT INTO THIS CATEGORY. IT'S A DISABLING DISEASE. SO THIS IS SHOWING THE PATIENTS WITH MILD MODERATE SEVERE CHRONIC GBHD. IT'S COMPARABLE DISABILITY TO SOME OF THE MOST SEVERE DISEASE IN MEDICINE LIKE SYSTEMIC SCLEROSIS, SYSTEMIC LUPUS, PARA PLEGIA OR CONGESTIVE HEART FAILURE. FINALLY IT'S IMPORTANT TO PLACE OURSELVES IN THE SHOES OF PATIENTS FROM THEIR PERSPECTIVE. WHAT DO PATIENTS MOSTLY CARE ABOUT? THIS IS AN INTERESTING SURVEY THAT CAME OUT JUST RECENTLY THROUGH THE INFO NET PATIENT ADVOCACY GROUP ASKING WHAT PATIENTS CARE ABOUT, ABOUT TOP ISSUES THAT CARE ABOUT TO BE ADDRESS IN THEIR CARE WITH GRAFT-VERSUS-HOST DISEASE. SO NUMBER ONE THING IS HOW TO IMPROVE STAMINA AND STRENGTH. EFFECT OF CHRONIC GBHD ON MEMORY AND ATTENTION. HOW TO PROVE BALANCE, FATIGUE, SLEEP, MOOD, HOW TO FIND GBHD SPECIALIST THAT WE THINK IS MOST IMPORTANT IS ACTUALLY OVER IN THEIR PERSONALLY SO THIS IS ILLUSTRATING HOW WE HAVE TO LOOK AT BOTH SIDES WHEN TRYING TO IMPROVE LIFE OF THESE INDIVIDUALS. SO EARLY IN 2000 IT WAS CLEAR SOMETHING HAD TO BE DONE ABOUT CHRONIC GBHD, NUMBER OF TRANSPLANTS GOING UP. NUMBER OF CHRONIC GBHD PATIENTS GOING UP SO THERE WERE NO& PROGRESS AND TREATMENT OF CHRONIC GBHD UNDERSTANDING OF BIOLOGY. NO STANDARDS CRITERIA FOR DIAGNOSIS AND STAGING. NO RESEARCH NETWORKS AND NO FDA APPROVED DRUGS FOR CHRONIC GBHD, VERY DAUNTING TIME NOBODY WANTED TO WORK WITH US AS A FIELD BECAUSE YOU NEED CRITERIA, YOU NEED TO KNOW WHAT -- HOW TO MEASURE THINGS AND GOING FORWARD. GOOD EXAMPLE HOW TO APPROACH TO NEW DISEASES IN MEDICINE. 2003 CHRONIC GBHD STUDY GROUP WAS FUNDED, INTERACTIVE WITH EIGHT INSTITUTES OF FOUR CLINICAL CENTER DEPARTMENTS, IT IS A WONDERFUL EXAMPLE WHEN PEOPLE ASK WHY THINGS ARE DONE IN INTRAMURAL, THIS IS WHERE WE COME UP, IT WAS WONDERFUL EXAMPLE OF BRINGING CAPACITY AND TALENT AND BASELINE INTEREST IN THIS AREA ACROSS THE INSTITUTES ACROSS THE CLINICAL SPECIALTIES AS WELL AS LABORATORY RESEARCH TISSUE BANKING, WE DEVELOP NEW ASSESSMENT TOOLS STARTED BIOLOGY AND PURSUED THE INTERNATIONAL AND NATIONAL COLLABORATION. THIS IS A FIGURE SHOWING THE CHAIN OF APPROACH TO STUDYING TISSUES. WE HAVE THE LARGEST BY FAR OPPORTUNITY IN THE BANK OF TISSUES AND SAMPLES IN THESE PATIENTS WITH CHRONIC GBHD THROUGH NATURAL HISTORY STUDY AND POST TRANSPLANT SAMPLING. GIVE CREDIT TO FRED HAYKIM WHO DEVELOPED THIS CONCEPT AND HOW TO STUDY DIFFERENT TISSUE BIOPSIES INTO GENE EXPRESSION BLOOD SAMPLING. FRIEND IDENTIFY SYSTEMIC INTERFERENCE SIGNATURE TYPE ONE INTERFERENCE BEING OVEREXPRESSED, THIS IS WHAT LED US TO PURSUE SPECIFIC DRUG APPROACHES TO CHRONIC DRUG INHIBITORS AND OTHERS. THIS IS ONE OF THE EARLY PHOTOGRAPHS OF THE TEAM, SOME OF YOU WHO MAY BE AROUND FOR LONGER TIME MAY REMEMBER SOME OF THESE PEOPLE, THERE ARE MANY OF THOSE ALL AROUND BUT THE TEAM IS GROWING AND IT'S A DYNAMIC GROUP. I WANT TO GIVE CREDIT ACROSS THE INSTITUTES AND GROUPS AND INDIVIDUALS THAT OVER YEARS COMPLETED THE NUMBER OF PIONEERING TREATMENT PROTOCOLS FOR CHRONIC GRAFT-VERSUS-HOST DISEASE. TOPICAL TREATMENT FOR EYES MOUTH, LUNGS, SKIN, MOST OF THIS EARLY CONCEPTS DEVELOPED HERE AT NIH AND TRANSPORTED TO BROADER STANDARDS OF CARE IN THE COMMUNITY. IN 2005 AS MENTIONED AND 2014 WE HAVE TWO CONSENSUS CONFERENCES. WE NEEDED TO DEVELOP DIAGNOSIS AND STAGING CRITERIA, CRITERIA FOR PATHOLOGY DIAGNOSIS, BIOMARKERS, RESPONSE FOR -- NOTHING EXISTED. FIRST CONSENSUS WAS EXPERT OPINION DRIVEN SECOND CONSENSUS WAS BASED ON EVIDENCE. THIS 13 PAPERS HAVE BEEN REFERENCED ALMOST FIVE THOUSAND TIMES IN THE PEER REVIEW LITERATURE. ALL PUBLISHED IN BIOLOGY BLOOD AND MARROW TRANSPLANTATION JOURNAL OF AMERICAN SOCIETY OF BLOOD MARROW TRANSPLANTATION, IN 2017 THERE WAS A FIRST FDA DRUG APPROVAL OF A CHRONIC GBHD SPECIFICALLY CITED THERE IN THE FDA LANGUAGE THAT THE RESPONSE BASED ON NIH RESPONSE CRITERIA FOR CHRONIC GRAFT-VERSUS-HOST DISEASE SO CREDIT TO ALL THIS WORK OVER DECADES. 2018 FIRST PAPER NEW ENGLAND JOURNAL OF MEDICINE A SYMBOLIZING DISEASE BEING GALLERY OF DISEASES IN MEDICINE WHEN YOU HAVE A REVIEW ARTICLE ON TOPIC IN NEW ENGLAND JOURNAL OF MEDICINE AND WE ARE NOW IN THE AREA OF DEVELOPMENT OF NOVEL TARGETED THERAPIES. FIRST LINE IS PREDNISONE. YES NOT HAPPY WITH THIS BUT IT IS HOW IT IS. THESE ARE DRUGS FOR SALVAGE THERAPY, IN THIS PAPER CHANGING TRENDS MOVING TO MORE TARGETED TREATMENT IN THE COMMUNITY PRACTICE ALREADY AHEAD OF CLINICAL TRIALS NOW FDA APPROVED. WE ARE NOT HAPPY WITH CURRENT ACCOMPLISHMENTS WITH STATUS OF THERAPY, FIVE YEARS STILL ONE-THIRD PATIENTS NEED SYSTEMIC TREATMENTS, HALF NEED MORE THAN THREE LINES OF SYSTEMIC THERAPIES EMPHASIZING HOW CONSECUTIVE TREATMENTS AFTER PATIENTS FAIL PREDNISONE ARE INSUFFICIENTLY GOOD. THE OTHER THING ARE TOP TEN DRUGS WE ARE USING. YOU CAN SEE BROADER SPECIFIC IMMUNE TARGETING TO ADDRESS DIFFERENT CHRONIC PATIENTS WITH GBHD. THERE'S NO STANDARD, PIT'S IN OUR APPROACH TO PATIENTS, ALL THESE DRUGS HAVE SIDE EFFECTS, THEY