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.
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effort in training today's investigators and discovering
tomorrow's cures.
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WE'RE HONORED TO HEAR FROM TWO
COLLEAGUES, DR. STEVEN
ROSENBERG, CHIEF NATIONAL CANCER
INSTITUTE AND DR. ANNA LAU, NIH
CLINICAL CENTER DEPARTMENT
LABORATORY OF MEDICINE. OUR
FIRST SPEAKER IS DR. ROSENBERG.
NATIONAL CANCER INSTITUTE AND
PROFESSOR AT THE UNIFORM SURGERY
HEALTH SCIENCES GEORGE
WASHINGTON UNIVERSITY SCHOOL OF
HEALTH AND MEDICAL SCIENCES AND
DEPARTMENT OF LABORATORY
MEDICINE AT THE KAROLINSKA
INSTITUTE STOCKHOLM, SWEDEN. DR.
ROSENBERG EARN HIS M.D. AT JOHNS
HOPKINS UNIVERSITY AT BALTIMORE
AND Ph.D. IN BUY PHYSICS AT
HARVARD UNIVERSITY. AFTER
CLEATING RESIDENCY TRAINING IN
SURGERY 1974 AT THE PETER
BRIGHAM HOSPITAL IN BOSTON DR.
ROSENBERG BECAME THE CHIEF
SURGERY BRANCH AT THE NATIONAL
CANCER INSTITUTE, A POSITION
HELD SINCE PRESENT TIME. AS
CHIEF OF THE SURGERY BRANCH DR.
ROSENBERG OVERSEES THE BRANCHES
EXTENSIVE CLINICAL PROGRAM AIMED
TRANSLATING ADVANCES INTO
EFFECTIVE IMMUNOTHERAPIES FOR
PATIENTS WITH CANCER. DR.
ROSENBERG PIONEERED THE FIRST
IMMUNOTHERAPIES FOR PATIENTS
WITH ADVANCE CANCER, HIS STUDIES
OF THE ADOPTIVE TRANSFER OF
GENETICALLY MODIFIED LYMPHOCYTES
DEMONSTRATE PROGRESSION OF
METASTATIC CANCER IN PATIENT
WITH MELLOWNA SARCOMAS AND
LYMPHOMAS. HE PIONEERED THE
DEVELOPMENT OF GEN GENE THERAPY AND
FIRST TO SUCCESSFULLY
INTERCHANGE TO HUMANS AS WELL AS
FIRST INVESTIGATOR DEMONSTRATE
EFFECTIVENESS OFFER GENETICALLY
ENGINEERED CAR T-CELLS TO
MEDIATE REREGRESSION OF B CELLS
IN MALIGNANCIES. HIS RESEARCH
AIMS TO FIND HOST IMMUNE
RESPONSE TOP PATIENTS WITH
CANCER. THESE EMPHASIZE ABILITY
OF LYMPHOCYTES TO RECOGNIZE
UNIQUE CANCER ANTIGENS AND THE
IDENTIFICATION OF ANTITUMOR
T-CELL RECEPTORS EXPLOITED TO
DEVELOP NEW CELL TRANSFER
IMMUNOTHERAPIES FOR TREATMENT OF
CANCER PATIENTS. FOR THESE
CONTRIBUTIONS DR. ROSENBERG HAS
RECEIVED HIGHEST AWARDS IN
MEDICAL SCIENCE. TO INCLUDE
KAGEL MEDICAL SCIENCE PRIZE,
AMERICAN CANCER SOCIETY OF
MEDICAL HONORS, THE NOVARTIS
PRIZE FOR CLINICAL IMMUNOLOGY,
AMERICAN ASSOCIATION OF
IMMUNOLOGY STEINMAN AWARD FOR
HUMAN IMMUNOLOGY RESEARCH,
GEORGE PRIZE FOR PROGRESS IN
CANCER RESEARCH. THE LLOYD J.
OLD AWARD IN CANCER IMMUNOLOGY
AND AMERICAN PHILADELPHIA
ACADEMY OF SURGERY. IN 2020, THE
SOCIETY FOR IMMUNOTHERAPY OF
CANCER ESTABLISHED A STEVEN A
ROSENBERG SCHOLARS PRIZE IN
CANCER IMMUNOTHERAPY. DR.
ROSENBERG IS MEMBER OF THE
INSTITUTE OF MEDICINE OF THE
NATIONAL ACADEMY OF SCIENCES. HE
PUBLISHED OVER 1100 PAPERS IN
PEER REVIEWED LITERATURE AND H
INDEX OF 206 MAKES HIM ONE OF
THE HIGHEST CITED CLINICIAN
SCIENTISTS IN THE WORLD. OUR
SECOND SPEAKER, DR. ANNA LAU.
CHIEF OVERSTEER RILLETTESSING
SERVICE DEPARTMENT OF LABORATORY
MED SEN. DR. LAU EARNED HER
Ph.D. FROM UNIVERSITY OF
SIDNEY, AUSTRALIA, WHERE HER
RESEARCH FOCUSED ON DEVELOPMENT
OF NOVEL DIAGNOSTIC PLATFORMS
FOR INNOVATIVE PUBLIC DISEASES.
IN 2011 SHE JOINED THE NIH TO
COMPLETE A FELLOWSHIP AND
CLINICAL MICROBIOLOGY, IN THE
DEPARTMENT OF LABORATORY
MEDICINE. UPON HER FELLOWSHIP
SHE JOINED A CLINICAL
MICROBIOLOGY SERVICE AS A STAFF
SCIENTIST, SHE CO-DIRECTED THE
BACTERIOLOGY SPECIMEN PROCESSING
PARACYTOLOGY AND MO LEK LEER
EPIDEMIOLOGY SECTION. IN 2018
DR. LAU PROMOTED TO CHIEF OF THE
NEWLY CREATED STERILE TESTING
SERVICE TO SUPPORT THE NIH WIDE
CGMP PROCESSING AND
MANUFACTURING CELLULAR THERAPY
AND NIH CLINICAL PROTOCOLS. DR.
LAU TRANSDIVISIONAL RESEARCH --
TRANSLATIONAL RESEARCH USES
MOLECULAR BASED TECHNIQUES AND
MASS SPECTROMETRY. CURRENT
RESEARCH INVOLVES ADVANCING
TESTING PLATFORMS AND FDA
REQUIREMENTS FOR CLINICAL
QUALITY AND PATIENT SAFETY. HER
WORK REFLECTED NEARLY 50
PUBLICATION BOOK CHAPTER AND
RECOGNIZED NUMEROUS AWARDS
INCLUDING 8 NIH CLINICAL
CERTAINTY CEO AND DIRECTORS
AWARDS AND RECOGNIZE BY FORBES
FOR THE 30 UNDER 30 AWARD FOR
HEALTHCARE SCIENCE. DR. LAU
SERVES AS ON THE EDITORIAL BOARD
TORR JOURNAL CLINICAL
MICROBIOLOGY AS MEMBER OF THE
AMERICAN SOCIETY FOR
MICROBIOLOGY, THE PARENTAL DRUG
ASSOCIATION AND THE U.S.
PHARMACO PEEDIA. SHE CHAIRS THE
NIH ENVIRONMENTAL MONITORING
ADVISORY COMMITTEE FOR CGMP AND
DR. LAU ALSO BOARD CERTIFIED TO
THE AMERICAN BOARD OF MEDICAL
MICROBIOLOGY. PLEASE WELCOME OUR
FIRST SPEAKER, DR. ROSENBERG,
WHOSE TALK IS ENTITLED
LYMPHOCYTES AS A LIVING DRUG FOR
TREATMENT OF CANCER.
>> GOOD MORNING, I'M GOING TO BE
DISCUSSING THE SUBJECT OF USING
LYMPHOCYTES AS A LIVING DRUG FOR
THE TREATMENT OF CANCER. NOT
USING CHEMOTHERAPY AGENTS BUT
RATHER THAN THAT USING A
PATIENT'S OWN NORMAL IMMUNE
CELLS, FOR THERAPY AND OUR
ATTEMPTS TO DEVELOP THESE
APPROACHES TO CANCER TREATMENT.
I HAVE NO PERSONAL DISCLOSURES
OF COURSE. THOUGH THE NCI AND
SURGERY BRANCH COOPERATIVE
RESEARCH AND DEVELOPMENT
AGREEMENTS CREDAS WITH
BIOTHERAPEUTICS AND ONCOLOGY.
USING CELLS AS A CELL TRANSFER
THERAPY, FOR PATIENTS WE CAN SEE
A LARGE NUMBER OF POTENTIAL
ADVANTAGES, WE CAN IDENTIFY AND
GROW A LARGE NUMBERS OF HIGHLY
SELECTIVE CELLS WITH HIGH
AVIDITY FOR RECOGNIZING TUMOR.
