TRACO: Prostate cancer and CAR-T cells

TRACO: Prostate cancer and CAR-T cells


FIRST SPEAKER IS RAVI MADAN AND HE GOT HIS M.D. AT NEW JERSEY MEDICAL CENTER, THEN HE DID AN INTERNAL RESIDENCE THERE AND HE JOINED THE NCI MEDICAL ONCOLOGY BRANCH IN 2005. HE HOLD AS JOINT APPOINTMENT WITH THE MEDICAL ONCOLOGY BRANCH, LAB OF TUMOR IMMUNOLOGY AND BIOLOGY. HE WILL TALK TO US ABOUT PROSTATE CANCER CURRENT APPROACH IN ADVANCED DISEASE.>>THANK YOU, DR. MOODY. APPRECIATE THE INTRODUCTION. I HAVE A LITTLE COLD SO I APOLOGIZE IN ADVANCE IF ANYTHING HAPPENS UP HERE LIKE COUGHING BUT WE’LL GET THROUGH THIS LECTURE AND FIGURE OUT WHERE WE ARE IN 2019 WITH PROSTATE CANCER. S THAT COMPLICATED DISEASE. I WILL FOCUS ON PAICIALT WHOSE HAVE ADVANCED CAS STRAIGHTS RESISTANT DISEASE AND I’LL REDEFINE THAT FOR FOLKS BUT THERE’S NEW ADVANCES GOING ON IN WHAT’S CALLED CAS STRAIGHTS SENSITIVE META STATIC DISEASE, A PLETHORA OF ADVANCE WHERE IS THERAPIES MOVE EARLIER IN THE DISEASE PROCESS. IF THERE’S TIME AT END I’LL ANSWER QUESTIONS ABOUT THAT. BUT FOR SAKE OF REALLY UNDERSTANDING WHERE THE FIELD IS COME FROM, LET’S LOOK AT THIS TREATMENT LANDSCAPE OVER BASICALLY THE LAST 20 YEARS SHOW HOW FAR WE HAVE COME SO AT THE TURN OF THE CENTURY THERE WAS NO PROVEN THERAPY THAT COULD EXTEND THE LIFE OF A MAN WITH META STATIC PROSTATE CANCER. SO CIPC HERE CAS STRAIGHTS RESISTANT PROSTATE CANCER I’LL DEFINE IN A COUPLE OF SLIDES. HERE IS WHAT THE LANDSCAPE LOOKED LIKE, IT WAS A MAJOR ADVANCE IN 2004 WHEN DOE SI TACK SOLVE, A CHEMOTHERAPY DEMONSTRATED ABILITY TO EXTEND LIVES OF MEN WITH META STATIC PROSTATE CANCER SO IT’S WORTH NOTING MOST PATIENTS ARE DIAGNOSED WITH LOCAL DISEASE, AND RADIATION SURGERY CAN CURE THEM WHEN LOCALIZED, HOWEVER, EVEN AMONG THOSE PATIENTS 20 TO 40% WILL HAVE RECURRENCE AND MANY PROGRESS TO META STATIC DISEASE. A SUBSET OF PATIENTS ARE ALSO DIAGNOSED WITH META STATIC DISEASE BUT FOR SAKE OF TIME I’M FOCUSING ON THE TREATMENT ADVANCE META STATIC PROSTATE CANCER SO DOSYTAXOL DEMONSTRATED OVERALL SURVIVAL ADVANTAGE AND LONG GAP THE FIELD TRIED TO COMBINE A BUNCH OF EMERGING TARGETING THERAPIES WITH DOSYTAXOL TO MAY RECOLLECT IT WORK BETTER AND IT DIDN’T PAY OFF. FEW PEOPLE TALK ABOUT THE IMMUNOTHERAPY REVOLUTION STARTING A PROSTATE CANCER BUT IT DID. THE FIRST TREATMENT OUT OF IL 2 ARE — TNF ALPHA TYPE THERAPIES FOR MELANOMA OR KIDNEY CANCER, THE FIRST IMMUNOTHERAPY BEYOND THAT WAS — IMMUNOTHERAPY FOR PROSTATE CANCER BASED ON PATIENT IMMUNE CELLS. THAT DEMONSTRATED A SURVIVAL ADVANTAGE IN A SECOND PHASE 3 TRIAL, THAT WAS DONE IN COMPLETED IN 2010. SHORTLY THEREAFTER MUCH TO SURPRISE OF MANY PEOPLE, A SECOND CHEMOTHERAPY, SIMILAR TO THE FIRST DOSYTAXOL, SUR SURPRISING UNCLEAR AT THE TIME WHY TO TAXANES WORK IN CHEMOTHERAPY WHEN YOU USE A TAXANE IN A TRIAL WHERE THEY ALREADY PROGRESSED ON THE FRONT LINE TAXANE BUT I WILL EXPLAIN IT LATER AND MAYBE MAKE MORE SENSE. AS TIME WENT ON HERE SLOWLY WE MADE ADVANCES. REALLY BIG ADVANCES WERE ON THE HORIZON AS THE OTHER TWO AGENTS WERE IMPROVED. (INDISCERNIBLE) WERE TARGETED THERAPIES THAT WERE PROSTATE CANCER SPECIFIC, RS AS I’LL TALK ABOUT PROSTATE CAIRPS IS REALLY DRIVEN BY TESTS TO ROANE AND THESE AGENTS TARGET TESTOSTERONE PREVENTING CELLULAR ACTIVATION AND ACTIVATION OF PROLIFERATION SIGNALS. THESE AGENTS REALLY WERE HIGHLY ANTICIPATED AND VERY LARGELY POSITIVE TRIALS IN 2011, 2012, FIRST APPROVED IN PATIENTS WHO PROGRESSED ON FRONT LINE CHEMOTHERAPY AND STUDIES ALSO STARTED AROUND THE SAME TIME CAME OUT COUPLE OF YEARS LATER DEMONSTRATED THAT REALLY NOT SURPRISINGLY BEFORE CHEMOTHERAPY AGENTS WORKED WELL AND SINCE NOT CHEMOTHERAPY THEY ARE BETTER TOLERATED. SEVERAL AGENTS (INDISCERNIBLE) AND EVEN SIMILAR AGENTS TO (INDISCERNIBLE) HAVE MOVED EARLIER IN THE DISEASE PROCESS AND NEWLY DIAGNOSED META STATIC POPULATION I WON’T TALK ABOUT TODAY ARE JUST AGAIN TO KNOW THAT. RADIUM 223 IS A DIFFERENT TYPE OF THERAPY THAN WHAT I HAVE LISTED ON THE SCREEN, IT WAS AT THE — APPROVED IN 2013, THIS WAS A FUSION FORM OF RADIATION THERAPY, THAT BASICALLY I’LL TALK LATER BUT BASICALLY LOOK WAS AREAS IN THE BONE EMITS ALPHA PARTICLES THAT DESTROY PROSTATE CANCER CELLS IN 2013 DEMONSTRATED ABILITY TO EXTEND SURVIVAL IN PATIENTS. SO YOU SEE THERE’S REALLY A REMARKABLE ADVANCEMENT THAT HAPPENS VERY RAPIDLY OVER THREE OR FOUR YEARS, DESPITE VERY LITTLE THAT HAPPENED BEFORE. AS MENTIONED EARLIER, SOME OF THESE TREATMENTS GOT MOVED UP EARLIER, (INDISCERNIBLE) PATIENTS CAS STRAIGHTS RESISTANT BUT NOT ME STA STATIC. I’LL DEFINE IN A SECOND, A TRIAL DEMONSTRATED EFFICACY THERE. (INDISCERNIBLE) A SLIGHT MODIFICATION AND DIFFERENT VERSION OFTEN DEMONSTRATED EFFICACY IN THE SETTING AND APPROVED IN 2018 WITH SOME OTHER AGENTS THAT COME OUT IN THIS PAST YEAR AS WELL. SO THESE ARE THE TREATMENTS FOR THE FOR PATIENTS NON-CAS STRAIT SPECIFIC. THESE ARE PATIENTS WHO BASICALLY SHOW UP IN DOCTOR’S OFFICE AND THEY ARE META STATIC SO THEY DIDN’T KNOW THEY HAD PROSTATE CANCER AND THEY JUST HAD SOME ACHES AND PAINS AND DIAGNOSED WITH META STATIC DISEASE OR THEY HAD TREATMENT FOR THEIR PROSTATE CANCER AND WHEN IT CAME BACK, IT CAME BACK IN A WAY THAT IT SHOWED UP IN ORGANS OR BONE. SO IT’S NOT A COMMON POPULATION THOUGH IMPRESSION IS IT SEEMS TO BE GROW BUG I DON’T KNOW IF THAT’S DATA TO SUPPORT THAT. BUT WHAT HAPPENED BASICALLY THE LAST FEW YEARS IS DOSYTAXOL AND (INDISCERNIBLE) HAVE DEMONSTRATED ABILITY IF GIVEN EARLIER AT THE DIAGNOSIS DOSE TACK SOLVE TO IMPROVE SURVIVAL AS WELL AS INZALUDAMIDE ALSO APPROVED IN THIS SETTING. OR DEMONSTRATED EFFICACY. SO I THINK IT’S WORTH ALSO NOTING THESE ARE DIFFERENT THAN CASTRATION RESISTANT PATIENTS WHO THEY WERE NOT ON HORMONE DISEASE, I CAN ANSWER QUESTIONS LATER IF IT’S HELPFUL. SO I GUESS FOR PEOPLE WHO ARE HERE FEEL FREE TO ASK, I’M NOT BEING CLEAR ON A CERTAIN POINT. BUT FOCUSING ON CASTRATION RESISTANT PROSTATE CANCER SO LET ME CLARIFY WHAT THAT IS. THESE ARE MEN WITH PROGRESSIVE PROSTATE CANCER DESPITE CASTRATION LEVELS OF TESTOSTERONE, GENERALLY BELOW 50 NOW LOWER THAN THAT. BUT WHAT THIS IS TELLING YOU IS TESTOSTERONE ALONE IS NOT DRIVING THE DISEASE, TESTOSTERONE NOT DERIVED FROM THE TESTICLES THE PRIMARY SOURCE IN MEN. THE FORM OF PROGRESSION BASED ON EVALUATION CAN BE ON RADIO GRAPHIC OR IMAGING OR COULD BE BASED ON TSA PROGRESSION BUT BASICALLY IF THE CAS STRAIT LEVELS OF TESTOSTERONE OR PSA IS RISING THAT TELLS CASTRATION RESISTANT OR CRPS CASTRATION RESISTANT PROSTATE CANCER. WHAT THIS DEFINITION HIGHLIGHTS AGAIN, IS THAT EARLY ANDROGEN RECEPTOR DRIVES GROWTH OF PROSTATE CANCER BY BINDING RECEPTOR ANDROGEN SPECIFICALLY TESTOSTERONE CAN BASICALLY TRIGGER A PROCESS THAT THAT ENDS IN CELLULAR PROLIFERATION AND TUMOR GROWTH. BY TARGETING THAT WITH DIFFERENT THERAPIES THAT I WILL TALK ABOUT, SPECIFIC MANNER, THOSE ARE SOME OF THE MOST EFFECTIVE THERAPIES IN TREATING PROSTATE CANCER, JUST UNFORTUNATELY NOT CURATIVE. ONE QUESTION THAT COMES UP IN CLINIC IS HOW CAN WE STILL USE TESTOSTERONE OR ANDROGEN TARGETING THERAPIES OR TESTOSTERONE LOWERING THERAPIES IN PATIENT WHOSE ARE CASTRATION RESISTANT? THIS ALSO USED TO BE A TERM THAT OR A STATE CALLED ANDROGEN SENSITIVE WHICH IS PROBABLY INAPPROPRIATE BUT UNDERSTANDING THE SLIDE WILL EXPLAIN WHY. CASTRATION RESISTANT PROSTATE CANCER HIGHLIGHTS MECHANISM IT IS CANCER CELLS DEVELOP SUCH THAT IT CAN GROW DESPITE CASTRATE LEVELS OF TESTOSTERONE. ONE COMMON MECHANISM ARE AMPLIFICATION OF AR RECEPTOR INITIALLY. IN RECENT YEARS IT’S BECOME CLEAR THERE’S A SECONDARY SOURCE OF ANDROGEN PRODUCTION. SO BY LOWERING THE BODY TESTOSTERONE WITH GMH AGONIST IN EARLIER DISEASE STATES GENERALLY OR WHEN THEY BECOME META STATIC, WHAT YOU WIND UP DOING IS SUPPRESSING LEVELS OF TESTOSTERONE PRODUCED BY TESTICLES. THAT IS GOOD ENOUGH TO CONTAIN THE CANCER ON AVERAGE FOR ONE TO TWO YEARS BUT PSA IS RISE AND SCANS GET WORSE OVER TIME. REASON BEING IS THERE ARE OTHER SOURCES OF ANDROGENS IN YOUR BODY BUT WHAT RECENT DATA SHOWED AGAIN OVER LAST 5, 10 YEARS IS SOME SOURCES INCLUDE CANCER CELLS THEMSELVES SO THEY ARE PRODUCING THEIR OWN ANDROGENS IN ALMOST AUTOCRINE OR PAIR CRIN FORM TO FUEL THE GROWTH OF THEIR OWN TUMORS. THERE’S ALSO MODIFIATIONS THAT HAPPEN IN CANCER CELLS OVER TIME WHERE I MENTION THERE’S A CASCADE OF REACTIONS TRIGGERED BY THE ANDROGEN RECEPTOR BINDING TO ANDROGEN BUT OVER TIME THERE COULD BE MUTATIONS SUCH THAT THAT CASCADE OF ACTIVITY OR PATHWAY REMAINS ACTIVE REGARDLESS OF WHETHER OR NOT ANDROGEN IS BINDING RECEPTOR. SO IN OTHER WORDS THEY LIGAND INDEPENDENT GROWTH MECHANISM AND THIS IS SOMETHING DEMONSTRATED