ARE DIFFERENT OVERLAP AND NON-OVERLAPPING. DECISIONS ARE MADE BASED ON WHAT PATIENTS HAVE FAILED, TOXICITY SPECTRUM WHAT ARE COSTS AND PATIENT PREFERENCES, THIS IS WHY TITLE OF THIS EDITORIAL SICK AND TIRED OF CURRENT GBHD THERAPY ON THE OCCASION OF SEQ INHIBITORS TARGETING B CELL SIGNALING POTENTIALLY IN ANIMAL MODEL FOR CHRONIC GBHD. OVER YEARS, THE UNDERSTANDING HAS IMPROVED OF BIOLOGY OF I DON'T KNOW MICROGRAFT-VERSUS-HOST DISEASE THROUGH PRE-CLINICAL IN VIVO MODELS AND EX-VIVO HUMAN MODELS. WE BETTER UNDERSTAND DIFFERENT POINTS FOR POTENTIAL ENGAGEMENTS. IT'S A DISEASE OF CHRONICALLY ACTIVATED IMMUNE SYSTEM THAT INFUSE T-CELLS DAMAGE TARGET TISSUES. CASCADE ANTIGEN PRESENTATION OF THE HISTOCOMPATIBILITY ANTIGEN THROUGH THE LYMPH NODES P MODELLIZATION THROUGH PRIMARY LYMPHOID ORGANS IN CIRCULATION, IT'S ONGOING IMMUNE DISREGULATION THAT THE CLINICAL PHENOTYPE LOOKS LIKE CHRONIC GRAFT-VERSUS-HOST DISEASE. WITH BETTER UNDERSTANDING OF APPROACHING TO PATHOPHYSIOLOGY AND BIOLOGY, WE DEFINED DIFFERENT ENGAGEMENT POINTS AND WHAT IS IN HERE IN RED ARE CLINICAL STUDIES THAT WE CURRENTLY HAVE AT THE NIH PLANNING TO ADDRESS THIS PROBLEM. DIFFERENT B CELL SIGNALING AND EXPANDING TREGS. I WILL TELL YOU MORE ABOUT THIS ASPECT BLOCKING ACTIVATION CYTOKINE INDUCE SIGNALS WITH JACK INHIBITORS. SO OUR APPROACH TO DRUG DEVELOPMENT IS NOT MORE RATIONAL, IT'S A RARE DISEASE, MAYBE PER YEAR LIKE THREE TO FOUR THOUSAND CASES IN NEW INCIDENCE. WE CAN'T AFFORD MOVING FROM FIRST IN HUMANS FROM ANIMALS, IT'S STILL NOT PARADIGM SO A DRUG THAT IS A CANDIDATE TO BE IDENTIFIED Z HAS TO HAVE BIOLOGICALLY PLAUSIBLE MECHANISM OF ACTION BASED ON NON-MECHANISMS, OTHER INFLAMMATORY DISEASE, SAY RHEUMATOID ARTHRITIS OR FIBROSIS, ESTABLISH SAFETY PROFILE IN HUMANS, IT'S IMPORTANT BECAUSE WE THESE PATIENTS HAVE NOTORIOUS DYSFUNCTION AND POLL PHARMACY, THE DRUG MUST BE AVAILABLE FOR CLINICAL TESTING, THOSE WITH CAN APPRECIATE HOW THIS CAN BE CHALLENGING. NO MATTER HOW YOU LIKE TO HAVE CERTAIN AGENT. SO OUR STRATEGY DRUG DEVELOPMENT IS NECESSARY, TO MOVE FORWARD, IS SO THIS IS THE TIME LINE AFTER ALLOGENEIC TRANSPLANTATION. THIS IS A DELAYED EFFECT SO THE CHRONIC GBHD AND REFRACTORY WE LIKE TO ENTER HERE WITH PHASE 1, 2 STUDIES TO DETERMINE PRELIMINARY INFORMATION ABOUT SAFETY, AND PRELIMINARY INFORMATION ABOUT EFFICACY, IT'S IMPORTANT TO ENTER DRUGS INTO ALLOGENEIC TRANSPLANTATION INTO THE WORLD AND MOVE EARLIER, FIRST LINE THERAPY IS IMPORTANT. PREEMPTION WE WOULD LIKE TO BE THERE BUT WE ARE ELECTING GOOD MARKERS OF HIGH RISK IDENTIFICATION, EVEN THE BEST TARGETS. THEN THERE HAS BEEN SUBSTANTIAL PROGRESS OVER LAST DAY PREVENTION OF CHRONIC GRAFT-VERSUS-HOST DISEASE, BY DOING EX-VIVO T-CELL DEPLETION, IN VIVO T-CELL DEPLETION WITH ANTIBODIES OR POST TRANSPLANT CYCLOPHOSPHAMIDE INCREASE CHRONIC GBHD SUBSTANTIALLY. HOWEVER THERE'S OTHER PROCESS IN MIND. WHERE WE SEE THIS VISION DOING THIS TO CREATE BETTER MORE PERFECT ALLOGENEIC TRANSPLANTATION FOR PATIENTS SO WE THINK THERE'S THINGS THAT COME TOGETHER TO THIS PLATFORM THAT'S SO EXCITING AND COMPLEX NOWADAYS IT WILL HAVE ULTIMATE IMPORT AND BENEFIT NOWADAYS WHEN EVERYBODY SINGLE PATIENT HAS POTENTIAL ALLOGENEIC DONOR AVAILABLE IN DIFFERENT FORMS OF PRODUCTS. IN TERMS WHAT WE DO HERE, I GO BRIEFLY TO JACK INHIBITING -- INHIBITORS, (INDISCERNIBLE) AND NCI GETS CREDIT AND HIS COLLABORATORS FOR PURSUING THIS AREA. THIS PATHWAY MEDIATED EFFECTS OF 50 PLUS DIFFERENT CYTOKINES. NUMBER OF DRUGS HAVE BEEN NOW MOVEDDED INTO CLINICAL REALM, THIS IS ONLY ONE SUMMARY OF WHAT'S BEEN DEVELOPED SO (INDISCERNIBLE) IS NOW FDA APPROVED FOR MYELOFIBROSIS AND ACUTE GBHD SINCE LAST YEAR, BARE SIT ANYBODY IS APPROVED FOR RHEUMATOID ARTHRITIS, WE ARE STUDYING GBHD LIKE IN DEVELOPMENT THAT IS A JAK1 INHIBITOR. BUT JACK 2 INHIBITORS SO THESE ARE DRUGS WE HAVE INTEREST HERE AND AT THE SAME TIME THESE DRUGS HAVE INTEREST IN ANTI-PROLIFERATIVE EFFECTS AS WELL SO PEOPLE ARE STUDYING THESE MALIGNANT DISEASES SO IT'S A DYNAMIC FIELD AND EACH AGENT IS IN SOMEWHAT DIFFERENT AND WE NEED TO TEST AND REALLY DECIDE WHICH TO TAKE INTO CLAY IN THIS CASE. THE GROUP AT JOHN WASU DID LOTS OF WORK IN CLINICAL DEVELOPMENT OF JACK INHIBITORS. IDENTIFIED MODELS OF GBHD, SO NOT ALL THESE DRUGS ARE THE SAME. AT THE CLINICAL LEVEL THEY ARE NOT THE SAME. THAT PERFECT BALANCE BETWEEN JACK ONE AND TWO AND ON TOP IS (INDISCERNIBLE) SO JACK ONE AND TWO INHIBITORS HAVE OTHER INHIBITORY EFFECTS AND SO ON. SO ON TOP, THIS IS HOW WE TOOK THIS INTO PHASE 1, 2 STUDY HERE AT THE NIH. SO THIS IS THE ONLY BARASITNIB STUDY IN THE WORLD FOR CHRONIC GRAFT-VERSUS-HOST DISEASE. WE ARE FORTUNATE TO THIS BECOME AVAILABLE FOR STUDYING HERE. SO THIS IS A PHASE 1, 2 STUDY STARTS AT FDA APPROVED DOSE NOW FOR RHEUMATOID 2 MILLIGRAMS AT FOUR MILLIGRAMS THREE MONTHS AND GOES OUT TO A YEAR. IT WAS A TWO STEP DESIGN AIMING AT 21 PATIENTS SO THIS PRELIMINARY WANTED TO SHARE WITH YOU, THAT