BECAUSE WE HAVE THESE CELLS IN
TEST TUBE WE CAN POTENTIALLY
IDENTIFY EXACT CELL
SUBPOPULATIONS AND EFFECTIVE
FUNCTIONS REQUIRED FOR CANCER
REGRESSION IN VIVO, AND FINALLY
WE CAN MANIPULATE THOSE PRIOR TO
CELL TRANSFER, TO PROVIDE AN
ALTERED MICROENVIRONMENT FOR THE
TRANSFERRED CELLS, THIS TURNED
OUT TO BE QUITE IMPORTANT CHANGE
AND ONE THAT'S ONLY AVAILABLE
CELL TRANSFER THERAPY BECAUSE
THE IMMUNE CELLS HAVE BEEN
REMOVED FROM THE BODY AND WILL
NOT BE DAMAGED BY OTHER
MANIPULATIONS OF THE HOST. NOW,
THERE ARE TWO KINDS OF RECEPTORS
THAT A LYMPHOCYTE CAN USE TO
RECOGNIZE ANY ANTIGEN INCLUDE
TAUGHT MORE ANTIGENS,
CONVENTIONAL T-CELL RECEPTORS
ARE USED BY NATURALLY OCCURRING
IMMUNE LYMPHOCYTES THAT USE THE
ALPHA BETA CHAIN OF T-CELL
RECEPTOR TO RECOGNIZE A SMALL
PEPTIDE FROM AN INTRACELLULAR
PROTEIN, PRESENTED ON SURFACE
MHC POLL MOLECULE. A LABORATORY
CREATION HOWEVER IS GIVEN RISE
TO A DIFFERENT RECEPTOR CALLED
THE CHIMERIC ANTIGEN RECEPTOR OR
CAR RECEPTOR. THIS WAS DEVELOPED
BY GESHAR AT THE WISEMAN
INSTITUTE A DOZEN YEARS AGO. ONE
CAN TAKE THE HEAVY AND LIGHT
CHAINS OF ANTIBODY, MAKE A
SINGLE CHAIN AND CONNECT THAT
SINGLE CHAIN ANTIBODY TO
INTRACELLULAR SIGNALING CHANGE
THAT ENABLED LYMPHOCYTES TO
RECOGNIZE ANTIGENS BASED ON ANT
ANTIBODY RECOGNITION RATHER THAN
CONVENTIONAL T-CELL RECEPTOR
RECOGNITION. WE WILL SPEND A
MOMENT TALKING APPLICATION OF
CHIMERIC ANTIGEN RECEPTORS
BECAUSE THIS REPRESENTS THE
FIRST FDA APPROVED EXAMPLE OF
CELL AND GENE THERAPY FOR THE
TREATMENT OF CANCER PATIENTS.
THIS DEVELOPMENT OF THIS
CHIMERIC ANTIGEN APPROACH
TARGETED CD 19 WHICH IS A CELL
SURFACE MOLECULE ON B
LYMPHOCYTES AND MANY P IF NOT
MOST B CELL LYMPHOMAS AND
LEUKEMIAS. JAMES COPE INMDORFER
A FELLOW IN ONCOLOGY HEMATOLOGY
PROGRAMS AT NIH CAME TO MY
LABORATORY ABOUT 2008 TO EXPLORE
WHETHER OR NOT WE CAN UTILIZE
CAR C TELLS TARGETING CD 19. TO
TREAT CANCER. IN THESE EARLY
STUDIES T-CELLS TRANSDUCED WITH
A ANTI-CD 19 CAR ELIMINATE
LYMPHOMAS AND SYNGENEIC MOUSE
MODEL, HE PUBLISHED THAT IN
20106789 WE WENT ON TO UTILIZE
SURGERY BRANCH RESOURCES TO
TREAT THE FIRST PATIENT WITH
ANTI-CD 19 CAR SHOWING TO
MEDIATE REGRESSION OF LYMPHOMA
IN HUMANS, DONE IN 2009,
PUBLISHED IN 2010 AND SINCE THEN
THE FIRST TEN PATIENTS WE
TREATED EXPERIENCED A COMPLETE
REGRESSION FIVE OF WHOM ARE
ONGOING TEN YEARS LATER. THIS
PATIENT HAD LARGE AMOUNTS OF
LYMPHOMA, NO RELATIONSHIP
BETWEEN AMOUNT OF DISEASE AND
ABILITY TO ACHIEVE A COMPLETE
REGRESSION, THIS PATIENT
RECEIVED FOUR DIFFERENT
TREATMENTS AND OCCURRED AND HAS
PROGRESSIVE DISEASE YOU CAN SEE
LARGE LESIONS IN THE MEDIA STY
NUMBER, LYMPH NODES IN BOTH
AXILLA, HUGE SPLEENS, AND THE
LARGE AMOUNTS OF TUMOR
SURROUNDING THE AORTA AND THE
VIENA CAVA, LARGE ILIAC LYMPH
NODES ALL WHICH WENT ON TO
DISAPPEAR AND REMAIN SO TEN
YEARS LATER THIS PATIENT HAD A
BONE MARROW FULL OF TUMOR THAT
CLEARED AS WELL AND HAS GONE ON
NOW TO LIVE NORMALLY. ONE OF MY
FORMER FELLOWS WAS WARE OF THE
RESULTS HE STARTED A BIOTECH
COMPANY CALLED KITE PHARMA, IN
2012, SURGERY BRANCH SIGNED A
COOPERATIVE RESEARCH DEVELOPMENT
AGREEMENT AND WE TRANSFERRED
TECHNOLOGY FOR THIS CAR T-CELL
TREATMENT TO PHARMA. IT
PERFORMED A MULTI-INSTITUTIONAL
STUDY TO EVALUATE ANTI-CD 19 CAR
AND THE PATIENTS WITH DIFFUSE
LARGE B CELL LYMPHOMA, THEY
CORROBORATED THE RESULTS WE HAD
SEEN OBJECTIVE RESPONSES IN
ALMOST THREE QUARTERS OF
PATIENT, WITH COMPLETE RESPONSE
AND OVER 40% REPRODUCE THOSE
RESULTS IN MULTI-INSTITUTIONAL
STUDY, AND IN 2017 THEY RECEIVED
FDA APPROVE TO OFFER THIS
TREATMENT AND SOLD TO GILIAD
SCIENCES FOR $11.9 BILLION. THIS
IS AVAILABLE THROUGHOUT THE
UNITED STATES AND EUROPE AND
ASIA AND REPRESENTS A PROUD
EXAMPLE OF HOW NIH TECHNOLOGY IS
TRANSFERRED TO WIDESPREAD USE.
CAR T-CELLS ARE GENERALLY ARE
NOT AVAILABLE FOR THE TREATMENT
OF NOT ONLY LYMPHOMAS BUT NOW
PATIENTS WITH MULTIPLE MYELOMA
AS WELL, BUT THE CONVENTIONAL
T-CELL RECEPTORS ON LYMPHOCYTES
THAT WOULD BE MOST APPLICABLE TO
TREATMENT OF SOLID CANCER. IF
WE LOOK AT CANCER DEATH IN 2021
USING AMERICAN CANCER SOCIETY
STATISTICS TOTAL OF OF 608,000
AMERICANS WHO DIED OF CANCER,
550,000 OR ABOUT 90% DIED OF THE
SOLID EPITHELIAL CANCER. SO THE
MAYOR CHALLENGE THAT CONFRONTS
CANCER IMMUNOTHERAPY IS THE
DEVELOPMENT OF EFFECTIVE
IMMUNOTHERAPIES FOR PATIENTS
WITH METASTATIC EPITHELIAL SOLID
CANCER. THAT CANNOT BE CURED BY
ANY AVAILABLE TREATMENT AND
RESULT IN 90% OF CANCER DEATH IN
THIS COUNTRY AND AROUND THE
WORLD. TWO BASIC QUESTIONS I
WOULD LIKE TO ADDRESS FROM OUR
BOTH SCIENTIFIC LABORATORY AND
CLINICAL RESEARCH RELATED TO
HUMAN CANCER IMMUNOTHERAPY,
USING A PATIENT'S OWN AUTOLOGOUS
LYMPHOCYTES ARE THE FOLLOWING.
THAT IS WHAT ARE THE PHENOTYPIC
CHARACTERISTICS OF LYMPHOCYTES
CAPABLE OF DESTROYING CANCER, IN
PATIENTS, AND WHAT DO THESE
ANTI-CANCER LYMPHOCYTES
RECOGNIZE WHEN WE ARE USING
T-CELL RECEPTORS, THEY ARE
RECOGNIZING INTRACELLULAR
PROTEINS THAT ARE THEN PRESENTED
ON THE CELL SURFACE. SO HERE IS
A CARTOON THAT TALKS HOW
ADOPTIVE CELL THERAPY WORKS WE
EXCISE A THANK YOU NO, IF YOU
FOLLOW ALONG CLOCKWISE WE EXCISE
A TUMOR, IDENTIFY WITHIN THE
TUMOR LYMPHOCYTES, THAT WE CAN
GROW IN VITRO TO LARGE NUMBERS,
WE ASSAY FOR ANTITUMOR
REACTIVITY WHEN WE CAN. AND
SELECT CELLS EXPAND TO LARGE
AMOUNTS AND REINFUSE BACK TO
PATIENT AFTER ADMINISTERING
LYMPHODEPLETING CHEMOTHERAPY
THAT ELIMINATES THE BODY'S
NATURAL IMMUNE LYMPHOCYTES TO
MAKE ROOM FOR THE CELLS THAT WE
THEN ADMINISTER. WE TREATED 192
PATIENTS WITH ADVANCE CANCER,
ADVANCE ME MELANOMA USING
AUTOLOGOUS TUMOR LYMPHOCYTES AND
PATIENTS NAIVE TO CHECK POINT
MODULATORS, 192 CONSECUTIVE
PATIENTS YOU CAN SEE A COMPLETE
RESPONSE RATE OF 25% WITH A
PARTIAL RESPONSE RATE OF 31%
MANY OF THESE ONGOING BEYOND TEN
YEARS FOR OBJECTIVE OVERALL
RESPONSE RATE OF 56%. NOTICE
PATIENT HAS A COMPLETE
REGRESSION ONLY TWO PATIENTS
HAVE EVER RECURRED AT 26 AND 19
MONTHS, REMAINING PATIENTS HAVE
ONGOING DISEASE. SO WHEN
ADMINISTERING NORMAL TUMOR
INFILTRATING LYMPHOCYTES FROM A
PATIENT THAT GROWING THEM IN
VITRO AND TO LARGE NUMBERS AND
THEN READMINISTERRING THEM, IT
APPEARS AS IF THIS ADOPTIVE CELL
THERAPY IS CAPABLE OF
ELIMINATING A LAST MELANOMA CELL
IF YOU CAN SEE COMPLETE
RESPONDERS HAVE NOT RECURRED NOW
WELL BEYOND TEN YEARS AND
ONGOING TO 15 YEARS. SO BECAUSE
WE HAD PATIENTS THAT HAD
RESPONDED AND SOME THAT HAD NOT
RESPONDED WE WERE ABLE TO ASK
WHAT WERE THE PHENOTYPIC
CHARACTERISTICS OF THE CELLS
THAT MEDIATE HUMAN CANCER
REGRESSION IN VIVO? WHAT KIND OF
CELL DO WE HAVE TO DEVELOP IF WE
ATTACK SOLID EPITHELIAL CANCER
THAT RESULT IN SO MANY CANCER
DEATHS. TO DO THIS WE USED A
HIGH DIMENSIONAL SINGLE CELL
TRANSCRIPTOME ANALYSIS OF UP TO
10,000 INDIVIDUAL CELLS FROM
EACH PATIENT AND THEN CAN USE
ANALYSIS TSNE ANALYSIS, A T
DISTRIBUTED O STOCHASTIC
NEIGHBOR EMBEDDING TECHNIQUE, TO
LOOK AT DIFFERENT TYPES OF
LYMPHOCYTES THAT EXIST IN ANY
POPULATION. WHEN WE DID THIS
ANALYSIS, BY BREAKING LYMPHOCYTE
POPULATIONS IN OUR INFUSION
SAMPLES, THEY CAN DIVIDE TO 22
DIFFERENT LYMPHOCYTES TYPES AND
WHEN SRI KRISHNA AND FRANK
LOWERY DOING THIS WORK IN
SURGERY BRANCH COMPARED
RESPONDERS TO NON-RESPONDERS
THEY IDENTIFIED A PARTICULAR
CLUSTER THAT APPEARED VERY
DIFFERENT IN RESPONDERS AND
NON-RESPONDERS. WE LOOK AT THESE
22 CLUSTERS, IT WAS ONLY CLUSTER
NUMBER 1 THAT SEPARATED
RESPONDER -- (LOST AUDIO) CANCER
IN THESE AUTOLOGOUS PATIENTS.