FIRST COMMON — FIRST IN LAND MARK PUBLICATION AT JOHNS HOPKINS HIGHLIGHTING THAT AN DROA JN REANDROGEN SPLICE VECTOR 7 IS ONE VARIANT THAT CONSTITUTIVELY ACTIVE AND DID NOT REQUIRE THE BINDING OF AN ANDROGEN RECEPTOR. SO THERE’S ALSO ONE OTHER THING THAT’S WORTH HIGHLIGHTING FOR UNDERSTANDING HOW PROSTATE CANCER WORKS. PSA IS VERY IMPORTANT IN DIAGNOSING PROSTATE CANCER, IT’S IMPORTANT FOLLOWING PATIENTS WITH PROSTATE CANCER, WHAT HAPPENS CAN BE SOMEWHAT TRICKY BIOMARKER. IT IS A BIOMARKER, I THINK, AND IT’S FUNNY BECAUSE WE TRY TO DEVELOP BIOMARKERS IN PROSTATE CANCER WE GOT PROBABLY ONE OF THE MOST COMMONLY USED BIOMARKER THAT EVERYBODY GETS ANGRY WITH. IT’S INTERESTING TO ME BUT BASICALLY THE REASON BEING, PSAs CAN OFTEN GO UP BEFORE CANCER GETS WORSE. THIS CAUSES PROBLEMS BECAUSE PATIENTS AND DOCTORS SOMETIMES GET ANXIOUS AND TAKE PATIENTS OFF EFFECTIVE THERAPIES WHEN THEY ARE STILL WORKING SO HOW IS THAT POSSIBLE? IN MOST ALMOST NO OTHER CANCER DO WE STOP A TREATMENT BECAUSE BIOMARKER IS INCREASING BUT SCANS ARE STABLE. THE TRIALS ALMOST ALL THE TRIALS WHICH I’M GOING TO SHOW YOU USE CRITERIA SUCH THAT PSA ALONE DIDN’T TAKE PATIENTS OFF THE THERAPIES. SO GENERALLY THE RECOMMENDATIONS ARE TO WAIT UNTIL — UNTIL RADIO GRAPHIC PROGRESSION TO TAKE PATIENTS OFF THERAPIES. UNFORT MATILY WHAT HAPPENS TOO OFTEN IS WHEN THE PATIENT GETS ANXIOUS OR DOCTORS GET ANXIOUS THEY WIND UP STOPPING EFFECTIVE THERAPY TOO EARLY AND UNFORTUNATELY IT SHORTCHANGES THE PATIENT SOME DEGREE OF CLINICAL BENEFIT. IT’S SOMETHING OUR GROUP IS LOOKING AT IN OUR OWN WORK TO KIND OF GET OUT THERE A LITTLE BIT SOME OF THE INTERESTING DATA WE HAVE ON THAT TOPIC. BUT I THINK IT’S WORTH HIGHLIGHTING WHAT PROGRESSION IS IN PROSTATE CAIRPS WHEN META STATIC CASTRATION RESISTANT IT PIECE CLINICAL SYMPTOM RADIO GRAPHIC PSA THOUGH WE FOLLOW IT IT’S AT THE BOTTOM OF THE LIST. THE OTHER THICK IMPORTANT TO REALIZE I SHOWED YOU THESE GREAT TREATMENTS AND HOW THEY DEVELOPED OVER THE YEARS BUT THERE’S NO CLEAR DATA HOW TO OPTIMALLY USE IT SO THERE ARE SOME TRIALS ONGOING THAT ARE TRYING TO LOOK AT THIS TO THIS DAY WE DON’T HAVE A CLEAR ANSWER TO THIS QUESTION. TRYING TO COMBINE MULTIPLE THERAPIES DEMONSTRATED MULTIPLE THERAPIES INCREASE TOXICITY WITHOUT CLEAR SYNERGISTIC OR ADDITIVE BENEFIT OPPOSED TO SEQUENCING THEM. SO WHAT I’LL PRESENT TO SOME DEGREE, ALL THESE TREATMENT OPTIONS AND THEN MY OPINION ON HOW TO DEPLOY THEM, I THINK THAT THERE’S DEFINITELY OTHER OPINIONS OUT THERE AND I WILL TRY TO RATIONALIZE WHY I’M PRESENTING MY OPINION IN THIS WAY. BUT I THINK FUNDAMENTALLY SPEAKING WITH PRACTITIONERS TRY THE DECIDE HOW TO TREAT PATIENTS WITH PROSTATE CANCER YOU HAVE TO FIGURE OUT WHO YOU ARE LOOKING AT IN YOUR OFFICE, WHAT ARE THEIR CO-MORBIDITIES, WHAT ARE THEIR QUALITY OF LIFE COMPONENTS THAT ARE IMPORTANT TO THEM. WHAT’S THE PACE OF THEIR DISEASE, AND WHAT ARE THE TOXICITIES OF THE THERAPIES YOU ARE GOING TO GIVE THEM. SO I WILL HIT ON SOME OF THAT AS WE GO THROUGH THE DIFFERENT THERAPIES. SO AGAIN I THINK THIS HIGHLIGHTS WHAT I JUST SAID PATIENT CHARACTERISTICS ALSO THAT FACTOR IN ARE AGE AND SOMETIMES TREATMENT LOGISTICS, IT’S HARDER FOR PATIENTS TO TRAVEL GREAT DISTANCES SO THAT MAY INFLUENCE THERE’S SOME DEGREE HOW THEY HAVE DONE ON PREVIOUS THERAPIES THAT INFORM HOW YOU WILL TREAT THEM WHEN YOU ARE SEEING THEM. THIS IS A POSSIBLE AL GOOR RHYTHM — ALGORITHM, I LOOK AT CASTRATION RESISTANT PROSTATE CANCER SO THE MPRPC IS ME STA STATIC RESISTANT PATIENTS WITH PROSTATE CANCER, IN PATIENTS WITH NORMAL PACE OF DISEASE, IN OTHER WORDS DIDN’T HAVE A MINIMAL RESPONSE TO HORMONES SUPPRESSION THERAPY ALONE OR THEY DON’T HAVE EXPLOSIVE PROGRESSION OF DISEASE ON IMAGING. SO I’LL GO THROUGH THIS SEQUENTIALLY, THIS IS HOW I WOULD LAY OUT THE TREATMENT OPTIONS. FOR PATIENT WHOSE COME IN AND HAVE REALLY RAPIDLY GROWING DISEASE, MAWB THEY WERE ON HORMONE SUPPRESSION THERAPY, FIRST LINE OF THERAPY FOR PATIENTS THAT ONLY WORKED SIX MONTHS AND NOW THEY HAVE SIMILAR TOMENTS OR THE CANCER — SYMPTOMS OR THE CANCER SPREAD FROM ONE OR TWO AREAS IN THE BONES TO 15. THEN I MAY BYPASS EARLIER THERAPIES AND GO RIGHT TO SOMETHING LIKE CHEMOTHERAPY OR RADIO 223 PHARMACEUTICAL THAT HAVE PAILIATIVE EFFECTS IN PATIENTS WITH HIGH LEVELS OF PAIN, THOUGH THEY MAY COME AT GREATER TOXICITY. BUT HOPEFULLY THE TRADE OFF IS BETTER WITH MORE SYMPTOMS. LET’S START OFF WITH PATIENTS WITH KIND OF NORMAL MOVING PROSTATE CANCER, THIS IS A GUY WHO IS ON THE HORMONE SUPPRESSION THERAPY TWO OR THREE YEARS, OFFICE PSA RISING AND NOW HE HAS META STATIC DISEASE IN THE BONES WHICH IS MOST MEN WITH PROSTATE CANCER SPREAD. WHAT I CONSIDER AN OPTION FOR THIS PATIENT UP FRONT WOULD BE SIMPLE SOT. A THERAPEUTIC VACCINE OR IMMUNOTHERAPY DERIVED FROM THE PERIPHERAL BLOOD IMMUNE CELLS GENERATED FROM BASICALLY TAKING A PATIENT’S TUMOR APHERESIS CENTER AND AFREESING MONONUCLEAR CELLS, SHIPPING TO THE PROCESSING FACILITY IN ATLANTA OR SEATTLE, EXPOSING TO THE TARGET ANDROGEN WHICH IS PHOSPHOTASE AND CYTOKINE, GMCSF. SO THEN IMMUNOLOGIC BOOT CAMP FOR TWO OR THREE DAYS WHERE THE IMMUNE CELLS EXPOSE TO THE ANTIGEN AND ACTIVATE WITH A CYTOKINE AND THEN REINFUSE BACK INTO THE PATIENT. AND A FULL COURSE OF THERAPY WITH SIMPLE SOT AND PROSTATE CANCER IS THREE INFUSIONSES BASICALLY ONCE EVERY TWO WEEKS OVER A MONTH, THAT’S THE COMPLETE COURSE OF THERAPY. SO THIS IS THE CLINICAL TRIAL THAT WAS PUBLISHED IN 2010, THAT WAS THE SECOND THERAPY THAT DEMONSTRATED SURVIVAL ADVANTAGE OF PATIENT WITH META STATIC PROSTATE CANCER AND BASICALLY YOU SEE RANDOMIZE PEOPLE SIMPLE SOT OR PLACEBO, THERE WAS A CROSS OVER HERE BUT THE RESULTS OF THE TRIAL DEMONSTRATED A 4.1 MEDIAN IMPROVEMENT IN SURVIVAL WHICH IS STATISTICALLY SIGNIFICANT AND CLINICALLY MEANINGFUL YOU SEE SEPARATION IN CURVES AT LEAST IN MY OPINION, CLINICALLY MEANINGFUL. I THINK THAT THIS IS ACTUALLY THE SECOND PHASE 3 TRIAL THAT DEMONSTRATED VERY SIMILAR FINDING IN TERMS OF MAG STEWED MAGNITUDE AN AMOUNT OF IMPROVEMENT AND SURVIVAL IN PATIENTS AT THIS TIME WHEN THERE’S NO OTHER THERAPY BUT CHEMOTHERAPY. THERE’S CONTROVERSY WHEN THIS TREATMENT WAS DEVELOPED. I THINK SOME OF THIS PERSISTS TO THIS DAY THOUGH AGAIN I BELIEVE PHASE 3 DATA LIKE THIS BUT PEOPLE WILL REALLY CONFUSE AT THE TIME IN 2010 WHEN THIS DATA THAT DIDN’T CHANGE PFS OR PROGRESSION FREE SURVIVAL IMPROVE OVERALL SURVIVAL. HOW COULD A TREATMENT THAT DOESN’T CAUSE PSA TO GO DOWN MAKE PEOPLE LIVE LONGER. FUNNY BECAUSE I JUST WENT OVER TELLING YOU PSA ISN’T THE END ALL BE ALL IN PROSTATE CANCER YET SOME REASON STILL CONTROVERSY TWO YEARS AFTER A — THE PROSTATE CANCER WORKING GROUP ALL THE SMART PEOPLE WHO DO PROSTATE CANCER DEPOSIT TOGETHER AND SAID PSA IS NOT THE END ALL BE ALL BUT THIS IS A CONTROVERSY THAT LIMITED PEOPLE USING THIS. FURTHERMORE, FAST FORWARD FIVE OR EIGHT YEARS AND YOU HAVE IMMUNE CHECK POINT INHIBITORS WHERE WE SEE THE BENEFITS IN STUDIES WHERE YOU DON’T NECESSARILY SEE SEPARATION IN THE CURVES VERY QUICKLY OR PFS DIFFERENCES EARLY ON SO IT WAS A TIME PEOPLE WEREN’T ACCUSTOMED HOW TO EVALUATE IMMUNOTHERAPY TRIALS. BUT AGAIN, I THINK THIS IS A VERY CONVINCING STUDY THAT WAS DONE TWICE, THERE WAS DIFFERENT REASONS TESTIFY DONE IN SMALLER VERSION EARLIER, RESULTS WERE CONSISTENT AND I DO THINK THIS IS A GREAT OPTION FOR MEN WHO HAVE MINIMALLY SYMPTOMATIC DISEASE WHICH IS KIND OF WHERE THEY ACCRUED THESE PATIENTS. OFTEN TIMES I GET ASKED WHO SHOULD BE TREATED WITH THIS? AND THERE’S SOME DATA FROM THAT PHASE 3 TRIAL THAT I THINK HIGHLIGHTS THE ANSWER. THEY LOOK AT PSA QUARTILES AND WHAT YOU SEE IS BASED ON LOWER PSA SO LESS THAN 22 PAICIALTS WITH WHO GOT SIMPLE SOT DID SUBSTANTIALLY BETTER THAN PATIENTS WHO DID NOT. 13 MONTH DIFFERENCE YOU CAN SEE THE HAZARD RATIOS. AS P SA QUARTILES GO UP THE BENEFIT DECREASES. SO I DON’T THINK PSA IS REALLY THE STORY HERE, WHAT THIS IS TELLING US A CRUDE MARKER FOR TUMOR GROWTH F YOU HAVE A PATIENT WITH TWO OR THREE BONE LESIONS AND MODERATE PSA, IT’S REASONABLE TO TRY SIMPLE SOT AND SEE WHAT THE BENEFIT IS, AND THE DATA SUGGESTS THAT WITH LOW TUMOR BURDEN THEY WILL DO WELL OVER TIME. BUT I THINK THIS ALSO TELLS US THAT IF YOU HAVE GOT A GUY WITH LIVER METS AND PSA 300 THOUGH THAT SHOULDN’T BE THE PRIMARY CRITERIA BUT IF THEY HAVE LIVER METS MAYBE TEN LESIONS IN THE BONE MAYBE THIS IS NOT THE BEST THERAPY FOR THEM SO THIS IS KIND OF TELLING US A LITTLE BIT THAT PATIENTS WITH LOWER TUMOR BURDEN ARE GOING TO DO BETTER. I THINK IT MAKES SENSE IMMUNOLOGICALLY, WE KNOW TUMOR BURDEN CORRELATES WITH DEGREE OF IMMUNE SUPPRESSION. THE TOXICITIES