WE TREATED 17 PATIENTS, MOST OF THESE SEVERE CHRONIC GBHD HEAVILY PRE-TREATED, MEDIAN TIME FOUR AND A HALF YEARS. AFTER ALLOGENEIC TRANSPLANTATION. THEN HERE YOU CAN SEE AT SIX MONTHS IT'S PRIMARY END POINTS FOR THIS STUDY. THE 65% PATIENTS ON INTENT TO TREAT HAVE RESPONSES AT SIX MONTHS, IMPORTANT TO KNOW ALL PATIENTS HAD OVERALL PARTIAL RESPONSE BY THREE MONTHS. SOME OF THEM LOSE LATER SO IT'S FAIRLY EARLY EFFICACY DOSE WHO CONTINUED BEYOND SIX MONTHS TIME POINT, EVERYBODY MAINTAINED PARTIAL RESPONSE. SO WE ARE WELL TOLERATED SO WE ARE STUDYING STILL IN PROGRESS. YOU CAN SEE TIME TO RESPONSE IS FAIRLY EARLY, DOING FIRST 12 WEEKS FAILURE FREE SURVIVAL PATIENTS WHO FAIL, NOBODY HAS DIED ON THIS STUDY BUT THEY PROGRESS AND DEVELOP TOLERANCE AND WE HAVE DIFFERENT TYPES OF ORGANS INVOLVED AND WE -- SAW RESPONSES IN EACH OF THOSE ORGANS. IT'S BEEN WELL TOLERATED, NOT MANY SAE. YOU CAN SEE JOINT EFFECT IS POSSIBLY DRUG RELATED THOUGH REMEMBER THESE PATIENTS ARE HEAVY IMMUNOSUPPRESSION, MULTIPLE DRUGS PRE-TREATED. TWO PATIENTS DOSE ESCALATE BECAUSE OF NEUTROPENIA AND THEN UPPER RESPIRATORY INFECTION YOU CAN SEE, GRADE ONE OR TWO BUT IT'S SORT OF LIKE NOTORIOUS FOR THIS PATIENT POPULATION BUT AS AN AID THAT CAME UP, THAT'S ONE PATIENT, THAT YOU CAN SEE QUICKLY, DEVELOPMENT OF SOFTER SKIN. SPECIFIC PERMISSION TO SHOW THIS PHOTOGRAPH BUT I THINK SMILE PATIENT COMPLETED 12 MONTHS THERAPY, IT THE SMILE TELLS MORE THAN A THOUSAND WORDS. IN ALLOGENEIC TRANSPLANT, THE CAUSE OF MORTALITY ACTUALLY THIS REGISTRY PIE GRAPH YOU CAN SEE MALIGNANCY RELAPSE FOR CANCER STILL THE MAIN PROBLEM, HERE WE HAVE CAUSES OF DEATH GBHD AND BALANCING THESE TWO EFFECTS IS VERY DELICATE CHALLENGE. IF YOU SUPPRESS GRAFT-VERSUS-HOST YOU HAVE MORE RELAPSE. SO JUST TO MENTION HERE IN THIS SLIDE WE HAVE INTEREST IN AGENTS THAT HAVE A POTENTIAL BOTH SUPPRESS INFLAMMATION AND ANTITUMOR EFFECTS LIKE PACRITNIB, JACK INHIBITOR BUT AT THE SAME TIME SUBPOENA FLIT 3 INHIBITOR AND RAC ONE INHIBITOR SO WE ARE ABOUT TO OPEN STUDY THAT TREATS CHRONIC B GBHD PATIENTS BUT WELL TEST IF YOU CAN MOVE FORWARD INTO TRANSPLANT. VERY QUICKLY THE 2 INHIBITORS ANOTHER SIGNALING PATHWAY THAT REALLY IS -- DOWN REGULATE TH 17 INFLAMMATION AND IT'S PRO TREG PROMOTING AND AS WELL HAVE ANTI-FIBROTIC EFFECTS OF DRUG ADVANCE STAGES OF CLINICAL DEVELOPMENT AND WE PARTICIPATED IN THIS PROCESS. THIS IS A PHASE 1 STUDY COMPLETED AND PRESENTED THAT WAS A TWO DOSES 70% RESPONSE RATE OCCURS DIFFERENT MANIFESTATIONS. I WANT TO EMPHASIZE, SO THERE'S A PIVOTAL TRIAL THAT'S COMPLETED ACCRUAL, 200 MILLIGRAMS AND 200 BAD, IT WILL BE PRESENTED IN FEBRUARY AT ASDCT AND WE -- WE ARE ACTIVELY ENGAGED IN BOTH TRIAL BUT AS WELL IN STUDY BIOLOGY MECHANISTIC EFFECTS AND BODY SECRETIONS PARTICULARLY FOCUSED ON AUTO MUCOSA AND DR. MAYS WILL TELL US MORE ABOUT THIS. SO TOWARD THE THIRD NIH CONSENSUS CONFERENCE, HERE WE GO AGAIN BUT WE THINK -- I MADE A GOOD CASE TO SHOW HOW MUCH WE ACCOMPLISHED IN THE FIELDA DISEASE NOBODY WANTED TO TO WORK WITH. NOW INSTEAD OF FOCUSING ON STANDARDS AND EVALUATION TOOLS WE WANT TO TURN THE TABLES OVER REALLY TRY TO CHANGE THE REALITY THAT'S DIFFERENT ON THERAPY HOW WE CAN BETTER PREVENT HOW WE CAN BETTER PREEMPTED BETTER TREAT DIFFICULT MANIFESTATIONS AND NUMBER OF THINGS THAT WILL HAPPEN NEXT NOVEMBER ACROSS INDUSTRY AND EDUCATIONAL EFFORTS. THESE ARE MY COLLEAGUES ACROSS THE COUNTRY AND INTERNATIONALLY THAT ARE PART OF THIS CONSENSUS EFFORT. STEVEN, STEPHANIE LEE, FRED HUTCHINSON CANCER RESEARCH CENTER. DR. WOLF GERMANY, DR. AND OTHERS. AND I WILL END MY PRESENTATION HERE THIS SLIDE. WE HUE VERY MUCH FOR YOUR KIND ATTENTION. IT'S ALL THIS THANKLESS, EMPHASIS TO PUT ALL NAMES AND COLLEAGUES WHO CONTRIBUTED TO THIS OVER YEARS, CHRONIC GBHD STUDY GROUP CONSENSUS PROJECT. NATIONAL CONSORTIUM THAT WAS EXTREMELY INSTRUMENTAL TO TEST PERSPECTIVELY NIH CRITERIA AND MOVE THIS INTO APPLICATION AND THEN MAINLY OF COURSE OUR PATIENTS IN COLLABORATORS AND THEN OUR COLLEAGUES AT THE IDCP AS WELL, MANY OTHERS MAKE THIS WHOLE WORK POSSIBLE. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU VERY MUCH, THANK YOU TO EVERYBODY FOR BEING HERE. WE'RE GOING TO TAKE JOINT QUESTIONS AT THE END OF THE SESSION. WE HAVE TREMENDOUS OPPORTUNITY IN GRAFT-VERSUS-HOST DISEASE, IT'S OBVIOUSLY A PROBLEM IN THE ORAL CAVITY BUT WE HAVE AN OPPORTUNITY IN THE ORAL CAVITY BECAUSE IT IS SUCH A HIGHLY ACCESSIBLE SITE. TO LEARN ABOUT BOTH MUCOSAL IMMUNITY THAT IS SOMEWHAT UNDERSTUDIED FIELD IN ORAL MUCOSA. AND ALSO TO LEARN MORE ABOUT THE BIOLOGY OF CHRONIC GRAFT-VERSUS-HOST DISEASE BY LOOKING CAREFULLY AT THIS TISSUE, AT THIS SITE. OF ORAL GBHT MANIFESTATION BECAUSE WE DO HAVE SUCH ACCESS TO TISSUE, TO LOCAL BIOFLUID AND THE MICROBIOME PRESENT IN THE ORAL CAVITY. THIS IS WHAT I'M HOPEFULLY GOING TO TELL YOU MORE ABOUT TODAY. NO DISCLOSURES BUT WE WILL TALK ABOUT SOME UNAPPROVED USES OF DRUGS IN THE CONTEXT OF CLINICAL TRIALS