OUR FIRST SPEAKER IS ELIZABETH NICHOLS, SHE WAS AN UNDERGRAD AT DUKE, THEN WENT TO UNIVERSITY OF MARYLAND MEDICAL CENTER, GRADUATED IN 2004, DID A RESIDENCY IN RADIATION ONCOLOGY, AND SHE'S STILL THERE. SHE'S AN ASSISTANT PROFESSOR AT THE UNIVERSITY OF MARYLAND, THE GREENEBAUM CANCER CENTER. >> THANK YOU FOR HAVING ME TODAY. I WILL MAKE SURE TO USE THE MOUSE SO EVERYONE ONLINE CAN FOLLOW WITH US AS WELL. I HAVE NO DISCLOSURES. THE OUTLINE OF OUR TALK TODAY IS FIRST TO REVIEW SOME GENERAL GOALS OF CANCER THERAPY, AND THEN OFFER SOME GOALS SPECIFIC TO RADIATION THERAPY. WE'LL BRIEFLY TALK ABOUT SOME BASICS OF RADIATION ONCOLOGY, SPECIFICALLY CATCHING A COUPLE SLIDES ON THE PHYSICS OF RADIATION, RADIATION BIOLOGY, AND AS WELL AS DIFFERENT TECHNIQUES IN RADIATION THERAPY. I'LL DISCUSS A COUPLE COMMON PATIENT PRESENTATIONS AND OFFER SOME FUTURE DIRECTIONS OF RADIATION ONCOLOGY, QUITE EXCITING AND MIGHT PERMEATE THROUGH SOME ADDITIONAL LECTURES IN THIS COURSE AS WELL. STARTING OFF WITH PRINCIPLES OF CANCER THERAPY YOU CAN SEE THE BULLET ITEMS HERE. IN GENERAL EVERYTHING WE'RE DOING IS TRYING TO HIT AT LEAST ONE IF NOT SEVERAL OF THESE BULLET POINTS. THE FIRST IS MINIMIZING THERAPY, WE WANT TO MINIMIZE TOXICITIES, MINIMIZE AMOUNT OF TIME PATIENTS ARE COMING IN AND OUT OF OR OFFICES OR THE HOSPITAL, MINIMIZING COST OF THERAPY OVERALL. WE'RE TRYING TO MINIMIZE NEGATIVE IMPACT ON QUALITY OF LIFE THROUGH TOXICITY, MAINTAINING AS MUCH FUNCTION AS PATIENTS CAN AND ALSO MAINTAINING COGNESI, FOR EXAMPLE HAVING A PORTION OF FACE REMOVED WE'RE MINIMIZING THAT, AND QUALITY OF LIFE, MANY THERAPIES ARE FOCUSED ON PALLIATION OF CANCER-RELATED SYMPTOMS, MAJORITY OF CANCER PATIENTS END UP DEVELOPING -- NOT THE MAJORITY BUT MANY DEVELOP METASTASES, AND MINIMUMMING IMPACT ON QUALITY, AND IMPROVING OUTCOMES, ACTUALLY CANCER CURE OUTCOMES OR IMPROVING SOME OTHER PARAMETERS THAT I JUST MENTIONED. WE THINK OF RADIATION BIOLOGY, RADIATION PHYSICS AND THERAPEUTIC RADIATION AS WELL. IF WE DO A COUPLE BASICS OF RADIATION ONCOLOGY, IF WE LOOK AT WHAT IS THE DEFINITION OF RADIATION, IT'S THE COMPLETE PROCESS BY WHICH ENERGY IS EMITTED BY ONE BODY, TRANSMITTED AND ABSORBED BY ANOTHER BODY. THERE ARE MULTIPLE TYPES, THIS IS A CLASSIC SLIDE DEMONSTRATING DIFFERENT TYPES OF RADIATION, YOU SEE ALPHA PARTICLES, BETA PARTICLES, GAMMA RAYS AS WELL AS PHOTONS. ALPHA PARTICLES ARE THE WEAKEST PARTICLE, THEY CAN BE STOPPED BY A SHEET OF PAPER. IF WE THINK ABOUT THE FUKUSHIMA DISASTER SEVERAL YEARS AGO, ONE OF THE THINGS WE TOLD PEOPLE TO DO IS WEAR CLOTHING, LONG SLEEVES, LONG PANTS, THE REASON IS YOU CAN BLOCK ALPHA PARTICLES WITH SOMETHING VERY THIN. BETA PARTICLESES ARE THE NEXT STRONGEST AND CAN BE STOPPED BY A SHEET OF ALUMINUM, SOME LIVER DIRECTED THERAPIES WE USE BETA RADIATION, AND THEN GAMMA RAYS WHICH ARE OUR MAINSTAY WITH TECHNOLOGY SUCH AS GAMMA KNIFE, PHOTON THERAPY AND LAYERS OF CONCRETE TO STOP THEM. WHEN WE LOOK AT THE ELECTROMAGNETIC SPECTRUM AND TALK ABOUT RADIATION THERAPY WE'RE LOOKING ALL THE WAY OVER IN THIS END OF THE SPECTRUM, GAMMA RAYS AND X-RAYS. AND WE TALK ABOUT HOW ARE X-RAYS GENERATED, THE BASIC FUNCTIONALITY OF A LINEAR ACCELERATOR ON THE RIGHT, HOW WE DO RADIATION THERAPY NOW, IT GOES BACK TO THE SIMPLE MOD WHERE WILL YOU AN ANODE, CATHODE, VACUUM CHAMBER, ELECTRICITY GENERATES ELECTRONS. SO WHAT ARE THE DIFFERENT PARTS OF A LINEAR ACCELERATOR? IF I FLIP BACK TO THIS SLIDE HERE, SO THIS PORTION OF LINEAR ACCELERATOR IS SOMETIMES ACTUALLY BEHIND A WALL, SO PATIENTS MAY NOT ACTUALLY SEE THIS. THIS IS WHERE A LOT OF DIFFERENT COMPONENTS ARE LOCATED. HERE IS WHAT WE CALL THE GANTRY, THE RADIATION COMES OUT OF THE HEAD OF THE MACHINE HERE, AND THIS WHOLE PIECE CAN ROTATE 360 DEGREES AROUND THE PATIENT AND DELIVER RADIATION FROM ANY OF THOSE ANGLES. THE MODERN LINEAR ACCELERATORS CAN MOVE WITH 6 DEGREES OF FREEDOM, IN, OUT, UM, DOWN, SIDE TO SIDE AND DO ROTATIONAL CHANGES AS WELL. AND IN ADDITION THIS WHOLE APPARATUS CAN ROTATE IN 180-DEGREE ARC AROUND THE LINEAR ACCELERATOR. SO LINEAR ACCELERATORS CAN PRODUCE HIGH ENERGY PHOTONS, HAVE UNIFORM BEAM CHARACTERISTICS, IF WE MAP OUT RADIATION DOSES OF EXITS FROM THE HEAD OF THE MACHINE IT WOULD BE EQUAL AS YOU GO FROM LEFT TO RIGHT. WE HAVE ABILITY TO DO PRECISE FIELD SHAPING, IN THE HEAD OF THE MACHINE, ELECTRONS COME IN THROUGH THIS TUBE AND THERE'S A BENDING MAGNET WHICH FLIPS THEM AROUND AND HAS THEM COME OUT THROUGH THE HEAD OF THE MACHINE. ACTUALLY IN THIS HEAD OF THE MACHINE THERE'S NUMEROUS JAWS THAT MOVE IN DIFFERENT DIRECTIONS TO HELP SHAPE THAT BEAM BASED ON HOW WE DETERMINE IT FROM THE TREATMENT PLANNING. WE'RE ABLE TO DO PRECISE DELIVERY BECAUSE OF THE GRANTRY ROTATION, COUCH ROTATION, AND IMMOBILIZE PATIENTS, I'LL SHOW PICTURES OF WHAT THAT CAN LOOK LIKE. WE TALK ABOUT RADIATION THERAPY BASICS, WE TALK ABOUT A COUPLE PARAMETERS, SO ONE IS THE GTV, GROWTH TUMOR VOLUME, BASED ON CT PLANNING. WE HAVE A CONCEPT CALLED CTV, CLINICAL TARGET VOLUME, THIS IS TYPICALLY A MARGIN ADDED AROUND THE GROSS TUMOR THAT CAN ACCOUNT FOR MICROSCOPIC EXTENSION, DOING PLANNING BASED ON CT AND OTHER IMAGES LIKE MRI OR PET SCAN AND KNOW AT MICROSCOPIC LEVEL IT MAY NOT CORRELATE WITH WHAT'S IN THE PATIENT. WE TALK ABOUT A PTV, PLANNING TARGET VOLUME, ISOTROPIC MARGIN WHICH WILL ACCOUNT FOR SETUP UNCERTAINTY AND ALSO ITV OR INTERNAL TARGET OR TUMOR VOLUME, AND WE CAN DRAW THIS BASED ON TUMOR MOTION, DOING A 4D CAT SCAN. WE TALK ABOUT DIFFERENT RADIATION PLANNING TECHNIQUES, DID THIS SKIP AROUND? I'M SORRY. WHEN WE TALK ABOUT RADIATION PLANNING, THERE'S A COUPLE DIFFERENT TECHNIQUES WE CAN UTILIZE, SO THERE'S 3D, CONFORMAL RADIATION THERAPY, WHERE WE USE CT TO PLAN FROM, THE ANATOMY, THIS ALLOWS MULTIPLE DEGREES OF FREEDOM FOR THE PATIENT, CREATE VIRTUAL PATIENT FROM THIS TECHNIQUE AND HAVE IMRT, WHICH IS A LITTLE BIT MORE OF A COMPLEX PLANNING ALGORITHM, INTENSITY MODULATED RADIATION THERAPY. THIS HAS A DOSE CLOUD AND IS MORE COMPLEX, INVERSE PLANNING. WHAT THAT MEANS IS WE CAN TELL THE COMPUTER I WANT THIS, THIS, TO MY TARGET VOLUME, THIS DOSE TO MY ORGANS AT RISK, AND COMPUTER WILL CREATE A PLAN THAT ACCOMPLISHES ALL OF THOSE DIFFERENT GOALS. HERE IS ANOTHER PICTURE, SO WHAT THIS DEPICTS IS IF WE HAVE HERE A DIFFERENT TARGET VOLUME, WHICH IF YOU CAN SEE I'M DRAWING IN RED HERE WITH THE ARROW, WE CREATE MULTIPLE DIFFERENT BEAMS AND BASICALLY WHAT HAPPENS IS COMPUTER SYSTEM CAN CREATE RADIATION PLAN LOOKING AT THAT SPECIFIC ANGLE AND BLOCKING OUT ORGANS WE DON'T WANT TO TREAT. SO, FOR EXAMPLE, HERE THIS COULD BE A PROSTATE PATIENT, AND SO AT THIS BEAM ANGLE YOU'LL HAVE THIS TYPE OF DOSE SHAPE, BUT IF YOU LOOK BACK HERE BECAUSE OF THE RECTUM IS IN THAT AREA YOU CAN SEE A LITTLE BIT OF THE CARVEOUT HERE FOR THE RECTAL DOSE. AGAIN WE'RE ALLOWED TO TARGET TUMORS TO HIGHER DOSE BUT KEEPING OTHER ORGANS AT A LOWER DOSE WITH THIS TECHNIQUE. HERE IS ANOTHER DEPICTION OF WHAT CAN HAPPEN FOR A HEAD AND NECK PATIENT. SO THIS IS WITH AN IMRT APPROACH, EACH SLIDE LOOKS AT DOSE DISTRIBUTION FROM THAT BEAM ANGLE. ANOTHER TYPE OF RADIATION THERAPY IS CALLED VOLUMEMETRIC IN A 360-DEGREE ARC. THE TREATMENT MACHINE IS MOVING ALLOWING FOR QUICKER TREATMENT DELIVERY AND MORE CONFORMAL DOSE OF THE PRESCRIPTION FOR PATIENTS, DOSE HOMOGENEITY, AT THAT LEVEL WE'RE TREATING AND TARGETING THE DOSE LOOKS THE SAME ACROSS THE WHOLE AREA. WE DON'T HAVE HOT SPOTS OR COLD SPOTS. BUT THE COST OF THIS THERAPY IS A LITTLE BIT MORE LOW DOSE OF RADIATION TO SOME SURROUNDING TISSUES. THIS IS AN EXAMPLE OF A PATIENT WHERE WE SEE THIS IS AN IMRT PLAN ON THE LEFT, AND THEN VMAT PLAN ON THE RIGHT. THE HIGH DOSE AREA IN RED IS PRETTY SIMILAR TO BOTH -- ACROSS BOTH IMAGES, IF WE LOOK AT MODERATE DOSES IN GREENS AND BLUES THEY ARE MORE CONFORMALLY SHAPED IN VMAT COMPARED TO IMRT PLAN. ANOTHER IS BRACHYTHERAPY, WE PLACE A RADIATION SOURCE INSIDE OR ADJACENT TO A TUMOR. THIS ALLOWS FOR RAPID DOSE FALLOFF AND MAXIMAL SPARING OF NORMAL TISSUES SO WHEN WE GIVE BRACHYTHERAPY BECAUSE WE'RE PUTTING RADIATION INSIDE OF THE TUMOR OR BODY CAVITY, WE DON'T HAVE TO GO IN FROM THE OUTSIDE THROUGH SOME NORMAL TISSUE. THIS IS USED FOR TUMORS OF THE GYM ORIGIN LIKE CERVICAL, ENDOMETRIAL, VAGINAL CANCERS, HEAD AND NECK AND TUMORS CLOSE TO BODY SURFACES, PROSTATE CANCER, SARCOMAS, TONGUE, LIP AND BREAST CANCERS AS WELL. THIS IS ONE EXAMPLE FOR EYE TUMOR, OCULAR MELANOMA, WE CAN PUT A LITTLE PLAQUE AND THIS IS WHAT A DOSE DISTRIBUTION CAN LOOK LIKE, SIMULATING THE LENS, RETINA, BACK HERE, THIS IS WHERE THAT TUMOR WAS LOCATED. AND WE CAN SEE WE CAN GET A NICE DOSE OF RADIATION TO THE TUMOR AND NO DOSE OF RADIATION TO THE OTHER PART OF THE EYE. THIS IS AN EXAMPLE OF A CERVICAL CANCER WHERE PATIENTS -- THIS IS OUR TANDEM AND RING APPARATUS, THE STRAIGHT PIECE GOES INTO THE CERVIX AND UTERUS, THIS TOUCHES THE OUTER PORTION, CT SCAN AND DIFFERENT LEVELS OF RADIATION BUT WE GET A HIGH DOSE OF RADIATION TO THE TUMOR, UTERUS AND CERVIX AND MINIMAL DOSE