ASSOCIATED WITH SIMPLE SOT ARE MINIMAL. MOSTLY INFUSIONS TYPE REACTIONS OR OTHER KIND OF CYTOKINE LIKE REACTIONS LIKE WHEN YOU GET A COLD OR FLU WHICH SOUNDS LIKE I HAVE RIGHT NOW. WHERE YOU HAVE A LITTLE BIT OR CHILLS AND FATIGUE. WELL TOLERATED THERAPY, ADMINISTRATION. SEVERAL YEARS AGO A GROUP OF PEOPLE MET UNDER AUSPICES OF IMMUNOTHERAPY FOR CANCER. AND CAME UP WITH SOME CONSENSUS STATEMENT ON THE ROLE IMMUNOTHERAPY PROSTATE CANCER, KIND OF WHAT I SAID EARLIER. SIMPLE S OT HAS A CLEAR BENEFIT IN PATIENTS WITH MINIMAL SYMPTOMS. DON’T EXPECT PSA TO GO DOWN AND USE IT EARLIER IN THE DISEASE PROCESS IN PATIENTS WHO PROBABLY HAVE LESS AGGRESSIVE DISEASE FEATURES. MY PERSONAL THING ALSO IS TO GIVE THIS TREATMENT AND THEN RUN. VERY OFTEN I THINK THOUGH WE KNOW PSAs DON’T CHANGE I TALK TO NUMBER OF PEOPLE THAT SAID I GAVE THIS TREATMENT AND THEN I WATCHED THEM FOR A YEAR AND PSA NEVER WENT DOWN THEN THEY GOT SYMPTOMS. I WAS LIKE REALLY WASN’T CLEAR WHY THEY WOULD WAIT SUCH A LONG TIME TO MOVE ON WHEN WE ARE NOT EXPECTING PSA TO GO DOWN SO IN OTHER WORDS LOOK AT THIS AS A WAY TO SUPER CHARGE THE IMMUNE SYSTEM AND MOVE FORWARD WITH OTHER THERAPIES THAT PIGGY BACK ON BENEFITS OF IMMUNOTHERAPY AND PROSTATE CANCER. SO I THINK THAT WHAT DO YOU MOVE ON TO? OPTIONS ARE REALLY (INDISCERNIBLE) THERAPIES THAT DEMONSTRATED ABILITY TO EXTEND SURVIVAL IN PATIENTS WITH MINIMAL TO MODERATE SYMPTOMS. I THINK DEPENDING ON YOUR OPINIONS YOU CAN BYPASS THAN AND GO RIGHT TO THESE AGENTS IF LOGISTICS OR OTHER REASONS PREVENTED YOU FROM USING SIMPLE SOT OR YOUR UNCONVINCED BY THE DATA BUT I THINK THESE ARE WELL TOLERATED AS WELL. SO I WILL TALK ABOUT AN ANTERO JN RECEPTOR ANTAGONIST. WE USED TO HAVE ANDROGEN RECEPTOR ANTAGONIST WE USE IN PROSTATE CANCER, ONE SECOND GENERATION TYPE 1 WAS DEVELOPED IN THE ’90s, FIRST GENERATION DEVELOPED IN THE ’80s BUT YOU CAN SEE THIS VERSION, THIS IS A BETTER MOUSE TRAP SO LITERALLY LIKE THE PEOPLE WHO DEVELOP THIS CHARLES SAWR AND HIS GROUP BUILT A BETTER MOUSE TRAP WORTH BILLIONS OF DOLLARS WHICH IS GREAT AND WORTH MORE THAN MEN WHO BENEFITTED FROM THE THERAPY OVER THE YEARS. IT BINDS BY MAGNITUDE OF 30 FOLD HIGHER TO THE RECEPTOR OLDER VERSIONS OF THE SAME TREATMENT. THAT OLDER VERSION. UNLIKE IT PREVENTS TRANSLOCATION OF RECEPTOR TO NUCLEUSND CO-ACTIVATION WITHIN THE NUCLEUS SO JUST AGAIN HAS DOWNSTREAM EFFECTS IN PROLIFERATION CAS STAID I MENTIONED CASCADE THAT LEADS TO CELLULAR PROLIFERATION AND PROSTATE CANCER. IT’S GETTING TO BE AN ARCHAIC, THE OLDER AGENTS HAVING ANISTIC PROPERTIES OVER TIME — AGONISTIC PROPERTIES OVER TIME IF THERE WAS MUTATIONS IN THE ANDROGEN RECEPTOR BINDING SITE. (INAUDIBLE) IS THOUGHT TO HAVE THAT, IT’S CERTAINLY NOT AS NOTE SEEN AS MUCH AS PREVIOUSLY. SO HERE IS THE FIRST TRIAL IN 1200 MEN WHO ALREADY HAVE BEEN TREAT WITH DOCETAXEL WITH META STATIC RESISTANT CANCER, PATIENTS WERE GIVEN (INAUDIBLE) OR PLACEBO. NOT SURPRISINGLY BECAUSE WE GET SUCH GOOD DATA AT THIS POINT IT’S NOT SURPRISING THAT THERE WAS A SUBSTANTIAL IMPROVEMENT IN SURVIVAL THAT WAS CLIPICALLY SIGNIFICANT AND STATISTICALLY AS WELL. YOU SEE PROGRESSION WAS 8.3 MONTHS VERSUS 3 MONTHS AND OVERALL SURVIVAL BENEFIT WAS LITTLE UNDER 5 MONTHS. I THINK THAT EVERYONE WAS VERY PLEASE WHEN THIS DATA CAME OUT AND IT WAS GOOD TO SEE BECAUSE AT THE TIME WE ONLY HAD CHEMOTHERAPY AND JUST HAD IMMUNOTHERAPY BUT PEOPLE WERE HAPPY TO HAVE A LESS TOXIC OPTION THAN CHEMOTHERAPY OR AFTER CHEMOTHERAPY FOR ADVANCE DISEASE. COUPLE OF YEARS LATER AS I MENTIONED EARLIER IN THE BEGINNING, IN PATIENTS WHO HAD NOT BEEN TREAT WITH CHEMOTHERAPY, AGAIN THERE WAS A SUBSTANTIAL IMPROVEMENT IN PROGRESSION FREE SURVIVAL IN THE FIRST YEAR. 65 HAVINGS 14%. THIS IS A 1700 PATIENT TRIAL. YOU CAN SEE A COMMON THEME IN THESE STUDIES WORTH NOTING FOR ANY CLINICAL TRIALS, IN CANCER, THAT HAVE CROSS OVER SO I JUST FOR SIMPLICITY THESE ARE CAP PLAN MIRE CURVES. JUST HIGHLIGHTS PATIENTS AND OVER TIME YOU SEE NUMBER OF PATIENTS SURVIVING UNFORTUNATELY DECREASES BUT WE LIKE TO SHOW ONES WITH BIG SEPARATIONS LIKE THIS. IT IS WORTH NOTING THAT I’M TELLING YOU HOW GREAT THIS DRUG IS AND LOOK AT THE OVERALL SURVIVAL AND YOU CAN SEE THE CURVES AND THEY ARE NOT AS GREAT AS SEPARATIN AND YOU ARE LIKE OH, TWO MONTHS, DOESN’T SEEM LIKE A BIG DEAL. SO IT’S ALWAYS IMPORTANT TO REALIZE THAT IN STUDIES LIKE THIS WITH A CROSS OVER, WHICH BASICALLY MEANS ONCE THEY REALIZE THAT THE TREATMENT WAS EFFECTIVE, THEY MADE IT VAIL TO BELIEVE THE PATIENTS ON PLACEBO GROUP YOU HAVE THESE CURVES THAT ARE GOING TO GET CLOSER. SO ANY TIME THERE’S A CROSS OVER LIKE THERE WAS IN THIS STUDY, ULTIMATE OUTCOME IN THIS CASE OVERALL SURVIVAL OVER LONG TERM IS GOING TO BE AN UNDERESTIMATE OF WHAT THE ACTUAL BENEFIT IS BECAUSE ESSENTIALLY PATIENTS IN BOTH ARMS OFTEN GOT THERAPY THAT WORKED. PLACEBO THOUGH TWO MONTH DIFFERENCE IS STATISTICALLY SIGNIFICANT BUT WORTH TALKING ABOUT AND I WILL COME BACK TO THAT LATER FOR IMPORTANT REASONS. (INDISCERNIBLE) IS A VERY EFFECTIVE DRUG, VERY WELL TOLERATED. THE BIGGEST SIDE EFFECT THAT PERHAPS CLINICIANS UNDERAPPRECIATE IS THE FATIGUE. AND SOME PATIENTS IT CAN BE PROFOUND, I HAVE HAD PATIENTS WHO HAD TREMENDOUS DROPS IN THEIR PSA AND DONE REALLY WELL WITH IT CLINICALLY EXCEPT FATIGUE WAS SO BAD THEY HAD TO STOP THE TREATMENT. SO THAT’S SOMETHING YOU HAVE TO BE AWARE OF OTHER SIDE EFFECTS ARE A LITTLE LESS FREQUENT. IT IS WORTH NOTING THESE PILLS ARE A LITTLE BIT ON THE LARGER SIDE SO THAT’S SOMETHING TO TAKE INTO ACCOUNT TOO IF PATIENTS HAVE SWALLOWING ISSUES WHICH YOU SEE IN OLDER POPULATION. THE OTHER PART WITH THE FATIGUE YOU CAN REDUCE THE DOSE SO MY INCLINATION IS FIND A PATIENT DOING WELL ON THIS TREATMENT AND FATIGUE, MORE TIME TO DROP THE DOSE AND DISCONTINUE MEDICATION SMG I HAVE HAD PATIENTS WHO HAVE GONE TO 50% DOSE LEVEL STILL HAD GREAT RESPONSES, BUT FATIGUE ABATES TO GREAT DEGREE. SO NEVER THROW SOMETHING AWAY THAT WORKS TOO QUICKLY. THERE’S BEEN CAUTION OVER THE YEARS ABOUT ENZALUDMIDE IN ISHT PAS WITH SEIZURES OR SEIZURE RISK. THERE’S A STUDY THAT LOOKED AT THIS IN PATIENTS AT RISK FOR SEETURES WHICH ALLAYED SOME CONCERNS BUT I THINK THERE IS SOME POTENTIAL FOR IT TO LOWER THE SEIZURE THRESHOLD SO IF YOU HAVE A PATIENT WHO HAD A RECENT STROKE OR MAYBE ON DRUGS OTHERWISE LOWER THE SEIZURE THRESHOLD, YOU MAY WANT TO BE A LITTLE MORE CAUTIOUS AND YOU WILL FIND (INDISCERNIBLE) AS I HIGHLIGHTED EARLIER THIS FRONT LINE SETTING, CAN BE USED PERHAPS INTERCHANGEABLY AS FIRST THERAPY. SO IT’S CAI HIGHLIGHTED HERE, OFTEN TIMES YOU ARE CHOOSING BETWEEN ONE OF THE TWO REALIZING THAT WHICHEVER ONE THESE PATIENTS GO ON THEY MAY GET TO USE THE OTHER BUT PROBABLY NOT GOING TO BE ON IT AS LONG SO GOES BACK TO WHAT I SAID IN THE BEGINNING WHICH IS CONSIDER THE PATIENT’S MORBIDITY AND — I’M SORRY, CO-MORBIDITIES WHEN YOU CHOOSE YOUR OPTION. SOFT DIDZ DIZ IS — (INDISCERNIBLE) IS ANOTHER ONE WITH MINIMAL TO MODERATE SYMPTOMS. THIS IS A TARGETED THERAPY THAT WORKS A LITTLE DUFNTLY. I MENTIONED EARLIER ONE OF THE RECENT UNDERSTANDING TELLS US SECONDARY PRODUCTIONINGS OF AN DRO — PRODUCTIONS FROM ANDROGENS FROM TUMOR CELLS IS WAY BY WHICH ALMOST IN A AUTOCRINE FASHION THAT CANCER CELLS FUEL THEIR OWN GROWTH. THIS IS COMPLEX META BOLLIC PATHWAY ANDROGENS ARE CREATESSED. (INDISCERNIBLE) INITIALLY ANTI-FUNGAL FOUND TO HAVE NONSPECIFIC EFFECTS THAT DIDN’T AFFECT PROSTATE CANCER IN THE 80s BUT IT’S A BETTER MOUSE TRAP WAS MORE SPECIFIC IN TARGETING THE 17 ENZYMES. UNFORTUNATELY THE SUB 17 HYDROXYLACE IS INHIBITED TO SOME DEGREE AS WELL AND THAT LEADS TO COURT SOLVE WHICH LUDZ TO FLUID COLLECTION HYPERTENSION WHICH IS SOME TOXICITY BUT BY BLOCKING ENZYMES PREVENTS THE CELLS FROM THE SECONDARY PRODUCTION OF ANDROGENS TO FUEL THEIR OWN GROWTH SO THAT’S VERY IMPORTANT TO STOPPING SOURCES OF ANDROGEN BEYOND JUST TESTICLE. THIS IS THE TRIAL SIMILAR TO THE PREVIOUS TRIAL, IT TOOK PATIENTS ALREADY PROGRESSED ON CHEMOTHERAPY AND GAVE THEM (INDISCERNIBLE) OR PLACEBO. THIS WAS KIND OF CONCURRENTLY ACCRUED WITH THE (INDISCERNIBLE) TRIALS. THERE WAS HIGH ENTHUSIASM ON PRELIMINARY DATA SHOWING 80% HAD MARKED RESPONSES BY PSA. SO THIS IS OVERALL SURVIVAL INITIALLY PRESENTED, 14.8 MONTHS OR 7.9 MONTHS AND SUBSTANTIAL IMPROVEMENT IN SURVIVAL. ALSO LAKE TO TAKE A STEP BACK AND PROVIDE PERSPECTIVE. SOMETIMES YOU HAVE CYNICAL PEOPLE OUT THERE AND THEY SEE A TRIAL LIKE THIS AND THEY ARE PEOPLE WHO LOOK AT THIS AND SAID THESE ARE LATE STAGE PATIENTS WHO HAD CHEMOTHERAPY AND PROBABLY DIDN’T HAVE LONG TO LIVE BUT SIN CL PEOPLE OR CYNICAL FOLKS OUT THERE SAY BIG DEAL