CME LEARNING OBJECTIVES. THE ORAL CAVITY IS SITE OF FIRST ENCOUNTERS. SO THE MOUTH AND NASOPHARYNGEAL PASSAGES ARE THE SITE WHICH ANY ENVIRONMENTAL PATHOGENS, VIRUSES BACTERIA, FUNGI ENTER OUR BODIES, YOU HAVE EXPOSURE, NOT JUST TO MICROBES BUT ALSO THE SITE WHERE FOOD ENTERS, WE HAVE CONSTANT MICROTRAUMAS FROM CHEWING THAT OCCUR IN THE ORAL TISSUES. AND THE IMMUNE SYSTEM HAS ADAPTED TO BE ABLE TO CHRONICALLY SURVEY THE ORAL CAVITY WITHOUT ENDING IN A STATE OF CHRONIC EXHAUSTION WHICH IS VERY IMPORTANT TO HAVE A FUNCTIONING MILLIONTHY IMMUNE SYSTEM. THERE'S SPECIFIC FEATURES OF THE ORAL CAVITY THAT ALLOW THIS TO HAPPEN, IT'S A HIGHLY VASCULAR SITE, IT HAS ITS OWN IMMUNE TISSUES IN THE TONSILS THAT ARE PRESENT. CLICKING ONE MORE SLIDE FORWARD, THERE IS ALSO TREMENDOUS RESIDENT POPULATION OF IMMUNE CELLS THAT ARE PRESENT EVEN IN STATES OF HEALTH IN THE ABSENCE OF DISEASE, IF YOU CLICK THAT GINGER HAVE IN HEALTHY INDIVIDUAL AND RUN ON A FLOW CYTOMETER YOU CAN PICK UP ADAPTIVE IMMUNE CELLS, ANTIGEN PRESENTING CELLS IMMUNE CELLS, THE WHOLE CADRE OF THE IMMUNE SYSTEM IS THERE WAITING AND SURVEILLING THE ORAL CAVITY AS THESE PATHOGENS COME IN. AS STEVE MENTIONED GRAFT-VERSUS-HOST DISEASE STARTS WITH ANTIGEN RECOGNITION SO TRANSPLANTS ARE MATCHED, TRANSPLANT RECIPIENTS ARE MATCHED TO DONORS AS CLOSE AS POSSIBLE. BUT THERE ARE ALWAYS MINOR HLA OR MHC MISMATCHES THAT ALLOW FOR PRESENTATION OF HOST ANTIGENS. THESE PEPTIDES IN CONTEXT OF MHC TO DONOR CELLS ALLOWING FOR ALLO ANTIGEN RECOGNITION. OF RECIPIENT TISSUE, THIS STARTS OFF THE GRAFT-VERSUS-HOST RESPONSE AND THINKING ABOUT ALL THE IMMUNE CELLS PRESENT. BASAL STATES AND ORAL MUCOSA. YOU CAN THINK THIS IS AN INTERESTING SITE FOR STUDYING SITE SPECIFIC TISSUE SPECIFIC IMMUNITY. THAT IS NOT THE TOPIC TODAY LOOKING AT THE NUMBERS IN 2017 THERE ARE APPROXIMATELY 9400 PATIENT OR 9400 ALLO TRANSPLANTS DONE IN THE UNITED STATES. WE ASSUME BASED ON HISTORICAL NUMBERS ROUGHLY 50% OF THOSE PATIENTS WILL DEVELOP DEMENTIA DISEASE AT SOME POINT. AND OF THOSE PATIENTS, 40 TO 83% ARE EXPECT TO HAVE ORAL MANIFESTATIONS OF CHRONIC GRAFT-VERSUS-HOST DISEASE. SO ORAL GBHD IS RELATIVELY COMMON. WE ALSO KNOWNA PATIENTS WHO PRESENT WITH ORAL MANIFESTATIONS BASED ON A STUDY THAT STEPHANIE LEE PUBLISHED IN DECEMBER OF 2019, PATIENTS WHO PRESENT WITH ORAL GRAFT-VERSUS-HOST DISEASE ARE MORE LIKELY TO BE -- TO SCORE HIGHER ON DISABILITY CHARTS OR DISABILITY ASSESSMENTS. 18 MONTHS AFTER CHRONIC GBHD DIAGNOSIS. DESPITE THE FACT THAT ORAL GBHD IS NOT LETHAL, IT HAS A MAJOR IMPACT ON QUALITY OF LIFE, ON NUTRITION, AND ON PATIENT ABILITY TO MOVE ON WITH THEIR NORMAL LIFE. WE TYPICALLY THINK OF MANIFESTATIONS OF ORAL GRAFT-VERSUS-HOST DISEASE AS OCCURRING IN THREE SEPARATE DOMAINS. THE EASIEST OF THESE TO SEE ARE THE MUCOSAL LESIONS. MUCOSAL LESIONS. THESE ARE EASY TO SEE ON CLINICAL EXAM, PATIENTS CAN OPEN THEIR MOUTH AND YOU CAN GET CLEAR ASSESSMENT OF WHAT'S HAPPENING HERE. SO YOU HAVE HYPERKERATOSIS ON TISSUES, THIS OCCURS IN PATCHY FORMS THROUGHOUT THE ORAL MUCOSA AND ALSO IN THESE MORE LIKE AND PLANTIS LIKE LACI LOOKING LESIONS. WE HAVE ALSO ORAL MUCOSA THESE OCCUR WHEN IMMUNE SYSTEM ATTACKS THE JUNCTION BETWEEN EPITHELIUM AND THE SUBMUCOSA. SO RESULTING IN LIFTING AWAY OF THAT EPITHELIUM FROM THE SKIN. WE SEE THEM INITIALLY COVERED WITH PSEUDOMEMBRANES. THEN THEY LEAVE BEHIND FRANK ULCERATIONS. THERE'S ERYTHEMA INVOLVED. SO WHEN LYMPHOCYTES INFILTRATE AND PINCH OFF DUCTS FOR THE MINOR SALIVARY GLANDS, RATHER THAN RELEASING SALIVA INTO THE ORAL CAVITY, WE SEE THESE FLUID FILLED BLISTERS, THESE MUCOSILLS IN PATIENTS. A SEPARATE MANIFESTATION OF ORAL GRAFT-VERSUS-HOST DISEASE IS FLUOROSIS WHICH CAN RESULT IN MICROSOMEIA. THIS IS OFTEN BECAUSE OF JOINT MANIFESTATIONS IN THE TEMPORAL MANDIBULAR JOINT OR PERIORAL SKIN INVOLVEMENT. IF YOU THINK ABOUT WHAT EXACTLY HAPPENS TO YOU IF YOU COULD OPEN YOUR MOUTH ONE FINGER WIDTH YOU CAN APPRECIATE THIS IS A SIGNIFICANT DISABILITY IN THESE PATIENTS SO THEY HAVE TROUBLE WITH ORAL HYGIENE, THEY HAVE TROUBLE EATING AND HEAVEN FOR BY THEY NEED DENTAL TREATMENT OR INTUBATION. THE THIRD DOMAIN THAT ORAL GBHD EFFECTS ARE SALIVARY GLANDS, THIS IS A SILENT PROCESS, SALIVARY GLANDS ARE OFTEN AFFECTED QUITE EARLY AFTER TRANSPLANT. IT BEGINS AS A LYMPHOCYTIC INFILTRATE AND ENDS UP REPLACING MOST SALIVARY GLANDS ACINAR TISSUE WHICH MAKE SALIVA WITH COLLAGEN BUNDLES. SO CLINICAL PRESENTATION EVEN WITHIN THE ORAL CAVITY CAN BE QUITE DIFFERENT WHEN WE LOOK AT OUR NIH COHORT A FEW YEARS AGO, ABOUT 250 PATIENTS WE FOUND PATIENTS WITH ORAL MUCOSAL LESIONS DIDN'T OVERLAP WITH PATIENT WHOSE HAD SALIVARY GLAND DYSFUNCTION, DIDN'T NECESSARILY OVERLAP WITH PATIENTS WHO HAD LIMITED ORAL OPENING. THOSE WERE LESS RELATED THAN WE EXPECTED WITH PATIENTS WHO HAD SKIN ERYTHEMA, SKIN SCLEROSIS AND LACRYMAL DYSFUNCTION. SO SEEMINGLY RELATED TO THOSE THINGS WE SEE IN THE ORAL CAVITY. SO CLINICAL PRESENTATION