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TRACO 2019 – Pancreatic cancer and Nanotechnology


TODAY OUR FIRST LECTURE IS CHRISTINE ALEWINE, LABORATORY OF MOLECULAR BIOLOGY AND AN INVESTIGATOR AND CLINICAL RESEARCH SCHOLAR AND SHE GOT HER M.D. AT THE UNIVERSITY OF MARYLAND. AND DID HER INTERNSHIP IN INTERNAL MEDICINE AT JOHNS HOPKINS AND DOING A LECTURE ON PANCREATIC CANCER FROM BENCH TO BEDSIDE. CHRISTINE.>>HELLO TO EVERYONE OUT IN THE WEB I CAN’T SEE. PANCREATIC CANCER IS A GREAT TOPIC FOR TRANSLATIONAL RESEARCH. I’M A CLINICIAN SO THIS TALK IS A LITTLE BIT IN THAT DIRECTION BUT WE’LL GO BACK AND FORTH BETWEEN THE TWO. IT’S ONE OF THE MOST DEADLY CANCERS IS PANCREATIC CANCER. THERE’S ABOUT 50,000 CASES DIAGNOSED EACH YEAR IN THE 9 TO 11 RANK AS THE MOST COMMON CANCERS IN THE SUSPEU.S. AND NOW
THE THIRD LEADING CAUSE OF DEATH BECAUSE THE MAJORITY OF PATIENT GET DIAGNOSED DIE AND THE PERCENTAGE OF PEOPLE THAT LIVE FOR FIVE YEARS AFTER DIAGNOSIS IS 5% BUT THAT’S UP FROM LESS THAN 10 YEARS AGO. THE MEDIAN SURVIVAL IS STILL LESS THAN 6 MONTHS. THE MAJORITY OF PATIENTS SUCCUMB QUICKLY AND WE NEED MORE RESEARCH FOR MORE ANSWERS. THE OTHER PROBLEM IS PANCREATIC CANCERS ARE INCREASES UNLIKE OTHER TYPES. IT’S THOUGHT TO BE FUELED IN PART TO THE OBESITY EPIDEMIC BECAUSE IT’S A RISK FACTOR FOR PANCREAS CANCER AND THE FACT WE DON’T HAVE ANY GOOD EARLY DETECTION OR SCREENING MECHANISMS AS WE DO FOR COLON AND BREAST CANCER WHICH YOU CAN SEE ARE DECLINING IN THE OVERALL POPULATION. SO WHAT ARE THE RISK FACTORS FOR PANCREAS CANCER? NONE OF THE MOD FINALLY RISK FACTORS ARE PARTICULARLY STRONG. TO GIVE YOU AN IDEA, IT’S ESTIMATED SMOKING GIVES A 15 TO 18 TIMES APPROXIMATE RISK OF LUNG CANCER. IF YOU LOOK THAT THE MODIFIABLE CANCERS FOR PANCREAS AND OBESITY AND OTHERS DON’T GIVE MORE THAN A TWO-FOLD INCREASE IN THE RISK OF GETTING PANCREAS CANCER AND MOST OF MY PATIENTS WILL HAVE NONE OF THESE THINGS WHEN THEY’RE DIAGNOSED. THE THING WE THINK THEY ALL HAVE IN COMMON AND WHY THEY INCREASE THE RISK OF PANCREAS CANCER IS THEY INCREASE INFLAMMATION IN THE PANCREAS AND THINK THAT’S WHAT DRIVES PANCREAS CANCER GENESIS AND THERE’S GENETIC SYNDROMES ALL OF WHICH ARE QUITE RARE WHICH CAN INCREASE THE RISK OF PANCREAS CANCER SHOWN BELOW. HEREDITY PANCREATITIS IS THE MOST COMMON FIFTYFOLD RISK AND THERE’S MELANOMA AND PANCREAS CANCER SYNDROME THAT ARE RARE. PATIENTS WITH BRCA MUTATION DO HAVE INCREASED RISK OF PANCREAS CANCER AND THAT’S SOMETHING WE’LL TALK TO AND THERE’S A PTA SYNDROME THAT CAUSES SKIN LESIONS IN ADDITION TO THE PANCREAS CANCER VERY RARE BUT HIGH RISK. LYNCH SYNDROME IS MORE COMMON AND COMMONLY KNOWN FOR