OF RADIATION ELSEWHERE. ANOTHER FORM OF RADIATION THAT PEOPLE MAY BE FAMILIAR WITH IS STEREO TACTIC RADIO SURGERY, USED TO TREAT BRAIN HUMANS AND KIND OF THE MACHINE NAME IS GAMMA KNIFE. AND THEN THIS TECHNOLOGY WAS SO SUCCESSFUL IN THE BRAIN WE'VE DEVELOPED WAYS TO DO THIS IN OTHER PARTS OF THE BODY WHICH WE NOW CALL SBRT, AND SO THE TOP RIGHT PICTURE HERE IS A PICTURE OF GAMMA KNIFE PLAN, AND THE BOTTOM RIGHT PICTURE WOULD BE LUNG SBRT, SO SUCCESSFUL WE USE FOR LUNG, BONE, LIVER TUMORS, AND IN LUNG CANCER THERE'S NOW A RANDOMIZED STUDY OPEN COMPARING THIS THERAPY TO SURGICAL RESECTION IT'S BEEN THAT SUCCESSFUL. MANY PEOPLE HEARD ABOUT CYBER KNIFE, A TYPE OF MACHINE THAT DELIVERS STEREOTACTIC SURGERY, LIKE A BRAND NAME THAT DOES THAT. NOW IF WE TALK ABOUT RADIATION BIOLOGY, THIS IS WHAT A CLASSIC RADIATION SURVIVAL CURVE WOULD LOOK LIKE FOR A TUMOR. AND SO WHAT THIS PICTURE SHOWS, SO THIS SQUARE DO THE WOULD BE IF WE USED SPARSELY IONIZING X-RAYS OR PHOTONS. DARK LINE HERE SIMULATES DIFFERENT TYPE OF RADIATION, NEUTRONS OR ALPHA RAYS, AND YOU CAN SEE THIS IS WHAT A CELL SURVIVAL CURVE WOULD LOOK LIKE WITH SINGLE OR VARYING DOSE OF RADIATION, THE HIGHER DOSE THE MORE CELL KILL WE HAVE. WHAT YOU CAN CLEARLY SEE HERE IS THERE'S A DIFFERENCE BETWEEN DIFFERENT TYPES OF RADIATION PARTICLES IN RESPONSE OF TUMOR. THERE'S AN EFFECT OF FRACTIONATION, RARE WE GIVE A SINGLE DOSE OF RADIATION. AS WE FRACTIONATE RADIATION WHICH LEADS TO IMPROVED TOXICITIES FOR PATIENTS THIS IS THE TYPE OF CURVE WE WOULD SEE HERE. THIS IS THE SAME CELL LINES, SINGLE DOSE OF RADIATION, FRACTIONATED RADIATION CORE, WE CAN WE WE HAVE TO INCREASE THE DOSE OVER TIME TO GET THE SAME LEVEL OF CELL KILL, THE RATIONALE WE WANT TO TAKE ADVANTAGE OF SMALLER DOSES OVER NUMEROUS TREATMENTS TUMOR AND EARLY RESPONDING TISSUES LOOK WHEN WE COMPARE DOSE TO SURVIVING FRACTIONS. WHEN IT COMES TO RADIATION BIOLOGY, WE TALK ABOUT THE FOUR Rs OF FRACTIONATED RADIATION. REPAIR, REASSORTMENT, REDISTRIBUTION, REOXYGENATION AND REPOPULATION. HEALTHY CELLS ARE ABLE TO REPAIR DNA DAMAGE, SOME TUMOR CELLS CAN DO THAT IN REAL TIME AS WELL. WE LOOK AT REASSORTMENT, RADIATION CAUSES CELLS TO ACCUMULATE IN CERTAIN PHASES OF THE CELL CYCLE, MORE SUSCEPTIBLE TO RADIATION DAMAGE. SO WE EXPLOIT THAT WITH VARIETY OF OTHER TECHNIQUES WHICH I'LL TALK ABOUT IN A LITTLE BIT AS WELL. WE KNOW TUMORS REOXYGENNATE AFTER RADIATION THERAPY ALLOWING FOR DNA REPAIR, THAT'S SOMETHING WE SOMETIMES TRY TO HARNESS. AND THERE'S REPOPULATION, THAT TUMOR AND NORMAL CELLS CAN REPOPULATE AND RESPOND TO DOSE AND FRACTIONATION DUE TO BASELINE REFRACTIONATION. REPAIR, DNA IS THE PRIMARY TARGET OF RADIATION, THERE CAN BE A COUPLE DIFFERENT WAYS THAT RADIATION TARGETS -- THE RADIATION EFFECTS CAN HAPPEN AT THE CELL LEVEL. THERE'S AN INDIRECT EFFECT WHERE BASICALLY A PHOTON OR GAMMA RAY COMES IN AND KICKS AN ELECTRON OFF, CAUSES A FREE RADICAL THAT CAN DAMAGE DNA THAT'S SITTING RIGHT NEXT TO IT. AND THERE'S ALSO A DIRECT EFFECT OF RADIATION WHERE THE PARTICLE CAN COME IN AND DIRECTLY DAMAGE THE DNA. WHEN WE TALK ABOUT DIRECT DAMAGE OF DNA, THERE CAN BE THINGS CALLED SINGLE STRAND BREAKS, CERTAINLY VERY EASY FOR YOUR BODY TO REPAIR BECAUSE THE DNA TEMPLATE IS PRESENT BUT DOUBLE STRAND WAY BEST WAY TO DAMAGE SO WE WENT TO GET AS MANY AS POSSIBLE. CELLS THAT CAN CORRECT DNA DOUBLE-STRAND BREAKS LIVE ANOTHER DAY AND ULTIMATELY REPAIR THEMSELVES. ONE OTHER THING TO POINT OUT, DEPICTED IN THIS PICTURE, PHOTONS BECAUSE THEY ARE SMALLER CAUSE A LITTLE BIT LESS DAMAGE THAN PARTICLES WHEN WE TALK ABOUT DNA DOUBLE STRAND BREAK, GETTING INCREASED INTEREST IN PROTONS AND CARBON IONS. WHEN WE TALK ABOUT REDISTRIBUTION, AS I MENTIONED, SOMETIMES WE GIVE RADIATION IT CAUSES CELLS TO ACCUMULATE IN DIFFERENT PHASES OF THE CELL CYCLE. SO, AGAIN, HERE'S OUR CELL CYCLE CIRCLE HERE, AND SO WHAT WE ALSO KNOW IS THAT DNA DAMAGE FROM RADIATION IS MOST EFFECTIVE IN CERTAIN PHASES LIKE G2 PHASE AND MITOTIC PHASE. G1 AND G2, THIS IS ONE OF THE TARGETS OF SOME DRUGS, CHECKPOINT INHIBITORS GIVEN IN COMBINATION WITH RADIATION CAN ALLOW RADIATION TO BE MORE EFFECTIVE. SO RADIATION AGAIN CAN INDUCE CELL CYCLE ARREST, TO REPAIR THE DNA DAMAGE. AGAIN AS I MENTIONED THERE'S DIFFERENT PHASES, MORE SENSITIVE, SO, AGAIN, HERE YOU CAN SEE THE DIFFERENT PHASES OF THE CELL CYCLE. , AGAIN, M AND G2 PHASE MOST SENSE ACTIVE TO RADIATION, LS PHASE IS RECENT TO THIS. WHEN WE LOOK AT REOXYGEN REOXYGENATION, TUMORS THAT ARE HYPOXIC ARE LESS RESPONSIVE THAN TUMORS MORE HYPOXIC. IF ADDITIONAL DRUGS OR THINGS WE DO TO IMPROVE OXYGENATION, THERE BY HELP IMPROVE THE RADIATION RESPONSE. SO THESE CURVES HERE LOOK AT HYPOXIC TUMORS VERSUS AERATED TUMORS. THIS IS A TARGET OF VARIOUS DRUG INVESTIGATIONS TO HELP IMPROVE TUMOR OXYGENATION. THIS LEADS TO THE CONCEPT OF RADIATION MODIFIERS, RADIOSENSITIZERS, TRYING TO LOOK AT HERE IS OUR NORMAL CURVE HERE WHERE LET'S SAY FOR EXAMPLE WE GAVE 60 GRAY OF RADIATION, WHICH IS SIMULATED BY THE DOTTED LINE, LOOK AT TUMOR CURVE AND NORMAL TISSUE CURVE, IF I GIVE 60 GRAY IN THIS EXAMPLE THAT LEADS TO 65% LOCAL CONTROL OF THE TUMOR, AND ABOUT 15% NORMAL TISSUE DAMAGE. GENERALLY WHAT WE'RE ALWAYS TRYING TO DO IS TRYING TO GIVE THAT SAME DOSE OF RADIATION BUT RESULT IN HIGHER LOCAL CONTROL WITH EITHER SAME NORMAL TISSUE DAMAGE OR LESS, SO THIS IS AN EXAMPLE OF RADIOSENSITIZER. EXAMPLES IN THE CLINIC ARE CERTAIN CHEMOTHERAPEUTIC AGENTS, SAFE TO ADD SOME OF THOSE INTO RADIATION, MOST COMMON IS ELODA, TRADE NAME, TO GIVE RADIOS SENSITIZATION TO PATIENTS. THE OTHER CONCEPT IS RADIOPROTECTION, SO CAN WE GIVE A HIGHER DOSE OF RADIATION WHICH WOULD RESULT IN HIGHER LOCAL CONTROL, BUT ACTUALLY DECREASE OUR NORMAL TISSUE DAMAGE. SO THIS IS ALSO AN AREA OF ACTIVE RESEARCH, LOOKING AT DIFFERENT WAYS WE CAN PROTECT OUR NORMAL TISSUES ALLOWING FOR DOSE ESCALATION. SOME OF THE EXAMPLES OF RADIATION TARGETS, SOME MIGHT BE TALKED ABOUT IN OTHER LECTURES, THESE CAN BE GROUPED INTO SINGLE TARGET AGENTS, MULTI-TARGET AGENTS, RADIATION INDUCIBLE AGENTS. SOME EXAMPLES OF SINGLE TARGET AGENTS ARE THINGS THAT TARGET EGFR AND VEGF RECEPTOR, TRANSCRIPTION FACTORS, P53 AND SIGNAL TRANSFECTION PROTEINS, KINASE INHIBITORS AND SO FORTH. MULTI-TARGET INHIBITION, CHAPERONE PROTEINS, MICROBIOME, ANGIOGENESIS AND EPIGENETIC MODIFICATION AND ANTIGENS, RECEPTORS SUCH AS FAS LIGAND AND CEA. HERE IS ONE EXAMPLE OF THE EGFR FAMILY. WHAT THIS DEPICTS IS SOME DIFFERENT DRUGS OUT THERE NOW, MANY OF THESE ARE ON THE MARKET WHICH TARGET VARIOUS ASPECTS OF THE EGFR FAMILY, SO, FOR EXAMPLE, USED TO TARGET BREAST CANCERS HER-2 POSITIVE, BEVACIZUMAB FOR BRAIN TUMORS, AND NON-SMOKER LUNG CANCERS AND YOU CAN SEE HERE. WHAT ARE ISSUES FOR TARGET AGENT DEVELOPMENT? WE HAVE TO THINK ABOUT MECHANISM, IS THIS CELL TYPE SPECIFIC OR CONDITION SPECIFIC. LOOK AT METHOD OF TARGETING, ANTIBODY, SMALL MOLECULE OR GENE THERAPY, AND LOOK AT THERAPEUTIC RATIO, AFFECT JUST TUMOR CELLS OR NORMAL CELLS OR BOTH, AND OFTENTIMES SOMETHING IS AFFECTING BOTH MAY NOT BE A GOOD AGENT FOR DEVELOPMENT. SO ONE OF THE MOST COMMON THINGS THAT WE'RE LOOKING AT ARE SOME IMMUNOMODULATORY AGENTS, WE SEE MANY OF THESE DRUGS ADVERTISED ON TV EVERY DAY. ONE OF THE THINGS REALLY INTERESTING IS THESE ARE COMBINED WELL WITH RADIATION THERAPY AND INDUCE ABSCOPAL EFFECT, IS PATIENT IS GETTING IMMUNOMODULATORY AGENT AND WE TARGET ONE AREA WITH RADIATION IT CAN INDUCE SOME RESPONSE TO ALL LESIONS WE CAN SEE ON CT IMAGING. SO THOSE ACTUALLY -- THIS IS KIND OF THE SEMINAL PAPER PUBLISHED ON THIS CONCEPT IN THE NEW ENGLAND JOURNAL IN 2012, AND THIS WAS THE PATIENT WHO HAD A MELANOMA, RECEIVED THE DRUG IPILUMINAB, AND THIS AGENT OR THIS AREA WAS TARGETED WITH RADIATION THERAPY, AND THEN WHAT YOU SAW AS THAT WAS TARGETED THE LESION UP HERE RESPONDED AND LESIONS DOWN HERE RESPONDED EVEN THOUGH THE PATIENT -- I'M SORRY, THIS IS THE AREA THAT WAS TARGETED, RADIATION PLAN HERE, AND WHAT WE SAW IS THESE OTHER TWO LESIONS RESPONDED VERY NICELY WITHOUT ANY ADDITIONAL RADIATION THERAPY, PATIENT WENT INTO PERCEIVED REMISSION AS A RESULT. AGENTS ARE PD-L1 AND PD-1 INHIBITORS AND MANY OTHERS, THIS IS THE FASTEST GROWING AREA IN ONCOLOGY AT THE PRESENT TIME. NOW IF WE SWITCH GEARS TO RADIATION THERAPY, GOALS OF RADIATION, CURE, TRYING TO CURE CANCER, LOCALIED TO ONE ORGAN OR REGION AND ALSO ONE OF THE OTHER BIG AREAS THAT WE THINK ABOUT, PALLIATING SYMPTOMS ESPECIALLY IN PATIENTS WITH METASTASES. 