IF WE STUDY THE CHARACTERISTICS
OF CELLS IN THIS CLUSTER 1, WE
CAN SEE THESE CELLS HAVE A HIGH
CONCENTRATION OF CD 39 CD 69
NEGATIVE CELLS INDICATIVE OF
STEM LINE LYMPHOCYTE POPULATION
THAT APPEARED TO BE THE EFFECTOR
CELLS RESPONSIBLE FOR MELANOMA
TREATMENT. IN FACT IF WE LOOK
AT THE TOTAL NUMBER OF CELLS
THAT WE ADMINISTER TO PATIENTS,
THERE WAS NO DIFFERENCE BETWEEN
PATIENTS GETTING HIGH OR LOW
NUMBERS OF THESE CELLS IN TERMS
OF THEIR ABILITY TO RESPOND.
WHEN WE LOOK AT NUMBER OF DOUBLE
NEGATIVE CELLS ADMINISTERED WE
CAN SEE A DRAMATIC DIFFERENCE
BETWEEN RESPONDERS AND
NON-RESPONDERS SEPARATING THEM
AT THE POINT 001 LEVEL
INDICATING IT WAS THESE CD 3969
DOUBLE NEGATIVE CELLS THAT WERE
RESPONSIBLE FOR CAUSING TUMOR
REGRESSION. THEY HAD THE
APPROPRIATE PROPERTIES NECESSARY
TO RECOGNIZE AND DESTROY THIS
MELANOMA MET TA STATIC DEPOSITS
IN VIVO. -- METASTATIC DEPOSITS
IN VIVO. USING THIS INFORMATION
WE WENT BACK TO THE LABORATORY
IN ANIMAL STUDIES AND COMPARED
THE CD 3969 DOUBLE NEGATIVE
CELLS AT TWO CONCENTRATIONS WITH
THEIR ABILITY THE TREAT AND
ESTABLISH VASCULARIZED TUMOR.
YOU CAN SEE THE DOUBLE POSITIVE
CELLS HAD SOME STRONG, SOME
SLIGHT IMPROVEMENT COMPARED TO
NO TREATMENT BUT DOUBLE NEGATIVE
CELLS HAD A SIGNIFICANT
IMPROVEMENT SHOWING IN ONLY IN
HUMAN BUT ANIMAL MODELS IT WAS
THIS STEM LIKE POPULATION OF
3969 DOUBLE NEGATIVE CELLS THAT
HAD THE PROPERTIES NECESSARY TO
DESTROY CANCER. THAT LED US TO A
SECOND QUESTION, THAT IS, WHAT
DO THESE TUMOR INFILTRATING
LYMPHOCYTES RECOGNIZE THAT
ENABLES THE IN VIVO CONTROL OF
THE LAST MELANOMA CELL AND CAN
WE USE THIS INFORMATION THEN TO
ATTEMPT TO FIND THESE ANTIGENS
IN THE SOLID EPITHELIAL CANCERS
THAT ARE THE MAJOR KILLERS. OUR
CLUE TO THE KIND OF ANTIGEN THAT
MIGHT BE RECOGNIZED CAME FROM
OBSERVATION IN MELANOMA PATIENTS
THAT THERE WAS SPECIFIC CANCER
REGRESSION IN ABSENCE OF ANY OFF
TUMOR ON TARGET TOXICITIES IN
THESE PATIENTS. THAT LED US TO
STUDY THE ROLE OF THE MOST
SIGNIFICANT DIFFERENCE BETWEEN
CANCER CELLS AND NORMAL CELLS
AND THAT IS THE DEVELOPMENT OF
SPECIFIC CANCER MUTATIONS THAT
LEADS TO THE MALIGNANT PHENE
TYPE, SO WE LOOK AT MUTATIONS AS
POSSIBLE TARGETTERS BECAUSE OFS BECAUSE OF THIS
HIGHLY SELECTED REACTIVITY. TO
DO THIS WE DEVELOPED AN ASSAY
THAT WE FIRST REPORTED ABOUT
FOUR AND A HALF YEARS AGO. AND
TO IDENTIFY NATURE OFFER THESE
ANTIGENS AND YOU CAN SEE THAT IN
THIS CARTOON. WE IDENTIFY TUMOR
SAMPLE THAT CAN BE RESECTED AND
SUBJECT THAT TUMOR SAMPLE TO DNA
AN RNA SEQUENCING TO IDENTIFY
ALL OF THE CANCER MUTATIONS THAT
ARE PRESENT IN THAT MALIGNANCY
COMPARED TO NORMAL CELLS. ONCE
WE IDENTIFY ALL MUTATIONS
PRESENT IN THESE CANCERS AND
MELANOMA IS ABOUT 300, MOST
EPITHELIAL CANCER IS AROUND
HUNDRED OF THESE MUTATIONS THAT
RESULT IN THE CANCER. WE THEN
TAKE EVERY ONE OF THE SEQUENCES
SURROUNDING THE NON-SYNONYMOUS
MUTATION IN THE CANCER, AND
INTRODUCE THOSE MUTATIONS AS 25
PEPTIDES OR MINI GENES INTO THE
PATIENTS ANTIGEN PRESENTING
CELL, WHICH CONTAINS ALL THE MHC
MOLECULES THAT COULD POTENTIALLY
PRESENT ANY MUTATION PRODUCT TO
T-CELLS. WE THEN TAKE T-CELLS
AND ISOLATE FROM THE TUMOR, OR
NOW FROM BLOOD. WE CO-CULTURE
THAT WITH ANTIGEN PRESENTING
CELLS FROM THAT SAME PATIENT,
WHICH CONTAIN ALL OF THE TUMOR
MUTATIONS TO SEE IF ANY OF THE
LYMPHOCYTES THAT MEDIATED
COMPLETE TUMOR REGRESSION
RECOGNIZE ANY OF THESE ANTIGENS.
WE CAN THEN IDENTIFY EXACT
ANTIGEN BY USING CYTOKINE
ELISPOT ASSAY ELISA ASSAYS OR
CYTOKINE SECRETIONS TO IDENTIFY
THE ANTIGEN. THIS ASSAY DOESN'T
REQUIRE ANY PREDICTION OF
PEPTIDE BINDING. EVERY CANDIDATE
MUTATION AND ALL OF THE MHC LOCI
OF ANY OF THAT PARTICULAR
PATIENT ARE INCLUDED IN THE
SCREEN AND THERE'S NO TUMOR CELL
LINES NECESSARY WHICH HAS
INHIBITED RESEARCH IN THIS AREA
BECAUSE IT IS VERY DIFFICULT TO
ESTABLISH EPITHELIAL CANCER
LINES FROM MOST PATIENTS. WE
UTILIZE THIS TECHNIQUE FIRST TO
LOOK AT PATIENTS WITH METASTATIC
MELANOMA. AND THEN OTHER MORE
COMMON EPITHELIAL CANCERS AND
THESE 76 CONSECUTIVE PATIENTS
THEY HAD 44,000 PLUS MUTATIONS
COLLECTIVELY, WE ONLY SCREENED
13,400 OR 30% BECAUSE THOSE WERE
THE ONES THAT WERE EXPRESSED IN
THE CANCER BY RNA SEQ ANALYSIS.