CAUSING ENDOMETRIAL AND COLON CANCER. SO WHEN WE TALK ABOUT PANCREAS CANCER, THERE’S MULTIPLE KINDS BUT BY LARGE PART THE MAJOR CANCER THAT GROWS IN THE CANCER IS ADENO CARCINOMA. ABOUT 90% OF ALL TUMORS ARE ADENOCARCINOMAS AND THEY FORM IN THE HEAD OF THE PANCREPAPS WE’RE LOOKING AT LOOK AT THE CARTOON OF THE PANCREAS AND SITS CLOSE TO THE DUE ODD NUMB — DUODENUM AND THESE DETERMINE RECEPTABILITY BY SURGERY WHETHER THE BLOOD VESSELSES — VESSEL INVOLVED AND THE BILE DUCT THAT COMES DOWN COMES THROUGH THIS AREA NEAR THE HEAD OF THE PANCREAS AND WHAT GIVES YOU DIGESTIVE ENZYMES COMES THROUGH HERE AS WELL. SO IF YOU HAVE A TUMOR THAT FREQUENTLY OBSTRUCT THE BIODUCT AND CAUSE PEOPLE TO GET JUANDICE AND TURN YELLOW BECAUSE THE BILE STAYS IN THE BODY AND THEY HAVE TROUBLE DIGESTING FOOD BECAUSE THEY DON’T GET ENOUGH OF THE ENZYME AND YOU GET ENDOCRINE TMORS THAT HAS A BETTER PROGNOSIS AND IT’S CAN BE CAUGHT EARLIER. THE RARE TYPE OF EXO GEN CANCER THAT EVOLVE FROM PARTS OF THE PANCREAS THAT MAKE DIGESTIVE ENZYMES ARE ADD — ADENOCARCINOMA AND IT’S LESS THAN 1500 PEOPLE A YEAR SOME MANY LESS THAN THAT. WHEN PANCREAS CANCER IS DIAGNOSED THE MAJORITY OF PATIENT DIAGNOSED WITH LATE STAGE DISEASE CALLED METASTATIC. THERE’S FEW DIAGNOSED IN AN EARLY STAGE AND THAT CAN MEAN THERE’S OBSTRUCTERS NEARBY AND THAT MAY OR MAY NOT BE AMENABLE TO CURE AND WHY CAN’T WE DETECT PANCREAS CANCER EARLIER? ONE PROBLEM IS THE EARLY SYMPTOMS ARE NON SPECIFIC IN MEDICINE. THAT MEANS YOU COME IN AND COMPLAIN YOUR STOMACH HURTS. THERE’S A LOT OF THINGS THAT MAKE YOUR STOMACH ACHE OR MAKE YOU FEEL LIKE YOU CAN’T DIGEST AS WELL AND PANCREATIC CANCER IS NOT THE MOST COMMON. PEOPLE SAY MAYBE YOU HAVE ACID REFLUX OR ULCER AND THERE’S A LONG LIST OF MAKES BEFORE SOMEONE SAYS YOU HAVE PANCREAS CANCER AND THE MOST COMMON CAUSE OF TURNING YELLOW OR JUANDICE IS BILE DUCT STONES AND MORE COMMON IN POON — PANCREAS CANCER. IF YOU GET JUANDICE AND GO FOR IMAGING, THE IMAGING METHODS CAN RARELY DETECT SMALL LESIONS. IT’S VERY HARD TO SEE THAT PARTICULAR AREA OF THE BODY BECAUSE OF WHERE IT IS AND HOW IT LOOK IN CONTRAST OR DOESN’T. EVEN IN PATIENTS WHERE WE’RE SURE THEY HAVE A TUMOR IT CAN SOMETIMES BE DIFFICULT TO FIND IT. NEXT IS WHY CAN’T WE JUST LOOK IN PEOPLE’S BLOOD. THIS COMES DOWN TO A PROBLEM OF MATHEMATICS. IF YOU HAVE TO FIND A BIOMARKER TO DIAGNOSE SOMEONE WITH A DISEASE IT’S AN INTERESTING LESSON AND WHEN I TAUGHT THIS IN MEDICAL SCHOOL, IF PANCREAS CANCER IS RARE, 12 PEOPLE WERE .4,000 THAT GET IT AND — 12 PEOPLE PER 100,000 AND IF YOU HAVE A TEST TO DETECT ALL 12 OF THOSE 100,000 PATIENTS WITH ONLY ONE OF 100 PATIENTS WILL SAY HAVE YOU A