IS REALLY IMPORTANT AND IT'S ONE OF THE CRITICAL FACTORS WHEN THINKING TREATMENTS THAT COULD BE EFFECTIVE FOR GRAFT-VERSUS-HOST DISEASE. WE KNOW DIFFERENT TYPES OF CHRONIC GBHD NEED DIFFERENT TREATMENT. WE BASED ON A LOT OF DATA LABORATORY BELIEVE THE UNDERLYING PATHOLOGY AND PROGNOSIS DEPENDING EFFECTED SITES MAY DIFFER. AGAIN, THERE ARE EVEN WITHIN ORAL CAVITY QUITE DISTINCT FORMS OF DEMENTIA DISEASE MANIFESTATIONS. SO THE NEXT QUESTION IS HOW WE TREAT ORAL GRAFT-VERSUS-HOST DISEASE. WE DON'T HAVE GREAT THERAPIES. WE OFTEN TRY TO APPROACH THIS TOPICALLY BECAUSE IT IS SUCH AN AN ACCESSIBLE SITE. FIRST LINE THERAPY IS PROGRESSIVE STEROID RINSES, SO STEROID RINSES OF PROGRESSIVE STRENGTH. THE FIRST IS A DEXAMETHASONE ORAL SUSPENSION. BASED ON RESPONSE RATES WE EXPECT 29 TO 58% PATIENTS TO RESPOND AND THESE RESPONSE RATES ARE NOT BASED ON RESOLUTION OF ORAL GBHD BUT BASED ON PATIENT REPORTING A ONE OR TWO NUMBER SHIFT IN PAIN SCORE 0 TO 10 SCALES AND THIS WERE YOUR AMOUNT YOU WOULD WANT BETTER THERAPY. SECOND LINE TREATMENT IS NOT WELL ESTABLISHED TO THAT END. TO THAT END WE DESIGNED A CLINICAL TRIAL TO IMPROVE DELIVERY VEHICLE FOR AN ULTRAHIGH POTENCY STEROID FOR TOPICAL TREATMENT OF ORAL GRAFT-VERSUS-HOST DISEASE THIS IS A TRIAL RUN AT THE NIH, PHASE 2 PLACEBO CONTROLLED DOUBLE BLIND STUDY SO PATIENTS USE .05% ORAL RINSE THREE TIMES A KAY FOR TOTAL OF 28 DAYS TO PRIMARY END POINT. FOR THE FIRST 14 DAYS THEY WERE RANDOMLY ASSIGNED TO PLACEBO OR ORAL RINSE. ANY PATIENTS WHO WERE INITIALLY RANDOMIZED TO PLACEBO WERE ABLE TO CROSS OVER AFTER UNBLINDING OF THAT DAY 14 SO EVERYBODY AT THE END OF THE TRIAL RECEIVED 28 DAYS OF ORAL RINSE THERAPY. WE HAVE TISSUE BIOPSIES AT BASELINE AND DAY 28, THESE WERE OPTIONAL BUT ABLE TO GET 23 MATCH SETS WHICH I WILL TELL YOU MORE ABOUT IN A LITTLE BIT. RESPONSE RATES ON STUDY WERE QUITE GOOD. WE DEFINED A PARTIAL RESPONSE AS 25% IMPROVEMENT AND CLINICIAN ASSESSED CLINICAL SCORE. FOR ORAL DISEASE IN ORDER TO ACHIEVE PA COMPLETE RESPONSE PATIENTS NEEDED TO HAVE COMPLETE RESOLUTION OF ERYTHEMA IN THE ORAL CAVITY AS WELL AS ULCERATIONS WITHIN ORAL CAVITY SO THIS WAS A HIGH BAR TO REACH BUT WE DID HAVE 19% PATIENTS WHO HAD CR. A TOTAL OF 91% PATIENT HAD COMPLETE OR PARTIAL RESPONSE WHILE ON STUDY. I WANT TO POINT OUT THAT SIX PATIENTS HAD NEW ONSET ORAL GRAFT-VERSUS-HOST DISEASE BUT THE REST OF THE 34 PATIENTS WE ENROLLED ON STUDY HAD REFRACTORY ORAL GRAFT-VERSUS-HOST DISEASE. THEY HAD MEDIAN OF TWO PRIOR THERAPIES ORAL TOPICAL THERAPIES THEY FAILED, 11 PATIENTS USED UNSUCCESSFULLY PRIOR OINTMENT AND MAJORITY OF THOSE PATIENTS WERE ABLE TO RESPOND ONCE IN ORAL RINSE FORM. THIS IS WHAT THINGS LOOK LIKE CLINICALLY. THIS PARTICULAR PATIENT CAME ON WITH A LOT OF ERYTHEMA AND THESE DEEP ULCERATIONS ON THE BUTCAL MUCOSO SO INSIDE OF CHEEK. WE HAD RESOLUTION BY DAY 14 AND BY DAY 28 YOU CAN APPRECIATE THE TISSUE LOOKS MORE OR LESS NORMAL WITHIN THE ORAL CAVITY OF THIS PATIENT. LOOKING AT THAT SAME PATIENT UNDER THE MICROSCOPE, IN THE BASELINE BIOPSY YOU CAN APPRECIATE APOPTOTIC KERATINYTE LEUKOCYTIC INFILTRATES, AND BY DAY 28 YOU SEE BUCKCAL MUCOSA FROM THE ORAL CAVITY MORE OR LESS NORMAL UNDER MICROSCOPE. WE GRADED THESE ACCORDING TO THE 2005 NIH CONSENSUS CRITERIA FOR HISTOPATHOLOGIC DIAGNOSIS OF CHRONIC GBHD, THIS IS FOUR POINT SCALE. YOU CAN APPRECIATE THINGS MORE RED MORE SEVERE DIAGNOSIS. ON THE HISTOPATH SCALE AND WE HAD LESS -- A SIGNIFICANT IMPROVEMENT IN THE SEVERITY OF HISTOPATH DIAGNOSIS FROM BASELINE TO DAY 28 ON THIS TRIAL SO THE PATIENTS WEREN'T JUST LOOKING BETTER CLINICALLY, THEIR DISEASE WAS RESOLVING WITHIN THEIR TISSUES AND PATIENT REPORTED ORAL PAIN ORAL SENSITIVITY AND ORAL HEALTH RELATED QUALITY OF LIFE HAD SIGNIFICANT IMPROVEMENT. WE WEREN'T ABLE TO TOUCH SALIVA PRODUCTION. SO FUNCTION OF THE SALIVARY GLAND WAS UNCHANGED THROUGHOUT THE COURSE OF THE STUDY. BASED ON THE ROBUST EFFICACY OF THIS TOPICAL THERAPY WE WANTED TO LOOK WITHIN THE TISSUES AND SEE WHAT CELL POPULATIONS WERE RESPONDING. WE USED IMMUNOHISTOCHEMISTRY TO LOOK FIRST AT T-CELLS UNSURPRISINGLY T-CELL LAYERTY WAS REDUCED POST TREATMENT BOTH WITHIN THE CD4 COMPARTMENT AND WITHIN THE CD8 COMPARTMENT AND JUST TO ORIENT YOU A LITTLE BIT TO THESE SLIDES, THE EPITHELIUM WHICH FACES INTO THE ORAL MUCOSA IS SHOWN HERE ON TOP AND THIS HASH LINE DENOTES BORDER BETWEEN THE EPITHELIUM AND THE SUBMUCOSA. YOU CAN APPRECIATE THAT PRE-TREATMENT, WE HAVE SORT OF A FRUITY PEBBLES APPEARANCE OF THIS TISSUE WHERE YOU HAVE GOT THE DENSE INFILTRATE OF T-CELLS RESOLVE BY THE TIME THE PATIENT HAD MADE IT TO 28 DAYS OF TREATMENT. BASED ON DATA FROM OUR LABORATORIES SUGGESTING TH 17 SIGNATURE WITHIN THE ORAL CAVITY, AND A LOT OF DATA COMING OUT OF LABS LOOKING AT GASTROINTESTINAL GRAFT-VERSUS-HOST DISEASE WE WANTED TO LOOK FOR TH 17 CELLS AND SEE WHAT HAPPENED TO THEM. DURING THE COURSE OF THIS TRIAL. SO WE WENT -- WE DID A PANEL AND WE STAIN FOR