IF YOU LOOK AT THE NUMBER OF
IMMUNOGENIC MUTATIONS THAT TURN
OUT RECOGNIZED BY A PATIENT'S
LYMPHOCYTES, TUMOR ANTIGENS, IT
TURNED OUT TO BE 1.3% AND
MELANOMA PATIENTS THESE WERE
LARGELY IDENTIFIED BY CD8
POSITIVE CELLS. SURPRISING
OBSERVATION WAS THAT IN THESE
PATIENTS EVERY ANTIGEN RECOGNIZE
WAS UNIQUE TO THE INDIVIDUAL
PATIENT, NONE SHARED BETWEEN TWO
PATIENTS AND THERE IS A WIDE
VARIETY OF THE ACCUMULATION OF
CANCER MUTATIONS THAT CAN RESULT
IN A MALIGNANT PHENOTYPE. WE
THEN LOOKED AT VARIETY OF
DIFFERENT EPITHELIAL CANCERS,
THIS STUDY FROM BREAST CANCER IS
NOW IMPRESS BY NIKOS ZAKARAKIS A
FELLOW IN THE SURGERY BRANCH WHO
STUDIED 43 CONSECUTIVE PATIENTS
WITH METASTATIC BREAST CANCER
WITH A MEDIAN NUMBER OF
MUTATIONS ABOUT 119. THERE WERE
7900 PLUS MUTATIONS IN THESE 43
PATIENTS, WE SCREENED 4722, AND
COULD IDENTIFY 100 DIFFERENT
IMMUNOGENIC EPITOPES. 67% OF
THESE METASTATIC BREAST CANCER
PATIENTS HAD MUTATIONS, THAT
COULD BE RECOGNIZED BY THE
PATIENTS ON AUTOLOGOUS
LYMPHOCYTES, ABOUT 2.1% OF THESE
MUTATIONS WERE RECOGNIZED BY
T-CELLS, BUT IN BREAST CANCER,
EPITHELIAL CANCER PATIENTS,
ABOUT THREE QUARTERS OF THESE
ANTIGENS ARE RECOGNIZED BY CD4
CELLS AND NOT CD8 CELLS AND ONCE
AGAIN, ALL OF THESE 100
IMMUNOGENE EPITOPES WERE UNIQUE
TO THE INDIVIDUAL PATIENT NONE
SHARED AMONG PATIENTS. NOW
STUDIED 195 PATIENTS WITH A
VARIETY OF DIFFERENT CANCER FROM
THE GASTRO INTESTINAL CANCER YOU
MENTIONED BREAST CANCER, LUNG
CANCER, OVARIAN AND PROSTATE
CANCER, AND IF YOU LOOK HERE AT
THE NUMBER OF PATIENTS THAT HAVE
NEOANTIGEN REACTIVITY,
IDENTIFIED BY THESE ASSAYS, YOU
CAN SEE IT IS ABOUT 77% ON
AVERAGE BUT YOU CAN SEE
VIRTUALLY EVERY HISTOLOGY HAS --
EVERY PATIENT WITH DIFFERENT
HISTOLOGIC TYPES OF CANCER HAVE
T-CELLS, THAT CAN RECOGNIZE
THEIR TUMORS. ABOUT THREE
QUARTERS OF THESE PATIENTS ARE
INCLUDED. THEY RECOGNIZE ABOUT
363 DIFFERENT NEOANTIGENS. LET
ME EMPHASIZE THIS POINT AGAIN,
BECAUSE IT HAS A LOT OF
IMPLICATIONS FOR THE DEVELOPMENT
OF CANCER TREATMENTS. AMONG
THESE 363 ANTIGENS RECOGNIZED BY
PATIENT OWN T-CELLS, ALL WERE
UNIQUE EXCEPT TWO PATIENTS WHO
SHARED THE SAME KRAS MUTATION
RESTRICTED BY RELATIVELY RARE
CLASS 1 ANTIGEN CW 0802. AN
ADVANTAGE OF TARGETING
MUTATIONS, IS POTENTIAL
APPLICABILITY TO TARGET MULTIPLE
CANCER TYPES BECAUSE VIRTUALLY
ALL CANCERS HAVE MUTATIONS THAT
RESULTED IN THE MALIGNANT
PHENOTYPE. SO THESE -- THIS KIND
OF APPROACH TO TREATMENT IS NOT
UNIQUE TO ANY INDIVIDUAL
HISTOLOGY. LET ME JUST PRESENT A
FEW EXAMPLES BEFORE I SHOW YOU
OVERALL RESULTS. THE FIRST
PATIENT TREAT WITH HIGHLY
SELECTED CELLS AGAINST MUTATIONS
IS A PATIENT WITH METASTATIC
BILE DUCT TUMOR, FA LAIN JOEL
CARCINOMA. THAT KARAT HAD A
RIGHT HEAPECTOMY, RECEIVED
MULTIPLE CHEMOTHERAPY REGIMENS
RECEIVED UNSELECTED TIL AS WE
DID IN PATIENTS WITH MELANOMA
BUT DIDN'T WORK, MELANOMA IS THE
ONLY HISTOLOGY UNSELECTED CELLS
CAN CAUSE REGRESSION WHEN GROWN
IN VITRO. IN THIS PATIENT WE
UTILIZED OUR PEPTIDE POOL
APPROACH TO IDENTIFY CELLS THAT
REACT WITH UNIQUE ANTIGEN IN ERB
TRANSMUTATION AND ERIC TRAN
REPORTED RESULTS OF COMPLETE
TUMOR REGRESSION IN THIS
PARTICULAR PATIENT. YOU CAN SEE
THE TUMORS THAT ARE PRESENT IN
THE LUNG OF PATIENTS, SHE
PROGRESSED ONCE AND RECEIVED A
SECOND TREATMENT A FEW MONTHS
LATER, RESULTING IN THE COMPLETE
DISAPPEARANCE OF ALL OF HER
TUMOR AS WELL AS THREE DIFFERENT
LIVER METASTATIC DEPOSITS AS
WELL AND SHE REMAINS NOW DISEASE
FREE OVER EIGHT YEARS. OVER
EIGHT YEARS LATER. THIS IS A
PATIENT WITH METASTATIC BREAST
CANCER REPORTED BY DR. ZAKARAKIS
WHO HAS ER POSITIVE BREAST
CANCER, WITH SEVEN TREATMENTS
AND PROGRESSED THROUGH UNTIL
COMING TO THE NIH FOR TREATMENT
WITH CELLS THAT RECOGNIZE FOUR
DIFFERENT CANCER MUTATIONS IN
HER TUMOR. THESE ARE NOT
NECESSARILY DRIVER MUTATIONS,
AND YOU CAN SEE THEIR FUNCTIONS
HERE, 23% INFUSED CELLS CONTAIN
NEOANTIGEN REACTIVITY AND THIS
PATIENT UNDERWENT COMPLETE
RESPONSE AFTER THIS TREATMENT
YOU CAN SEE TUMOR BEGINNING TO
GROW THROUGH THE CHEST WALL,
MULTIPLE LIVER METASTATIC
DEPOSITS DISAPPEARED COMPLETELY
AND SHE REMAINS DISEASE FREE NOW
OVER FIVE YEARS LATER. THIS
PATIENT WITH VERY AGGRESSIVE
METASTATIC CERVICAL CANCER HAD A
FUN GATING SEARCHCAL MASS WITH
MULTIPLE DEPOSITS IN THE LUNG
INTRAPERITONEALLY, SHE HAD
UNDERGONE RADIATION THERAPY,
CHEMOTHERAPY, PROGRESSED
UNDERWENT FURTHER SURGE RITES,
DEVELOPED LIVER LYMPH NODE
INTRAABDOMINAL MA TA STATIC
DISEASE, SHE WAS TREATED OVER
SEVEN YEARS, TREATED WITH OUR
OWN TUMOR REACTIVE CELLS,
EXPERIENCED COMPLETE REGRESSION
OF ALL HER DISEASE, AND I SHOW
YOUR X-RAY HERE YOU CAN SEE
THESE YELLOW ARROWS POINTING TO
MULTIPLE DEPOSITS, THIS WAS A
LYMPH NODE BLOCKING HER URETER,
UNDERWENT COMPLETE REGRESSION
BUT FIRST YEAR AFTER TREATMENT
WE CAN REMOVE THAT CATHETER AND
AGAIN SHE REMAINS DISEASE FREE
NOW. OVER SEVEN YEARS LATER.
FINALLY A PATIENT WITH A COLON
CANCER, WHO HAD SIGMOID
COLONECTOMY, RECEIVED CHEM
CHEMOTHERAPY, TREATED, SHE HAS
SEVERAL LUNG DEPOSITS
PROGRESSING, SIX OF SEVEN
DISAPPEARED, ONE GREW HOWEVER,
AND WE RESECTED THAT ONE LESION,
LEAVING HER DISEASE FREE AND
SHE'S REMAINED DISEASE FREE NOW
OVER FIVE YEARS AFTER TREATMENT.
THAT ONE LESION WHEN WE LOOK AT
COPY NUMBER OF OUR CHROMOSOMES,
HAD LOST ONE COPY OF CHROMOSOME
6. WHICH ENCODES THE MAJOR
COMPATIBILITY ANTIGENS THAT HAVE
TO PRESENT ANTIGENS TO
LYMPHOCYTES AND THAT EXPLAINS
WHY THAT ONE LESION DIDN'T
RESPOND TO REPRESENTS ESCAPE
MECHANISM POTENTIALLY USED BY
TUMOR TO ESCAPE THIS KIND OF
TREATMENT. WE NOW COMPLETE THREE
SMALL PILOT STUDIES FIRST
LOOKING AT BULK UNSELECTED TIL
FOR TREATMENT, WE SAW NO
RESPONSES. EXCEPT PATIENTS WITH
MEL MONA, ONLY TALKING
EPITHELIAL CANCER. IF WE SELECT
TIL WE ADD THREE OUT OF FIRST 25
PATIENTS RESPOND, 12% WHEN WE
ADDED PEMBROLIZAMAB TO TREATMENT
BECAUSE WE HAD SHOWN SUBMITTED
CELLS INFUSED REEXPRESS PD 1,
THIS CHECK POINT MODULATOR WHEN
WE CAN ELIMINATE THAT, NOW IN
THESE HOYLY PRE-TREATED PATIENTS
SIX OUT OF 26 OR 23% RESPONDED
AND WE ARE NOW RESUMING TO TREAT
OUR STUDIES TO TREAT LARGE
NUMBERS OF PATIENTS WITH THIS
LAST REGIMEN AS WE CONTINUE TO
TRY TO IMPROVE IT. THERE ARE
TWO HYPOTHESES ONE TAKES FROM
THIS WORK. FIRST IT IS A
RECOGNITION OF RANDOM SOMATIC
MUTATIONS WHICH REPRESENTS A
FINAL COMMON PATHWAY THAT
EXPLAINS CANCER REGRESSION FOR
MOST IMMUNOTHERAPIES FOR SOLID
CANCERS, IT IS SHOWN FOR AND PD
1, ANTI-CTLA 4 AS WELL AS TUMOR
INFILTRATING LYMPHOCYTES.