50% OF OUR PATIENTS FALL INTO THIS CATEGORY FOR PALLIATION. AND THIS I THINK IS GOING TO CONTINUE TO GROW, ALL SYSTEMIC THERAPIES CONTINUE TO GROW, PATIENTS ARE LIVING LONGER WITH METASTATIC DISEASE AND WE'RE SEEING DISEASE PATTERNS ANT METASTASES WE'VE NEVER SEEN BEFORE BECAUSE PATIENTS NEVER LIVED THAT LONG. IF WE LOOK AT INDICATIONS FOR RADIATION THERAPY, IF WE LOOK AT CURATIVE CONDITIONS THINK ABOUT ALMOST ALL THE SOLID TYPES OF TUMORS, RADIATION THERAPY USUALLY HAS A WHOLE FOR WHAT WE CALL LIQUID TUMORS, LEUKEMIA, LYMPHOMAS, IT'S INSTITUTIONAL-SPECIFIC. AND WE LOOK AT PALLIATION, JUST SOME OF THE MAIN EXAMPLES USING RADIATION, BONE METASTASES FOR PAIN, SHORTNESS OF BREATH, NEUROLOGIC SYMPTOMS WITH BRAIN METASTASES OR DISCONTRACT FROM SPACE-OCCUPYING LESION. ONCOLOGY TEAM IS A MULTI-DISCIPLINARY TEAM. THIS IS ONE OF THE THINGS THAT DRAWS A LOT OF PEOPLE TO THE ONCOLOGY FIELD, AGAIN THIS IS MADE UP OF RADIATION ONCOLOGY, MEDICAL ONCOLOGY, SURGICAL ONCOLOGY, NOW INTERVENTIONAL RADIOLOGY ONCOLOGY FELLOWSHIPS, THIS IS CONTINUING TO BE A GROWING FIELD. WE WORK VERY CLOSELY WITH SOCIAL WORK AND SUPPORT SERVICES AND ADDITIONAL OTHER SPECIALTIES. SO WHEN A PATIENT COMES IN TO SEE US ONE OF THE MAIN THINGS IS WE DO DEVELOP A MULTI-MODALITY PLAN, SO IT'S PRETTY RARE ANY ONE CANCER IS CURED BY ONE THERAPY. ALMOST ALL CANCERS NEED SEVERAL DIFFERENT DISCIPLINES AS PART OF THEM. AGAIN, THIS MAY INCLUDE SURGERY, RADIATION, SYSTEMIC THERAPY LIKE CHEMOTHERAPY OR OTHER TARGETED AGENTS, AS WELL AS LOCALIZED THERAPIES SO THERE'S THINGS LIKE RSA, OTHER FOCAL ABLATION TECHNIQUES AND FOCAL DRUG DELIVERY SUCH AS ISOLATE PERFUSION. THE THERAPY PROCESS, WE SEE PATIENCE IN CONSULTATION VISIT, ONCE COMPLETED AND PATIENT IS A CANDIDATE FOR RADIATION THERAPY THEY UNDERGO A CT SIMULATION OR PLANNING SESSION FOR RADIATION, WE TAKE THOSE IMAGES AND TRANSFER THEM TO OUR TREATMENT PLANNING SYSTEM AND DO HAVE THE ABILITY TO FUSE IN OUTSIDE IMAGES LIKE MRs, PET SCANS, DIFFERENT SCANS IN DIFFERENT POSITIONS OR IV CONTRAST. FROM THERE WE CREATE THE PLAN AND SO WHAT THAT PROCESS ENTAILS IS CONTOURING OUT NORMAL AND TARGET STRUCTURES, CREATE A PLAN DONE BY DOSIMETRY, THE PLAN IS EVALUATED BY A DOC AND MEDICAL PHYSICIST, TRANSFERRED TO THE TREATMENT MACHINE AND THERE'S THE ACTUAL TREATMENT DELIVERY. ALL IN ALL THAT PROCESS FROM KIND OF A CT SIMULATION TO TREATMENT DELIVERY TAKES A WEEK TO WEEK-AND-A-HALF DEPENDING ON EXACTLY THE TYPE OF RADIATION THERAPY BEING DELIVERED. ONE OF THE COMMON QUESTIONS WHEN PATIENTS COME IN, I'M NOT GETTING RADIATION TODAY, THE ANSWER IS NO, UNLESS IT'S AN EMERGENCY YOU'RE NOT GETTING IT TODAY. YOU'RE GETTING IT IN A COUPLE DAYS OR ABOUT A WEEK. THIS IS JUST ONE EXAMPLE OF TREATMENT PLANNING AT THE UNIVERSITY OF MARYLAND, ONE OF MY HEAD AND NECK CANCER PATIENTS, AND I WANT TO DEPICT SOME DIFFERENT THINGS WE CAN CONTOUR OUT WHEN WE'RE DOING TREATMENT PLANNING, THIS PATIENT HAD A HEAD AND NECK CANCER, SURGERY, WE SEE ALL THESE BRIGHT SURGICAL CLIPS AND THE YELLOW HERE AND PINK ARE MY TARGET VOLUMES, THESE WERE THE NECK LYMPH NODES WE WERE TARGETING. THE BLUE AND GREEN ARE THAT PTV, PATIENT SETUP UNCERTAINTY, AND HEAD AND NECK CANCERS WE FEEL WE HAVE A 3-MILLIMETER CERTAINTY OF WHERE WE'RE TARGETING. AND WHAT YOU CAN SEE HERE SOME OTHER ORGANS WE'VE DRAWN, THE SPINAL CORD, THE MANDIBLE, THIS RED HERE IS ACTUALLY WHAT WAS THE PAROTID GLAND AND PUT THAT INTO THE COMPUTER AND THAT HELPS IT CREATE INVERSE PLAN USING IMRT OR VMAT IN THIS CASE. MOVING TO JUST SOME PATIENT PRESENTATIONS, SO THIS FIRST PATIENT HERE WE'LL TALK ABOUT THE DIFFERENT STEPS THEY WENT THROUGH. THIS PATIENT IS A COMMON SCENARIO, 55-YEAR-OLD FEMALE, DEVELOPED NEW LUMP IN LEFT BREAST, HAD WENT TO PRIMARY CARE PHYSICIAN, MAMMOGRAM ORDERED, SUSPICIOUS ABNORMALITY, BIOPSY SHOWED INFILTRATING DUCTAL CARCINOMA, MOST COMMON TYPE, AND THIS PATIENT HAD NO FAMILY HISTORY OF BREAST CANCER, CERTAINLY SOMETHING THAT WE ALWAYS ASK ALL OUR PATIENTS SO THIS PATIENT COMES IN, WE HAVE TO DISCUSS HER TREATMENT OPTIONS, SOME TREATMENT OPTIONS MAY INCLUDE MASTECTOMY, KIND OF ONE OF THE OLD, OR BREAST CONSERVING THERAPY INCLUDING LUMPECTOMY AND RADIATION, SOME OF THE DIFFERENT TYPES OF SURGERIES, RADICAL MASTECTOMY, REMOVE THE ENTIRE BREAST AND MUSCLE, WHAT THIS DEPICTS, MODIFIED RADICAL, THE TYPE COMMONLY PERFORM TODAY AND LUMPECTOMY REMOVING TISSUE AND HUMAN, PATIENTS HAVE ADVANTAGE OF BEING ABLE TO KEEP THE BREAST AND MAINTAIN COSMESIS. THIS PATIENT AFTER HEARING THE PROS AND CONS, ELECTS BREAST CONSERVATION, LUMPECTOMY, SENTINEL LYMPH NODE BIOPSY, FOUR AXILLARY LYMPH NODES WERE POSITIVE FOR DISEASE. PATIENT GOES TO RECEIVE CHEMOTHERAPY, COME IN TO SEE US AS RADIATION ONCOLOGY. WHEN WE LOOK IN THIS SCENARIO, WE THINK ABOUT WHAT TYPE OF RADIATION MODALITY DO WE WANT TO USE AND WHAT DO WE WANT TO TARGET, SO THERE'S A COUPLE WAYS TO USE EXTERNAL BEAM RADIATION THERAPY, ONE IS PROTONS, ONE WITH PHOTONS, ONE WITH ELECTRONS. WE TALK ABOUT IS BRACHYTHERAPY AN OPTION FOR THIS PATIENT, SO THERE'S DIFFERENT TYPES OF BRACHYTHERAPY AGAIN, SEALED OR UNSEALED SOURCES, THIS IS AN EXAMPLE OF A TYPE OF BRACHYTHERAPY, INTERSTITIAL BRACHIOTHERAPY, WE PUT INTERSTITIAL CATHETERS, USUALLY DONE IN OTHER COUNTRIES. AND THEN RADIATION IS DELIVERED THROUGH CATHETERS. WE HAVE TO IDENTIFY THE TARGET AND OUR NORMAL TISSUE, UNDERGOING CT SIMULATION, AN EXAMPLE OF A CT IMAGE OBTAINED OF BREAST CANCER PATIENT, LEFT-SIDED BREAST CANCER. YOU CAN SEE IMAGES HERE, AND WE CREATE SOME BEAMS WHICH ARE DEPICTED HERE IN THESE COLORS, SO THIS YELLOW WOULD BE A BEAM WHICH WE CALL SUPER CLAY VIC LAR AND TANGENT AND RADIATION PLAN WORK OF DOSIMETRIST, I REVIEW THE PLAN, RED IS 100% ISODOSE LINES, WE HAVE VARIATIONS, AND WE GET A NICE DOSE OF RADIATION TO THE BREAST TISSUE, AND NORMAL DOSE OF RADIATION TO HEART AND LUNG HERE. WE DELIVER THE TREATMENT, SO WE DELIVER THE TREATMENT, ONE OF THE THINGS WE DO FIRST IS LINE THE PATIENT UP, PATIENTS HAVE SPECIAL MARKS ON THEIR BODIES WHICH WE HAVE A LASER BASICALLY GRID IN THE ROOM WHICH WE CAN USE TO LINE THEM UP. AND NOWADAYS WE HAVE THE ABILITY TO DO IMAGE GUIDED RADIATION THERAPY, YOU CAN SEE WE TAKE AN X-RAY OF THE PATIENT BEFORE WE DELIVER THEIR TREATMENT TO MAKE SURE WE KNOW THE EXACT LOCATION OF WHAT WE'RE TREATING AND CAN MAKE MILLIMETER AND INCREMENTAL SHIFTS IF NEEDED. A SECOND EXAMPLE, THE PATIENT B, THIS IS A PROSTATE CANCER CASE, 54-YEAR-OLD MALE, ELEVATED PSA ON ROUTINE SCREENING, NO PRIOR HISTORY, BIOPSY PERFORMED CONSISTENT WITH ADENOCARCINOMA OF THE PROSTATE, GLEASON SCORE OF 6, THE LOWEST VERSION OF PROSTATE CANCER. AGAIN IF WE THINK ABOUT DEVELOPING A TREATMENT PLAN, WE HAVE TO THINK ABOUT THIS PATIENT IS A LOT OF DIFFERENT OPTIONS, SURGERY, SURGERY AND RADIATION BASED ON SURGICAL FINDINGS, RADIATION ALONE BUT THIS PATIENT WOULD HAVE THE OPTION OF BRACHYTHERAPY OR EXTERNAL BEAM RADIATION OR POTENTIALLY A COMBINATION OR RADIATION AND HORMONAL THERAPY. THIS IS AN EXAMPLE OF A BRACHYTHERAPY PLAN OF A PROSTATE SEED, MANY PEOPLE HEARD OF PROS PROSTATE SEED IMPLANTS. WHAT IS DRAWN OUT HERE THAT I'M CIRCLING IS THE PROSTATE AS SEEN ON TRANSRECTAL ULTRASOUND, PROBE IS HERE IN THE RECTUM AND THIS IS RECTAL TISSUE, THIS IS THE PROSTATE, THAT'S IN DARK GRAY, AND ALL THESE GREEN DOTS SIMULATE RADIATION FEED AND WE CAN GET A HIGH DOSE OF RADIATION TO THE ENTIRE PROSTATE, MINIMAL DOSE TO SURROUNDING TISSUES AND ABILITY, WE SEE A GAP HERE, THIS IS WHERE THE THE URETHRA IS. THIS IS A VMAC TECHNIQUE. RED IS PROSTATE, BLUE IS CTV AND PTV MARGIN, A NICE DOSE DISTRIBUTION TO THE PROSTATE. THIS IS BLADDER AND RECTAL TISSUE, RADIATION CARVES NICELY AROUND BOTH OF THOSE. WE HAVE IMAGE GUIDED RADIATION THERAPY, SO ANOTHER WAY WE CAN DO THAT FOR PROSTATE CANCER PATIENTS ESPECIALLY IS GOLD MARKERS OR CALYPSO SYSTEM, A UROLOGIST CAN PLACE THREE RAIDO FREQUENCY BEACONS INTO THE PROSTATE, AND WE CAN TRIANGULATE THE LOCATION OF THE BEACONS, EACH DAY, AND DURING THE TREATMENT. THE REASON THAT'S IMPORTANT, AS MEN ARE HAVING PROSTATE CANCER TREATMENT THE BLADDER CAN BE FILLING, RECTUM CAN FILL OR A PATIENT CAN PASS GAS ON THE TABLE AND THE PROSTATE CAN MOVE ONE TO TWO CENTIMETERS AT MOVEMENT AND THIS ALLOWS TO TRACK THE PROSTATE IN REAL TIME AND STOP THE RADIATION IF WE SEE A CERTAIN MOTION. THIS IS GOLD FIDUCIAL MARKERS, TRIANGULATE BEACONS WITH PRETTY HIGH CERTAINLY, THIS IMAGE CREATED FROM PLANNING SESSION, AT THE TIME OF PLANNING CT, AND& THIS IMAGE HERE ON THE RIGHT WAS TAKEN RIGHT BEFORE THEIR TREATMENT WAS DELIVERED. WE CAN ROTATE AND MOVE THE œPATIENT. THE FIDUCIAL IS THE SAME FOR BOTH. THE OTHER THING WE HAVE THE ABILITY TO DO IS A CONE BEAM CT, WE CAN TAKE A MINI CAT SCAN OF THE PATIENT BEFORE WE DELIVER THE TREATMENT AND MAKE ADJUSTMENTS BASED ON THAT. IN THIS EXAMPLE OF A PROSTATE CANCER PATIENT WE WANT TO SEE IS THE BLADDER FULLNESS THE SAME TODAY, IMPORTANT IF WE'RE TREATING LYMPH NODE REGIONS BECAUSE THE IT CAN PUSH IT OUT OF THE WAY. IT'S HARD TO SEE IT SO UP TOP MOVING MY CURSOR THIS IS THE IMAGE FROM THE PLANNING SESSION, AND THEN THERE'S A RED BOX HERE WITH RED CORNERS, WHAT IT LOOKS LIKE TODAY DURING THE TREATMENT. YELLOW LINE HOW BIG THE DAY OF PLANNING SESSION, WE CAN SEE HERE RIGHT NOW THAT THIS BLADDER IS ISN'T AS FULL AS DAY OF PLANNING SESSION, THIS EXAMPLE THE PATIENT GETS OFF THE TABLE, DRINKS MORE WATER, FILL THE BLADDER AND MAKE SURE WE'RE GIVING THEM PRECISE TREATMENT WE PLANNED AT THE TIME OF THE PLANNING SESSION. AGAIN CERTAINLY DELIVERING THE TREATMENT. SO JOKINGLY