THAT’S A FOUR MONTHS IMPROVEMENT IN SURVIVAL IS THAT HOW IS THAT MATTER? SOME PATIENTS DID MCH BETTER THAN 14 MONTHS. OTHER THING, THIS TRIAL WAS DONE IN 2011, FAST FORWARD FIVE YEARS THEY DID IN EARLIER POPULATION AND MEN WHO GOT THIS DRUG IN THAT STUDY LIVED TWO OR THREE YEARS LONGER. SO YOU WILL SEE THAT START OFF SMALL AND THERE’S WAYS TO UNDERSTAND HOW TO USE IT BETTER AND MAYBE DIFFERENT POPULATIONS GET MUCH BETTER RESULTS. SO WHILE I THINK IT IS IMPORTANT TO BE CYNICAL AND QUESTIONS THINGS YOU HAVE TO HAVE A BROAD PERSPECTIVE ABOUT THAT AS YOU MOVE FORWARD AND THIS PROVIDE AN EXAMPLE. FROM THAT TRIAL NOT SURPRISINGLY PATIENTS HAVE GREAT RESPONSES TO PSA AND IMPROVEMENTS IN PROGRESSION FREE SURVIVAL SO A LITTLE MORE DATA. HERE IS A LONG TERM FOLLOW-UP THEY DID SEVERAL YEARS LATER AND STILL SHOWED BIG SEPARATION BETWEEN THE CURVES. SO — I’M SORRY, EXCUSE ME. THIS IS THE STUDY THAT WAS DONE A FEW YEARS LATER OR PUBLISH AD FEW YEARS LATER, I APOLOGIZE WHEN PARENTS WHO — PATIENT WHOSE NOT RECEIVED CHEMOTHER CHEMOTHERAPY. POST CHEMO AND PRE-CHEMO (INDISCERNIBLE) DID THE SAME THING AND THIS STUDY DEMONSTRATED A SIMILAR 33 MONTH READ OUT SIMILAR STO THE STUDIES — TO THE STUDIES AND THERE WAS IMPROVEMENT SIGNIFICANT AND MEANINGFUL AND THAT’S WHY IT WAS ALSO APPROVED SUBSEQUENTLY IN PATIENT WHOSE NOT HAD CHEMOTHERAPY. SO THE TOXICITY LIST IS LONGER. PATIENTS DO — ARE CO-TREATED WITH PREDNY ZONE, FIVE MILLIGRAMS A DAY, THOUGHT IT CAN MINIMIZE TOXICITY FLUID COLLECTION AND EDEMA THAT PERHAPS SOME OF THE FLUID COLLECTION THAT LEADS TO HYPERTENSION RELATED TO THAT SUB 17 TARGETING I MENTIONED EARLIER. WITH THE PRED ANY ZONE COMES SIDE EFFECTS OF HIGH BLOOD SUGAR SO IF YOU HAVE A PATIENT WITH
HAIP TENSION OR DIABETES YOU MAY — A PATIENTWITH HYPERTENSION OR DIABETES, YOU CAN SEE ALSO WITH ALL THESE AGENTS YOU HAVE TO PAY ATTENTION TO LIVER ENZYMES AND OTHER THINGS THAT GENERALLY DESPITE THE LIST HERE MOST OF THESE PATIENTS TOLERATE THIS TREATMENT VERY WELL. AND ARE ON IT FOR A LONG TIME. SO I KIND OF SHOW BOTH THESE TREATMENT OPTIONS ARE GOOD FOR PATIENTS TO PATIENTS WHO HAD MINIMAL OR MODERATE SYMPTOMS BUT I HINTED THAT YOU ARE MAKING A CHOICE HERE. AND THE CHOICE IS REALLY BETWEEN WITHER PI YOU WANT TO USE FIRST, — WHICH, THERAPY YOU WANT TO USE FIRST, SEQUENTIAL USE IS NOT ADDITIVE, IN OTHER WORDS LIKE LIKE IF THE WAYS PROGRESSION BY 20 SOME ODD MONTHS WITH (INDISCERNIBLE) YOU GET 20 SOME ODD MONTHS AS WELL BECAUSE OF THE FACT THOUGH NOT SPECIFICALLY TARGETING THE SAME THING, THEY ARE STILL TARGETING ANDROGEN RECEPTOR PATHWAY OR THE ANDROGEN PATHWAY AND THEREFORE THERE’S RESISTANCE THAT DEVELOPS TO THE INITIAL THERAPY AND THAT RESISTANCE THE PROBABLY RELEVANT TO WHATEVER YOUR SECOND CHOICE IS. SO HERE IS SOME DATA PUBLISHED BY DR. (INDISCERNIBLE) AND HIS COLLEAGUES AT JOHNS HOPKINS. THEY LOOKED AT A SPLICE VARIANT, A POST TRANSCRIPTION SAL MODIFICATION THAT RESULTS IN A VARIANT OF ANDROGEN RECEPTOR THAT DOESN’T HAVE A RECEPTOR, AS MENTIONED EARLIER CAN BE CONSTITUTIVELY ACTIVE. SO YOU CAN SEE TWO WATER FALL PLOTS, PSA RESPONSES. I SAID IT WASN’T THE GREATEST BIOMARKER FOR CLINICAL USE BUT IT IS TELLING THE STORY VERY WELL HERE. SO IN PATIENTS WITH PREVIOUSLY TREATED WITH ENZALUD,MIDE U YOU,
IF YOU CAN SEE IF THEY HAVE HAD ARROWS WITH PREVIOUS APERADARONE, IF THEY ARE GOLD THEY HAVE THIS SPLICE VARIANT. SO MAJORITY OF PATIENTS WITH PREVIOUS APARADERONE ARE GOLD AND YOU CAN SEE FROM ARROWS AND DID NOT RESPOND TO PSA TO SUBSEQUENT TREATMENT WITH ENZALUDMIDE SO WHAT YOU SEE HERE IS RESISTANCE THAT LIKELY LED TO APARADERONE RESISTANCE PREVENTED THEM FROM GETTING ENZALUDMIDE. THIS EVOLVES OVER TIME MOST PATIENTS DON’T HAVE VARIANTS. YOU WILL SEE THE PATIENT WHOSE ARE SPLICE VARIANT NEGATIVE, WERE MORE LIKELY TO HAVE PSA DECLINES. THE SIMILAR IS TRUE WHEN YOU LOOK AT THE FLIP SIDE WHICH IS PATIENTS WITH APERADARONE FIRST AND THEN TREATED WITH (INDISCERNIBLE), FEWER PATIENTS BUT PATIENTS THAT HAVE THE SPLICE VARIANT ARE LESS LIKELY TO RESPOND. THERE’S ALSO MORE DATA THAT WAS PRESENTED AT THE — PRESENTED AT ASCO AND PUBLISHED THIS YEAR, THAT AGAIN SHOWED IN PATIENTS WHO HAD THIS SPLICE VARIANT LOOKING AT TWO SEPARATE BIOMARKER STRATEGIES THAT IF THEY HAD THE SPLICE VARIANT WHICH IS RED, THEY DO WORSE ON SUBSEQUENT THERAPIES. SO THERE’S LARGER DATA SETS NOW THAT SHOW THE SAME THING. ARV 7 IS NOT THE ONLY RESISTANCE MECHANISMS, THERE ARE OTHERS BUT HIGHLIGHTS THE REASON WHY YOU PROBABLY CAN’T EXPECT TO GET ABSOLUTE BENEFIT FROM BOTH AGENTS AND HIGHLIGHTS WHY YOU NEED TO BE CAUTIOUS AN THOUGHTFUL HOW YOU CHOOSE WHICH YOU GET BASED ONCO MORBIDITIES SO PATIENT WITH DIABETES MAYBE USE (INDISCERNIBLE) AND PATIENTS THAT LOWER SEIZURE THRESHOLD USE APERADARONE THINGS LIKE THAT FACTOR INTO YOUR CHOICES. IF PATIENTS PROGRESS ON THESE THERAPIES THEN IT’S COMMON THEY HAVE HIGHER DISEASE BURDEN AND SIGNIFICANT SYMPTOMS SO THEN WE START GETTING INTO THE REALM OF THE THERAPIES THAT HAVE BENEFIT BUT PROBABLY COME WITH MORE SIDE EFFECTS. OF COURSE THESE PATIENTS ARE MORE ADVANCED, HAVING MORE SYMPTOMS IS SOMETIMES SIDE EFFECT IS MORE ACCEPTABLE BECAUSE HOPEFULLY THAT’S A TRADE OFF IMPROVE SYMPTOMS THEY HAVE VERSUS EARLIER DISEASE STATES THEY MIGHT — IT’S NOT UNCOMMON FOR MEN WITH MULTIPLE BONE LESIONS, TEN OR 15 TO HAVE NO SYMPTOMS BUT OVER TIME THAT’S LIKELY TO CHANGE. THAT’S WHY THESE CHEMOTHERAPY OR 223 BECOMES AN OPTION. SOMETIMES IF A PATIENT IS ON (INDISCERNIBLE) FOR TWO OR THREE YEARS, THEY HAVE NO SYMPTOMS AND ONE OR TWO LESIONS THAT PROGRESSION ON SCANS THOUGH WE DON’T EXPECT THEM TO DO AS WELL SEQUENTIALLY, I MAY CONSIDER DOING THE ALTERNATIVE THERAPY. IF THEY HAVE RAPID PROGRESSION AGAIN OR SYMPTOMATIC DISEASE YOU MAY WANT TO MOVE FORWARD WITH SOMETHING WHICH IS MORE PROVEN BENEFIT IN THOSE TYPES OF PATIENTS LIKE THE CHEMOTHERAPY OR THE RADIATION. IF THEY SHOW UP IN YOUR OFFICE AND HAVE RAPIDLY PROGRESSING DISEASE, YOU PROBABLY MORE INCLINED TO START OFF WITH SOMETHING LIKE THIS TO ABATE SOME OF THOSE SYMPTOMS. SO WHAT IS DOCETAXEL, IT’S ACTUALLY A TYPE OF TAXANE WHICH IS INITIALLY DERIVED FROM PACIFIC NORTHWEST, WHI YOU DON’T WANT TO CUT DOWN YOUR TREES BECAUSE SOME MAY HOLD METABOLITES AND THINGS THAT HELP IN CANCER. SO IN THE 60s AND 70s PACLOTAXOL WAS DEVELOPED. FROM THE YOU TREE IN THE PACIFIC NORTHWEST AND REALLY IT WAS AN — AND SYNTHETIC VERSIONS OF THAT DOC DOCETAXEL DEVELOPED IN THE YEARS THAT FLOW. TAXANEs ARE TYPE OF CHEM THERAPY THAT INHIBIT MICROTUBULES, GENERALLY THOUGHT THEY ARE REQUIRED FOR MYTOSIS SELF-PROLIFERATION AND THEREFORE IF YOU BLOCK THE MICROTUBULES THEN YOU CAN BLOCK CELLULAR PROLIFERATION. SO THAT COULD BE WHY TAXANE WORK IN PROSTATE CANCER, ONLY TYPE OF CHEMOTHERAPY BUT THERE’S DATA LOOKED AT THE LAST DECADE THAT HIGHLIGHTS A STORY THAT MAY REMIND US THAT IN PROSTATE CANCER IT IS ALWAYS ABOUT THE APPROXIMATE DROA GENERAL RECEPTOR — ANDROGEN RECEPTOR. THE MICROTUBULES IN MOS STATE CANCER ARE ALSO THE MECHANISM BY WHICH ANDROGEN RECEPTOR TRANSLOCATES THE NUCLEUS IN THE CELLULAR PROLIFERATION CASCADE SO THE TRAIN TRACKS ANDROGEN RECEPTOR GETS PULLED IN FROM THE SURFACE TO THE NUCLEUS AFTER ACTIVATION. SO PERHAPS BY IMPAIRING THAT YOU IMPAIR AR TRANSLOCATION SO MAYBE SOME WAYS TAXANES ARE TARGETING THE ANDROGEN RECEPTOR PATHWAY. SO WE KNOW A LITTLE MORE ABOUT THAT BUT CERTAINLY AN INTERESTING DEVELOPMENT. SO IN 2004, THERE HAVE BEEN PRELIMINARY DATA SUGGESTING DOCETAXEL HAD SOME BENEFITS IN PROSTATE CANCER SO THIS TRIAL WAS DONE LOOKING AT TWO SCHEDULES. DOCETAXEL GIVEN EVERY THREE WEEKS OR EVERY WEEK, AND THEN COMPARED TO PREDNISONE. I MENTIONED IN 2004 DOCETAXEL WAS FIRST TREATMENT TO IMPROVE SURVIVAL IN PROSTATE CANCER BUT PRIOR TO THAT PREDNISONE WERE CONSIDERED STANDARD OF CARE THAT DEMONSTRATED PAILIATION. SO THERE AS NO CLEAR BENEFIT IT IMPROVED SURVIVAL BUT IT WAS STANDARD OF CARE BECAUSE IT IMPROVED SYMPTOMS. IT WAS KIND OF A BIG DEAL. I’M OLD ENOUGH THAT I WAS AT THIS ASCO WHEN PRESENTED AT PLENARY SESSION AND THIS TRIAL WAS POSITIVE AND PEOPLE WERE SUPER EXCITED, IT’S SUCH A MAJOR DISEASE IT’S ONE OF THE LEADING CAUSES OF CANCER IN MEN IN THIS COUNTRY, YES, SIR UNTIL 2004 WE DIDN’T HAVE A TREATMENT THAT MADE PEOPLE LIVE LONGER SO IT WAS A REALLY BIG DEAL AND THIS IS THE RESULT OF THE TRIAL. DOCETAXEL EVERY THREE WEEKS IN GREEN EXTENDED SURVIVAL OVER (INDISCERNIBLE) AS WELL AS OVER THE WEEKLY VERSION MORE RECENT DATA DEMONSTRATED IT’S STILL GOOD WITH LESS SIDE EFFECTS. BUT IF YOU LOOK AT THE DIFFERENCE HERE, IT’S 18.9 MONTHS VERSUS 16.4 MONTHS. SO AGAIN I THINK BRINGS BACK WHAT