THEM. WE FOUND A REDUCTION IN TOTAL IL 17 PRODUCING CELLS SO THIS IS NOT SIGNIFICANT FROM PRE-TRIAL TO POST TRIAL. BUT MORE INTERESTINGLY, WHEN WE STARTED LOOKING REALLY CAREFULLY AT THE CELLS PRODUCING IL 17, THESE ARE SHOWN IN GREEN, WE HAVE A NICE DISTRIBUTION BOTH EPITHELIUM AND A LITTLE BIT DEEPER IN THE SUBMUCOSA. THIS IS GOING TO ZOOM IN IN A SECOND. BUT WHEN WE STARTED LOOKING CAREFULLY AT SURFACE MARKERS THE CELLS WERE EXPRESSING THE IL 17 PRODUCERS, THAT'S SAY TOEPLASM FULL OF IL 17, MOST OFTEN HAD NICE SURFACE EXPRESSION OF CD4 BUT THEY WERE COMPLETELY NEGATIVE FOR CD 3 SO WE HAD A LOT OF CD 3 STAINING, THE ANTIBODY WAS WORKING. THE IL 17 PRODUCING CELLS SIMPLY WEREN'T MAKING OR SIMPLY DIDN'T HAVE SURFACE EXPRESSION OF CD 3. THIS MEANS THEY ARE NOT T-CELLS. SO THESE DEFINITELY WEREN'T TH 17 CELLS. WE WERE ABLE TO FIND TH 17 CELLS IN THREE PATIENTS PRE-TREATMENT THOSE TH 17S WERE GONE POST TREATMENT. BUT LESS THAN 1% OF IL 17 INTRODUCERS IN THE ORAL MUCOSA WERE BONA FIDE TH 17 CELLS. 40% OF THESE HAD THIS CD 3 NEGATIVE CD4 POSITIVE IL 17 POSITIVE PHENOTYPE, MOST CONSISTENT BASED ON THE STAINS AND OTHER STAINS WITH A TYPE 3 ILC PHENOTYPE, AND THEN 59% ARE IL 17 PRODUCERS THAT WE HAVE YET TO IDENTIFY THEIR NEGATIVE FOR CD 3 AND CD 4. AS YOU KNOW, IL 17 IS PRODUCE BY A NUMBER OF CELL TYPES, T-CELLS AND NON-T-CELLS. WE KNOW THESE CELLS ARE NOT NK CELLS, BUT WE ARE STILL WORKING ON IDENTIFYING EXACTLY WHAT THEY ARE AND WHAT THEY ARE DOING WITHIN THE CONTEXT OF GRAFT-VERSUS-HOST DISEASE. I DO WANT TO POINT OUT THAT WE DON'T THINK THAT THESE IL 17 PRODUCERS ARE THE MAIN EFFECTOR CELLS IN GRAFT-VERSUS-HOST DISEASE, WE KNOW ESPECIALLY IN THE ORAL TISSUES THAT'S A STRONG TYPE ONE INTERFERON SIGNATURE. AND WE ALSO KNOW WITHIN DISRUPTED AND DAMAGED TISSUES, THIS IS SALIVARY GLAND, THE MAIN EFFECTOR CELLS WE FIND ARE POSITIVE CD8 T-CELLS SO YOUR CLASSIC DAMAGE INDUCING CD8 T-CELLS SO WE FIND THEM HERE WITHIN A DISRUPTED ACINAR IN MINOR SALIVARY BLAND OF GBHD PATIENT. WE FIND THEM IN ORAL MUCOSA THAT'S ACTIVELY CLEFTING SO WE FIND THEM AT THE SCENE OF THE CRIME. SO WE THINK THAT THESE ARE STILL THE MAIN CELLS THAT ARE CAUSING TISSUE DAMAGE WITHIN GRAFT-VERSUS-HOST DISEASE. ALSO WHEN WE LOOK USING FLOW CYTOMETRY, WE FIND A COLOR CORRELATION BETWEEN NUMBERS AND SUBSETS OF CD8 T-CELLS IN THE ORAL TISSUES WITH CLINICAL SEVERITY ORAL GRAFT-VERSUS-HOST DISEASE. SO THIS LEAVES US WITH A MAJOR QUESTION ABOUT WHICH CELLS ARE INITIATING ALLO IMMUNE RECOGNITION OF ORAL TISSUES WHICH CELLS ARE DRIVING THIS GBH RESPONSE. WE THINK THAT IL 17 IS PLAYING AN IMPORTANT ROLE HERE DURING EARLY TISSUE DAMAGE AND IN ACTIVATION AND ATTRACTION OF SOME OF THESE ANTIGEN PRESENTING CELLS ACTIVATION OF DAMP AND PATCH PATHWAYS THAT DRIVE EXPRESSION OF T-CELL ATTRACTING CHEMOKINES WHICH LEADS TO STRUCTURAL ALTERATION AND CELL DEATH IN THE SALIVARY GLANDS AND OTHER ORAL TISSUES. ALSO IN HELPING TO DRIVE THIS FEET FORWARD CIRCUIT. THAT'S PUSHING THE INFLAMMATION FORWARD AND THE GBH RESPONSES. SO WE ARE ALSO VERY INTERESTED, THIS IS AN OBVIOUS TOPIC CHANGE. NOT -- QUITE A TOPIC BUT A LITTLE BIT OF A SHIFT. SO WE ARE ALSO VERY INTEREST IN THE INFORMATION THAT WE CAN GET FROM THE LOCAL ORAL BIOFLUID SO FROM SALIVA, ABOUT WHAT IS HAPPENING WITHIN THE LOCAL ENVIRONMENT OF THE ORAL CAVITY. WE KNOW PROTEIN AND WHOLE SALIVA COMES FROM MULTIPLE SOURCES, PRODUCED NOT ONLY BY SALIVARY GLANDS THEMSELVES AND SECRETED INTO THE SALIVA, PROTEIN ALSO GETS INTO THE WHOLE SALIVA FROM SERUM BY GIN JOY HAVE CAPILLARY FLUID, YOU HAVE THIS THAT SURROUND THE TEETH MUCOSAL EPITHELIAL ARE SHED INTO THE ORAL CAVITY AND YOU HAVE A PROTEIN CONTRIBUTION FROM THE ORAL MICROBIOME. WE ALSO KNOW SALIVARY GLANDS ARE A TARGET OF GRAFT-VERSUS-HOST DISEASE, THESE ARE A LITTLE BIT BIGGER PICTURES THAN THE ONES I SHOWED YOU EARLIER, WE FIND DISRUPTION IN THE ACINAR IMMUNE CELLS SURROUNDING THE DUCTS THAT TAKE THE SALIVA OUT INTO THE ORAL CAVITY AND WE ALSO FIND A LOT OF DENTAL DESTRUCTION IN THESE PATIENT WHOSE ARE MISSING THEIR SALIVA BECAUSE IT HAS ABOUT IMPORTANT ROLE IN KEEPING THE MOUTH CLEAN AND HEALTHY. THE INITIATED SALIVARY PROTEOMIC STUDY, TO IDENTIFY A DIAGNOSTIC BIOMARKER PROFILE FOR ORAL GRAFT-VERSUS-HOST DISEASE. WE USED A SHOTGUN PROTEOMICS APPROACH IN COLLABORATION WITH THE NHLBI PROTEOMICS CORE, USING AND I TRACK LABELING STRATEGY, THOSE FAMILIAR KNOW IT GIVES YOU EIGHT LABELS THAT YOU CAN USE SO WE POPPED TWO HEALTHY VOLUNTEERS THREE PATIENTS POST TRANSPLANT WITHOUT ORAL GBHD AND THREE WITH NEW ONSET ORAL GBHD. AT THE END OF MASS SPEC WE ANALYZED THE DATA AND THEN WE DID VALIDATION AND VERIFICATION USING WESTERN BLOTTING IN TWO SEPARATE PATIENT COHORTS. WE ALSO CAME WITH IMMUNOFLUORESCENCE TO TRY TO UNDERSTAND WHERE OUR PROTEINS ARE BEING EXPRESSED. OF THESE 77 DIFFERENCIALLY EXPRESSED PROTEINS WE APPLIED FOUR FILTERS AND CAME UP WITH SIX INITIAL VALIDATION TARGETS. FIVE OUT OF SIX