THAT'S GOOD NEWS AND BAD NEWS.
WE HAVE SHOWN ANY INTRACELLULAR
PROTEIN CAN POTENTIALLY BE A
CANCER ANTIGEN IF MUTATED IN
PROCESS INTRACELLULARLY TO A
PEPTIDE THAT CAN BIND TO THAT
PATIENT MHC MOLECULES, THE BAD
NEWS IS TREATMENT THEREFORE HAS
TO BE HIGHLY INDIVIDUALIZED AND
THUS COMPLEX BECAUSE EACH
PATIENT IS RECOGNIZING UNIQUE
ANTIGEN BUT THE GOOD NEWS SINCE
ALL CANCER HAVE MUTATIONS, LARGE
NUMBERS OF CANCER PATIENTS ARE
POTENTIALLY WITH VARIETY OF
HISTOLOGIC TYPES OF CANCER COULD
POTENTIALLY BE ELIGIBLE FOR THIS
TREATMENT. THERE IS ANOTHER
CLASS OF ANTIGENS WE MIGHT LOOK
LIKE IN ADDITION TO THE UNIQUE
MUTATIONS, THAT IS THE TINY
NUMBER OF SHARED DRIVER
ONCOGENES OR TUMOR SUPPRESSER
GENES SHARED AMONG PATIENTS.
KRAS IS AN EXAMPLE OF 30% OF
CANCER, P53 IS PRESENT IN ALMOST
50% OF ALL CANCER, AND BY USING
A SERIES OF INTENSIVE SCREENING
TECHNIQUES AS WELL AS IN VITRO
SENSITIZATION, TWO FELLOWS IN
THE SURGERY BRANCH HAVE NOW BE
ABLE TO IDENTIFY T-CELL
RECEPTOR, FIRST AGAINST RAS HOT
SPOT MUTATIONS, SERIES OF
STUDIES BY NOEM LEVIN WHO
IDENTIFIED T-CELL RECEPTORS THAT
CAN RECOGNIZE SPA VARIETY OF
KRAS RECEPTORS ON A VARIETY OF
RESTRICTION ELEMENTS AS WELL AS
PETER KIM WHO IDENTIFIED A LARGE
NUMBER OF T-CELL RECEPTORS THAT
CAN RECOGNIZE P53 MUTATIONS, IN
PATIENTS, SO THAT POTENTIALLY
THESE T-CELL RECEPTOR CAN BE
USED FOR TREATMENT. WE JUST
STARTED THOSE STUDIES, AND
TREATED A SINGLE PATIENT WITH
BREAST CANCER WHO HAD RECEIVED
MULTIPLE TREATMENT WITH
PROGRESSIVE DISEASE, AS WELL AS
EXTENSIVE DISEASE IN OUR MEDIA
STINUM, FIRST PATIENT TREATED
WITH T-CELL RECEPTORS FROM
DIFFERENT PATIENT THAT RECOGNIZE
P53 MUTATIONS, A DRAMATIC
REGRESSION OF EXTENSIVE DISEASE
SURROUNDING PERICARDIUM,
INVADING INTO BREAST AND
UNDERWENT A DRAMATIC REGRESSION
THAT LASTED SIX MONTHS BEFORE
SHE DID RECUR. HOWEVER,
REPRESENTING PATIENT WHO COULD
BE TREATED BY T-CELL RECEPTOR,
MODIFIED AUTOLOGOUS LYMPHOCYTES.
YOU CAN SEE HERE IN BREAST EVERY
ONE OF THESE IS A CANCER NO
DUAL, A BIG MASS -- NODULE, A
BIG MASS UNDER NECROTIC LESION
THAT WENT AWAY ALMOST COMPLETELY
LASTING SIX MONTHS. SO IN
CONCLUSION I WOULD LIKE TO JUST
EMPHASIZE THAT CELL TRANSFER
THERAPY CAN MEDIATE DURABLE
COMPLETE REGRESSION IN PATIENTS
WITH METASTATIC CANCER
REFRACTORY TO OTHER TREATMENTS.
TIL RECOGNIZE UNIQUE SOMATIC
MUTATIONS CAN BE FOUND IN
PERIPHERAL BLOOD THAT
IDENTIFYING THESE CAN RESULT IN
CANCER REGRESSION AND THAT GENE
SIGNATURES CAN BE GENERATED TO
IDENTIFY ANTI-T-CELL RECEPTORS
THAT RECOGNIZE A CANCER. SURGERY
BRANCH WILL BE MOVING AS JUST
MOVED IN THE PAST MONTH INTO A
NEW FACILITY TO CELL TRANSFER
GENEROUSLY SUPPORTED BY THE
NATIONAL CANCER INSTITUTE.
BEFORE I FINISH I WOULD LIKE TO
THANK DR. ANNA LAU THE NEXT
SPEAKER WHO IS RESPONSIBLE FOR
ALL STERILITY PROCEDURES AND
DEVELOPMENT SO THAT WE COULD
DEVELOP HE CANTIVE GOOD
MANUFACTURING PRODUCT --
EFFECTIVE GOOD MANUFACTURING
PRODUCT CELLS FOR TREATMENT. MY
THANKS TO DR. LAU FOR HER
EFFORTS IN THIS. THANK YOU, VERY
MUCH FOR YOUR VERY KIND
ATTENTION.
>>HI, THANK YOU SO
MUCH FOR JOINING IN TO TODAY'S
GRAND ROUNDS. IT IS A PLEASURE
TO BE SHARING A STAGE WITH DR.
ROSENBERG, AND HAVE THIS
PLATFORM TO SHOWCASE THE GMP
PROGRAM AVAILABLE AT THE NIH TO
SUPPORT PATIENT CARE
INNOVATIONS. NO DISCLOSURES AND
EVERYTHING I SAY IS MY OWN
OPINION AND NOT THE VIEWS OF
NIH. SO CLEARLY THE INTRAMURAL
PROGRAM AT THE NIH HAS A VERY
LONG HISTORY AND MASSIVE IMPACT
ON GLOBAL PUBLIC HEALTH. MANY
SUCCESS STORIES, THE DISCOVERY
OF NEW DRUGS AND PIONEERING OF
NEW METHODS AS DR. ROSENBERG
EXEMPLIFIED, IMPACT OF HUMAN
HEALTH CANNOT BE UNDERESTIMATED
AND CLEARLY HAVE BEEN MANY
FIRSTS THAT HAVE COME EXACTLY
FROM THIS BETHESDA CAMPUS AND
INTRAMURAL PROGRAM. IN FACT, IN
NATURE ARTICLE PUBLISHED IN
2014, WE CAN SEE HERE IN THIS
FIGURE, THE NUMBER OF
APPLICATIONS OF NEW DRUGS AND
NEW BIOLOGICS THAT THE FDA
APPROVED BETWEEN 1991 AND 2006.
AND WHAT YOU CAN SEE HERE TOTAL
NUMBER OF APPROVED APPLICATIONS
AN BLUE BARS ARE REPRESENTING
THOSE THAT ORIGINATED
SPECIFICALLY FROM THE INTRAMURAL
PROGRAM INVENTIONS AT THE NIH.
SO IF THERE ARE INVESTIGATORS
LISTENING IN ON THIS TALK AND IT
MAY FEEL LIKE OVER THE LAST FEW
YEARS THERE'S BEEN EXTREMELY
CUMBERSOME AND AMOUNT OF
PAPERWORK AND UPHILL BATTLE WITH
REGARDS TO REGULATIONS TO GET
NEW PROTOCOLS UNDERWAY, I FEEL
YOUR PAIN AND I AGREE, IT HAS
QUITE A TIRE SOME PROCESS.
HOWEVER, IT IS IMPORTANT TO
REMEMBER THAT THE REGULATIONS
THAT ACTUALLY ALWAYS EXISTED,
AND IN FACT WHAT HAS CHANGED
OVER THE LAST FEW YEARS IS
LANDSCAPE AND CULTURE THAT THE
NIH ADOPTED IN RESPONSE TO
CERTAIN EVENTS OVER LAST DECADE.
SO IT IS IMPORTANT TO REMEMBER
BIOLOGICS CELL THERAPIES, ET
CETERA, HAVE EMERGED RAPIDLY ON
TO THE SCENE OVER THE LAST 10 TO
20 YEARS. IT IS DIFFICULT FOR
REGULATORY AGENCIES SUCH AS THE
FDA TO KEEP ON PACE WITH THAT.
THERE IS INCREASE AWARENESS ON
THE NIH CAMPUS WITH REGARD TO
THESE REGULATIONS OF GMP,
PARTICULARLY AFTER THE RED TEAM
REPORT WAS RELEASED IN 2016
FOLLOWING TWO HYPERCONTAMINATION
EVENTS IN 2015. THE FDA IS ALSO
CHANGING ITS CURRENT WAY OF
THINKING. SO WHILE THE
REGULATIONS MAY EXIST IN BLACK
AND WHITE, THE FDA'S COMMITTED
TO CHANGE THAT YOU ARE WAY OF
THINKING, AND THAT IS BECAUSE
THERE IS INCREASED LEVEL OF
MANUFACTURING THAT IS NOW DONE
AT ACADEMIC CENTERS WHERE
PREVIOUSLY BEFORE MANY OF THE
FOCUS OF THE FDA WAS ON BIG
PHARMA AND ITS GLOBAL IMPACT ON
PUBLIC HEALTH. CELL AND GENE
THERAPIES NOW CONSIDERED FRONT
LINE TREATMENT FOR MANY DISEASE
STATES. AND ACADEMIC CENTERS ARE
NOW DRAWK FOCUS FROM THE FDA
WITH REGARD TO GMP. THERE HAVE
BEEN THIS PERCEIVED GRAY ZONE
REFERS TO EARLY PHASE STUDIES SO
EXACTLY HOW MUCH GMP MUST BE
APPLIED FOR PHASE 1 AND PHASE 2
STUDIES. SO IT IS A SLIDING
SCALE, OF RISK BENEFIT, AND
RECENTLY LAST YEAR THE FDA
RELEASED A GUIDANCE DOCUMENT FOR
HOW TO ASSESS THAT BENEFIT AND
RISK FOR NEW DRUGS AND
BIOLOGICAL PRODUCTS. SO WHAT I
WOULD LIKE TO DO OVER THE NEXT
20 MINUTES OR SO IS TELL YOU OUR
STORY. FROM A MICROBIOLOGICAL
PERSPECTIVE AND HOW THE GMP
PROGRAM AT THE NIH BEGAN TO
EMERGE.