I BROUGHT UP EARLIER. I OFTEN HAVE PATIENTS IN SUPPORT GROUPS OR WHO COME TO CLINIC AND THEY KNOW THIS DATA. THEY ARE FAMILIAR WIT, THEY WROTE IT DOWN ON THE INTERNET, THEY LOOKED AT ME, OR THE SUPPORT GROUP WILL TELL ME THERE’S NO WAY IN HECK I’M GOING TO TAKE CHEMOTHERAPY, DOC, IT ONLY MAKESES ME LIVE TWO MONTHS LONGER NOT WORTH IT BECAUSE IT HAS SITED EFFECTS. IT DOES AND WE’LL COME TO THAT. BUT WHAT ARE WE MISSING? THEY ARE MISSING THE CROSS OVER EFFECT. SO WHAT NEVER GETS TALKED ABOUT WHEN PEOPLE CRITICIZE THIS DATA IN CERTAIN SETTINGS IS THAT THE EXPECTATION FOR PREDNISONE IN PREVIOUS STUDIES WAS CLOSER TO TEN MONTHS. BUT WHAT HAPPENED WAS IN THIS TRIAL, WAS THAT THEY ALLOWED PEOPLE WHO PROGRESSED ON PREDNISONE TO GO ON TO GET CHEMOTHERAPY SO THIS IS ANOTHER EXAMPLE OF UNDERESTIMATE OF LONG TERM BENEFIT OF THERAPY BECAUSE OF THE CROSS OVER EFFECT AND TRIAL DESIGN. SO YOU HAVE THE FACTOR THAT INTO ACCOUNT. USUALLY IF I TELL THE PATIENT THAT IN THE OFFICE, HIS WIFE WILL USUALLY HIT HIM ON THE ARM AND HE USUALLY LISTENS A LITTLE BETTER. AND IT’S AGAIN JUST KIND OF IN A VERY IMPORTANT NUANCE BUT HIGHLIGHTS HOW SOMETIMES GETTING PART OF THE STORY CAN BE A LITTLE BIT TRICKIER, CREATE FALSE IMPRESSIONS FOR PATIENTS. AND VERY IMPORTANT PART OF WHAT WE DO IS EDUCATION. THAT IS IMPORTANT TO REMEMBER SOME OF YOU MAYBE ADAMANT ABOUT SOMETHING BUT NEED TO TAKE TIME TO UNDERSTAND WHERE THEY ARE COMING FROM. IF THEY ARE ADAMANT BECAUSE OF SIDE EFFECT THERE’S NO DENYING TOXICITY. I DON’T PUT IT UP HERE TO MEMORIZE BUT THERE ARE MORE SIDE EFFECTS FROM DHEEM THERAPY. THE BIG SIDE EFFECTS AS A CLINICIAN ARE BASICALLY FE BRIEL KNEW TRA PEENIC INFECTIONS WHICH BASICALLY COME ABOUT BECAUSE CHEMOTHERAPIES DIMINISH THE WHITE BLOOD CELL COUNT IN PATIENTS AND MAKE THEM SUSCEPTIBLE TO INFECTIONS AND THOSE INFECTIONS WITH OVERRUN A PATIENT WITHOUT A COMPETENT IMMUNE SYSTEM KNOCKED DOWN BY CHEMONER — CHEMOTHERAPY SO PATIENTS HAVE TO BE AWARE WHAT TO LOOK FOR. NEUROOPATHY IS ANOTHER THING NUMBNESS AND TINGLING IN THE PATIENTS. QUALITY OF LIFE, FLUID RETENTION, YOU CAN GET HAIR THINNING, RASHES, THINGS LIKE THAT. THE OTHER BIG THING IS FATIGUE, USUALLY FOUR TO TEN DAYS AFTER THESE PATIENTS GENERALLY ARE A LITTLE BIT MORE FATIGUED. I HAVE HAD 80, 90-YEAR-OLD MEN WITH CHEMOTHERAPY, IT’S PROPERTY STATE CANCER SO YOU CAN’T SAY YOU’RE TOO OLD. NOT THE BEST STRATEGY, THE OLDEST GUY WAS 94, 95, HE DID WELL. MOST PATIENTS STILL WORK ON CHEMOTHERAPY. IT IS WELL IT WILL RATED BUT WE HAVE TO BE AWARE OF SIDE EFFECTS. ANOTHER THING TO CONSIDER IN PATIENTS A T THIS POINT WHERE EARLIER DISEASE WHERE SYMPTOMATIC OR RAPIDLY MOVING CANCER IS RADIAL 223, A PHARMACEUTICAL SO THIS IS BASICALLY AN AGENT THAT’S INFUSED IN TO THE VEIN THROUGH IV AND LOCALIZES TO IRAIAS IN THE — AREAS IN THE BONE WITH HIGH TURN OVER LIKE META STATIC CANCER. WHAT MAKES THIS DIFFERENT THAN OTHER RADIO PHARMACEUTICALS WHICH WERE FDA APPROVED FOR PAILIATION IN PROSTATE CANCER IS THESE FIRE OFF ALPHA PARTICLES INSTEAD OF BETA PARTICLES. NOT PHYSICIST, I DIDN’T DO THAT WELL IN PHYSICS IN COLLEGE IF I REMEMBER CORRECTLY. FROM WHAT I REMEMBER. BUT WHAT SMART PEOPLE HAVE TOLD ME AND I BELIEVE THEM IS THAT THE BETA PARTICLES ARE MUCH LIGHTER SO THE STRUCTURE RADIUS WHEN THEY FIRE OFF IS GREATER. WHAT DOES THAT MEAN? WHEN TALKING BONE LESIONS THAT MEANS BYSTANDERS GETTING KILL AND THEY ARE BLOOD CELLS. SO YOU GET ANEMIA, A LOT OF PLATELETS MANUFACTURED IN THE BONE MARROW AND THAT CAN LEADS TO TREATING LIMITED TOXICITIES WITH THE OLDER AGENTS. RADIUM 223 BEING ALPHA PARTICLE IS BIGGER HEAVIER PARTICLE SO MAY HAVE A MORE DESTRUCTIVE EFFECT BUT ALSO DOESN’T GO AS FAR SO THEREFORE YOU DON’T GET AS MUCH OF THE INNOCENT BYSTANDERS IN THE BONE MARROW THE COMPARTMENT BUT BLOOD CELLS GETTING ATTACKED SO LIMITED THE TOXICITY SEEN WITH PREVIOUS GENERATION OF THIS TYPE OF THERAPY. THIS WAS A TRIAL DONE THAT WAS UNLIKE OTHER TRIALS WITH EXPOSURE WITH DOSE ARBITRARILY CHOSEN FUSED EVERY MONTH FOR SIX MONTHS AND THIS IS THE BENEFITS DEMONSTRATED IN A TRIAL AGAIN, STATISTICALLY AND CLINICALLY SIGNIFICANT, LEADING TO FDA APPROVAL IN MEN WITH SYMPTOMATIC PROSTATE CANCER IN THE BONES. WHICH AGAIN IS 90% OF MEN HAVE THEIR PROSTATE CANCER. WHAT THEY WERE ABLE TO DEMONSTRATE CLEARLY IN THIS TRIAL THAT REGARDLESS OF WHETHER THEY HAD PREVIOUS CHEMOTHERAPY AT UCF HERE THERE WAS A CLEAR BENEFIT FROM THIS THERAPY. SO LITTLE LESS CLEAR HOW PAILIATIVE IT WAS, THESE ARE SMALLER NUMBERS BUT I THINK THAT ONE THING THAT COMES UP IS DO YOU HAVE TO HAVE CHEMOTHERAPY TO GET THIS AND THE ANSWER IS NO. AGAIN, IT DID LEAD — UNLIKE OTHER AGENTS IT DID LEAD TO A SURVIVAL ADVANTAGE. WHAT ARE WE TALKING ABOUT WITH TOXICITYS? TOXICITYS? THERE’S CHEMO TOXICITIES BUT NOT AS SEVERE AND LONG LASTING, AND THEREFORE IT’S SOMETHING TO TAKE INTO ACCOUNT WHEN TALKING ABOUT TREATING PATIENTS AND HOW TO FOLLOW THEM. WHAT DO YOU DO AFTER THEY HAVE HAD ALL THE THERAPIES? WE WILL TALK ABOUT THAT NOW BECAUSE THAT’S WHERE WE ARE A LITTLE FLOWCHART HERE. AND YOU WILL SEE PATIENTS WHO ALREADY PROGRESSED ON CHEMOTHERAPY, WE TALK ABOUT RADIUM AND (INDISCERNIBLE), I HAVE SHOWN YOU DATA THAT SHOWS THAT THIS TREATMENT WORKS IN THEM BUT ONE OTHER AGENT THAT I HAVEN’T MENTIONED IS ANOTHER CHEMOTHERAPY LIKE DOSE TACK SAL IN THAT THEY ARE TAXANES. I WAS NOT GOOD AT ORGANIC CHEMISTRY EITHER HOWEVER I SHOULD FIND OUT WHO MAKING THIS DIAGRAM, I APOLOGIZE FOR THAT BUT YOU CAN SEE THAT THERE’S METH OBJECTIONXYL SIDE CHAINS THAT LOOKED DIFFERENT THAN DOCETAXEL. THERE’S RATIONAL THAT MAYBE THIS HAS LESS AFFINITY FOR PUMPS THAT LEAD TO RESISTANCE. BUT UNLIKE SOME OF THE OTHER THERAPIES I MENTIONED THERE WAS NOT A LOT OF ENTHUSIASM, A LOT KNOWN ABOUT THIS AGENT WHICH WAS LARGELY TESTED OUTSIDE THE UNITED STATES. WHEN THE PHASE 3 TRIAL CAME OUT IN 2011 IT DEMONSTRATED SURVIVAL ADVANTAGE SO THEY TOOK PATIENTS WHO PROGRESSED ON DOCETAXEL AND GAVE THEM (INDISCERNIBLE) BECAUSE IT WAS A PAILIATIVE CHEMOTHERAPY AVAILABLE. THERE WAS A THREE MONTHS IMPROVEMENT IN SURVIVAL THAT WAS STATISTICALLY SIGNIFICANT. AND THIS LED TO BASICALLY APPROVAL OF THIS AGENT IN PATIENTS WHO ALREADY HAD CHEMOTHERAPY. THERE WAS STUDIES TO SEE IF THIS IS SUPERIOR DOCETAXEL AND FRONT LINE SETTING THOSE TRIALS WERE NEGATIVE. MY PREFERENCE IS TO GIVE DOCETAXEL UP FRONT IN PATIENT WHOSE NOT PROGRESSED ON IT PREVIOUSLY. THERE WAS SOME KNEW TRA PEENIC FEVER EVENTS THAT WERE PART OF THIS THE STUDIES SUBSEQUENT STUDIES DEMONSTRATED GIVING CLINICALLY AS EFFECTIVE AS GIVING 25 SO THAT THAT IS MORE COMMONLY DONE NOW. MUCH LIKE CHEMOTHERAPY, THERE’S SIDE EFFECTS, KNEW TRAPENIA OHIO KNEW PATIENTS HAD DOSE TAX SOLVE MAY HAVE BEEN ABLE TO FIGURE OUT IF THEY HAD NEUROPATHY THEREFORE A LOT OF TRIALS SO THERE MIGHT BE AS CERTAINMENT BIAS THERE BUT NONETHELESS IT DOES APPEAR BASED ON THE DATA THERE’S LESS NEUROPATHY. I DID MENTION HEME TOXICITY IN KNEW TRAPENIA. FATIGUE IS STILL THERE. AND A LOT OF OTHER SIDE EFFECTS YOU EXPECT FROM CHEMOTHERAPY. SO ONE OF THE THINGS THAT CHANGED I’LL HIT ON THIS THE LAST TEN MINUTES IS MORE RECENT EVOLVING THERAPEUTIC POINTS OF DISCUSSION IN PROSTATE CANCER, IS HOW DO WE USE PATIENT UNDERSTANDING TO TARGET TUMORS. THE REASON IS QUESTION IS RELEVANT IS THAT 2015 THERE WAS A STUDY PUBLISHED THAT DEMONSTRATED THAT FROM SEVERAL HUNDRED PATIENTS THAT PROSTATE CANCER HAS MUTATIONS. THAT WAS SURPRISING TO SOME BECAUSE THEY THOUGHT IT WAS NOT A HIGH MUTATION DISEASE BUT IT’S CANCER SO IT SHOULDN’T HAVE BEEN A SURPRISE BUT WHAT WAS A SURPRISE IS ROUGHLY SOMEWHERE IN THE NEIGHBORHOOD OF 20 TO 25 — TO 30% OF PATIENTS HAD MUTATIONS IN THE DNA REPAIR PATHWAY. SO THAT’S VALUABLE FOR DIFFERENT REASONS BUT PERHAPS MOST IMPORTANTLY BECAUSE THERE ARE THERAPIES THAT TARGET PATIENTS WITH DNA DAMAGE REPAIR THAT WAY DEFECTS SUCH AS — SO LATER THAT YEAR IT’S KIND OF ALL CAME TOGETHER FT THERE WAS A TRIAL THAT DEMONSTRATED PATIENTS WHO HAD THOSE TYPE OF MUTATIONS DID VERY WELL CLINICALLY. SO FAST FORWARD FOUR YEARS LATER THAT TRIAL WAS FOLLOWED UP ON WITH A LARGE PHASE 3 TRIAL THAT IS DEMONSTRATED THAT ELAPARIN WHICH TARGETS PATIENTS WITH BRACA 2 MUTATIONS WHICH IS A CERTAIN TYPE OF DNA DAMAGE REPAIR PATHWAY MUTATION, AND KAPLAN MEYER CURVE TO SHOW YOU THAT BECAUSE THEY HAVEN’T PUBLISHED THAT. BUT THE PRESS RELEASE TOLD US THE PHASE 3 TRIAL DEMONSTRATED IN ISHT PAS WITH THESE MUTATIONS, ESPECIALLY BRACA 2 MOSTLY BRACA 2s THAT ELAPERIB SPECIFICALLY TARGETS DNA DAMAGE REPAIR PATHWAY IS EFFECTIVE IN EXTENDING SURVIVAL. SO IT’S EXPECTED THE FDA WHICH ALREADY GIVEN BREAK THROUGH STATUS