WE SAY IS IT THAT EASY? OF COURSE IT'S NOT. WE HAVE TO TALK ABOUT NORMAL TISSUE TOXICITY AND MANAGING SIDE EFFECTS, THERE CAN BE ACUTE OR SHORT-TERM SIDE EFFECTS DURING RADIATION AND LATE AND LONG-TERM SIDE EFFECTS. WHEN IT COMES TO ACUTE SIDE EFFECTS, WE TELL PATIENTS, ONE, RADIATION AFFECTS THE AREA WE'RE AIMING THE BEAM AT, I JOKE IF I'M TREATING A BREAST CANCER PATIENT AND THEY START TO HAVE DIARRHEA, IT'S NOT FROM ME, BECAUSE I'M NOT GETTING ANY RADIATION TO THEIR GI TRACT. THE OTHER THING CUMULATIVE, AT THE BEGINNING THEY DON'T HAVE ANY, THROUGH THE TREATMENT THEY DEVELOP, ONCE TREATMENT IS DONE THEY TAPER OFF AGAIN. MOST PATIENTS THE WORST TIME FOR RADIATION IS THE WEEK AFTER, BECAUSE THEY HAVE RECEIVED ALL THE DOSE, SO SOME OF THE SIDE EFFECTS ACTUALLY CAN GET A LITTLE BIT WORSE FOR THREE TO FOUR DAYS AFTERWARDS. SO IT'S ALWAYS VERY IMPORTANT FOR US AS CLINICIANS TO MAKE SURE WE COUNSEL PATIENTS ON THAT BECAUSE IT'S PRETTY FREQUENT YOU'LL GET A PATIENTS, PATIENTS SAY IT'S GETTING WORSE, I DON'T KNOW WHAT TO DO, SHOULD I GO TO THE HOSPITAL, NO, THIS IS WHAT WE EXPECT BECAUSE OF HOW RADIATION THERAPY WORKS. WE TALK ABOUT LATE EFFECTS, THINGS THAT OCCUR 90 DAYS AFTER COMPLETION OF RADIATION. THERE'S A SET SERIES OF LATE SIDE EFFECTS DEPENDING ON WHICH PART OF THE BODY WE'RE TREATING WE HAVE TO MONITOR FOR. SO, FOR EXAMPLE, FOR LUNG CANCER PATIENTS, WE HAVE TO MONITOR AFTER TREATMENT FOR SOMETHING CALLED RADIATION PNEUMONITIS, INFLAMMATION OF THE LUNG AS IT'S HEALING FROM TREATMENT. IN ADDITION WE HAVE TO THINK ABOUT STEM CELL DEPLETION, CHRONIC OXIDATIVE DAMAGE, VASCULAR DESTRUCTION, FIBROSIS AND MORE, THINGS THAT ACCOUNT FOR SOME OF THESE LATE SIDE EFFECTS PATIENTS CAN EXPERIENCE. AGAIN, ONE OF THE THINGS THAT'S IMPORTANT TO HEAR IS RADIATION ISN'T DISCOED -- RADIATION IS DOSED TO THE NORMAL TISSUE AND NOT THE TUMOR. I COULD KILL EVERY TUMOR IF I COULD GIVE IT 100 OR 200 GRAY BUT OUR NORMAL TISSUES CAN'T TOLERATE THAT. WHAT WE'RE ALWAYS DOING IN RADIATION ONCOLOGY IS TRYING TO FIGURE OUT HOW MUCH RADIATION CAN NORMAL ORGANS NEXT TO IT CAN TOLERATE, THAT DEFINES HOW MUCH DOSE THE TUMOR GETS. AS I MENTIONED, ONE OF THE THINGS THAT CAN HAPPEN IN THE LONG TERM IS LUNG FIBROSIS, THIS IS THE PATHWAY, NOW AN OLDER SCHEMA, CERTAINLY NOW THERE'S PROBABLY TEN MORE ARROWS TO ADD. WE KNOW WHEN PATIENTS GET READATION THEY ACTIVATE TGF-BETA, THIS IS RESPONSIBLE FOR PATIENTS GETTING RADIATION PNEUMONITIS AND EVEN RADIATION FIBROSIS, THIS IS AN EXAMPLE OF A REALLY, REALLY OLD WAY WE USED TO DELIVER RADIATION, JUST TO POINT OUT THE DATE IS 1992, THIS IS NOT HOW WE DELIVER RADIATION ANYMORE. BUT THIS WAS THE SHAPE OF THE BEAM, AND WHAT YOU CAN SEE HERE, THIS IS A CORRESPONDING CT IMAGE FOR PATIENT WITH LUNG FIBROSIS, YOU CAN SEE EXACTLY WHERE THAT BEAM WENT. IT WENT FRONT TO BACK, ONE EDGE HERE, ONE EDGE WAS HERE. BREAST CANCER SOMETHING WE OFTEN HAVE TO THINK ABOUT IS LYMPHEDEMA. IT IS BECOMING A LITTLE BIT LESS COMMON NOW, AS SURGICAL TECHNIQUES IMPROVED, AS WE ADDED NEOADJUVANT CHEMO AND CHEMOTHERAPY BEFORE SURGERY, BUT THIS STILL IS A PROBLEM THAT SOME WOMEN DO EXPERIENCE, TIMES IT'S BECAUSE THE TUMOR DAMAGED LYMPH NODE, LYMPHATICS, SOMETIMES IT'S PART OF THE TREATMENT, SURGERY AND RADIATION. AND SO WHAT CAN HAPPEN WHEN IT COMES TO RADIATION IS THAT RADIATION -- SO, AGAIN, THIS IS THE -- IT'S ALL ABOUT PRESSURES, HIGH PRESSURE, LOW PRESSURE, HOW THE BLOOD FLOWS THROUGH BUT WHAT CAN HAPPEN IS RADIATION CAN AFFECT THE EXPANSION AND CONTRACTION OF OUR VARIOUS BLOOD VESSELS, CAUSE FIBROSIS LEADING TO PRESSURE CHANGES AND THAT'S HOW THE LYMPHEDEMA BEGINS TO HAPPEN. LEUKOCYTE IS INVOLVES ANY MUCOSAL SURFACE, ESOPHAGEAL, RECTAL, PATIENTS CAN GET SUNBURN ON THE SKIN, THEY CAN GET ON THE MUCOSAL SURFACE,S, STEM CELL DEPLETION TO THE AREA. BELIEVE IT OR NOT THIS RECOVERS WITHIN TWO WEEKS AFTER A PATIENT IS FINISHED BECAUSE YOUR BODY IS ABLE TO HEAL VERY QUICKLY FROM THIS AS LONG AS THERE'S GOOD NUTRITION INVOLVED. BUT THIS IS ONE OF THE MAIN SIDE EFFECTS OF HEAD AND NECK CANCER PATIENTS AND ONE WE'RE MANAGING THE MOST. THIS CAN BE PAINFUL FOR PATIENTS, AFFECTS EATING, TASTE BUDS AND ALL THOSE TYPES OF THINGS. SO SOME FUTURE OF RADIATION, AGAIN WHEN IT COMES TO RADIATION BIOLOGY, WE'RE SEARCHING FOR WAYS TO USE RADIATION TO INDUCE TARGETS FOR OTHER AGENTS, USING RADIATION AS A SENSITIZER, MAINLY FOR CHEMOTHERAPY, STUDIES AT OUR INSTITUTION ARE LOOKING FOR THAT, LOOKING FOR BETTER SENSITIZERS AND PROTECTORS. ONE THERAPY AT OUR INSTITUTION IS HYPERTHERMIA, HEAT THERAPY. THAT WHAT DOES IS IMPROVES BLOOD FLOW AND OXYGENATION AND EFFECT OF RADIATION IF WE GIVE IT WITHIN A CERTAIN TIME FRAME OF RADIATION. WE'RE LOOKING AT COMBINING RADIATION AND TARGETED AGENTS. LOOKING AT IMPROVING TARGETING AND IMAGING ON TREATMENT TABLE AND DELIVERY METHODS AND EQUIPMENT. SO AT OUR INSTITUTION AND OTHERS AROUND HERE THERE'S NO RADIATION THERAPY MODALITIES, PROTON THERAPY, LOOKING AT IMPROVING THE DELIVERY OF RADIATION. AND FROM A CLINICAL VIEWPOINT WE'RE LOOKING TO TRANSLATE OUR EXCITING LABORATORY FINDINGS INTO THE CLINIC. CERTAINLY WE HAVE A VARIETY OF PHASE 1 STUDIES, MANY ACADEMIC INSTITUTIONS DID, CONTINUING TO DEVELOP CLINICIAN SCIENTISTS. ONE OF THE MOST EXCITING THINGS IS LOOKING AT THE SYNERGY WE CAN HAVE WITH IMMUNOTHERAPY AGENTS ESPECIALLY BECAUSE THEY ARE WELL TOLERATED FOR MANY PATIENTS. PROTON THERAPY IS A LITTLE BIT OF A DIFFERENT FORM, PARTICLE AS OPPOSED TO X-RAY, THE DIFFERENCE IS SUMMARIZED IN THIS PICTURE. WITH OUR X-RAY RADIATION, PHOTON RADIATION, THIS IS WHAT THAT CURVE LOOKS LIKE IN THE BODY. IT STARTS IN THE BODY A LITTLE BIT WEAKER, GETS STRONGER, A COUPLE CENTIMETERS INTO THE TUMOR AND WE CAN VARY THE SPACE ON THE ENERGY OF THE PHOTON AND THEN WEAKER AND WEAKER AND WEAKER AS IT PASSES THROUGH. X-RAYS HAVE THIS TAIL WHERE IT GETS WEAKER AND WEAKER. PROTON THERAPY WORKS DIFFERENT, IT STARTS IN THE BODY WEAKER THAN PHOTONS, WE DON'T WORRY ABOUT THIS TOO MUCH. IT GETS STRONG WHERE WE TELL IT TO IN THE TUMOR AND THEN STOPS AND HAS THIS SHAPE AND THIS IS CALLED THE BRAGG PEAK. WE CAN AVOID THIS AREA HEAR AND WHAT'S IN THIS AREA ARE INCIDENTAL NORMAL TISSUES GETTING RADIATION THAT DON'T REALLY NEED IT. BREAST CANCER, I CAN AVOID RADIATION DOSE TO A WOMAN'S HEART, OFTEN AVOID DOSE TO THE LUNG. FOR CNS TUMORS AVOID DOSE TO THE BRAINSTEM OR OPTIC CHIASM OR COCHLEA. PROTON THERAPY AND PHOTON THERAPY FOR BEST CANCER PATIENT, YOU CAN SEE THE SHAPE OF THE RED, ABOUT THE SAME. NOT TOO MUCH DIFFERENT. WHEN WE LOOK AT THESE LOW AND MODERATE DOSES OF RADIATION IN THE YELLOW AND GREEN, THIS HERE IS THE HEART IN THE MIDDLE, WITH PHOTON THERAPY THIS IS THE BEST PLAN, WE STILL ARE BATHING THE HEART IN THE GREEN DOSE, LESS PROTON THERAPY YOU DON'T THAT. THERE'S THESE GRAY CIRCLES HERE WHICH ARE WHERE THE CORONARY ARTERIES LIE, WE HAVE AVOID THOSE WITH PROTON RADIATION. THIS IS A SUBTRACTION IMAGE. THIS MIGHT BE IMPORTANT FOR BREAST CANCER PATIENTS, FOR EXAMPLE, THERE'S BEEN THREE BIG STUDIES PUBLISHED IN THE LAST COUPLE YEARS SHOWING THE LOWER DOSE OF RADIATION TO THE HEART WE CAN GET THE LEST HEART SIDE EFFECTS WOMEN HAVE DOWN THE LINE LIKE HEART ATTACK, HEART FAILURE DOWN THE LINE. THE LOWER WE GET THAT THE BETTER. AGAIN, PROTON THERAPY CAN BE A TOOL TO DO THAT IN THIS EXAMPLE. WE HAVE A PROTON CENTER IN BALTIMORE, RIGHT NEXT TO THE HOSPITAL, THE MARYLAND PROTON TREATMENT CENTER. AND THE MOTTO IS THAT WE'RE A RESOURCE TO A LOT OF PROVIDERS IN THE AREA, WE'VE PARTNERED WITH INSTITUTIONS LIKE GEORGETOWN, NOVA FAIRFAX, FOLKS IN PENNSYLVANIA, SO ALL PATIENTS HAVE ACCESS TO THE BEST MODALITY. WE HAVE FIVE TREATMENT ROOMS, UNIQUE GROUP OF PROCESS TO TREAT 150 TO 190 PATIENTS HER DAY, WE'RE NOT THERE YET, USUALLY AROUND 100 NOW. RADIATION IS A TOOL USED IN CANCER THERAPY. IT WORKS BY CAUSING DNA DAMAGE WHICH CAN ULTIMATELY LEAD TO CELL DEATH. THE EFFECTS OF RADIATION CAN BE ALTERED BY VARIETY OF DIFFERENT FACTORS SUCH AS PHYSICAL FACTORS, PHYSIOLOGIC FACTORS, FRACTIONATION, DRUGS, AND OTHER VARIABLES, AND WE'RE CONSTANTLY LOOKING AT WAYS TO IMPROVE AND GIVE THE PATIENT THE BEST BENEFIT. RADIATION CAN CAUSE COMPLICATIONS AND THEN LASTLY RADIATION IS INTERESTING. ANY QUESTIONS? [APPLAUSE] YES. >> (INAUDIBLE). >> SURE. YOU SAID INAPPROPRIATE? >> YES. >> OKAY. >> (INAUDIBLE, OFF MIC) >> SURE, YEAH. GOOD QUESTION. FOR THE ONLINE PEOPLE, THE QUESTION WAS WHICH PATIENTS ARE INAAPPROPRIATE CANDIDATES FOR RADIATION, CERTAINLY ONE OF THE MAIN FACTORS IS CHILDREN, SO WE KNOW RADIATION ACTUALLY HAS POTENTIAL TO INDUCE CANCER DOWN THE LINE, NOW THAT RISK IS RARE, 1 IN 10 TO 20,000, AND 10 TO 20 YEARS FROM NOW, PEDIATRIC TUMORS LOOKING AT WAYS TO DECREASE DOSE OF RADIATION WE NEED TO DELIVER OR POTENTIALLY TRY TO AVOID RADIATION IN CERTAIN CANCERS SO EVEN IF WE LOOK AT PEDIATRIC MALIGNANCIES OVER LAST 10, 20 YEARS, IT'S A GOOD THING FOR PATIENTS, SOME REMOVED RADIATION. WE CAN'T GIVE RADIATION TO PREGNANT WOMEN BECAUSE THE FETUS IS SUSCEPTIBLE TO