POSITIVE TEST EVEN WHEN YOU DON’T HAVE PANCREAS CANCER, IF YOU TALK TO THE GENERAL POPULATION YOU’LL HAVE 83 FALSE POSITIVES FOR EVERY REAL CASE OF PANCREAS CANCER AND A FALSE POSITIVE IN THE CASE OF PANCREAS CANCER WOULD BE DIFFICULT TO DEAL WITH BECAUSE IT’S SO DIFFICULT TO IMAGE THAT AREA OF THE BODY AND IT’S ALSO VERY DIFFICULT TO BYPA BIOPSY IN THAT AREA AND IN PATIENTS WHERE WE CAN SEE THE TUMOR, WE CAN’T GET A BIOPSY BECAUSE IT’S DIFFICULT TO REACH AND DO YOU REMOVE THE PANCREAS IN 83 PEOPLE FOR EVERY ONE REAL CASE AND MAKE EVERYONE AN INSULIN DEPENDENT DIABETIC AND THE BAR FOR HAVING A TEST TO IDENTIFY PANCREAS CANCER EARLY VERY VERY HIGH. SO THIS IS WHAT PEOPLE WHO ARE DEVELOPING BIOMARKERS ARE WORKING AGAINST. AND SO THE TEST USED CLINICALLY MOST OFTEN TO LOOK IN THE BLOOD IS CALLED CAT199 AND 10% DON’T GET IT BECAUSE IT DEPENDS ON IF YOU MAKE THE ANTIGEN OR IN THE AND IT HAS A SENSITIVITY MEANING IT WILL DETECT 80% OF THE PATIENT HAVE PANCREAS CANCER WHEN YOU TAKE FOR BLOOD AND SPECIFICITY IS IS WRONG 20% OF THE TIME AND YOU WOULD THINK THEY HAVE IT WHEN THEY HAVE SOMETHING ELSE CAUSING IRT TO BE HIGH. SO WE CAN’T USE THIS TO DIAGNOSE PEOPLE. WHAT WE DO USE IT FOR IS TO FOLLOW PEOPLE WHO ALREADY KNOW HOW HAVE PANCREAS CANCER AND SEE HOW THE TREATMENT IS WORKING BECAUSE IT WIL GO DOWN IF YOU GIVE THEM A TREATMENT AND IT WILL GO UP IF THE TREATMENT’S NOT WORKING. THIS SPECIFICITY AND SENSITIVITY GET WORSE IF INSTEAD OF COMPARING TO A HEALTHY INDIVIDUAL YOU’RE COMPARING TO SOMEBODY WITH PANCREATIC DISEASE. FOR INSTANCE, JUANDICE FOR ANOTHER REASON YOU DO EVEN LESS WELL IF YOU IMAGINE THE SPECIFICITY WITH 20% IS GOING TO BE 83 TIMES 20 PEOPLE IS GOING TO BE THE FALSE POSITIVE RATE FOR THE STUDY FOR EVERY ONE PERSON YOU DETECT. SO YOU NEED SOMETHING MUCH BETTER THAN THIS. NOW, THERE’S A LOT OF RESEARCH IN THIS AREA AND IN GENERAL THE WAY IT’S BEING OVERCOME IS THAT PEOPLE ARE TESTING THESE BLOOD TESTS IN HIGHER RISK POPULATIONS RATHER THAN THE WHOLE POPULATION. FOR INSTANCE WITH PATIENTS THAT ARE NEW ONSET DIABETICS WHERE 1% TO 5% WILL HAVE PANCREAT CANCER RATHER THAN ADULT ONSET DIABETES. THERE’S ONE BIOMARKER TEST. THIS PAPER WAS PUBLISHED IN NATURE IN 2015 IN LOOKING AT CIRCULATING EXOSOMES AND WHAT YOU CAN SEE IS THAT THEY HAD NICE DISCRIMINATION BETWEEN PATIENTS WITH CANCER SHOWN IN RED HERE AND PATIENTS WITH BENIGN DISEASE OR HEALTHY DONOR AND REPORTED 100% SPECIFICITY WHICH MOST OF US FIND VERY DIFFICULT TO BELIEVE BECAUSE THERE’S USUALLY NOT ANY TESTS WITH 100% OF BOTH BUT MY UNDERSTANDING IS IT’S MOVED TO THE CLINICAL TESTING IN THE PERSPECTIVE SETTING TO SEE IF YOU CAN IDENTIFY PATIENTS