COUPLE OF YEARS AGO WILL LIKELY LEAD THE APPROVAL IN THE NEAR FUTURE. SO AGAIN, THERE GOES THE QUESTION OF MAKE SURE — THERE’S OTHER MUTATIONS TARGETED IN PROSTATE CANCER. M SI HIGH IS ACTUALLY A MUTATION BASICALLY ACROSS ALL CANCERS, LEADS TO PROBABLY A 50% CHANCE OF RESPONDING TO IMMUNE CHECK POINT INHIBITOR. NOTEWORTHY FROM MY ENTIRE PRESENTATION IS DISCUSSION ABOUT IMMUNE CHECK POINT INHIBITORS. IN MOST PROSTATE CANCER PATIENTS THEY DO NOT WORK. TRIALS HAVE BEEN NEGATIVE BUT IN PATIENTS WITH MSI HIGH STATUS BASED ON BIOPSIES BY IS 2 OR 3%, 50% OF THOSE RESPOND. ANOTHER THING IN RECENT YEARS IS CDK 12 INACTIVATION. THIS IS VERY EARLY BUT THERE’S SUGGESTION THESE PATIENTS MIGHT ALSO RESPOND. SO PUT THEM TOGETHER IT’S HER 4 OR 5%. GOES BACK TO THE QUESTION, WHEN YOU BIOPSY PATIENTS. UNDERSTANDING MUTATIONS. OFTEN TIMES IF THEY BIOPSY DONE INITIALLY BEFORE THEY BECOME META STATIC IT COULD BE TEN YEARS SO SOMETIMES THAT TISSUE IS NOT AVAILABLE OR A LOT CAN CHANGE. IT’S NOT CLEAR BUT DATA SUGGESTS REGARDLESS OF MUTATION STATUS THAT (INDISCERNIBLE) MIGHT BE EFFECTIVE UP FRONT. I THINK THE CLINICAL QUESTION IS LIKE SAID EARLIER WHEN YOU BIOPSY. ONCE THEY PROGRESS ON KIND OF ANTI-ANDROGEN TARGETING THERAPY (INDISCERNIBLE) IS WHAT I WOULD CONSIDER BIOPSYING ONE OF THE META STATIC SITES ANALYZING THE TISSUE. IF IT’S POSITIVE FORM BRACA MUTATION, LIKE A PARP INHIBITOR COMES INTO PLAY, MSI STATUS IS THERE WHICH AGAIN IS LIKE 2 OR 3% OR IF CDK 12 ACTIVATION THAT’S IMMUNE CHECK POINT SO WE ARE AT A POINT NOW WHERE MAYBE 20 TO 30% OF MEN WITH ADVANCED PROSTATE CANCER HAVE HARBOR MUTATIONS THAT ARE TARGETABLE AND THEREFORE IS THAT WOULD BE WHAT I WOULD DO THE BIOPSY SO I THINK I WON’T TALK ABOUT NON-META STATIC PROSTATE RHESUS CAN’T PROSTATE CANCER, WRAPPING UP ON TIME HERE BUT WHAT I WOULD — LET’S SKIP THAT IN THE SPHWERS OF TIME T I WANT TO MACK SURE WE HAVE TIME FOR QUESTIONS OR COFFEE BREAK BEFORE THE NEXT TALK BUT I WANT TO THANK EVERYONE FOR COMING AND WATCHING ONLINE. I GUESS THAT’S AN OPTION NOW SO THAT’S GREAT. IF THERE ARE ANY QUESTIONS HAPPY TO TAKE THEM HERE OR SEPARATELY HOWEVER YOU WOULD LIKE TO DO IT. [APPLAUSE]>>FOR PROSTATE CANCER YOU HAVE MANY THERAPIES. ANY (INAUDIBLE)?>>YEAH, IN OTHER WORDS — LIKE MOLECULAR SUBSETS? SO ONE THING I DID TALK ABOUT WHICH IS A LARGE FOCUS RIGHT NOW IS SMALL CELL PROSTATE CANCER. SO MOST OF PROSTATE CANCER IS ADINOCARCINOMA. RIGHT NOW THERE IS A SUBSET OF PROSTATE CANCER PATIENTS THAT DO ESPECIALLY POORLY NO MATTER THE THERAPY CALLED SMALL CELL PROSTATE CANCER. WHAT I THINK IS A LARGE FOCUS OF RESEARCH IS, DO OUR TREATMENTS THAT I TALKED ABOUT HERE DRIVE THESE PATIENTS TO SMALL CELL AND THAT IS WHY THE CANCERS GET WORSE AND DON’T RESPOND TO THERAPIES. I THINK FROM MY PERSONAL PERSPECTIVE MOST PATIENTS DIE WITH ADINOCARCINOMA OF THE PROSTATE. THERE’S THIS ALTERNATIVE EXPLANATION THESE ANDROGEN RECEPTOR NULL POPULATIONS AND WE ARE TRYING TO FIGURE HOW TO DEAL WITH THEM. WE ARE ALSO TRYING TO UNDERSTAND WHAT GENOMICS AND OTHER MOLECULAR MARKERS UNDERSTAND IF THERE ARE WAYS TO SELECT THERAPY. BEYOND THINGS LIKE BRACA 2 MUTATIONS OR MSI STATUS THOSE ARE THE ONLY ONES WE HAVE RIGHT NOW IN THE SUBSET.>>OTHER QUESTIONS? THANK YOU.>>THANKS. NEXT SPEAKER IS LEKHA
MIKKILINENI AND SHE GOT HER M.D. AT TULANE UNIVERSITY SCHOOL OF MEDICINE, SHE THEN THOMAS JEFFERSON AND SHE CAME HERE TO THE NIH. SHE’S WORKING IN THE SURGERY BRANCH WITH JAMES KOKENDORFER ANTIGEN RECEPTOR T-CELL THERAPY FOR HEMATOLOGIC MALIGNANCIES.>>THANK YOU. I’M ONE OF THE DOCTORS WHO WORKS FOR DR. KOKENDERFER, WE WORK ON HIS CAR T-CELL THERAPIES TO CLINIC. SO ALL THE TRIALS ARE PHASE 1. I WILL GO OVER WHAT CAR T-CELL THERAPY IS AND I WILL PRINCIPALLY FOCUS ON CAR T-CELL THERAPY IN MULTIPLE MYELOMA BUT WILL UNDERGO CONCEPTS IN CAR T-CELLAR THERAPY AND MALIGNANCIES. FIRST, WHAT IS A CAR T-CELL? IT IS A T-CELL ENGINEERED TO EXPRESS A CHIMERIC ANTIGEN RECEPTOR. SO BASICALLY THE IDEA IS THAT YOU ARE HARNESSING THE SPECIFICITY OF AN ANTIBODY TO THE KILLING CAPACITY OF A T-CELL. THE WAY WE DO THIS IS WE INSERT GENES THAT CODE FOR DIFFERENT PARTS OF THE CAR AND THEN CREATE A CAR EXPRESSING T-CELL. SO WHAT ARE THOSE DIFFERENT PARTS THAT ARE REQUIRED TO MAKE A CAR T-CELL WORK? THE FIRST PART IS YOUR ANTIGEN RECOGNITION DOMAIN THAT IS DERIVED FROM AN ANTIBODY. SO CAR T-CELLS RECOGNIZE THEIR TARGET WITH THIS RECEPTOR THAT IS BASICALLY A VERY SPECIFIC ANTIBODY THAT HAS A VERY SPECIFIC COGNATE ANTIGEN IT RECOGNIZES. IT IS THEN LINKED BY HINGE AND TRANSMEMBRANE REGION TO A T-CELL CO-STIMULATORY DOMAIN AND T-CELL ACTIVATION DOMAIN. IN THE INITIAL ITERATIONS OF CAR T-CELL THERAPY THEY TRIED MAKING CAR T-CELLS WITHOUT THIS CO-STIMULATORY DOMAIN AND REALIZED IT WAS NECESSARY FOR ACTIVITY. SO THE INNOVATION CAR T-CELL AND THE CAR T-CELL DOMAIN IS REALLY TRYING TO OPTIMIZE WHAT THIS CONSTRUCT IS. SO TRYING TO FIND THE BEST RECOGNITION MOIETY, TRYING TO UNDERSTAND HOW THE HINGE TRANSMEMBRANE REGION TRANSLATES TO ACTIVITY AND THEN TRYING TO FIGURE OUT HOW TO CO-STIMULATORY DOMAINS IN T-CELL ACTIVATION DOMAINS ALSO TRANSLATE TO ACTIVITY. WE KNOW THAT CO-STIMULATORY DOMAINS REALLY CONFER CERTAIN PROPERTIES ON CAR T-CELLS. SO THE TWO FLAVORS YOU SEE MOST COMMONLY IN THE FDA APPROVED PRODUCTS IN LYMPHOMA AND IS A CD 20A. EACH OF THEM HAVE DIFFERENT PROPERTIES THAT ARE ASSOCIATED WITH THEM. WE ARE STILL UNDERSTANDING WHAT THESE PROPERTIES ARE. WE THINK THAT 41BB CAR T-CELLS TEND TO HAVE A LOWER RATE OF RISE OF ACTIVATION AND THEY TEND TO PERSIST LONGER. CD 28 CAR T-CELLS HAVE A MORE ROBUST CIB TICK ACTIVITY IN THE BEGINNING AND POTENTIALLY DON’T LAST AS LONG. THIS TRANSLATES TO CLINICAL OUTCOME FOR PATIENTS THAT WE SEE. BUT AGAIN THIS IS AN AREA OF INVESTIGATION AND WE DONE REALLY KNOW WHAT THE OPTIMAL CONSTRUCT IS. SO I WILL CONCENTRATE ON TALKING CAR T-CELL THERAPY IN MULTIPLE MYELOMA. WE WERE THE FIRST GROUP IN THE RELATIVE RING CAR T-CELL THERAPY TO MULTIPLE MYELOMA PATIENTS. SO WE TARGETED B CELL MATURATION ANTIGEN INITIALLY. SO WHAT IS MULTIPLE MYELOMA? IT IS A HEMOTO LOGICAL MALIGNANCY OF PLASMA CELLS AND IT EFFECTS YOU — THE BLOOD, IT AFFECTS BONE AND CAN ALSO EFFECT THE SOFT TISSUE, SO YOU CAN HAVE AN ACCUMULATION OF MALIGNANT PLASMA CELLS AND REALLY ANY PART OF YOUR BODY, COMMONLY WE SEE LIVER LESIONS, WE HAVE SEEN CNS LESIONS, LITTIC LESIONS OF THE BONES ARE VERY COMMON AS WELL. SO WHY DID WE TARGET BCMA? THE IMPORTANT THING TO DO WHEN TRYING TO FIND A GOOD TARGET FOR YOUR CAR T-CELL, FIND A TARGET THAT IS SPECIFIC TO YOUR MALIGNANT CELL BUT NOT FOUND ON ANY NORMAL ORGAN. THE REASON WHY, CAR T-CELLS ARE GOING TO TRAFFIC DIRECTLY TO HAVE THEY HAVE RECOGNITION WHERE THEY RECOGNIZE THEIR TARGET. SO IF YOU HAVE A TARGET THAT IS FOUND NOT ONLY ON YOUR MALIGNANT CELL BUT ALSO YOUR HEART OR YOUR LUNG, YOU CAN HAVE PROFOUND TOXICITIES THAT COULD POTENTIALLY KILL YOUR PATIENT. SO BCMA IS A RESTRICTED PROTEIN WE FIND ON PLASMA CELLS, ON MALIGNANT MASS MA CELLS AS WELL AS SOME B CELLS AND NORMAL PLASMA CELLS. WE THOUGHT THIS WAS A GOOD TARGET BECAUSE IT IS NOT FOUND ON ANY OTHER MAJOR ORGAN NOR IS IT FOUND ON HEMATOPOIETIC STEM CELLS. SO THE LAB TESTED THE FIRST SERIES OF ANTI-BMA CARS. THIS WAS WHAT THE DESIGN WAS. YOU HAVE THE ANTIGEN RECOGNITION DOMAIN, 11D 53 SCFB. IT IS LIKED TO A CD8 CD 28 CO-STIMULATORY MOLECULE AND CD 3 SE TA ACTIVATION. THE T-CELLS THE WAY WE DO THIS IS WE ENROLL PATIENTS WE AFOR REECE THEM, CHECK THEIR T-CELLS. WE ISOLATE T-CELLS AND STIMULATE THEM WITH AN ANTI-CD 3 MONTH CLONAL ANTIBODY — MONOCLONAL ANTIBODY AND THEN GENETICALLY MODIFY AND CULTURE FOR NINE DAYS BEFORE INFUSIONS. THEN WE TREAT THE PATIENT. SO WE INITIATED THE FIRST IN HUMAN CLINICAL TRIAL OF ANTI-BCMA CAR IN 2014. SO BEFORE WE ACTUALLY GIVE THE CAR WE DO GIVE THREE DAYS OF CONDITIONING CHEMOTHERAPY TO OUR PATIENTS WITH A LOW DOSE SIGH TOXIN. CYTOXIN HAS ACTIVITY IN MYELOMA BUT THAT IS NOT WHEY WE GIVE THIS CHEMOTHERAPY. WE KNOW FROM PREVIOUS TRIALS AND STUDY PRE-CLINICAL DATA THAT THE CAR T-CELLS REALLY THRIVE IN AN ENVIRONMENT WHERE THERE IS HIGH LEVEL IL 15 AND DEPLETION OF ENDOGENOUS T LYMPHOSITES INCLUDING T REGULATORY CELLS WHICH CAN BE IMMUNOSUPPRESSIVE. SO WE GIVE THESE THREE DAYS OF LOW DOSE CHEMOTHERAPY TO CREATE THIS PERFECT INFLAMMATORY MILIEU CAR T-CELLS CAN PROPAGATE AND BECOME ACTIVE. SO ON DAYS MINUS 5 TO MINUS 3 WE GIVE CYCLOTOES FAMIDE AND FLU DER BEAN. SO THIS WAS THE FIRST TRIAL CHARACTERISTICS OF THE PATIENTS IN THE FIRST TRIAL, HEAVILY PRE-TREATED PATIENTS, AT THAT& TIME CAR T-CELL THERAPY WAS A NOVEL THERAPY, SO PATIENTS WHO ENROLLED REALLY HAD NO OTHER OPTIONS. THE MEDIAN NUMBER OF LINES OF THERAPY WAS 9.5. MULTIPLE MYELOMA IS AN AN INCURABLE MALIGNANCY, UNLIKE LYMPHOMA IN THAT CASE. IF YOU CAN GET A CR IN LYMPHOMA, YOU POTENTIALLY CAN GET A CURE. MULTIPLE MYELOMA AT THIS TIME RECURSE NO MATTER WHAT THERE WOULD BE. VERY FEW PATIENTS WHO MAY ATTAIN LONG TERM REMISSIONS. SO THESE PATIENTS HAD NO OTHER OPTIONS, THEY HAD GONE THROUGH ALL STANDARD THERAPY. THE ONE PATIENT ON THIS TRIAL HAD UP TO ABOUT 15 PRIOR LINES OF THERAPY. THESE PATIENTS HAD PRETTY BAD DISEASE WITH HIGH CYTOGENETICS AND INCLUDING DONATION 17P ASSOCIATED WITH P-53 MUTATION. 