SO WHAT I'M SHOWING IN THIS
FIGURE HERE IS TAKING FROM A
TECHNICAL REPORT, PHARMACEUTICAL
DRUG ASSOCIATION AND WHAT YOU
CAN SEE HERE IS THE NIH IS VERY
GOOD SUCH AS RESEARCH
DEVELOPMENT AND PRE-CLINICAL
STUDIES WHICH GOOD DOCUMENTATION
PRACTICES, GOOD LABORATORY
PRACTICE, ARE ALL THAT IS
REQUIRED. CALIBRATED EQUIPMENT
AND QUALIFIED TESTING METHODS.
HOWEVER AS WE START TO MOVE
TOWARDS CLINICAL TRIALS STARTING
AT PHASE 1 AND 2, THERE IS
EXPECTATION BY THE FDA THAT GMP
PRACTICES ARE STARTING TO BE
APPLIED AND IN FACT THOSE
EXPECTATIONS START TO INCREASE,
AS THE PHASE OF THE STUDY
INCREASE INTO PRODUCT
COMMERCIALIZATION. AS PART OF
THE GMP PROCESS REQUIRES USE OF
QUALIFIED VALIDATED EQUIPMENT,
VALIDATED TESTING METHODS, AS
WELL AS MICROBIAL CONTROLS TO
LOOK FOR CONTAMINATION. AS I
SAID WE WILL FOCUS ONLY ON THE
MICROBIOLOGICAL PORTION OF THAT.
SO CLEARLY STERILITY ASSURANCE
IS OBVIOUS, AND THE REGULATION
FOR THAT HAVE EXISTED FOR A
VERY, VERY LONG TIME AND WHAT I
AM SHOWING HERE IS A SHIP PET
FROM THE CODE OF FEDERAL
REGULATIONS ABOUT 6, 10, 12, ITS
TALKS ABOUT STERILITY TESTING.
CLEARLY THE POINTS OF STERILITY
TESTING IS TO ENSURE THE PRODUCT
IS SAFE FOR HUMAN USE, WE WANTS
TO MAKE SURE THERE IS AN ABSENCE
OF VIABLE MICROORGANISMS USING A
VALIDATED TEST METHOD. HOWEVER
THERE ARE SOME ISSUES THAT
SURROUND THE TYPE OF TESTS THAT
THE FDA CURRENTLY REFERS TO AS
THE COME PENDIAL OR GOLD
STANDARD TEST. THE TEST LISTED
HERE FORESTER RILLTY IN
MICROPLASM THEY DEVELOP BACK
MANY THE 1930s. THEY ARE
EXTREMELY OLD SCHOOL, AND
ADOPTION OF MORE MODERN METHODS
MAKES IT A LITTLE DAUNTING FOR
MOST LABORATORIES GIVEN THE
VALIDATION WORK REQUIRED.
HOWEVER ADOPTION OF THESE GOLD
STANDARD METHODS FOR TESTING OF
BIOLOGIC IS FLAWED. THESE
STERILITY TESTING METHODS WERE
DEVELOPED ON STERILE DRUG
PRODUCTS NOT FOR BIOLOGICS SO
THEY DEVELOP ORIGINALLY FOR DRUG
PRODUCTS THAT COULD BE
TERMINALLY STERILIZED. THEY
ALSO HAVE AN EXTREMELY SLOW TURN
AROUND TIME OF 14 TO 28 DAYS
CULTURE AND THIS CLEARLY IS NOT
CONDUCIVE TO FRESH PRODUCT FOR
INFUSION AND CELL THERAPIES THAT
HAVE A SHORT SHELF LIFE FOR CELL
VIABILITY. WE ALSO RUN INTO THE
ISSUE OF TEST INTERFERENCE
CAUSED BY THE BIOLOGICAL BECAUSE
OF NATURAL CELL AVIDITY SO THERE
IS A VERY LONG HISTORY OF
STERILITY TESTING AT NIH. FIRST
AND FOREMOST TESTING IS
CONDUCTED IN THE CLINICAL
LABORATORY WITHIN DLM STARTING
BACK IN IN 1980s AND 1990s
WERE FIRST IN HUMAN TRIALS
STARTED, CLINICAL MICRODIRECTOR
AT THE THAT TIME AGREED TO DO
STERILITY TESTING FOR THESE
PRODUCTS, USING OLD SCHOOL GOLD
STANDARD METHOD EXTREMELY
TEDIOUS, LABOR INTENSIVE AND
VERY SLOW. FORTUNATELY THEN IN
THE EARLY 2000s THERE WAS A
CHANGE IN THE CLINICAL
MICRODIRECTOR AND HE APPLIED A
VERY INNOVATIVE APPROACH WHICH
IS TO USE AUTOMATED BLOOD
CULTURE SYSTEMS THAT WE USE FOR
PATIENT CARE, AND TO USE THAT
INSTEAD FOR PRODUCT STERILITY
TESTING. MAKING THE ENTIRE
PROCESS AUTOMATE AND LESS
ONEROUS ON THE LAB IRTO. THESE
HERE TWO PAPERS PUBLISHED IN
COLLABORATION OF LABORATORY
MEDICINE AND TRANSFUSION MEDS
SIN AT THAT TIME IN THE EARLY
2000s AND THESE ARE THE
FOUNDATIONAL STUDIES, THAT WERE
ACCEPTD BY THE FDA FOR 15 YEARS
OR SO THAT SHOWED THAT THE
AUTOMATED BLOOD CULTURE SYSTEMS,
WERE EQUIVALENT METHOD TO THE
TRADITIONAL TESTING METHOD AND
COMPLIANT TO MEET THE FDA
STANDARDS. SO ESSENTIALLY
PRODUCT STERILITY TESTING WHAT
HAPPENING IN CLIP MICRO USING
THE BLOOD CULTURE SYSTEM FOR
MANY YEARS WITH NO DEDICATED
FACULTY OVERSIGHT. THEN IN 2015
THE PROGRAM STARTS. THIS IS
BECAUSE OF THE FIRST
CONTAMINATION EVENT WHICH
OCCURRED IN APRIL, TWO VIALS OF
ALBUMIN, IN THE CLINICAL CENTER
PHARMACY. FOUND TO BE GROSSLY
CONTAMINATED WITH TWO DIFFERENT
SPECIES OF MOLD. THERE WAS A
FOUR INSPECTION BY THE FDA SPENT
SEVERAL DAYS ON CAMPUS, THEY
ISSUED A FORM 483 WHICH IS
ESSENTIALLY A LIST OF
OBSERVATIONS, AND HOSPITAL
PHARMACY WAS SHUT DOWN AT THAT
TIME. THESE CLOSELY FORWARDS A
FEW MONTHS LATER WITH SECOND CON
TAME NATION EVENT AND IN THIS
PARTICULAR CASE IT WAS A NATURAL
KILLER CELL PRODUCT SENT DOWN TO
THE MICROLAB, FOR US TO PERFORM
A GRAM STAIN AS PART OF
MICROMICROBIAL RELEASE PRODUCTS
TO THE PATIENT AND WHAT WE SAW
ON THE GRAM STAIN WAS WE WENT TO
THE ARABIC BOTTLE INCUBATING IN
THE INSTRUMENT AT THAT TIME AND
THERE WAS CLEARLY GROSS CON PAM
NATION OF MOLD THAT WAS VISIBLE
TO THE NAKED EYE, ACROSS
MULTIPLE BOTTLES OF THAT
PRODUCT. THAT WENT UNDETECTED BY
THE INSTRUMENTS SO THE
INSTRUMENT FAILED TO FLAG BEING
POSITIVE. THIS THEN WAS CLOSELY
FOLLOWED BY THE RED TEAM REPORT
WHICH WAS A REVIEW OF REDUCING
RISK AND PROMOTING PATIENT
SAFETY ACROSS THE ENTIRE NIH
INTRAMURAL PROGRAM, THEN CLEARLY
MANY SAFETY LESSONS LEARNED IN
THE CLINICAL CENTER. FROM A
MICROBIOLOGICAL PERSPECTIVE WHAT
DID WE DO IN LAB MEDICINE TO
REACT TO THESE FINDINGS? AS WE
STARTED RESEARCHING THE
REGULATIONS IT BECAME APPARENT
TO US THAT THE FDA EXPECTS THAT
THE TESTING LABORATORY SHOULD
EMPLOY FACILITIES AND CONTROLS
THAT WILL COMPARABLE TO THE USED
IN ASEPTIC OPERATIONS OR
MANUFACTURING AND CLEARLY A
CLINICAL DIAGNOSTIC LAB IS NOT
THE SAME AS A GMP LABORATORY. SO
CREATION OF MY LABORATORY
STERILITY TESTING SERVICE IN
2018, WHERE OUR GOAL WAS TO
CREATE A BRAND NEW GMP TESTING
LAB WHICH SERVES AS THE CORE
MICROBIOLOGY SUPPORT LAB FOR
INTRAMURAL PROGRAM, THIS IS
BUILDING ON NEW SYSTEMS
OPERATIONS FACILITIES,
PERSONNELS, ALL BUILDING FROM
THE GROUND UP WITH A CHALLENGE
BEING TO BUILD THAT UP, AND
REACH GMP COMPLIANCE ALL WHILE
MAINTAINING OPERATIONS AS THE
CLINICAL CENTER WAS STILL
ACCEPTING PATIENTS AT THAT TIME
FOR THESE INNOVATIVE THERAPIES.