FAILED WESTERN BLOTTING. SO THERE WAS NO CHANGE WHEN WE LOOKED USING WESTERN BLOTTING IN PATIENT SALIVA. THE ONE THAT CAME THROUGH THE SCREEN WAS THE PROTEIN WE KNEW THE LEAST ABOUT. WE PICKED IT BECAUSE IT WAS STRONG SIGNATURE, THIS IS THE SIGNAGE GRANULE PROTEIN 16B OR ZG 16B. THIS IS SIMPLY, THESE ARE SIMPLY THE BLOTS SHOWING A SIGNIFICANT DECREASE AS G 16B WITH ONSET OF GRAFT-VERSUS-HOST DISEASE. IN THE SALIVARY GLANDS. SO THEN WE WENT IN WITH IMMUNOHISTOCHEMISTRY TO TRY TO UNDERSTAND WHAT CELLS WERE EXPRESSING WITH 16B AND WHAT IT LOOKED LIKE WITHIN THE SALIVARY GLANDS. IT IS SHOWN HERE IN RED AND THIS IS HEALTHY VOLUNTEER TISSUE AND YOU CAN APPRECIATE THERE'S DWIGHT QUITE A BIT OF IT AROUND WHEN WE QUANTITATE IT'S NOT DIFFERENT. POST TRANSPLANT IN THE ABSENCE OF GBHD BUT IF YOU LOOK AT A PATIENT WITH ORAL GRAFT-VERSUS-HOST DISEASE, THE GD 60B IS ALMOST ABSENT IN THESE IMMUNOSTAINS SO WE DID HOSTING TO TRY TO UNDERSTAND WHAT CELLS WERE BEING -- PRODUCING ZD 16B, IT WASN'T CLEAR. SO WE TURNED TO A SINGLE CELL RNA SEQ APPROACH ON A 10X GENOMICS PLATFORM AND WE SEQUENCED THE MINOR SALIVARY GLANDS FROM THREE HEALTHY VOLUNTEERS. YOU CAN SEE HERE THE UMAP PLOTS SHOWING THE POPULATION DISTRIBUTION WITHIN THE SYSTEM VARY GLAND. I WILL POINT OUT THESE WERE HEALTHY VOLUNTEERS YET WE STILL HAVE REALLY LOVELY POPULATIONS ADAPTIVE IMMUNE INNATE CELLS IN EVEN STATES OF HEALTH. SO LOOKING AT THE FEATURE PLOTS WE WERE INTEREST IN SEEING WHICH CELLS HAD HIGH EXPRESSION OF CG 16B SHOWN HERE IN UPPER LEFT HAND PLOT. WE FOUND THAT PATIENTS OR THAT POPULATIONS WERE CO-LOCALIZING WITH MARKERS FOR BOTH SEROUS AND SEROUS MUCOUS ACINAR CELL, BUT ALSO TO A LESSER EXTENT MARKERS FOR DUCK TILE CELLS. LOOKING AT THE VIOLIN PLOTS YOU CAN SEE MORE CLEARLY WE HAVE HIGH EXPRESSION OF CD 16B IN ACINAR CELLS AND ALSO WITHIN THE SMALL DUCK TILE POPULATION. WHAT IS ZG 16B, IT'S A JACK TYPE LECTIN THAT IS SALIVARY AMYLASE, A LITTLE BIT IS KNOWN IN THE LACRYMAL GLAND, IT HELPS TO INDUCE RELEASE OF TEAR FLUID FROM THE ACINAR CELLS, IN THE LACRYMAL GLAND, ALSO HAS ASSOCIATION WITH PANCREATIC CANCER. BUT IN THE SALIVARY GLAND IT'S A BLACK BOX. WE DON'T KNOW A LOT ABOUT IT. SO THIS IS AN ONGOING TOPIC IN THE LABORATORY. A NICE EXAMPLE OF HOW WE HAVE BEEN ABLE TO TALK THINGS FROM THE CLINIC AND SO -- MAKE SOME THINGS WE THINK ARE GOING TO END UP BEING MAYBE BASIC SCIENCE. TYPE DISCOVERIES. SO THIS IS MY LAST ACTUAL SLIDE. WE THINK THAT ZG 16B LOSS MAY NOT BE SO RELATED TO GRAFT-VERSUS-HOST DISEASE, WE THINK IT MIGHT INDICATE EXOCRINE GLAND DAMAGE. WE KNOW UNDER THE MICROSCOPE THE LACRYMAL GLAND PANCREAS AND SALIVARY GLAND LOOK SIMILAR. SO WE ARE INTERESTED IN INVESTIGATING WHAT THIS PROTEIN DOES IN THESE THREE ORGANS. I SHOWED YOU DATA, THAT INDICATED A BETTER DELIVERY SYSTEM FOR -- THAT WAS TAYLOR TO THE TARGET ORGAN, GREATLY IMPROVED THE THERAPEUTIC OUTCOMES FOR ORAL CHRONIC GRAFT-VERSUS-HOST DISEASE. AND AS STEVE MENTIONED WE ARE INTERESTED IN P SEEING IF IL 17 PATHWAY BLOCKADE WILL IMPACT CLINICAL DISEASE AND THIS IS A STUDY THAT IS WORKING ITS WAY THROUGH THE PIPELINE CURRENTLY. THIS WORK WOULDN'T BE POSSIBLE WITHOUT MY VERY ENTHUSIASTIC AND ENERGETIC LABORATORY AND CLINICAL TEAMS. SO THESE SINGLE CELL RNA SEQ WORK AND ANALYSIS THAT WERE DONE WERE DONE BY DR. DESILVA IN MY LABORATORY. JOSH DODGE FORMER POSTBAC DID IMMUNOHISTOCHEMISTRY AND MICROSCOPY THAT I SHOWED TODAY. AND THESE WERE DONE IN COLLABORATION WITH THE NIDCR IMAGING CORE AND IN MIDCR SEQUENCING CORE AS WELL. I JUST WANT TO THANK DR. PAVLETIC WHO HAS BEEN MY PRIMARY CLINICAL MENTOR OVER THE PAST EIGHT YEARS AND ALSO THE OFFICE OF CLINICAL DIRECTOR AT THE NIDCR FOR THEIR OUTSTANDING SUPPORT OF OUR TEAM. AND I SEE NUMBER OF OUR REFERRING DOCS THAT WE HAVE. WE HAVE A NATURAL HISTORY STUDY WE ARE RUNNING LIEU THE DENTAL CLINIC CURRENTLY TRYING TO ENROLL ALL THE TRANSPLANT PATIENTS AT THE NIH SO THAT WE CAN SCREEN THEIR ORAL CAVITY AND CAREFULLY TRACK OUTCOMES TO BETTER DEFINE SOME OF THESE BIOLOGICAL AND CLINICAL END POINTS. I WANT TO THANK THE TEAMS THAT I SEE HERE IN THE AUDIENCE FOR YOUR KIND COOPERATION WITH THAT STUDY. WITH THAT, I THINK WE WILL TAKE QUESTIONS. THANK YOU VERY MUCH. [APPLAUSE] >> LET'S GET GOING WITH QUESTIONS. YES. >> HAVE YOU FOUND OVERALL THAT THE PROGNOSIS OF CHRONIC GRAFT-VERSUS-HOST DISEASE IS DEPENDENT ON THE DONOR CHARACTERISTICS OF AGE OR SEX MATCHING WITH THE RECIPIENT? >> THAT IS OF COURSE A GOOD QUESTION. WE DO KNOW ACTUALLY FOR EXAMPLE, IF YOU USE PERIPHERAL BLOOD STEM CELL SOURCE INSTEAD OF BONE MARROW, THAT'S ONE OF THE MOST POWERFUL PROGNOSTIC FACTORS FOR ONSET OF CHRONIC GRAFT-VERSUS-HOST DISEASE. A GOOD EXPLANATION FOR THAT IS ACTUALLY STILL MATTER OF INTERESTING RESEARCH BUT I THINK ONE OF THOSE IS FOR SURE TOTAL NUMBER OF T-CELLS PLAYS A ROLE AS WELL. BLOOD VERSUS MARROW. BIG PROGNOSTIC FACTOR. GENDER FEMALE DONOR TO MALE RECIPIENT P BIG PROGNOSTIC FACTOR FOR HIGHER