RADIATION DAMAGE. SO IF WE DO HAVE SOMEONE WITH A PREGNANCY, THAT WOULD BE A CONTRAINDICATION TO RADIATION. AND THERE ARE SOME RELATIVE CONTRAINDICATIONS TO RADIATION. THERE'S CERTAIN CONNECTIVE TISSUE DISEASES LIKE SCLERODERMA IS THE BIG ONE, PATIENTS ALREADY ARE AT RISK FOR A LOT OF FIBROSIS IN THEIR BODY IN GENERAL AND RADIATION CAN INDUCE FIBROSIS, THAT'S A CONDITION WE OFTEN WILL TRY TO THINK TWICE AND MAYBE DEVELOP A TREATMENT PLAN THAT MAYBE DOESN'T INVOLVE RADIATION FIRST AND ONLY GIVE RADIATION MAYBE IF TREATMENT PLAN A DOESN'T WORK. SOME OF THE OTHER DISEASES LIKE RHEUMATOID ARTHRITIS AND OTHER CONNECTIVE TISSUE DISEASES WE'RE FINDING IT'S OKAY ESPECIALLY WITH NEWER TECHNIQUES. ANOTHER CONTRAINDICATION IS WE ALWAYS, IF A PATIENT HAS RECEIVED RADIATION AT THAT BODY SITE ONCE ALREADY, IT'S AGAIN SOMETHING WE NEED TO THINK TWICE ABOUT BECAUSE NORMAL ORGANS MIGHT NOT BE ABLE TO TOLERATE ADDITIONAL RADIATION WITHOUT PERMANENT DAMAGE LIKE THE SPINAL CORD. A LOT OF THINGS GOING INTO THAT, IT'S RELATIVE. THE BOOK ANSWER IS NO BUT A LOT OF SOMETIMES WE CAN SAFELY GIVE EXTRA RADIATION USING MAYBE PROTON THERAPY OR MAYBE GIVING IT TWICE A DAY INSTEAD OF ONCE A DAY AND SO FORTH. THOSE ARE SOME EXAMPLES. YEAH, WE DON'T JUST OFFER IT TO EVERYONE, BUT THERE ARE SOME CONTRAINDICATIONS AND THE LAST ONE THAT MIGHT BE RELEVANT FOR THIS GROUP THERE ARE CERTAIN GENETIC CONDITIONS WHETHER WE TRY TO AVOID IT SPECIFICALLY THINGS LIKE ATEXIA, A CLINIC HERE WE ALWAYS TRY TO MINIMIZE RADIATION IN THOSE PATIENTS, BECAUSE WE KNOW THAT THEY ARE HIGH RISK OF DEVELOPING RADIATION-INDUCED MALIGNANCY. AND THE SECOND QUESTION WAS -- OH, YEAH. THE PATIENT A EXAMPLE, THE INTERSTITIAL BRACHYTHERAPY PICTURE I SHOWED, PART OF THE REASON IS NOT IN FAVOR, WE CAN DO IT HERE IN THE U.S. BUT IT'S NOT KIND OF THE FAVORED TREATMENT. ONE, BECAUSE AS THE PICTURE LOOKS IT CAN BE MORBID FOR PATIENTS TO -- THEY HAVE CATHETERS IN THE BREAST AND THAT EXAMPLE FOR LIKE A WEEK OR TWO WEEKS. SO IT CAN BE DIFFICULT TO WALK AROUND WITH THAT AND SO FORTH. ALSO IT DOES TAKE A HIGHER SKILL SET AND SOME SPECIAL MACHINERY TO HAVE THAT AND A LOT OF OFFICERS ESPECIALLY SMALLER ONES OPT NOT TO INVEST IN THOSE TECHNOLOGIES AND IF THEY HAVE A PATIENT WHO NEEDS THAT THEY WOULD SEND THEM TO ONE OF THE UNIVERSITIES LIKE US OR HOPKINS OR GEORGETOWN OR SOMETHING LIKE THAT. SO THERE'S ALSO IT'S KIND OF A LITTLE BIT OF A DYING ART, WHERE FEWER PEOPLE ARE DOING IT AND GETTING EXPOSED BUT THE CONVERSE IS WE HAVE OTHER THERAPIES THAT HAVE TAKEN ITS PLACE THAT HAVE THE SAME OUTCOMES. >> (INAUDIBLE). >> UH-HUH. >> (INAUDIBLE). >> RIGHT. YEP. >> (INAUDIBLE). >> THE YES IS THE EXAMPLES OF PROSTATE CANCER PATIENTS WHERE THERE'S A PUSH TO HAVING RADIATION ONCOLOGY INVOLVED AN CONSULTED UP FRONT BEFORE PATIENTS DECIDE ON TREATMENT. SO THIS IS STILL A BIG ISSUE IN OUR COUNTRY TOO. AND SO PART OF IT IS IF WE TAKE THE PROSTATE CANCER EXAMPLE, WAY PROSTATE CANCER IS DIAGNOSED IS BY A UROLOGIST DOING A BIOPSY, THE UROLOGIST WILL GIVE PATIENTS THE RESULTS AND THEY ARE THE FIRST STEP INTO KIND OF THE OPENING THE DOOR TO THE CANCER DISCUSSION, AND SO THEY TALK ABOUT THE DIFFERENT MODALITIES AND CERTAINLY AS A SURGEON THEY KNOW SURGERY BEST. SO THERE HAS BEEN A MOVEMENT IN THE U.S. AS WELL, MANY COUNTRIES THAT HAVE THE RESOURCES WHERE IT IS VERY HIGHLY RECOMMENDED BY LIKE RADIATION ONCOLOGY SOCIETIES AND EVEN UROLOGIC SOCIETIES, THAT WHEN A PATIENT FOR EXAMPLE WITH PROSTATE CANCER GETS A NEW DIAGNOSIS THEY SHOULD MEET WITH A RADIOLOGIST TO SEE OPTIONS, THEY CAN'T COUNSEL A PATIENT ON ALL THE INS AND OUTS OF RADIATION ONCOLOGY. A LOT OF METROPOLITAN AREAS LIKE THIS THERE ARE CANCER PROGRAMS BUILT TOGETHER WHERE THEY ARE GROUPS THAT WORK TOGETHER ALL THE TIME. SO LIKE WE HAVE CERTAINLY UROLOGIC SURGEONS, RADIATION ONCOLOGISTS, MEDICAL ONCOLOGISTS, ALL THE SPECIALTIES, AND SO WHAT A LOT OF PLACES DO, MULTI-DISCIPLINARY CONFERENCES WHERE ONCE A WEEK WE ALL GET TOGETHER AND TALK ABOUT THE NEW CASES, TALK ABOUT THE DIFFERENT TREATMENT OPTIONS FOR THAT PATIENT AND USUALLY COME UP WITH A CONSENSUS RECOMMENDATION, THIS IS WHAT WE THINK WOULD BE BEST FOR YOU OR THESE TWO ARE EQUAL, HERE IS THE PROS AND CONS YOU AND YOUR FAMILY NEED TO DECIDE WHAT'S BEST. I THINK IN THE REST OF COUNTRY, TO BE HONEST MAJORITY OF THE COUNTRY, IT'S A BIGGER PROBLEM, WHERE I HEAR STILL EVEN IN THIS AREA SOMETIMES ALL THE TIME LIKE THEY NEVER TOLD ME I WOULD GET RADIATION OR NEVER TOLD ME TO MEET WITH A RADIATION ONCOLOGIST AND NOW MY CANCER IS BACK. IT DOES HAPPEN, THERE'S ROOM FOR IMPROVEMENT IN OUR COUNTRY AS WELL. BUT, AGAIN, IT GOES TO THE BIGGER PICTURE I THINK OF OVERALL HEALTH CARE ISSUES, INSURANCE ISSUES, ALL THOSE TYPES OF THINGS. >> (INAUDIBLE). >> THE QUESTION IS ABOUT WHY DO SOME DO BETTER WITH MORE OXYGENATION. MORE OXYGEN IN THE TISSUES, A FREE RADICAL, THE RADIATION COMES IN, KICKS OFF THAT ELECTRON, CREATES FREE RADICAL AND THEN THAT OXYGEN MOLECULE IS NEXT TO DNA IT CAN CAUSE INDIRECT DAMAGE. SO THAT'S HOW THAT WORKS. THAT'S ACTUALLY HOW THE MAJORITY OF RADIATION DAMAGE WORKS WITH PHOTONS AT LEAST. THAT'S OUR BIGGEST EFFECT. FOR THAT REASON THAT'S WHY WE COUNSEL PATIENT NOT TO TAKE A LOT OF ANTIOXDANTS, BECAUSE THERE'S HYPOTHESIS THAT IT WILL REDUCE THAT RATIO. THAT WAS THE LAST QUESTION. THANK YOU ALL SO MUCH. [APPLAUSE] OUR LAST SPEAKER IS JIM KOCHENDERFER, WITH THE EXPERIMENTAL TRANSPLANT AND IMMUNOLOGY BRANCH, M.D. FROM WEST VIRGINIA, RESIDENCY AT VANDERBILT, INTERNAL MEDICINE, AND DID A HEMATOLOGY AND ONCOLOGY FELLOWSHIP AT M.D. ANDERSON AND BAYLOR, AND HE'S BEEN HERE FOR ABOUT A DOZEN YEARS, THE TITLE CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY. JIM? >> ALL RIGHT. THANK YOU VERY MUCH FOR INVITING ME, TERRY. I'LL GO AHEAD AND GET STARTED. SO, I'VE BEEN WORKING ON CAR T CELLS AND NOTHING ELSE SINCE 2007. FIRST I DID TWO POSTDOCS, ONE WITH STEPHEN ROSENBERG, ASSISTANT CLINICAL INVESTIGATOR, CLINICAL INVESTIGATOR DEVELOPMENT PROGRAM, SO -- NOW I'M A TENURE-TRACK INVESTIGATOR, BEEN WORKING ON THIS QUITE A WHILE. FIRST PART OF THE TALK IS ABOUT LYMPHOMA WITH CAR T CELLS. CAN EVERYBODY HEAR? OKAY, IS THAT BETTER? >> THIS ONE WORKS BETTER. >> OKAY, ALL RIGHT. THANKS. LYMPHOMA FIRST, FOR THOSE NOT FAMILIAR WITH CAR T CELLS, A CAR IS A FEW PROTEIN WITH A MOIETY DERIVED FROM MONOCLONAL ANTIBODY WHICH -- OOPS, SORRY. WHICH WE SEE -- IN THIS PART, YOU CAN'T REALLY SEE THE LASER, CAN YOU? SO AFTER THE MOIETY WE HAVE MEMBRANE DOMAIN, THAT'S BETTER, WHICH IS HERE. THERE'S ALMOST ALWAYS CD28 OR 4NBB, T CELL ACTIVATION DOMAIN, FUSION PROTEIN ENCODED BY DNA, DNA IS PUT IN SOME TIME OF VECTOR SUCH AS LENTIVIRUS, AND THIS VECTOR IS USED TO TRANSDUCE T CELLS, T CELLS TRANSFUSED, BECOMES A PERMANENT PART, GIVES THE T CELL TUMOR ANTIGEN IN THIS CASE CD19. ROSENBERGS LAB WORKING ON CD19, I MADE THIS CAR IN 2007, PUBLISHED RESULTS IN 2009, IT IS A CAR THAT HAS THE (INDISCERNIBLE) ANTI-CD19 MONOCLONAL ANTIBODY WITH DOMAIN FROM CD28, AND TC ACTIVATION DOMAIN. THE WAY WE PRODUCE CELLS, ONE OF THE SECRETS OF I THINK SUCCESS FOR SURGERY BRANCH AT NCI IS IT'S A SIMPLE SELF PRODUCTION PROCESS, THE CELL HERE HAS GROWN OR CULTURED IN AN INCUBATOR, AND THEN ONCE THE CELLS AFTER 7 TO 10 DAYS ARE READY TO INFUSE. IN VITRO ASSAYS, I DON'T HAVE TIME TO SHOW THAT. I'LL GO TO ONE OF THE EARLIER CLINICAL TRIALS, ONE OF THE EARLIER COHORTS IN THE TRIAL, AND THIS TRIAL WE USED FAIRLY HIGH DOSES OF CHEMOTHERAPY FOLLOWED BY INFUSION OF CAR T CELLS, WITH TWO CHEMOTHERAPY AGENTS, THE TOTAL DOSE, FIVE DAYS, MINUS 7 AND MINUS 6, CAR T CELL INFUSION ON DAY ZERO. THIS EXAMPLE, ONE OF THE PATIENTS WE TREATED, CHEMOTHERAPY REFRACTORY PRIMARY MEDIAL PANEL B CELL LYMPHOMA, ONE OF MANY TIMES OF LARGE B CELL LYMPHOMAS, OCCURRED AFTER FOUR PRIOR LINES OF TREATMENT, HAS ONGOING COMPLETE REMISSION, NOW ACTUALLY 70 MONTHS LONG, I NEED TO UPDATE THIS SLIDE. YOU CAN SEE THIS YELLOW ORANGE CIRCULAR SHAPE IS METABOLICALLY ACTIVE LYMPHOMA, THE MIDDLE PART IS NECROTIC, IT'S NOT LIGHTING UP. THIS MASS IS PRESENT DESPITE FOUR PRIOR LINES OF THERAPY INCLUDING RADIATION THERAPY, 23 MONTHS LATER DID ANOTHER SCAN, THIS MASS IS GONE, THIS IS AFTER THE 23-MONTH AFTER THE CAR T CELL TREATMENT. SO SUMMARIZE THIS PART OF THE TALK, WE HAD SEVEN PATIENTS ARE LYMPHOMAS, FIVE OUT OF SEVEN PATIENTS ATTAIN COMPLETE REMISSION, FOUR HAD LONG DURATION OF REMISSION, 70, 67, 38 AND 48 MONTHS. THESE ARE THE PATIENTS IN THE WHOLE WORLD WITH DIFFUSE B CELL LYMPHOMA WITH THE LONGEST FOLLOW-UP, AND THEY'VE HAD COMPLETE REMISSIONS THAT LASTED A LONG TIME. THIS IS ALL PUBLISHED IN MOLECULAR THERAPY IN 2017. SO MORE DETAIL, THESE PATIENTS HAD THESE TYPES OF LYMPHOMA, PRIMARY MEDIASTINAL, YOU MAY HAVE NOT HEARD OF THAT BEFORE IF YOU'RE NOT A HEMATOLOGIST, ONE TYPE OF DIFFUSE LARGE B CELL LYMPHOMA. TWO HAD THAT, TWO HAD DIFFUSE LARGE B CELL LYMPHOMA, NOT OTHERWISE SPECIFIED. REMISSION, DURATION OF RESPONSE IS IMPRESSIVE, PATIENTS ARE LIVING -- THREE LIVING NORMAL LEVELS, COMPLETELY