EARLY WITH A TEST LIKE THIS. THE OTHER BARRIER WHEN YOU’RE TALKING ABO TALKING ABOUT CANCER TEST IS HOW LONG OF A WINDOW DO YOU HAVE BETWEEN WHEN SOMEBODY GETS A PRECANCEROUS LESION AND WHEN THEY GET THE CANCER. YOU NEED TO DETECT IT EARLY ENOUGH THAT YOU CAN TREAT THEM BEFORE BAD THINGS HAPPEN. SO WHAT YOU’RE LOOKING AT HERE SAY MODEL THAT’S BEEN AROUND A LONG TIME LOOKING AT PROGRESSION OF CANCER. THEY’RE PRECANCEROUS AND THIS IS FROM THE ONE, TWO, THREE CATEGORY FROM LOW GRADE TO HIGH GRADE. IF YOU HAVE A LOW GRADE WHAT THEY CALL PRECANCEROUS LESIONS THERE’S A SMALL CANS IT GOES ON TO BE PANCREAS CANCER AND YOU SHUNT REMOVE IT — SHOULDN’T REMOVE IT BECAUSE MANY WILL NEVER DEVELOP PANCREAS CANCER. BY CONTRAST, THE HIGH GRADE PANNINS WE USED TO CALL PANNIN 3 ARE DIFFICULT TO FINE AND SO IT’S THOUGHT THERE MAY BE SOMETHING THAT HAPPENS IN A LESION THAT CHANGES IT INTO PANIN 3 AND RAPIDLY PROGRESSES INTO CANCER. THE WINDOW OF DETECTING THIS PRECANCEROUS LESION TIME LINE IS SMALL. THE WAYS YOU HAVE TO PERFORM THE SCREENING TEST TOGETHER HAS TO BE TOGETHER IF THAT’S TRULY THE CASE. AND THERE’S A LOT OF QUESTION OF THE TIMING HOW THIS HAPPENS. WHAT DO WE DO FOR PATIENTS IF THEY’RE DIAGNOSED EARLY? THE STANDARD OF CARE IS WE DO SURGERY FOLLOWED BY CHEMOTHERAPY. SURGERY IS POTENTIALLY CURE AND UNLESS YOU DO SURGERY, WE DON’T CURE PEOPLE WITH THIS DISEASE. THE TRUTH IS MOST THE TIME EVEN WHEN WE DO THIS IN PATIENTS WITH EARLY STAGE DISEASE WE’RE UNABLE TO CURE THEM. SO WHAT YOU’RE LOOKING AT HERE IS ONE OF THE FIRST STUDIES OF THE TYPE OF CHEMOTHERAPY THAT WORKED. THIS IS THE PERCENT OF PATIENTS ALIVE AFTER THIS AMOUNT OF TIME SHOWN ON THE X AXIS IF YOU HAVE SURGERY ALONE. EVEN IF YOU REMOVE ALL THE TUMOR THAT’S VISIBLE AND ALMOST ALL THE PATIENTS WILL RECUR AND DIE OF THEIR DISEASE BECAUSE IT TURNS OUT PANCREAS CANCER HAS MICRO MICROME — ME STAS SIS AND YOU HAVE TO GIVE CHEMOTHERAPY TO PEOPLE WHO DON’T LOOK LIKE THEY HAVE THE DISEASE KNOWING IT THE KOL — COME BACK. AND THERE’S A DRUG AND THERE’S ABOUT 7% OF PATIENT HAVE A LONG-TERM SURVIVAL. IT’S ABOUT 20% AT FIVE YEARS AND DROPS OFF A LITTLE BIT OF THAT. RECENTLY YOU CAN SEE WE MADE ADVANCES NOT ONLY IN SURGERY AS IN PATIENTS GETTING THIS CHEMO THERAPY OR LIVING 36 MONTHS AND WE HAVE NEW COMBINATION REGIMENTS THAT CAN POTENTIALLY BE CURED. THE QUESTION IS WHO ARE THESE SPECIAL PEOPLE IN THE TAIL OF THE CURVE THAT SURVIVAL PANCREAS CANCER SINCE IT’S SUCH A SMALL PERCENTAGE. WHAT MAKES THEM DIFFERENT? MOSTLY YOU THINK IT’S A LOWER GRADE OF TUMOR. NONE OF THOSE THINGS EXPLAIN. NOT TO DO INTO MORE DETAIL BUT IT’S OUT OF STEPHEN LEECH’S LAB AT MSK AND WHAT THEY FOUND