SO SOME OF YOU MAY BE CURIOUS
ABOUT WHAT HAPPENED BETWEEN 2015
AND 2018, CLEARLY KNEW WE HAD
FLAWED TESTING SYSTEM THAT WAS
BEING OPERATED THROUGH IN DLM.
SO WE APPLIED CLINICAL
MICROKNOWLEDGE WHERE WE KNOW
THAT THE BLOOD CULTURE SYSTEMS
ARE POOR, FOR DETECTION OF MODEL
AND IF YOU ARE LOOKING FOR FUNGI
IN A PATIENT WE SENDS FUNGAL
CULTURE RATHER THAN BOTTLES. WE
ADDED A SOLID MEDIA CULTURE TO
INCREASE SENSITIVITY FOR FUNGAL
CONTAMINANTS. HOWEVER THE
PROBLEM EXISTED THAT TESTING WAS
BEING PROCESSED IN THE CLINICAL
LABORATORY AND NOT IN A GMP
SPACE. THESE CLEARLY THEN
INCREASE RISK OF CONTAMINATION,
AND BETWEEN A SIX YEAR PERIODS
WE HAD 54 POSITIVE FUNGAL
CULTURES A PERCENTAGE CONSIDERED
LABORATORY CONTAMINANTS TO POOR
LABORATORY LAND MANAGELING
BECAUSE WE WERE IN UNCONTROLLED
NON-GMP ENVIRONMENT. IN A STUDY
IN COLLABORATION BETWEEN DLM AND
THE CENTER FOR ENGINEERING, THE
GROUP LOOKED AT A ONE YEAR
REVIEW OF POSITIVE STERILITY FOR
CELL MANUFACTURING AND WHAT YOU
CAN SEE HERE IS THERE WERE 13
POSITIVES OF WHICH EIGHT OF
THOSE 13 WERE CONTRIBUTED TO
POSSIBLE OR PROBABLE LABORATORY
CONTAMINANTS. THESE CULTURES
PERFORMED IN A CLINICAL SETTING
NOT IN GMP BUT THIS LEADS TO
CHALLENGING TIME CONSUMING RISK
ASSESSMENT TO WHETHER THE
PRODUCT IS SAFE OR NOT, WHEN YOU
HAVE CLEARLY A TERMINALLY ILL
PATIENT WHO MAY BENEFIT
SIGNIFICANTLY FROM RECEIVING A
TREATMENT. MAYBE DUE TO A FALSE
POSITIVE STERILITY TEST. THIS
LED TO A LARGE STUDY CONDUCTED
BY ONE OUR CLINICAL MICROFELLOWS
TO RE-EVALUATE THE BLOOD CULTURE
SYSTEMS BEING APPLIED AT THE
NIH. SO THIS WAS A LARGE STUDY
LARGEST THE DATE, AND WHEN YOU
LOOK AT STUDY RESULTS IF WE
NARROW TESTING TO THE GOLD
STANDARD METHOD AND TWO
AUTOMATED BLOOD CULTURE SYSTEMS
LOOKING ONLY AT SIX QC ORGANISM,
THE MINIMUM REQUIREMENT THE FDA
EXPECTS, WE SEE 100% DETECTION
ACROSS THE BOARDS AND IT GIVES A
FALSE SENSE OF SECURITY WHAT WE
WERE DOING WAS ABSOLUTELY FINE
BUT WE KNOW IN REALITY WE HAVE
PROBLEMS. IF THE ORGANISM TEST
SET WAS EXPANDED TO 118
ORGANISMS AND WE EXTEND
INCUBATION TO 14 DAYS YOU CAN
SEE IN THE GRAY BAR REPRESENTED
AT THE BACK TECH SYSTEM WHICH
WAS THE SYSTEM THAT FAILED TO
DETECT MOLD CONTAMINANTS IN THE
PRODUCT IN 2015. YOU CAN SEE THE
GRAY BARLOWER THAN THE GOLD
STANDARD AND ALSO LOWER THAN ITS
ALTERNATIVE METHOD HERE.
CLEARLY DETECTION OF FUNGI
CONTINUES TO BE PROBLEM MORE
IMAGES OF MOLD BALLS THAT FAILED
TO BE DECKED BY INSTRUMENT
THOUGH VISIBLE TO NAKED EYE AND
CLEARLY IF WE ADD ON THE MANUAL
FUNGAL CULTURE WE HAVE 100%
SENSITIVITY FOR DETECTING THE
CAN CONTAMINANTS SUPERIOR TO
THAT OF THE GOLD STANDARDS
METHOD. SO THIS REALLY LED TO A
REBACK OF THE ENTIRE STERILITY
TESTING PROGRAM OFFERED AT THE
NIH. WHAT YOU CAN SEE IN THE
BLUE BAR ARE RESULTS OF A GOLD
STANDARD METHOD AS OPPOSED TO
THE ALTERNATIVE METHOD THAT WAS
NOW OFFERED STARTING BACK IN
2019. HOWEVER WE STILL HAVE THE
SAME ISSUE OF PRODUCT BEING
MANIPULATED IN THE LABORATORY IN
TERMS OF THE ADDITIONAL FUNGAL
CULTURE. SO THEN THIS LED TO
ANOTHER STUDY CONDUCTED BY ANY
KY PUTNAM, ONE OF OUR
MICROFELLOWS LAST YEAR WHERE SHE
EVALUATED A NEW TYPE OF MEDIA
CALLED ILYM, ORIGINAL HI
MARKETED FOR THE FOOD AND
BEVERAGE INDUSTRY TO LOOK FOR
CONTAMINANTS IN THINGS LIKE CANS
TOMATOES B, ORANGE JUICE, EGG,
WHAT SHE FOUND WAS POTENTIAL
SOLUTION, TO MINIMIZE LABORATORY
HANDLING OF PRODUCTS WHICH IS A
LOW RISK CLOSE SYSTEM MODEL TO
IMPROVE FUNGAL CONTAMINATION. SO
ESSENTIALLY THIS IS THE SUMMARY
OF HER RESULTS HERE, AND WHAT
YOU CAN SEE GOING DOWN THE Y ACT
SEIZE IS 51 DIFFERENT FUNGAL
ISOLATES AND ACROSS THE TOP ON
THE X ARE JUST DIFFERENT CULTURE
CONDITIONS. SO DIFFERENT MEDIA,
DIFFERENT INCUBATION,
TEMPERATURES. WHAT YOU CAN
APPRECIATE IS THAT ALONG COLUMNS
ON THE RIGHT HAND SIDE OF THE
HEAT MAP YOU SEE RED BARS SO
BEHOLD DOESN'T LIKE TO GROW AT
HIGH TEMPERATURE AND THESE
SYSTEMS FAIL TO DETECT HIGH
PERCENTAGE OF FUNGI. AS WE MOVE
TOWARDS AUTOMATED SYSTEMS AT A
LOWER TEMPERATURE IT PERFORMS
MODERATELY BETTER BUT STILL HAS
SOME ISSUES AND CLEARLY AGAIN
THE MANUAL CULTURE HAS ALL GREEN
FOR EXCELLENT DETECTION, THE
GOLD STANDARD METHOD IS MOSTLY
GREEN, FAILING TO DETECT ONLY
TWO ORGANISMS. SO WIDE
VARIABILITY ACROSS ICE RATES IN
CULTURE CONDITIONS. HOWEVER,
WHAT NIKKI WAS ABLE TO FIND WAS
IF SHE COMBINED THE RESULTS OF
TWO DIFFERENT AUTOMATED METHODS
AND MEDIA, WE WERE ABLE TO
ACHIEVE A SENSITIVITY THAT WAS
NOT SIGNIFICANTLY INFERIOR TO
THE GOLD STANDARD. SO THIS
PROVIDES AN OPTION OR
POTENTIALLY CLOSE SYSTEM MODEL
THAT IMPROVES FUNGAL DETECTION
BEYONDS WHAT WAS ORIGINALLY
OFFERED AT THE NIH SO IT IS AN
EXCITING AREA TO EXPLORE
FURTHER. SO CLEARLY LESS SONS
LEARNED FROM THE MICROBIOLOGICAL
PERSPECTIVE IS CLINICAL IS NOT
SAME AS GMP. UNFORTUNATELY WHAT
STORY WE WENT THROUGH IN DLM IS
NOT UNUSUAL. WHAT I'M SHOWING
YOU HERE ARE SCREEN SHOTS OF
DISCUSSIONS THAT HAPPEN EITHER
THROUGH EMAIL OR ON LIST SERVE
FROM THE AMERICAN SOCIETY OF
MICROBIOLOGY, WHERE REQUEST
FORESTER RILLTY TESTING ON
CLINICAL MICROLABS IS INCREASING
AND THERE ARE QUESTIONS BEING
RAISED ABOUT THE ROLE OF
CLINICAL MICROBE MICROBE. WE HAVE
SOMEONE ASKING ABOUT THEY HAVE A
CELL THERAPY FACILITY, IS ANYONE
USING A BLOOD CULTURE SYSTEM, IS
IT DONE IN THE CLINICAL LAB, IF
NOT WHO PERFORMS STERILITY
TESTING. I RECEIVED AN EMAIL
FROM A COLLEAGUE COUPLE OF
MONTHS AGO WHO WANTS TO START
ISLET CELL TRANSPLANT PROGRAM,
THEY WANT TO ALLOW THE LAB TO DO
STERILITY TESTING AND WHAT
REGULATIONS APPLY. AN EMAIL FROM
ANOTHER COMPLYING ABOUT BONE
MARROW TRANSPLANT AND AGAINST
HARVEST ITSELF. THESE GO BACK
YEARS, ANOTHER IN 2018, COUPLE
MORE IN 2015 NOW TALKING ABOUT
PHARMACIES, AS WELL AS SOME OF
THE SETTLING PLACE AND MEDIA
BILLS ALL COMPONENTS THAT FORM
PART OF GMP THAT DON'T
NECESSARILY IN CLINICAL
MICROBIOLOGY SO WHY ARE CLINICAL
MICROLABS ASKED TO ASSIST,
CLEARLY PROXIMITY OF LABS TO
MANUFACTURING SUITES AS CELL
THERAPY CONTINUES TO BE FRONT
LINE TREATMENT AND MORE AND MORE
ACADEMIC SENORS BRING THIS ON
BOARD. -- CENTERS BRING ON
BOARD. THIS ON SITE BIOLOGICAL
EXPERTISE AND IN HOUSE TESTING
IS MORE CONVENIENT FROM A COST
AND RESULT TURN AROUND TIME
PERSPECTIVE. SO REALLY WHERE I
SAY OUR ROLE WITHIN STERILITY
TESTING SERVICE IS TO HELP
EDUCATE MY CLINICAL
MICROCOLLEAGUES AS TO THE
LESSONS LEARNED FROM THE NIH AND
WHAT THE ROLE IS FOR CELLULAR
THERAPY TESTING IN CLINICAL
MICROLABS. HELPING THEM WELCOME
AWARE OF REGULATIONS IN
STERILITY TESTING WITH END GOAL
OF PATIENT SAFETY. SO WITH THAT,
I JUST WANTED TO END BY
INTRODUCING THE GMP PROGRAM.