FREE OF LYMPHOMA FOR ALL THESE MONTHS, 70, 67, 48. PATIENT AGE WAS LYMPHOMA FREE FOR 38 MONTHS, AND CONTINUED TO BE LYMPHOMA FREE BUT UNFORTUNATELY DEVELOPED OTHER DISORDER, DYSPLASTIC SYNDROME, DISORDER OF BONE MARROW KNOWN TO BE CAUSED BY CHEMOTHERAPY, SHE HAD TON OF CHEMOTHERAPY BEFORE SHE GOT CAR T CELLS, SO SHE WAS DEVELOPED THIS SYNDROME AND HAD TO GO TO ALLOGENEIC STEM CELL TRANSPLANT, WHICH IS THE TREATMENT, THAT HAPPENED 39 MONTHS AFTER CAR T CELL TREATMENT SO WE CAN'T REALLY EVALUATE HER RESPONSE AFTER 38 MONTHS BECAUSE SHE HAD THE ALLOGENEIC STEM CELL TRANSPLANT. THIS COLUMN HAS THE MONTHS AFTER INFUSION BUT CAR T CELLS STILL DETECTABLE IN THE PATIENT'S BLOOD. SO PATIENTS 2 AND 7 HAD FAIRLY SHORT DURATIONS OF T CELL DETECTABILITY, PATIENT 2 ONLY FIVE MONTHS, PATIENT 7 FOUR MONTHS, PATIENT 8 HAVE A LOW LEVEL OF PPMC DETECTABLE AND 39 MONTHS, .08%, PATIENT 15 .02% DETECTABLE. WE DETECT CAR T CELLS BY PCR, QUANTITATIVE PCR ASSAY BECAUSE THE CAR IS AN ARTIFICIAL GENE WE CAN DESIGN PRIMERS TO DETECT THE CAR, ANY OTHER GENE IN THE HUMAN GENOME, SO WE CAN DETECT THIS CAR BY PCR FLOW CYTOMETRY, WE USE PCR ASSAY. THE LEVEL OF .02% DETECTABLE, STILL A LOW LEVEL OF CELLS. ALSO I SHOULD MENTION PATIENTS 2, 7 AND 8 HAD LYMPHOMA. ONE OF THE THINGS PEOPLE ARGUE ABOUT IS IMPORTANCE OF PERSISTENCE OF CAR T CELLS, TWO MAIN THEORIES, FIRST OF ALL CAN KILL ALL LYMPHOMAS AFTER INFUSION SO LONG-TERM T CELL PERSISTENCE IS NOT IMPORTANT, THE OTHER THEORY IS CAR T CELLS -- A FRACTION CAN GET ELIMINATED. THE CAR T CELLS NEED TO PERSIST TO SUPPRESS LYMPHOMA RELAPSE. THEORY TWO, NUMBERS ARE AT THEIR HIGHEST BUT CAN SUPPRESS LYMPHOMA FOR YEARS AFTER INFUSION. WE HAD A SIMPLE WAY TO ASSESS THIS. MEASURE THE RECOVERY OF THE NORMAL B CELLS IN THE PATIENT'S BLOOD AFTER CAR T CELL INFUSION. SO THIS GRAPH SHOWS LEVEL OF THE NORMAL B CELL IN THE PATIENT'S BLOOD, THESE ARE NORMAL POLYCLONAL CD19 POSITIVE B CELLS, AND BELOW WE SHOW THE RECOVERY B CELLS EXPRESS CD19, AND SO HERE WE HAVE B CELL LEVEL, ON THE Y-AXIS, THE MONTHS POST CAR T CELL INFUSION ON X-AXIS, DASHED LINE A NORMAL LEVEL OF B CELLS. SO NORMAL LEVEL OF B CELLS IS 61, THAT'S WHERE THE DASHED LINE IS. SO WE CAN SEE EARLY ON AFTER TREATMENT ALL FOUR OF THESE PATIENTS HAD NO DETECTABLE B CELLS IN THEIR BLOOD. SO THAT'S THE CAR T CELLS, COMBINED WITH CHEMOTHERAPY, DID ELIMINATE B CELLS EARLY ON, AND LIKE EIGHT MONTHS AFTER TREATMENT BEFORE THEY START TO RECOVER AT ALL. SO WE KNOW THIS CHEMOTHERAPY B CELLS RECOVER WITHIN TWO TO THREE MONTHS. SO THE CAR T CELL ELIMINATE THROUGH TIME AFTER INFUSION BUT B CELLS RECOVER IN THREE OUT OF FOUR PATIENTS, ALL THE PATIENTS EXCEPT PATIENT 8. SO DESPITE THE FACT NORMAL CD9 POSITIVE B CELLS RECOVER, THE PATIENTS STAYED IN COMPLETE REMISSION. SO RECOVERY OF THE NORMAL B CELLS SHOWED THERE'S NOT REALLY AN EFFECTIVE CAR T CELLS POPULATION BECAUSE THEY WOULD KILL THE NORMAL CD19 POSITIVE B CELLS. BUT THE FACT THEY DID NOT KILL TELLS US THERE'S NOT A FUNCTIONAL EFFECT OF CAR T CELL POPULATION IN THESE PATIENTS. AND AGAIN THESE GRAPHS GO OUT TO HERE, PATIENTS HAVE NORMAL CD19 POSITIVE B CELLS, YET LYMPHOMA DID NOT RELAPSE. ALL THE WAY OUT TO THE END OF THE GRAPH. THIS TELLS US THAT THE LYMPHOMA WAS MOST LIKELY ELIMINATED EARLY ON, AND THEN THE CAR T CELLS PROBABLY DIED OUT OR BECAME FUNCTIONALLY INEFFECTIVE. WE SHOWED IN THE LAST GRAPH THAT THE CAR T CELLS ARE NOT DETECTABLE IN TWO OUT OF FOUR, THE OTHER HAD EXTREMELY LOW LEVELS BUT AFTER TIME WE KNOW LYMPHOMA IS NEGATIVE BUT THE B CELLS RECOVER. AND THESE ARE POLYCLONAL SHOWN BY STAINING, NORMAL PHENOTYPE BY IGD STAINING. WE SOMETIMES GIVE IMMUNOGLOBULIN TO THE PATIENTS TO HELP REPLACE IMMUNOGLOBULINS NOT BEING PRODUCED BECAUSE THE PATIENT LACKS B CELLS, SO THE PATIENTS DID GET INTRAVENOUS REPLACEMENT HERE. IgG RECOVERED IN THREE OUT OF FOUR PATIENTS, IgM DETECTABLE IN THREE OUT OF FOUR PATIENTS, IgA ONLY RECOVERED IN ONE PATIENT. SO SEEMED LIKE WE'VE SEEN IgA SEEMS TO RECOVER. SO DIFFUSE LEVEL B CELL LYMPHOMA, LONG-TERM COMPLETE REMISSION LASTING FOUR YEARS, CONTINUING AFTER DISAPPEARANCE OF FUNCTIONAL CAR T CELLS, INFECTIONS NOT BEEN A MAJOR PROBLEM. ONLY ONE HOSPITALIZATION WAS REQUIRED FOR INFECTION. INFECTIONS HAVE NOT BEEN A MAJOR PROBLEM. EFFORT TO REDUCE TOXICITY WE CHANGED TO LOW DOSE CHEMOTHERAPY REGIMEN. SO NOW WE'RE GETTING INTO MORE RECENT WORK, AGAIN USING SAME CAR SAME CELL PRODUCTION PROCESS, REDUCE CHEMOTHERAPY DOWN FOR THREE DAYS, AND 30 MILLIGRAMS FOR THREE DAYS. THIS IS LIKE HALF TO ONE-THIRD OF CHEMOTHERAPY DOSE OF PREVIOUS REGIMEN I TALKED ABOUT. SO TWO DAYS OFF, THEN CELL INFUSION. WE DID THE CHEMOTHERAPY BECAUSE CAR T CELL INFUSION BECAUSE THERE'S A LOT OF EVIDENCE THAT SHOWS THE DEPLETING LYMPHOCYTES FROM MICE ENHANCES EFFECT OF TRANSFERRED CELLS, SO THIS IS SHOWN FIRST BY SOMEONE NAMED DR. NORTH WHO PUBLISHED PAPERS IN 1980s AND RECENTLY IN THE SURGERY BRANCH AT NCI. WHEN LYMPHOCYTES ARE DEPLETED FROM MICE, CERTAIN CYTOKINES DRAMATICALLY, CYTOKINES SUCH AS IL-7 AND IL-15 GO UP, NORMALLY CYTOKINES SURVIVE AND GROW, THERE'S NO T CELLS TO USE THE CYTOKINES, CYTOKINE LEVELS CONTINUE, IN THE BLOOD. THIS IS ALSO SHOWN IN HUMANS NOT SO MECHANISTICALLY AS MICE BUT MOST ALMOST ALL PRODUCTS INCLUDING CAR T CELL ARE PRECEDED BY CHEMOTHERAPY BECAUSE OF THIS EFFECT. IT'S TO ENHANCE T CELLS. SO WE DID THIS WORK, MEASURING CYTOKINES IN THE BLOOD OF THE PATIENT, 22 PATIENTS IN THEY THIS PROTOCOL, INDEED JUST LIKE THE MICE IL-15 GOES UP, IL-7 WENT UP, AND NCT 1 WENT UP, SOME OTHER CYTOKINES MODULATED ALSO BUT THESE ARE THE MOST PROMINENT. IL-15 IS IMPORTANT FOR CD8 T CELL PROLIFERATION SURVIVAL AND ACTIVATION. IT MAKES SENSE THESE WOULD HELP CAR T CELLS SURVIVE. PATIENT 35 INDICATED BY WHITE ARROW LARGE MASS OF LYMPHOMA IN RED, THIS IS KIDNEY, THAT'S BLADDER. YOU CAN SEE KIDNEYS HERE AGAIN AND HERE IN THE WHITE ARROW THE MASS IS GONE, PATIENT IN COMPLETE REMISSION 12 MONTHS AFTER TREATMENT WITH CAR T CELLS. ANOTHER PATIENT WITH A BIG RED MASS HERE INDICATING THE BRAIN IN RED, NOT A PROBLEM, HEART IS ACTIVE, A LOT OF DYE, KIDNEY IN RED. THE IMPORTANT PART ABOUT THE WHITE ARROW, BIG LYMPHOMA MASS HERE, AND ABDOMEN HERE, TUMOR FAILURE IS GONE. SAME PATIENT, DIFFERENT VIEW, THIS IS CT SCAN IN A DIFFERENT CUT, YELLOW AREA IS LYMPHOMA, INDICATED BY WHITE ARROW, TEN MONTHS LATER IT'S GONE. THIS PATIENT WAS VERY BAD SHAPE, LYMPHOMA REFRACTORY TO THREE COMMON LYMPHOMA REGIMENS, GDP AND R-EPOCH, TO TREAT LYMPHOMA, LYMPHOMA PROGRESSED, SHE WAS IN BAD SHAPE, CAR T CELL PUT HER INTO THIS COMPLETE REMISSION AND THAT WAS IN 2015, STILL IN COMPLETE REMISSION NOW. THE PREVIOUS PATIENT SHOWED COMPLETE REMISSION. THE OVERALL RESULT WERE AT 22 PATIENTS, OVERALL RESPONSE RATE 73%, COMPLETE REMISSION, COMPLETE DISAPPARANCE, 55%, PARTIAL REMISSION AT LEAST 50% SHRINKAGE AND 18%. AMONG THE 22 PATIENTS, 19 HAD B CELL LYMPHOMA, 68% OF THOSE OBTAINED COMPLETE REMISSIONS. WE HAD TWO PATIENTS WITH FOLLICULAR LYMPHOMA, COMPLETE REMISSION, ONE ALSO OBTAINED COMPLETE REMISSION WITH MANTLE CELL. WHEN YOU TALK TO PATIENTS AND PHYSICIANS THEY DON'T WANT TO HAVE A RESPONSE THAT LASTS THREE MONTHS. THE MOST IMPORTANT THING ABOUT CAR T CELL THERAPY IS RESPONSES ARE INDEED VERY DURABLE. SO WE HAVE 11 -- 12 PATIENTS WITH COMPLETE REMISSION, 11 STILL ONGOING AS FAR AS WE KNOW. HERE IS THE FOLLOW-UP WE HAVE, PLUS SIGN INDICATES RESPONSES STILL ONGOING, 48 MONTHS, 19 MONTHS, THAT WAS THE ONLY PATIENT TO RELAPSE, 46, 39, 41, STILL IN REMISSION. THIS PATIENT WITH 13 MONTH REFUSED TO COME BACK FOR FURTHER VISITS, WE DON'T KNOW WHAT HAPPENED AFTER 13 MONTHS BUT AT THAT POINT WAS IN COMPLETE REMISSION. YOU CAN SEE QUITE A BIT OF DURABILITY, IT WAS A SUCCESSFUL TRIAL. BUT THERE IS A DOWN SIDE, THAT'S TOXICITY. THE MOST TROUBLESOME THING WAS NEUROLOGIC TOXICITY, THE TYPE WE SAW WAS THINGS LIKE CONFUSION, DYSPHAGIA, INABILITY TO SPEAK, ENCEPHALOPATHY, GAIT DISTURBANCE, TREMORS MANIFESTED AS HANDSHAKING. TENSION, LOW BLOOD PRESSURE, MOST WERE NEUROLOGIC, ALL TOXICITIES COMPLETELY RESOLVED USUALLY WITHIN TWO WEEKS. SOMETIMES IT TOOK LIKE A MONTH FOR THINGS TO COMPLETELY RESOLVE BUT USUALLY TWO WEEKS THESE THINGS WENT AWAY. ONE THING ABOUT CAR T CELL TOXICITY, SEVERE BUT SHORT. ALSO COMPARED TO OTHER DISEASES NEUROLOGIC TOXICITY MORE PROMINENT FOR , ASSOCIATION OF PEAK LEVELS WITH RESPONSE, PATIENTS THAT OBTAINED RESPONSE OF COMPLETE REMISSION OR PARTIAL REMISSION, HIGH LEVELS, DETECTED BY PCR IN THIS CASE. AND IF WE LOOK AT NEUROLOGIC TOXICITY THE PATIENTS WITH THE SEVERE NEUROLOGIC TOXICITY OF GRADE 3 OR 4 HAD HIGHER LEVELS OF PEAK CAR T CELLS IN THE BLOOD COMPARED TO PATIENTS WITH LESS THAN GRADE 3 NEUROLOGIC TOXICITY. SO THE CAR T CELLS RESPONSE AND TOXICITY. WE FOUND IL-15 TO BE IMPORTANT CYTOKINE IN THESE PATIENTS, YOU CAN SEE PEAKS OF IL-15 IN THE PATIENT WITH COMPLETE REMISSION, PARTIAL REMISSION, ONLY VERY MUCH LOWER IN PATIENTS WITH DISEASE PROGRESSIVE DISEASE, THE SAME THING WITH IL-10, PATIENTS WITH HIGH PEAK OF IL-10 MORE LIKELY TO HAVE COMPLETE OR PARTIAL REMISSION, SIGNIFICANT, SO CYTOKINES ARE IMPORTANT. IL-15 THE MOST IMPORTANT CYTOKINE, MORE INFORMATION IN THE PAPER. SO ALL THIS WORK I MENTIONED SO FAR LED TO TRIALS AND COLLABORATION WITH PHARMACEUTICAL COMPANIES, THE COMPANY WHICH WE WORKED WITH WAS KITE PHARMA, WE CAN DISCLOSE THAT NOW, WE DID HAVE RELATIONSHIPS WITH KITE PHARMA, I STILL HAVE CRADAS WITH KITE PHARMA. THIS LED TO TRIALS WITH CARS TESTED IN CLINICAL TRIALS AROUND THE WORLD, ASIA, EUROPE, U.S., THERE'S AT LEAST EIGHT TRIALS IN THE U.S. FOR DIFFERENT DISEASES, BUT ONE OF THE BIG TRIALS IS ZUMA 1, AN EXTENSION OF THE WORK I SHOWED, SAME REGIMEN AND PROCESS, COMPANY TREATED 101 PATIENTS, MULTI-CENTER TRIAL, 99%, RESPONSE RATE OF 82%, COMPLETE REMISSION IN 54%, SIMILAR RESULTS. 