63% WERE REFRACTORY TO LAST TREATMENT REGIMEN. PATIENTS ON EVERY DOSE LEVEL IN THIS TRIAL HAD SIMILAR BASELINE CHARACTERISTICS, ALL HEAVILY PRE-TREATED AND DIDN’T HAVE MANY OPTIONS. SO THIS WAS A PHASE 1 DOSE ESCALATION. WE TREATED THREE PATIENTS FIRST DOSE LEVEL THEN ESCALATED TO SECOND DOSE LEVEL TO HIGHEST WHICH IS 9 MILLION CELLS PER KG. SO THIS IS PATIENT TEN WHO RECEIVED THE HIGHEST DOSE LEVEL. WE DID SEE A DOSE RESPONSE. PATIENTS ON THE LOWEST DOSE LEVEL DIDN’T HAVE LONG LASTING RESPONSES BUT PATIENTS ON THE HIGHEST DOSE LEVEL HAD VERY GOOD RESPONSES. THIS IS AN EXAMPLE OF ONE OF THOSE PATIENTS. THIS IS PATIENT NUMBER 10 BEFORE TREATMENT YOU CAN SEE THEIR BONE MARROW IS HEAVILY INFILTRATED BY MULTIPLE MYELOMA. AND YOU KNOW THAT BECAUSE CD 138, A MARKER OF MYELOMA, IS BASICALLY STAINING RED OR MA MAGENTA IN THIS CASE. THEY WERE — THIS PATIENT HAD BCMA ON THEIR MULTIPLE MYELOMA AS SHOWN BY THE THIRD BOX THERE. FOUR WEEKS AFTER TREATMENT YOU SEE AN ERADICATION OF DISEASE WHICH WAS PRETTY DRAMATIC AND EIGHT WEEKS AFTER TREATMENT THIS PERSISTED. THIS IS WHAT WE CONTINUE TO SEE, CAR T-CELLS TRAFFICKED TO THE BONE MARROW VERY EFFECTIVELY. SO IT IS A VERY GOOD TREATMENT FOR PATIENTS WHO HAVE BONE MARROW DISEASE. WE ALSO KNOW THOUGH THAT TOXICITY CAN BE ASSOCIATED WITH A PERCENTAGE OF BONE MARROW DISEASE THEY HAVE AT BASELINE SO PATIENT WHOSE HAVE MORE THAN 50% MYELOMA IN BONE MARROW HAVE MORE SEVERE TOXICITY. SO THIS IS ANOTHER EXAMPLE OF A PATIENT WHO ATTAIN AD VERY GOOD RESPONSE. SO PATIENT 14 WE MEASURE MULTIPLE MYELOMA IN MANY DIFFERENT WAYS. IT IS A COMPLICATED STAGING SYSTEM BUT ONE WAY IS BY LIGHT CHAINIOUS MEASURE IN SERUM. SO THIS IS SHOWING THE PATIENTS MONOCLONAL LAMB DA LIGHT CHAIN REALLY WENT FROM MEASURABLE AT 20 MGs PER METER SQUARED PER DECILITER TO UNDETECTABLE. THIS WAS VERY RAPID AND HIS RESPONSE LASTED 84 WEEKS. THESE ARE PATIENTS WHO HAD NO OTHER OPTIONS AND MOST LIKELY WILL PROGRESS AND DIE SOON. MOST PATIENTS HAD VERY BAD DISEASE AND PATIENT WAS ABLE TO RETAIN RESPONSE FOR 84 WEEKS. THIS SHOWS CAR T-CELLS TRAFFIC TO SOFT TISSUE TUMORS. SO THIS SHOW AS PATIENT WITH SOFT TUSH SHOE CYTOMA. PATIENT NUMBER 14 FOUR WEEKS AFTER INFUSIONS YOU SEE DECREASE IN PLASMA CYTOMA. NINE WEEKS IS A CONTINUED DECREASE AND BY 55 WEEKS YOU REALLY DON’T SEE VERY NUCH DISEASE THERE. THIS IS THE TUMOR. YES. (OFF MIC)>>SO YOU KNOW THIS IS THE KIDNEYS, SOME OF THIS IS MUSCLE FROM THE BACK. SO THIS IS NOT SUPPOSED TO BE THERE SO THIS IS SOFT TISSUE PLASMA CYTOMA. (OFF MIC)>>THAT IS JUST CONTRAST IN THE BOWEL. SO THIS THE SUMMARY OF RESPONSES OF ANTI-BCMA CAR T-CELLS AT ALL DOSE LEVELS. SO YOU CAN SEE HERE THAT IT REALLY WAS ASSOCIATED WITH A RESPONSES WERE ASSOCIATED WITH THE RIGHT DOSE. SO PATIENTS WHO GOT LOWER DOSES O THOUGH YOU HAD STABILIZATION OF DISEASE, WITH SIX WEEKS STABLE DISEASE ON FIRST DOSE LEVEL TO GOOD PR FOR EIGHT WEEKS ON THIRD DOSE LEVEL IT WASN’T UNTIL YOU GOT — DEEPER RESPONSES THAT WERE LONG LASTING. THE DIFFERENT STAGING JUST TO WALK YOU THROUGH IT, THE STRINGENT CR MEANS STRINGENT COMPLETE REMISSIONS. NO DETECTABLE MYELOMA IN THE BONE MARROW, THERE’S NO PLASMA CYTOMAS WHICH ARE COLLECTION OF PLASMASOLS IN YOUR BODY, YOU BLOOD DOESN’T SHOW ANY EVIDENCE OF MYELOMA. FOR ALL INTENTS AND PURPOSES THERE’S NO EVIDENCE OF MYELOMA YOU CAN THAT FIND. SO THIS PATIENT RETAINED REMISSIONS FOR 88 WEEKS. PR MEANS 50% REDUCTION IN DISEASE AND VERY GOOD PR IS 930% REDUCTION IN DISEASE. YOU STILL HAD PATIENTS WITH PROGRESSIVE DISEASE WHICH SHOWS YOU THERE IS SOME MYELOMA. I THINK THAT IS — HAS RESISTANT PHENOTYPE. TO ANY TYPE OF THERAPY. SO WE HAVE TO TALK TOXICITY WITH CAR T-CELLS. CAR T-CELLS WILL GO TO THEIR TARGET, KILL THE TARGET WITH T-CELL KILLING CAPACITY AND YOU GET RELEASE OF INFLAMMATORY SUBSTANCES. THIS INFLAMMATORY CYTOKINE RELEASE SYNDROME IS ASSOCIATED CLINICALLY WITH FEVERS, FAST HEART RATE, LOW BLOOD PRESSURE IN SOME CASES, ALSO ASSOCIATED WITH ARRHYTHMIAS, DEPRESSION IN HEART PUMPING FUNCTION. SO IT IS QUITE A LOT OF STRESS ON A PATIENT’S BODY. WE ARE PHASE — WE DO PHASE 1 TRIALS SO MOST PATIENTS HAVE TO MEET PRETTY RIGOROUS CRITERIA OF HAVING GOOD KIDNEY FUNCTION AND GOOD HEART FUNCTION BEFORE WE CAN ENROLL ON THIS TRIAL. THE REASON IS IS BECAUSE THE TOXICITY TOXICITIES MAYBE PRETTY SEVERE IN SOME CASES SO WE NEED TO MAKE SURE THESE PATIENTS ARE GOING TO BE ABLE TO TOLERATE THIS AS PHASE 1. AS CAR T-CELLS IN MULTIPLE MYELOMA, WORK THEIR WAY THROUGH THE DIFFERENT FADESES OF CLINICAL TRIALS AND HOPEFULLY EVENTUALLY GET FDA APPROVED, IT WILL BE TESTED IN PATIENTS WHO PROBABLY WOULDN’T MEET THE SAME CRITERIA THAT WE HAVE. PATIENTS HAVE TO HAVE GOOD HEART AND RENAL FUNCTIONINGS. MOST MOI LOW MA PATIENTS DO HAVE RENAL INSUFFICIENCY SO IT CAN BE TOUGH TO FIND A PATIENT WHO MEETS ALL OUR CRITERIA. SO TWO PATIENTS HAD GRADE 4 CRS FOR PATIENTS HAVE GRADE 3, TEN PATIENTS WITH LESS THAN GRADE 3. PATIENTS WHO HAD MORE THAN 50% DISEASE IN THE BONE MARROW HAD MORE SEVERE SIDE EFFECTS. THE OTHER — THE OTHER BUCKET OF TOXICITY ASSOCIATED WITH CAR T-CELL THERAPY IS NEUROTOXICITY. WE SAW THIS ON OUR LYMPHOMA TRIALS ESPECIALLY WHAT IS NOW THE TOE PRODUCT. PATIENTSWOULD HAVE TREMORS ALTERED MENTAL STATUS, AND SOME CASES CEREBRAL EDEMA. IN MYELOMA WE HAVEN’T SEEN SUCH PROFOUND NEUROTOXICITY IN THE THE SAME WAY WE HAVE SEEN IT ON OTHER CAR T-CELLS TRIALS. BUT IT WAS MUCH MORE MILD. SO IN TERMS HOW YOU MANAGE CRS, THE FIRST LINE IS SUPPORTIVE TARIFF SO IF THEY HAVE LOW BLOOD PRESSURE FAST HEART RATE GIVE THEM FLUIDS. IN SOME CASES TRANSFER THEM TO INTENIVE CARE UNIT THE GIVE MEDICATION CALLED PRESSERS TO KEEP THEIR BLOOD PRESSURE UP. BUT IN SEVERE CASES WE CAN GIVE AN ANTI-IL 6 RECEPTOR ANTIBODY TOSALIZMAB OR STEROIDS. IT IS UNCLEAR WHETHER OR NOT IT AFFECTS T-CELL FUNCTION, THERE ARE A LOT OF REPORTS TO SAY THAT IT DOES NOT. HOWEVER, WE ARE STILL CAUTIOUS WHEN GIVING IT. AND THEN STEROIDS AT HIGH DOSES, MAY IMPACT THE EFFICACY OF THE CAR T-CELL THERAPY. SO ONE MAJOR ONE REASON PATIENTS RELAPSE IS BECAUSE THEIR PLY LOW MA BECOMES BCMA NEGATIVE OR WE END UP SELECTING FOR BCMA NEGATIVE TO GROW. SO BCMA NEGATIVE DISEASE IS NOT GOING TO BE AFFECTED BY ANTI-BCMA CAR T-CELLS SO WE HAVE SEEN PATIENTS RELAPSE WITH BCMA NEGATIVE DISEASE. THIS IS A SUMMARY OF THIS TRIAL, TWO OUT OF TEN OBJECTIVE RESPONSES ON DOSE LEVEL 1 TO 3 BUT 13 OUT 16 OBJECTIVE RESPONSES AT THE OPTIMAL DOSE LEVEL AND OBJECTIVE RESPONSE IS 50% REDUCTION OF DISEASE OR MORE. FIVE OF 16 PATIENTS HAD DURATIONS OF RESPONSES GREATER THAN A YEAR. NINE OF 15 HAD RESPONSES GREATER THAN 6 MONTHS. THE REALLY BIG ADVANTAGE OF CAR T-CELL THERAPY IN MULTIPLE MYELOMA, IT ALLOWS PATIENTS TO BE OFF THE THERAPY. SO A NORMAL TREATMENT FOR MULTIPLE MYELOMA CONSISTS OF CONSTANT THERAPY THEY CONSTANTLY GET INFUSIONSES OF DRUGS FROM WEEKLY TO EVERYONE TWO WEEKS TO MONTHLY. MOST TAKE A DAILY PILL THRI ARE ALWAYS ON STEROIDS OF SOME SORT ESPECIALLY WHEN THEY GET TO THE END STATE OF THE DISEASE WHEN THEY HAVE GONE THROUGH A LOT OF PREVIOUS THERAPIES. SO CAR T-CELL ALLOWS THEM TO BE OFF OF THERAPY FOR MANY MONTHS. IT’S ONE INFUSION OF CAR T-CELL WITH NO OTHER THERAPY UNTIL THEY PROGRESS. SO MULTIPLE MYELOMA IS VERY DIFFICULT TO TREAT, IT IS HE ROW GENIUS. SO EVEN WITHIN A SINGLE PATIENT THERE ARE MULTIPLE MYELOMA CAN HAVE MANY DIFFERENT CLONES. THAT IS ONE REASON WHY TARGETING MULTIPLE ANTIGEN IS PROBABLY THE NEXT STEP IN MULTIPLE MYELOMA IN CAR T-CELL THERAPY MULTIPLE MYELOMA. THIS IS ANOTHER ANTI-BCMA CAR T-CELL TRIAL THAT WAS CARRIED OUT IN A MULTI-CENTER FASHION. WE PARTICIPATED, BB 2121 RUN BY CELL GENE. THE ANTIGEN RECOGNITION DOMAIN WAS THE SAME AS OUR CAR T-CELL PRODUCT. HOWEVER O THEY AD A 41BB CO-STIMULATORY DOMAIN, AND WHEREAS OURS WAS CD 28. THERE WAS A DIFFERENCE IN TOXICITY BETWEEN THE TWO TRIALS. SO THE BB 2121 HAD VERY MANAGEABLE TOXICITY AND ALSO HAD ABOUT 80% OVERALL RESPONSE RATE. MEDIAN PROGRESSION FREE SURVIVAL