WHICH IS ESSENTIALLY FORMED
FOLLOWING THE CONTAMINATION
EVENTS IN 2015. WHAT YOU CAN SEE
HERE ARE SEVEN BRANCHES OR
DEPARTMENTS ESSENTIALLY THAT
THESE GUYS ARE THE MANUFACTURING
OR THE ASEPTIC PROCESSING
FACILITIES. THERE'S HUNDREDS OF
FOLKS WITHIN EACH OF THESE
FACILITIES THAT FOCUS ON CELL AN
GENE THERAPY MANUFACTURING, KIT
AND RADIO PHARMACEUTICAL
MANUFACTURERS AS WELL AS
HOSPITAL PHARMACY. THERE ARE IN
FACT 13 FACILITIES CURRENTLY ON
THE NIH CAMPUS, THAT ARE DOING
THIS TYPE OF NOVEL DRUG
MANUFACTURING. WITH SIX MORE
FACILITIES SLATED TO ON BOARD
OVER THE NEXT TWO YEARS. I THINK
ALL OF US ARE AWARE THAT THERE
IS A LOT OF CONSTRUCTION
HAPPENING ON THE BETHESDA CAMPUS
AT THE MOMENT TO HELP BUILD
THESE NEW STATE OF THE ART
FACILITIES, MANY OF WHICH TAKE
SEVERAL YEARS TO BUILD FOUR TO
FIVE YEARS, IN FACT. WHAT YOU
CAN SEE HERE IS DR. ROSENBERG'S
T 30 FACILITY AND JMP FACILITY
FOR CLEAN ROOM ENVIRONMENTS
INCITE. THIS SLIDE HERE JUST
HELPS TO HIGHLIGHT THE WIDE
SCOPE OF THE PRODUCTS
MANUFACTURED AT THE NIH ACROSS
THOSE DIFFERENT FACILITIES.
VARYING FROM DIFFERENT TYPES OF
BIOLOGICS, PET RADIO LABEL
DRUGS, RAW MATERIALS THAT
REQUIRE TESTING AS WELL AS VIRAL
VECTORS. AND THEN TO SUPPORT
THESE MANUFACTURING GROUPS, WE
HAVE AN ENTIRE DIFFERENT SET OF
DEPARTMENTS THAT FOLLOW SUPPORT
AND REGULATORY FUNCTION. SO THIS
INCLUDES MY LAB FOR QUALITY
CONTROL TESTING, THE ORF HAS A
GROUP FOCUSING ON FACILITY
COMPLIANCE FOR CLEAN GREEN
SPACE, OFFICE OF RESEARCH
SUPPORT AND COMPLIANCE AS WELL
AS THE SPONSORS FROM VARIOUS
INSTITUTES AND CENTERS. AND
REALLY ALL OF US WORK TOGETHER,
THERE ARE HUNDREDS OF HANDS
INVOLVED IN THIS PROGRAM, TO
HELP MAKE A PRODUCT WHETHER CELL
THERAPY OR DRUG PRODUCT, THAT IS
READY TO INFUSE INTO A PATIENT.
SO IT HAS BEEN A VERY, VERY LONG
JOURNEY EVEN THOUGH THE PROGRAM
IS GOTTEN ONLY SEVEN YEARS OLD.
BUT HONESTLY BEFORE 2015 THERE
WAS LITTLE KNOWLEDGE OF GMP
ACROSS THE NIH CAMPUS AND IN
FACT I DOUBT THAT ACRONYM WAS
USED VERY READILY PRIOR TO 2015.
IT IS IMPORTANT REMEMBER THE
REGULATIONS ARE THE SAME WE ARE
JUST BEING HELD TO A DIFFERENT
STANDARD, WE HAVE CHANGED THE
CULTURE AND AWARENESS OF THE
REGULATIONS, WITH MANY, MANY
LESSONS LEARNED OVER SHORT
PERIOD OF TIME. I THINK FOR
MANY OF US IN INVOLVED IN THE
GMP PROGRAM, THE CHALLENGE COMES
WHEN IT COMES TO TRY TO
HARMONIZE THESE PROGRAMS THAT
HAVE EXISTED FOR MANY, MANY
DECADES SOMETIMES SPREAD ACROSS
NUMEROUS INSTITUTES AN CENTERS
AS WELL AS FACILITIES AND TRY TO
DEVELOP AN INTERDISCIPLINARY
APPROACH ACROSS THE NIH TO
IMPROVE THE GMP PROGRAM. WITH
END GOAL OF CLEARLY PATIENT
SAFETY AND OUR MISSION TO
CONTINUE TO SUPPORT INNOVATIVE
PATIENT CARE AND DRUG AND
BIOLOGIC DEVELOPMENT. SO WITH
THAT I WOULD LIKE TO END BY
THANKING DR. ROSENBERG SHORE
THEIR SHARING THE PLATFORM WITH
ME, THANKS TO DLM LEADERSHIP AND
STERILITY TESTING LAB, TAKEN
LAST WEEK AND THEN IT TAKES A
VILLAGE, THE GMP PROGRAM AT NIH
IS HUGE. HUNDREDS AND HUNDREDS
OF FOLKS WORK BEHIND THE SCENES
WITH MANUFACTURING FACILITY
SUPPORT, TESTING, AND REGULATORY
COMPLIANCE. THANK YOU VERY MUCH
FOR YOUR TIME, IF THERE IS TIME
WE ARE HAPPY TO TAKE QUESTIONS.
>> DR. ROSENBERG AND DR. LAU, I
WANT TO THANK YOU FOR VERY
POWERFUL PAIR OF TALKS. DR.
ROSENBERG WE ARE HONORED TO HEAR
ANT YOUR INCITES AND BREAK
THROUGHS AS PIONEER IN CELL
TRANSFER THERAPIES. AND PERHAPS
OFFERING A WINDOW WHAT THAT
LOOKS LIKE FUTURE BUT ALSO DR.
LAU FOR SHARING WITH US THE
COMPLEXITY WHAT IT MEANS SCALES
UP TO CLINICAL LEVEL OUTSIDE THE
WORLD. I THINK WE HAVE TIME
MAYBE FOR ONE QUESTION THAT CAME
IN, THIS MIGHT BE TO DR.
ROSENBERG. HUE FOR PHENOMENAL
TALK AND WORK. DO THESE MUTATION
SPECIFIC T-CELL RESPONSES
ULTIMATELY SPREAD B CELLS? DO
PATIENTS DEVELOP IGE SPECIFIC TO
THEIR CANCER MUTATION?
>> WE GENERALLY DO NOT FIND
ANTIBODIES CAPABLE OF
RECOGNIZING CANCER ANTIGENS
BECAUSE AGAIN THEY ARE NOT
PRESENTED WHEN USING
CONVENTIONAL T-CELLS AND T-CELL
RECEPTORS, THESE ARE NOT THREE
DIMENSIONAL PROTEINS PRESENTED
ON THE CELL SURFACE. BUT RATHER
PROCESS PEPTIDES FROM AN
INTRACELLULAR MOLECULE THEN
TRANSPORTED TO THE CELL TO THE
CELL SURFACE. SO IT IS VERY
DIFFICULT TO IDENTIFY ANTIBODIES
THAT ARE CAPABLE OF RECOGNIZING
CANCER ANTIGENS. THAT'S PART OF
THE REASON WHY CAR T-CELLS ARE
PREDOMINANTLY EFFECTIVE IN
PATIENTS WITH HEMATOLOGIC
CANCERS BECAUSE THERE ARE
MOLECULES SUCH AS CD 19 THAT ARE
EXPRESSED NOT ONLY ON NORMAL B
CELLS BUT ON TUMOR CELLS, AND
WHEN ONE ATTACKS THEM WITH A
CAR, AGAIN RECOGNIZING AN
ANTIBODY RECOGNITION, ONE
DESTROYS NORMAL B CELLS AS WELL
AS THE TUMOR CELLS, FORTUNATELY
THE STEM CELLS THAT GIVE RISE TO
B CELLS ARE SPARED Z SO AFTER
SEVERAL MONTHS NORMAL B CELLS
WILL APPEAR.
>> THANK YOU, DR. ROSENBERG,
THAT TAKES US TO HOUR. DR.
ROSENBERG, DR. LAU, THANK YOU
FOR SHARING YOUR EXPERTISE AND
INSIGHTS WITH US AND THE NIH
COMMUNITY. THANK YOU VERY MUCH,
I WISH EVERYONE A GREAT
AFTERNOON. THANK YOU AGAIN.