15.4 MONTHS OF FOLLOW-UP, OVERALL RESPONSE RATE WAS MAINTAINED AT 42%. 13% OF PATIENTS HAD GREATER THAN GRADE 3 CRS, 28% OF PATIENTS HAD GRADE 3 NEUROLOGIC TOXICITY. SO LOWER THAN WE HAD BUT STILL SIGNIFICANT AMOUNT. 43% MUTATIONS RECEIVED IMMUNOSUPPRESSIVE MEDICATIONS. MAINLY 42% RECEIVED AN IL-6 BLOCKER, 27% CORTICOSTEROIDS TO TREAT CAR TOXICITY. MUCH ROOM FOR IMPROVEMENT REMAINS. 55% OF PATIENTS OBTAINED COMPLETE REMISSION AT THE NCI, IT'S A SIMILAR PERCENTAGE ELSEWHERE. NEUROLOGIC TOXICITY A MAJOR PROBLEM. PUBLISHED RESULTS HAVE SHOWN THAT THERE CAN BE RECIPIENT T-CELL RESPONSE, MURINE CAR T CELL PROTEIN SEQUENCES, SO THAT'S ANOTHER PROBLEM. IMMUNE RESPONSE AGAINST THE CAR. SO CURRENT WORK AIMED AT IMPROVING MFC63-28Z CAR. SO I GUESS ONE WAY OF LOOKING IS IMPROVING EFFICACY, WE HOPE TO REDUCE TOXICITY BUT MAINTAIN EFFICACY OF TREATMENT. SO ONE OF THE THINGS WE DID WAS USE A FAIRLY HUMAN REGION INSTEAD OF MOUSE VARIABLE REGIONS IN EARLIER CAR AND EVALUATED HOW DIFFERENT HINGE AND TRANSMEMBRANES CAN AFFECT CAR T CELLS. WE HYPOTHESIZE CAR WOULD PROVIDE DIFFERENT ACTIVATION STIMULUS TO T CELLS, AFFECT FUNCTIONAL OUTPUT OF THE CAR T CELL SUCH AS CYTOKINE PRODUCTION. SO HERE WE HAVE A CAR, HU19 CD28Z, RECOGNITION DOMAIN, CD8 HINGE AND TRANSMISSION DOMAIN, AND WE COMPARED THAT TO HU 19-28Z, CD28 CO-STIMULATORY TRANSMEMBRANE DOMAIN, ALL THOSE DEMAINS COME FROM CD28, AND CD3 THETA. SIMILAR TO THE MFC63-28Z, IDENTICAL EXCEPT THIS. THE MAIN POINT IS WE GAVE THE CAR, HUMAN ANTIGEN RECOGNITION DOMAIN TO GET RID OF MOUSE PROTEIN SEQUENCE, AND COMPARING TWO HINGE REGION, FROM CD8 AND CD28. SO THIS WORK HAS BEEN PUBLISHED TOO. WE DID IN VITRO ASSAY, MOUSE STUDIES PUBLISHED BY ALABANZA IN MOLECULAR THERAPY, 2017. SOME WORK WE DID IS HERE. WE THINK THE CYTOKINES ARE VERY IMPORTANT, CYTOKINES OF TOXICITY OF CAR T CELLS, LOOKING FOR LOWER LEVEL CYTOKINES, HU19-28Z CAR WHICH HAS THE CD28 DOMAIN, YOU CAN SEE FOR INTERFERON GAMMA TLF AND IL-2 SAME PATTERN, A LOT LESS CYTOKINE THANS CARs WITH CD 28 DOMAINS, SO WE OBTAIN THE SAME RESULTS WITH MULTIPLE OTHER -- DIFFERENT CARs AND MULTIPLE TARGETS AND SO ON. THIS IS DONE USING ELISA ASSAY, CO-CULTURE CAR T CELLS AND TARGET CELLS OVERNIGHT AND SIMPLY MEASURE THE CYTOKINES IN THE CELL SUPERNATANT WITH LIVE ASSAY. I'M NOT SURE HOW MUCH WE'RE GOING INTO THIS. THIS IS ACTIVATION TO INDUCE CELL DEATH, THEY ARE STIMULATED WITH TARGET ANTIGEN, STIMULATES TOO MUCH BASICALLY AND THEY DIE. SO CAR T CELLS CAN UNDERGO ACTIVATION INDUCED CELL DEATH AND CARs, HERE YOU CAN SEE 20% VERSUS 67% FOR THIS DOMAIN, THIS GRAPH SHOWS THE HU19 CAR HAD LESS (INDISCERNIBLE) A MEASURE OF ACTIVATION -- MEASURE OF CELL DEATH, MEASURE OF ACTIVATION INDUCED CELL DEATH COMPARED TO THE 28Z CAR T CELLS. THIS IS JUST FURTHER EVIDENCE CD8 CAR CAUSES WEAKER ACTIVATION STIMULUS TO T CELL, AND DUE TO DIFFERENT DOMAINS. DESPITE ACTIVATION STIMULUS, THESE T CELLS CAN ELIMINATE TUMORS FROM MICE, YOU CAN SEE HERE MOUSE TUMOR SIZE, IMPLANTED TUMORS IN IMMUNOCOMPROMISED MICE, HUMAN TUMOR CELLS IN IMMUNOCOMPROMISED MICE AND TREAT THE MICE WITH CAR T CELL, WE DON'T GIVE CHEMO, THE TUMORS FORM, CELLS INFUSED ON DAY ZERO, TUMOR SIZES, YOU CAN SEE THE CONTROL GROUPS, CONTROL CAR AND UNTREATED MICE BOTH HAD STEADY INCREASE IN TUMOR SIZE WHILE BOTH GROUPS TREATED CAR BOTH HAD STABILIZATION ON AVERAGE OF THEIR TUMORS, SOME MICE HAD COMPLETE ELIMINATION, SOME TUMOR GROWTH, STABILIZATION FOR A WHILE, SURVIVAL YOU CAN SEE HERE, THERE'S NO STATISTICALLY SIGNIFICANT DIFFERENCE IN SURVIVAL. THERE WAS SOMEWHAT MORE MICE DYING IN THIS GROUP, AND WE DO THINK THE CD28Z CAR IS MORE EFFECTIVE IN THE MICE, THAT MAKES HIGH LEVELS OF CYTOKINE, THE DIFFERENCE IS SMALL, AND THE HU19 CD8 28Z CAN HAVE ANTI-TUMOR AFFECTED MICE SO BECAUSE THE HU 19 CD28Z HAS MUCH LOWER CYTOKINE PRODUCTION, AND BECAUSE IT CAN ELIMINATE TUMORS IN MICE, NOT AS WELL AS CD28Z, WE TEST CD28Z IN HUMANS AND SEE WHAT IT DOES AS FAR AS TOXICITY AND EFFICACY. SO WE PUT IN THIRD GENERATION LENTIVIRAL VECTOR, SHOWN HERE, THIS IS VECTOR WITH MST PROMOTER, MOUSE STEM CELL VIRUS, CD28 CO-STIMULATORY DOMAIN, THIS IS FULLY HUMAN, AND WE USE THIS VECTOR TO MODIFY THE PATIENT'S T CELLS AND INFUSE THE PATIENT'S T CELLS, WE USE PROCESS THAT TAKES 7 TO 9 DAYS TO MAKE THE CELLS, WE GAVE THE PATIENTS THE SAME CHEMOTHERAPY REGIMEN THAT I MENTIONED BEFORE, 300 MILLIGRAMS, 30 MILLIGRAMS, GIVEN FOR THREE DAYS, AND THEN PATIENTS GET TWO DAYS OFF, CAR T CELL INFUSION, PHASE 1 TRIALS THREE PATIENTS ON EACH DOSE LEVEL, TOXICITY IS NOT SEVERE YOU ARE ALLOWED TO GO TO THE NEXT DOSE LEVEL. THESE ARE DOSE LEVELS WE TESTED, STARTING WITH DOSE STARTING WITH 0.66. WE TREATED SIX PATIENTS ON EACH DOSE LEVEL, FIRST TWO DOSE LEVELS HAD ONE PATIENT WITH SEVERE TOXICITY ON EACH DOSE LEVEL. SO SEVERE TOXICITY.& SO WE TREATED SIX PATIENTS ON EACH DOSE LEVEL. AND WITH DOSE LEVEL THREE FOUND THAT WAS TOLERABLE SO WE DID END UP TREATING TWO EXTRA PATIENTS WITH THE SIX MILLION DOSE, TOTAL OF 20 PATIENTS, COMPLETED ACCRUAL EARLY THIS YEAR. THIS IS EXAMPLE OF THE ACTIVITY OF THESE T CELLS, THIS IS A PATIENT TREATING PATIENT 6, 0.66 MILLION CAR T CELLS LARGE MASS ABOVE HIS LIVER, ALSO IN HIS ABDOMEN HERE, INDICATED BY GREEN ARROWS, ONE MONTH LATER THE MASS WAS GONE, RESIDUAL ACTIVITY IN ABDOMEN, FOUR MONTHS LATER GONE, REMISSION 18 MONTHS LATER. THERE'S CERTAINLY ACTIVITY. BUT OVERALL HOW DID IT DO, OVERALL RESULTS WITH EFFICACY WERE SIMILAR, RESPONSE RATE OF 75%, 15 OUT OF 20 COMPLETE REMISSIONS, 55%, 11 OUT OF 20. YOU CAN SEE THESE NUMBERS ARE SIMILAR TO WHAT HAS BEEN FOUND, WE PUT THIS NEW CAR INTO PATIENTS, SIMILAR ANTI-LYMPHOMA EFFECT. THE MOST STRIKING THING, ONLY ONE OF 20 PATIENTS, 5%, HAS HAD GRADE 3 OR 4 NEUROLOGIC TOXICITY. SO THAT IS IN COMPARISON TO 55% ON PREVIOUS TRIAL. SO THIS WAS MUCH LOWER THAN THE GRADE 3 OR 4 NEUROLOGIC TOXICITY IN PREVIOUS TRIAL. SO RESULTS ARE PROMISING SO FAR. WE'RE IN THE PROCESS OF DOING STUDIES LOOKING AT CYTOKINES IN THE BLOOD. PRELIMINARIES SHOW THIS NEW CAR LOWER LEVELS OF CYTOKINES IN THE BLOOD OF PATIENTS COMPARED TO PREVIOUS WORK WITH THE 6328 Z CAR, NOT A PERFECT COMPARISON, DIFFERENT CLINICAL TRIALS, BUT IT IS KIND OF SUGGESTIVE WE'RE FINDING THE SAME THING IN VITRO WHERE DOMAIN MAKES LOWER LEFTS OF CYTOKINE. THIS IS A PAPER IN PREPARATION, WE HAVEN'T FINISHED IT YET, THERE'S BEEN ABSTRACTS SO FAR OF THIS WORK. SO CHANGE THE DESIGN CAN LEAD TO FUNCTIONALLY DIFFERENT CAR T CELLS, AND THE GOAL OF RESEARCH IS TO IMPROVE EFFICACY OF THESE TYPES, TARGETING MORE THAN ONE SIMULTANEOUSLY, THAT'S ONE THING WE'RE WORKING ON NOW, TARGETING TWO ANTIGENS AT THE SAME TIME SO TARGETING CD20 AND CD19 SIMULTANEOUSLY, ALSO IS A CLINICAL TRIAL FOR HODGKIN LYMPHOMA, GREAT OPPORTUNITY FOR IMPROVEMENT, IN CAR T CELL THERAPIES FOR LYMPHOMA. SO NOW IN PART 2, WE HAVE AN AREA OF MY WORK TREATING MULTIPLE MYELOMA. SO FAR WITH CAR SPECIFIC FOR BCMA. BCMA IS -- FIRST, WHAT'S MULTIPLE MYELOMA? ALMOST INCURABLE. IT'S EXPRESSED AT LEAST LOW LEVELS ON MYELOMA (INDISCERNIBLE) WE DESIGN NEW CAR, NEW TARGET, THE MOST IMPORTANT THING IS TO KNOW WHERE THE ANTIGEN IS EXPRESSED, IF ON IMPORTANT ORGANS IT'S NOT A GOOD ANTIGEN TO TARGET BECAUSE CAR T CELLS DESTROY EVERYTHING THEY TARGET. SO IF A TARGET ANTIGEN IS EXPRESSED, BRAIN OR HEART OR KIDNEYS OR SKIN OR ALMOST ANYTHING, CAN YOU NOT TARGET THAT ANTIGEN BECAUSE YOU WILL DESTROY THAT ORGAN. THERE'S BEEN SOME EXAMPLES OF THAT IN THE PAST AND DIFFERENT GROUPS, NOT VERY MANY BUT A FEW. SO WE LOOK FOR EXPRESSIONS CAREFULLY BY IMMUNOHISTOCHEMISTRY, PCR AND OTHER METHODS BEFORE WE TARGET THAT ANTIGEN SO TURNS OUT BCMA IS EXPRESSED ON PLASMA CELLS AND SMALL FRACTION OF B CELLS. PATIENTS COULD LIVE WITHOUT PLASMA CELLS SIMILAR TO THE WAY THEY CAN LIVE WITHOUT B CELLS BUT CD19 CAR T CELL, SO WE DESIGNED THESE CARs, THE FIRST EVER, AND PUBLISHED IN 2013. CARPENTER ET AL. WE DID THE FIRST IN HUMAN CLINICAL TRIAL IN ANTI-BCMA CAR, DESIGNED THE CAR SHOWN BELOW AND PUT IT IN GENE THERAPY VECTOR, STIMULATING T CELLS, TRANSDUCING WITH NEW -- THAT'S THE ANTIBODY THIS DOMAIN CAME FROM. CD8 HINGE AND TRANSMEMBRANE. THIS IS ALL GAMMARETROVIRAL VECTOR, PUBLISHED ALI ET AL. IN "BLOOD" IN 2016. SIMILAR SETUP. FOLLOWED SAME PATTERN, CONDITION REGIMEN, CAR T CELL INFUSION. THE PATIENTS AT BASELINE, RETREATED 24 ADVANCED LIE -- MYELOMA PATIENTS, NINE LINES OF THERAPY BEFORE THIS STUDY, SIX OUT OF 15 HAD HIGH RISK CYTOGENETICS, 63% REFRACTORY TO THE LAST TREATMENT REGIMEN. WE FOUND THAT PATIENTS TREATED WITH LOWER DOSE LEVELS HAD SAME BASELINE CHARACTERISTICS AS HIGHER, I'LL GO INTO MORE DETAIL IN A MINUTE, BUT WE FOUND THAT PATIENTS WITH HIGHER BURDENS OF MULTIPLE MYELOMA HAD WORSE TOXICITY THAN PATIENTS WITH LOW LEVELS OF MULTIPLE MYELOMA. SO IN AN ATTEMPT TO LIMIT TOXICITY, THE 14 PATIENTS REQUIRED TO HAVE LESS THAN 30% OF THEIR BONE MARROW TAKEN OVER BY MULTIPLE MYELOMA, WE MEASURED AND REQUIRE THAT THE BONE MARROW IS LESS THAN 30% MULTIPLE MYELOMA PLASMA CELLS. SO ALL THIS IS PUBLISHED IN GREATER DETAIL IN A JOURNAL, CLINICAL ONCOLOGY 2018, YOU CAN READ ABOUT IT. ANOTHER DOSE ESCALATION TRIAL, WE STARTED WITH 0.3, WENT TO 1, 3 AND 9. A MILLION CAR T CELLS PER KILOGRAM. ON THE FIRST TWO DOSE LEVELS NOT MUCH HAPPENED. SD IS STABLE DISEASE, MULTIPLE MYELOMA STAYED STABLE. ONE PATIENT HAD PARTIAL REMISSION, TWO WEEKS. REALLY NOT VERY IMPRESSIVE. THREE MILLION, WE HAD ONE PATIENT WITH GOOD PARTIAL REMISSION DECREASED BY 90% OR MORE. THIS PATIENT HAD SIGNS OF CYTOKINE RELEASE TOXICITY WITH FEVER, LOW BLOOD PRESSURE, THIS IS THE FIRST PATIENT WE FELT WE WERE CONVINCE WE HAD CAR T CELL ACTIVITY, WE HAD TO GO THROUGH EIGHT PATIENTS BEFORE WE HIT THAT ONE PATIENT THAT HAD A GOOD RESPONSE. LEVEL, NINE MILLION CAR T CELLS PER KILOGRAM, SEVERE TOXICITY IN SOME CASES, THEY HAD RESPONSE IN 13 OUT OF 16 PATIENTS. YOU CAN SEE WE HAVE COMPLETE REMISSION, NO EVIDENCE OF MYELOMA, PARTIAL REMISSION 66 WEEKS, ANOTHER VGPR, STRINGENT, COMPLETE REMISSION, 69 WEEKS. VERY GOOD PR, VERY GOOD PR, ANOTHER STRINGENT PR, STILL ONGOING, SO MUCH MORE RESPONSE RATE HERE. ONE THING WE NOTICE THOUGH, DIFFERENT FROM THE CD19 EXPERIENCE WHO HAD PLUS SIGNS BY THEIR NUMBERS WHICH MEANS TWO OF THEM HAVE ONGOING RESPONSES AS OF TODAY. A LOT OF PATIENTS WILL GET RESPONSES, BUT DEVELOP MYELOMA AFTER A YEAR OR SO, THAT'S ONE DIFFERENCE. SO OBVIOUSLY THE ANTI-BCMA CAR NEED IMPROVEMENT, WE WANT THEM TO STAY IN REMISSION. WE THINK WE HAVE BETTER CAR T CELLS THAN THIS, WE'RE TESTING THEM BUT JUST TO POINT THAT OUT. THIS AN EXAMPLE OF A PATIENT TREATED ON THIS PROTOCOL, THE OTHER THING TO REMEMBER THESE PATIENTS ONCE THEY GET CAR T CELLS DON'T GET ANY OTHER MYELOMA TREATMENT AFTER THAT UNTIL THE MYELOMA PROGRESSES. SO THIS GOES 66 WEEKS AFTER INFUSION, 66 WEEKS WITHOUT GETTING ANY TREATMENT. HE WAS BASICALLY LIVING A NORMAL LIFE FOR 66 WEEKS, THE PATIENTS APPRECIATE, THAT THEY DON'T HAVE TO GET CHEMO THAT TIME. PATIENT NUMBER 14, 16 PRIOR LINES OF THERAPY BEFORE WENT TO GET CAR T CELL, RESPONSE WAS VERY GOOD PARTIAL REMISSION, 84 WEEKS, AND THEN UNFORTUNATELY MYELOMA RELAPSED, IN HIS BRAIN, CENTRAL NERVOUS SYSTEM WHICH IS UNUSUAL. SO THIS IS A CHAIN, DROPS QUICKLY, ONE THING ABOUT CAR T CELLS THEY WORK FAST, WITHIN A WEEK OR TWO YOU CAN SEE A RESPONSE. IMMUNOGLOBULIN IS RECOVERED, NORMAL, HAD TO GET TWO INFUSIONS OF ARTIFICIAL OR NOT ARTIFICIAL BUT INTRAVENOUS IMMUNE GLOBULIN. HERE THE SAME PATIENT HAD THIS MASS, SOMETIMES MULTIPLE MYELOMA HAD A MASS OF PLASMA CELLS, PLASMACYTOMA. HERE INDICATED BY YELLOW ARROW, MUCH SMALLER FOUR WEEKS, NINE WEEKS SMALLER YET, 55 WEEKS ABSENT, CAR T CELL CAN GET RID OF MASSES IN MULTIPLE MYELOMA. SUMMARY OF TOXICITY, CYTOKINE RELEASE SYNDROME, THE OTHER PATIENTS DIDN'T HAVE MUCH TOXICITY, BUT FOUR HAD GRADE 4, TEN HAD GRADE 2, ONE OR NO CRS. WE GAVE 31% OF PATIENTS, FIVE. AND FOUR RECEIVED CORTICAL STEROIDS FOR ADRENAL INSUFFICIENCY. LOW BLOOD PRESSURE IS ONE OF THE IMPORTANT PROBLEMS OF THESE PATIENTS. AND TOXICITY AGAIN ASSOCIATED WITH HIGH LEVELS OF BONE MARROW PLASMA CELLS. ONE ISSUE IS SOMETIMES THE TARGET MALIGNANCY, MULTIPLE MYELOMA, CAN LOSE EXPRESSION OF BCMA. THIS IS FLOW CYTOMETRY DATA, EACH DOT IS A CELL, RED AREA IS INDICATING PLASMA CELL, MULTIPLE MYELOMA, THE PURPLE AREA IS CONTROL B CELLS IN THE BONE MARROW, IT'S A NEGATIVE CONTROL GROUP FOR BCMA. RED IS OFF THE X-AXIS INDICATING ALMOST ALL PLASMA CELLS WERE BCMA POSITIVE BEFORE TREATMENT. THE PATIENT'S RESPONSE WITH STABLE DISEASE, DIDN'T HAVE A GOOD RESPONSE TO TREATMENT, AND BONE MARROW BIOPSY TWO MONTHS LATER AFTER CAR T CELL INFUSION, A LOT OF PLASMA CELLS INDICATED IN RED BY X-AXIS, THEY DID NOT EXPRESS BCMA, SO A BCMA NEGATIVE POPULATION DEVELOPED IN THIS PATIENT OVER TWO MONTHS. ANOTHER EXAMPLE OF BCMA NEGATIVE MYELOMA THIS IS A PATIENT WITH A LONG REMISSION, BCMA POSITIVE, MYELOMA CELLS BEFORE TREATMENT, 56 WEEKS LATER DETECTED SMALL POPULATION OF BCMA NEGATIVE NEAR THE X-AXIS, EQUAL WITH B CELLS BUT AFTER 68 WEEKS DIVERSIFIED. MULTIPLE MYELOMA IS A COMPLICATED DISEASE, SOMETIMES CAN DEVELOP SUBCLONES IN THE SAME PATIENT, SO THERE CAN BE DIFFERENT PHENOTYPES IN THE SAME PATIENT, THIS PATIENT WE HAVE SOME BCMA NEGATIVE AND SOME BCMA POSITIVE. TWO OF TEN RESPONSES, 13 OUT OF 16 AT THE OPTIMAL DOSE LEVEL, 81% RESPONSE RATE ON OPTIMAL DOSE, EXAMPLE OF DOSE DEPENDENCE, HIGHER DOSES WORK GETTER. FOUR OUT OF 15 DURATION OF REMISSION GREATER THAN A YEAR. MULTIPLE MYELOMA IS DIFFICULT TO TREAT BECAUSE ITS PHENOTYPIC HETEROGENEITY, IMPROVEMENTS ARE UNDERWAY. SO TO IMPROVE THAT WE ARE NOW TESTING A CAR FULLY HUMAN, AGAIN THAT PREVIOUS HAD MOUSE COMPONENTS, NOW FULLY HUMAN CAR MADE OF ANTIBODY HEAVY CHAIN, HEAVY CHAIN OR LIGHT CHAIN, THIS IS HEAVY CHAIN ONLY. THIS IS THE DIAGRAM TO EXPLAIN THAT. THIS IS THE NEW CAR WE DESIGNED IN MY LAB, TESTING THIS. THIS IS A HEAVY CHAIN BINDING DOMAIN IN TRANSGENIC RAT, HEAVY CHAIN, FULLY HUMAN BINDING DOMAIN, CD8 ALPHA, THIS IS IN COMPARISON TO TRADITIONAL CAR WHICH HAS A SINGLE CHAIN WITH LIGHT CHAIN LINGER AND HEAVY CHAIN, FULLY HUMAN. THE JUNCTIONS BETWEEN THE LIGHT CHAIN LINGER AND LINKER AND HEAVY CHAIN, ELIMINATE THEM WITH THIS APPROACH TOO. THERE ARE OTHER IMPORTANT DIFFERENCES. THIS IS SHOWING IF WE LOOK AT THE 11D5 VERSUS HEAVY CHAIN, THERE'S MINIMAL DIFFERENCE IN CYTOKINE PRODUCTION, CAN YOU SEE BAR GRAPHS, .02, NOT THAT BIG OF A DIFFERENCE, NO SIGNIFICANT DIFFERENCE FOR INTERFERON GAMMA OR IL-2. CELLS THAT ACCUMULATE, THIS IS TALKING ABOUT DIFFERENCE IN CO-STIMULATORY DOMAINS. WE DID PROLIFERATION ASSAYS IN VITRO, PUT THEM IN CULTURE WITH TARGET CELLS EXPRESSING BCMA, LOOK TO SEE HOW THEY PROLIFERATE, NO DIFFERENCE IN PROLIFERATION BUT THERE WAS INCREASED ACCUMULATION OF THE CARS OF 4MBB. WE FOUND CARS OF 4MBB WERE MUCH LESS LIKELY TO INTEGRATE APOPS SO IS, WE THINK THE REASON MORE ACCUMULATE IS BECAUSE OF RESISTANCE AND FOUND GREATER ACCUMULATION IN VITRO, CONSISTENTLY, YOU CAN SEE HERE THIS IS THE 4MBB CAR, AFTER A 7-DAY IN VITRO CULTURE PERIOD, STRONG POPULATION OF CAR T CELLS AND POSITIVELY INDICATING APOPTOSIS IN 12.5% OF CAR T CELLS. CD 28 CAR WE HAVE THIS KIND OF MUCH SMALLER POPULATION AND 41% INDICATED APOPTOSIS, FOUND IN THREE OUT OF THREE PATIENTS WITH HIGHER LEVEL OF APOPTOSIS IN THE CD28 EXPRESSING CAR T CELL. AND TOTAL NUMBER OF T CELLS HIGHER IN THE -- IF WE LOOK AT ACCUMULATION, WE HAVE PRELIMINARY DATA SHOWING THE SAME THING IN MICE. THAT'S NOT READY TO PRESENT YET. IN THE MOUSE MODELS AS FAR AS EFFICACY GOES WE HAD ESTABLISHED TUMORS IN NSG IMMUNOCOMPROMISED MICE, DAY ZERO TREATED WITH CAR T CELL AND FOUND ALL THREE CARs ALL WERE CAPABLE OF ERADICATING TUMORS FROM MICE LEADING TO SURVIVAL. IF WE LOOK AT DIFFERENT MODEL WHICH I DIDN'T BRING TODAY WE HAVE DISSEMINATED MODEL, THE 4MBB IS SUPERIOR TO THE 28 CAR. THIS IS JUST KIND OF AN INTRODUCTION OF WHAT WE'RE DOING CURRENTLY, CAR T CELL THERAPIES AT EARLY STAGE OF DEVELOPMENT MORE MULTIPLE MYELOMA, HUGE AMOUNT OF PROGRESS CAN BE MADE, A HUGE AMOUNT OF WORK WE'RE DOING, IMPROVEMENT IS ANTICIPATED. WE OPENED A CLINICAL TRIAL, TREATED FIRST PATIENT LAST WEEK ON A TRIAL WITH HEAVY CHAIN LINK CAR. START TREATMENT ON NEXT PATIENT TOMORROW. I WANT TO THANK MY CO-WORKERS, MY BOSS, AND MY OTHER CO-WORKERS, DEPARTMENT OF TRANSFUSION MEDICINE, KITE, GILEAD, PATHOLOGY AND SURGERY BRANCH, STEVE ROSENBERG, DISCLOSURES FROM KITE AND PATENTS IN THE CAR FIELD. THANK YOU. [APPLAUSE] >> QUESTIONS? I KNOW THERE'S LOTS OF TRIALS GOING ON NOW ABOUT USING CAR T CELL THERAPY IN SOLID TUMORS. HOW IS THAT GOING? I DON'T REALLY STUDY SOLID TUMOR, HEMATOLOGIC MALIGNANCY, TOUGHER TO CREATE SOLID TUMORS, MAIN REASON THEE ARE NOT AS MANY GREAT ANTIGENS, SO WITH THE HEMATOLOGIC MALIGNANCY WE HAVE GOOD ANTIGENS BUT IN SOLID TUMORS THEY ARE EXPRESSED IN ORGANS, A BIG PROBLEM. PERHAPS THERE ARE A FEW GOOD ANTIGENS BUT HARDER TO COME BY. ALSO DIFFERENCES IN SOLID TUMORS AS FAR AS T CELLS PENETRATING CENTER OF BIG SOLID TUMOR MASS, THEY CAN ELIMINATE LYMPHOMA AND MYELOMA CELL IN MASSES, BUT THE SOLID TUMOR AREAS VERY MUCH BEHIND THE HEMATOLOGIC MALIGNANCY IN CAR T CELL WORK. >> THAT WILL DO IT. >> THANK YOU. THANK YOU VERY MUCH. [END OF PROGRAM]