WAS ROUGHLY 12 MONTHS AND ONE YEAR. THE PARADIGM OF TREATMENT WAS THE SAME. SO THEY GAVE THREE DAYS OF CONDITIONING CHEMOTHERAPY AND ON DAY ZERO WOULD GIVE INFUSION OF CAR T-CELLS, PATIENTS DID NOT HAVE ANY OTHER TREATMENT POST CAR T-CELL THERAPY UNTIL THEY PROGRESSED. THEY DID A DOSE ESCALATION AND IDENTIFIED 450 MILLION FLAT DOSE CELL FLAT DOSE AS OPTIMAL DOSE OF CAR T-CELLS. AND NOW THEY ARE CARRYING OUT MULTIPLE HIGHER PHASE CLINICAL TRIALS WITH THIS PRODUCT. SO CYTOKINE RELEASE SYNDROME WAS RELATIVELY MILD, ONLY TWO OUT OF 33 PATIENTS WERE TREATED HIGH GRADE 3 AND NOBODY HAD GRADE 4 CRS. ONLY ONE OUT OF 33 PATIENTS HAD GRADE 3 OR 4 NEUROLOGIC TOXICITY AND SEVEN RECEIVED TOSLUZMAB AND FOUR RECEIVED CORTICAL STEROIDS. SO THERE WAS A RELATIONSHIP WITH CAR T-CELL LEVELS AND RESPONSE. THIS IS SEEN IN OTHER TRIALS AS WELL. WHAT IS THE NEXT STEP? OUR LAB TOOK RESULTS OF CLINICAL TRIALS AND TRIED TO THINK OF WAYS TO MOVE FORWARD WITH THE TECHNOLOGY. WE DECIDED TO DEVELOP A FULLY HUMAN HEAVY CHAIN VARIABLE DOMAIN CAR T-CELL. WHAT DOES THAT MEAN? ONE POTENTIAL AREA OF WHY CAR T-CELL — WHY THE ORIGINAL TRIALS POTENTIALLY WERE NOT AS EFFECTIVE WAS THE IDEA THAT MAYBE PATIENTS WERE SEEING CAR T-CELLS AND NON-SELF AND DESTROYING THEM SO HAVING AN IMMUNOGENIC RESPONSE. THE SCFB USE FLD THE ORIGINAL CAR T-CELL TRIALS IN MYELOMA CONTAINED MURINE PARTS. SO WE DECIDED TO CREATE A FULLY HUMAN SEFE TO ELIMINATE ANYTHING POTENTIALLY IMMUNOGENIC. WE ALSO CHANGED THE RECEPTOR TO A SMALLER MORE SLEEP VERSION WITH THE IDEA THAT IT WOULD BE POTENTIALLY BENEFICIAL FOR A BY-SPECIFIC CONSTRUCT DOWN THE LINE. IT ALSO POTENTIALLY REDUCES IMMUNOGENICITY BECAUSE YOU DO NOT HAVE LINKERS AND IMMUNE RESPONSES CAN BE DIRECTED AT LINKERS AN JUNCTIONS. SO WE SHOWED IN OUR PRE-CLINICAL WORK THAT THIS CAR T-CELL PRODUCT WAS ABLE TO ELIMINATE TUMORS AND N SG MICE SO MALIGNANCY WAS E RAKED WAIT KATEED BY — ERADICATED BY APT BCMA CARS THAT YOU CAN SEE. AND REMISSIONSES WERE SHORT IN MICE GETTING THE FULLY HUMAN 28Z SO WE DECIDED TO GO WITH THE 41BB MODEL. SO THIS IS OUR CURRENT TRIALS WE HAVE OPEN, WE HAVE BEEN TREATING PATIENTS GOING THROUGH ELIGIBILITY AND TRIAL DESIGN, PATIENT VERSUS TO HAVE GOOD HEART FUNCTION AND GOOD KIDNEY FUNCTION IN ORDER TO UNDERGO THIS TREATMENT BECAUSE IT IS A PHASE 1 AND ITs FIRST TIME BRINGING FROM LAB TO CLINIC. SO THIS HAS SO FAR BEEN OUR RESULTS. SO IN COMPARISON TO THE PREVIOUS TRIAL THAT WE RAN, OUR FIRST DOSE LEVEL WE SAW GOOD RESULTS AND IN SOME CASES LONG LASTING SO WE HAVE A STRINGENT COMPLETE RESPONSE THAT IS NOW 42 WEEKS AND ONGOING. APPROACHING A YEAR. TWO PRs ONE PR APPROACHING A YEARND ONE PR IS 25 WEEKS. SO THIS HAS BEEN AGAIN THESE PATIENTS HAD RAPIDLY PROGRESSIVE MYELOMA, THESE RESPONSES ARE VERY PROMISING. THE SECOND DOSE LEVEL WAS NOT AS PROMISING. THESE THREE PATIENTS HAD VERY RHESUS ABOUT THE DISEASE. — RESISTANT DISEASE. ON THE HIGHER DOSE LEVELS WE ARE ACCRUING AND TREATING PATIENTS IN SO FAR THESE TWO PATIENTS HAD VERY, VERY BAD PROGNOSIS DISEASE AND THEY HAVE — THEY DIDN’T HAVE VERY MANY STANDARD OPTIONS AVAILABLE TO THEM. SO THEY ARE HAVING RESPONSE WHICH IS GREAT. SO THIS BRINGS US TO THE NEXT PHASE, OF CAR T-CELL THERAPY DEVELOPMENT WHICH IS OTHER POTENTIAL TARLGTS. SO IT IS VERY IMPORTANT TO PICK THE RIGHT TARGET THAT IS NOT GOING THE CAUSE OFF TUMOR TOXICITY. SO WE ARE TARGETING SLAM F 7 OTHERWISE KNOWN AS CD 319. FLAM F 7 IS HIGHLY EXPRESSED ON ALL MULTIPLE MYELOMA CELLS SO IT HAS LET OWE GENIUS EXPRESSION, ORIGINALLY THOUGHT TO BE A GOOD TARGET BECAUSE IT DOESN’T HAVE — IT HAS A VERY RESTRICTED EXPRESSION PATTERN. SLAM F 7 DOESN’T HAVE AS RESTRICTED A PATTERN AS BCMA. IT IS FOUND NOT ONLY ON ATYPICAL MYELOMA CELLS AND PLASMA CELLS BUT ALSO FOUND ON SUB — ON A FRACTION OF NK CELLS AND CD8 CELLS. AS WELL SAZ MONOCYTES AND DENDRITIC — AS WELL AS MONOCYTES AND DEN DRETTIC CELLS SO IMAGINE WHEN CAR T-CELLS RECOGNIZE NECESSARY TARGETS THEY WILL E ERADICATE THESE CELLS
WHICH MEANS YOU WILL GET A REDUCTION IN NK CELL POPULATION AND SOME CASES CD8 POPULATION. WE ARE VERY CONCERNED ABOUT THE NK CELLS BECAUSE AS YOU KNOW THEY ARE VERY IMPORTANT TO FIGHT OFF VIRAL INFECTIONSES SPECIALLY HER PEEZ INFECTION. IN ORDER TO HAVE CONTROL OVER POTENTIAL TOXICITY WE DECIDED TO INCORPORATE A SUICIDE GENE. A SUICIDE GENE IS BASICALLY AN ON OFF SWITCH. WHEN YOU INFUSE THE RIGHT MEDICATION, IT WILL DIMERIZE WITH THE PROTEIN IN THE CYTOPALACE M AND THEN YOU WILL GET APOPTOSIS OF YOUR T-CELLS. SO WE USE THE CLINICALLY TESTED SUICIDE SYSTEM WHICH IS THE ICAS 9 ACTIVATE WITH THE DRUG CALLED (INDISCERNIBLE). WE DESIGN A CAR CONSTRUCT, IT IS EXPRESSING TWO PROTEINS. SO ONE IS THE IC 9 WHICH IS SO SUICIDE GENE, CONSTRUCT, AND THE OTHER ONE IS THE ANTI-SLAM F 7 CAR. WE USE A RIBOSOMAL SKIP SEQUENCE SO BOTH PROTEINS ARE ABLE TO BE EXPRESSED. IN THE SAME CELL. THE SUICIDE GENE IS POTENT, IT ACTIVATES EXPOSURE FOR SIX HOURS IN VITRO ACTIVATES THE SUICIDE GENE. SO THIS IS THE SUMMARY OF CAR T-CELL THERAPY IN MULTIPLE MYELOMA. WE DEMONSTRATED ANTI-BCMA T-CELLS HAVE POWERFUL ACTIVITY AGAINST MULTIPLE MYELOMA. THERE’S A PLETHORA OF ANTI-BCMA TRIALS ALL OVER THE WORLD. AND MULTIPLE DIFFERENT PHASES. SOME ARE STILL PHASE 1, MANY ARE NOW GOING TO PHASE AND PHASE 3 AND HOPE FLIT ULTIMATE GOAL WILL BE FDA APPROVAL BUT BCMA IS AN IMPERFECT ANTIGEN BECAUSE IT IS PHENOTYPICALLY LET REGENIUS SO WE HAVE TO THINK ABOUT OTHER TARGETS. SLAM F 7 IS PROMISING BUT WE JUST STARTED THE CLINICAL TRIAL. ONLY THREE IN THE WORLD TESTING ANTI-SLAM F 7 CAR AND WE AT THIS POINT TREATED THE MOST NUMBER OF PATIENTS. WE STILL NEED TO LOOK MORE MYLOMEA GENES AND THE AREAS OF INNOVATION WILL BE INNOVATING HOW WE CONSTRUCT THE CAR. ANY QUESTIONS? [APPLAUSE]>>(OFF MIC)>>Q. TALK ABOUT WHO HAD BCMA NEGATIVE MULTIPLE MYELOMA, DID YOU FINE IT WAS MORE AGGRESSIVE OR LIKE WHAT HOW DIFFERENT WAS IT?>>THAT’S A REALLY GOOD QUESTION. WE DON’T KNOW WHAT THE KINETICS OF THE DISEASE IS AFTER THEY PROGRESS. IT’S AN AREA A LOT OF INVESTIGATORS ARE LOOKING INTO. BUT THE SHORT ANSWER IS IT’S UNCLEAR WHEN DISEASE COMES BACK AFTER CAR T-CELL HOW AGGRESSIVE IT IS.>>WHAT ARE THE OTHER REQUIREMENTS FOR TARGET ASIDE FROM RESTRICTED EXPRESSION?>>YOU MEAN WHEN LOOKING FOR A — SO YOU WANT SOMETHING THAT IS HIGHLY EXPRESSED ON TARGET SO WHEN CAR T-CELLS ARE GOING THEY HAVE A GOOD ANTIGEN THAT THEY CAN RECOGNIZE. BUT IN SOME CASES DEPENDING ON IF YOU ARE RECEPTOR IS VERY SENSITIVE POTENTIALLY COULD ALSO RECOGNIZE ANTIGEN, THAT IS LOWER IN DENSITY. SO THE MAIN KEYS ARE IT SHOULD BE EXPRESSED ON SURFACE OF MALIGNANT CELL AND SHOULD NOT BE EXPERIENCED ON ANY OR GAN, ANY VITAL ORGAN OR ANY STEM CELL. (OFF MIC)>>IT DEPENDS, EVERY CAR IS DIFFERENT. SO HOW YOU ENG NOOER THE CAR REA — ENGINEER THE CAR PLAYS INTO ITS ACTIVITY SO IN THE BCMA TRIAL, OUR ORIGINAL BCMA THAT HAD CD 28 MOLECULE WHEN IT GOT TO HIGHEST DOSE LEVEL IS QUICK. SOME CASES PATIENTS HAVE CRS IN 12 HOURS. ON THIS TRIAL IT’S BEEN VARIABLE. OUR TRIAL NOW. SOME PATIENTS IT’S WITHIN 24 HOURS ONE PATIENT IT WAS FIVE DAYS AFTER. SOME PATIENTS DON’T HAVE MUCH OF A — THEY HAVE MAYBE SLIGHT BUMP IN FEVER. BUT NOT VERY MUCH MORE. THEIR TOXICITY SEEMS ASSOCIATED WITH DISEASE BURDEN SO HOW MUCH DISEASE YOU HAVE GOING INTO THERAPY PROBABLY PLAYS INTO YOUR TOXICITY AND HOW MUCH BONE MARROW DISEASE YOU HAVE I THINK IS IMPORTANT FACTOR. (OFF MIC) THESE ARE PHASE 1 TRIALS SO DOSE ESCALATION SO TRYING TO FIND THE OPTIMAL DOSE. IN THE CELL GENE TRIAL THEY IDENTIFIED 450 MILLION AS OPTIMAL DOSE, GOING FORWARD THAT IS THE DOSE THEY ARE TESTING IN OTHER TRIALS BUT I’M NOT 100% SURE ON THAT. (OFF MIC)>>YEAH SO THIS IS KIND OF YOUR CLASSIC THREE BY THREE PHASE 1 TRIAL WHERE YOU ARE TRYING TO FIND AN OPTIMAL DOSE. IF YOU TREAT THREE PATIENTS BUT ONE HAS A DOSE LIMITING TOXICITY YOU EXPAND TO SIX AND THEN YOU TRY TO FIND –.>>HAVE THE CAR T-CELLS BEEN SHOWN TO BE EFFECTIVE AGAINST SOLID TUMORS?>>THAT’S AN AREA UNDER INVESTIGATION. I THINK FINDING THE RIGHT ANTIGEN TARGET THAT’S NOT FOUND ON NORMAL EPITHELIAL CELLS IS DIFFICULT. TO BE HONEST THOUGH, THAT’S NOT MY AREA OF EXPERTISE BUT THERE ARE LOTS OF STUDIES LOOKING INTO THAT. (OFF MIC)>>IS IT EASY TO GROW THEM?>>CAN YOU HEAR ME? IS IT EASIER TO GROW THE CAR T-CELLS IN TUBES OR IN MOUSE MODEL?>>U I’M NOT SURE I CAN ANSWER THAT QUESTION. WE ARE ABLE TO GROW IT IN CULTURE BECAUSE THAT’S HOW WE INFUSE THAT PRODUCT WE GROW THEM SEVEN TO NINE DAYS THEN INFUSE IT INTO PATIENTS BUT THE PRE-CLINICAL STUFF IS NOT SOMETHING THAT I CAN PROBABLY ANSWER OFFHAND.>>LET’S THANK HER AGAIN. [APPLAUSE]