INCIDENCE OF GBHD PARTICULARLY ASSOCIATED WITH POSITIVE MINOR HISTOCOMPATIBILITY SUCH AS H 1 ANTIBODIES. SO TWO EXAMPLE, AGE HAS BEEN LITTLE MORE COMPLICATED SO WE DON'T HAVE A CLEAR -- WE HAVE MORE CORRELATION OF HOST AGE, PATIENT AGE WITH CHRONIC GBHD THAN DONOR. DONOR AGE MATTERS IN TERMS OF NON-RELAPSE MORTALITY AND THERE'S A WHOLE OTHER CONVERSATION WHY THAT MATTERS SO WE TEND TO TAKE YOUNGER DONORS NOWADAYS, YOUNGER MEANS YOUNGER THAN 30 OR 35 IDEALLY. THIS IS THE KEY ELEMENTS. >> THE IMPLICATIONS ALSO FOR FEMALES WHO ARE PREGNANT, WHO GET SOME TRANSFUSION OF CELLS FROM THEIR MALE FETUS NOWADAYS MIGHT BE PRE-DISPOSED TO AUTOIMMUNE DISEASE SEEM TO BE A HOT TOPIC IN THE LITERATURE. PEOPLE DON'T TALK ABOUT IT ANY MORE BUT THAT SEEMS TO BE SOMETHING TO DO WITH CHRONIC GRAFT-VERSUS-HOST AS WELL, THAT TYPE OF HYPOTHESIS. HAVE YOU INVESTIGATED ANY OF THAT OR DOES ANY OF THAT EXIST IN THE LITERATURE IN BONE MARROW TRANSPLANT? >> YES, THAT'S FAIRLY WELL KNOWN ACROSS AREAS THAT FEMALE DONORS WITH HISTORY OF -- HAVE HIGH RISK OF MEDIATING ACCRUE OR CHRONIC GRAFT-VERSUS-HOST DISEASE. SO YES, THAT MATTERS. NUMBER OF PRIOR PREGNANCIES IS WELL RECOGNIZED RISK FACTORS KNOWN FOR A LONG TIME. >> THANK YOU VERY MUCH. >> I DID WANT TO ASK YOU ABOUT IS IT ZG 16B? >> A LOT OF O THE FEATURES YOU WERE DESCRIBING SEEM SIMILAR TO PATIENTS WITH SHOW GUN SYNDROME, I'M WONDERING, WHETHER IN FACT YOU HAVE INSIGHT FROM SHOW GRIN RELATIVE TO THIS PROTEIN THAT MIGHT SORT OF CLARIFY ISSUE WHETHER IT'S GBD SPECIFIC OR SOMETHING THAT JUST RELATES TO GENERAL AUTOIMMUNE PHENOMENON THAT AFFECT THE ORAL CAVITY AND SALIVARY GLANDS. >> SO WE DON'T HAVE ANY SPECIFIC DATA FROM THE SHOW GUN POPULATION, WE ARE QUITE INTERESTED IN LOOKING. HOWEVER, WE KNOW THAT -- I DON'T THINK IT'S GBH SPECIFIC, IT'S MORE MARKER OF SALIVARY GLAND DAMAGE WE SEE IN PROTEIN, SO WE WOULD EXPECT IN SHOW GRIN AND OTHER CONDITIONS THAT DAMAGE SALIVARY GLANDS ARE POTENTIALLY OTHER EXOCRINE TISSUES WE SEE SIMILAR TYPES OF CHANGES. >> OKAY. QUESTION. >> WONDERFUL, JUST WONDERFUL TALK. THANK YOU FOR THAT. SO I'M ASKING IF YOU COULD THINK A LITTLE BIT ALLOWED SO WE CAN DRAW CORRELATION WITH WHAT WE SEE IN LUNG TRANSPLANT PATIENTS. TWO QUESTIONS. FIRST QUESTION IS RACE AND COLOR GBHD YOU HAVE SEEN A RACIAL PREDILECTION OF THIS, LONG TERM PRESENTATION WE HAVE A SIMILAR CONDITION WHICH IS ALLO GRAPH DYSFUNCTION, IT SEEMS TO HAPPEN MORE IN PATIENTS WHO ARE NONCAUCASIAN OR NON-WHITE. SO THAT'S MY FIRST QUESTION. MY SECOND QUESTION, IS IN THE SERIES -- IF YOUR CLINICAL EXPERIENCE WITH A NEW DRUG THERAPY, IN YOUR PATIENTS WITH GBHD WHAT PERCENT HAVE LUNG MANIFESTATIONS? TWO, DO YOU SEE IMPROVEMENT IN THE LUNG FUNCTION WITH ANY OF THESE THERAPIES? >> THANK YOU FOR THIS QUESTION. IN TERMS OF RACIAL ORIGIN OF DONOR ETHNICITY, INTERESTING THE PEOPLE LOOKED A LOT INTO THIS AND THERE'S NO IMPACT ON CHRONIC GBHD AS ANY RISK FACTOR, IT'S REALLY WHAT MATTERS IS THE DEGREE AND QUALITY OF HLA MATCHING. IN TERMS OF LUNG TRANSPLANTATION AND LUNG CHRONIC GBHD, IT'S AN AMAZING COMMON THEME. WE DEAL WITH BRONCHIALITIS OBLITERATION, CHRONIC GBHD OF THE LUNGS, IT'S RARE, IT EFFECTS ABOUT 5% OF ALLOGENEIC TRANSPLANT RECIPIENTS BUT WHEN IT HAPPENS, IT COMES UNDER THOSE RECALCITRANT DIFFICULT MORBID ENTITIES WHERE ALL THIS PARADIGMS OF RESPONSES AND STEROID DON'T WORK. IT'S ONE OF THE BIG CHALLENGES AND WE WILL LIKE TO WORK MORE WITH LUNG TRANSPLANT COMMUNITY WHERE NOW ADAYS ALMOST IDENTICAL COMPLICATION THAT OCCURS IN TERMS OF MOVING THIS FORWARD. THERE'S SOME PROGRESS, WITH APPROACHES TO THIS BUT REALLY NO EFFECTIVE TREATMENT. WE HAVE TRIAL GOING ON, WITH NEUTRAPHIL ALLO STAYS INHIBITOR. BUT THERE'S OTHER IDEAS, BUT THAT'S VERY DIFFICULT NUT TO CRACK THAT WE NEED TO TRY TO AVOID PATIENTS THAT NEED LUNG TRANSPLANT. SO IT'S RARE BUT DEVASTATING. >> WITH THE EMERGENCE OF HAPLO TRANSPLANTATION NOW, ARE YOU SEEING DIFFERENCE IN GBHD IN TERMS OF SPECTRUM OF SYMPTOMS AND TREATMENT RESPONSES? >> WELL, THAT'S -- HAPLO IDENTICAL TRANSPLANTS, ARE PARTIAL HALF MATCHED DONOR, REALLY PROLIFERATED OVER LAST TEN YEARS. IT WAS ALMOST LIKE IMPOSSIBLE TO DO IN ADULTS BECAUSE NOW WITH THE POST TRANSPLANT CYCLOPHOSPHAMIDE IT'S REALLY -- WE CAME TO THE POINT EVERYBODY HAS A DONOR NOW. THE INCIDENCE OF CHRONIC GRAFT-VERSUS-HOST DISEASE USING POST TRANSPLANT CYCLOPHOSPHAMIDE, THAT HAS TO BE USED THERE'S OTHER APPROACHES WITH T-CELL DEPLETION AND SO ON BUT INCIDENCE OF CHRONIC GBHD IS LESS, WITH POST TRANSPLANT CYCLOPHOSPHAMIDE, IT DOES MATTER BLOOD OR MARROW SOURCE. SO IN TERMS OF CLINICAL MANIFESTATION, WE DON'T HAVE ANY HARD EVIDENCE, THEY ARE FUNDAMENTALLY DIFFERENT BUT SEEMS THERE IS HIGHER PREPONDERANCE OF LESS SEVERE CASES AFTER POST TRANSPLANT CYCLOPHOSPHAMIDE. >> WE ARE OUT OF TIME, IF YOU DO HAVE QUESTIONS, PLEASE COME ON DOWN AND I'M SURE OUR SPEAKERS WILL BE HAPPY TO ANSWER THEM. AND FOR ALL OF YOU WE'LL SEE YOU NEXT WEEK. [APPLAUSE]