IS THAT PATIENTS WHO WERE LONG TERM SURVIVORS OF CANCER HAS MORE AT SURGERY. THOUGH THEY DIDN’T HAVE TOO MUCH MORE IN THE WAY OF MUTATIONS IN THEIR TUMOR TO CAUSE THE CELLS TO COME AND INFILTRATE THE TUMOR WE HAD MUTATIONS IN THE TUMOR HAS DIFFERENT ONES AND THE ONES SOME PEOPLE HAD RESEMBLED SEQUENCES YOU WOULD FIND DURING VIRAL OR BACTERIAL MIGRATIONS. IT SEEMED THE IMMUNE SYSTEM WAS BETTER ABLE TO RECOGNIZE THE TUMOR. THAT’S A THOUGHT THAT’S BEEN PUT FORWARD FOR WHY THESE PATIENTS HAVE LONGER SURVIVAL. IF YOU LOOK AT THE PROGRESS OF ADVANCED PANCREAS CANCER WE STARTED WITH THIS AGAIN AND A MEDIAN SURVIVAL OF FIVE AND A HALF MONTHS. YOU CAN SEE THE REVIEW ARTICLES OF THINGS COMBINED IN AN ATTEMPT TO SEE IF WE CAN MAKE IT BETTER. ALL BUT TWO WORKED OUT. MUST HAVE BEEN THEM IS THIS. WHEN YOU GET IT WITH THE EGFR YIP HIBITOR AND EXTENDS MEDIAN SURVIVAL BY 10 DAYS IN THESE PATIENTS. WE LOOKED AT IT AND A SMALL PERCENTAGE OF PATIENTS DO EXTRAORDINARILY WELL THAT PROBABLY HAVE A MOLECULAR MARKER AND THE REST IT DOESN’T DO ANYTHING EXCEPT GIVE THEM A HORRIBLE RASH. THE OTHER THING THAT HAS SHOWN ADVANTAGE IS THE ADDITION OF A DRUG AND THAT ADDS ANOTHER TWO AND A HALF OF MEDIAN SURVIVAL. AND THE REGULAR ONE HAD NO ADVANTAGE. SO THERE’S THOUGHTS WHY HAVING THIS NANO ALBUMIN FORMULATION MAY BE FOREEFFECTIVE IN THE DISEASE. — MORE EFFECTIVE IN THE DISEASE. pON THE OTHER SIDE THERE’S AN A REGIMENT WITH THE MAJORITY OF PANCREAS CANCER PATIENTS ARE NOT WELL ENOUGH TO RECEIVE BUT EXTENDS MEDIAN OVERALL SURVIVAL TO 11 MONTHS AND THERE’S A LIGHT VERSION MADE WITH A DRUG MEANING IT’S AN ISOSOMAL TC AND THIS APPLIES IN COMBINATION WHERE WE SEE A SMALL SURVIVAL WHEN IT’S GIVEN IN THE SECOND LINE SIGHTING AFTER THE PATIENTS ALREADY RECEIVED THE THERAPY. WE DON’T HAVE ANYTHING NEW, EXCITING OR ADDRESSING THESE IN OTHER CLASS. HOW DO YOU KNOW WHO IS GOING TO RESPOND OR CHOOSE A THERAPY? THERE’S BEEN A GREAT DEAL OF EFFORT OVER THE PAST DECADE TO TRY AND IDENTIFY SUBTYPES OF PANCREAS CANCER. COLISON AND FRIENDS USE RNA SEQ AND A CLASSICAL TYPE AND ONE WITH A SIMILAR PROGNOSIS IN THE GREEN LINE AND THE BLUE LINE OF PATIENTS WITH POOR PROGNOSIS. HOUR ANOTHER GROUP WAS DOING THIS AND THEY PUBLISHED DID WITH A COMPUTER CONVOLUTION OF THE CANCER SAMPLES TO GET TO THE DATA AND RT PINES A CHRONIC AND BASAL TYPE WE SAW. AND THERE’S A THIRD STUDY WHERE THERE’S GROUP. THE THIS IS THE BAD KIND. THERE’S THIS PANCREATIC PROGENITOR WHICH IS THIS KIND OR THIS KIND. AND ALSO FOUND THE IMMUNOGENIC TYPE AND IT’S BEEN SUGGESTED MANY IN THEIR PATIENTS HAD LYMPH NODE CONTAMINATION BUT THESE DAYS PEOPLE THINK SIMPLEST IS BEST THE BASAL TYPE AND THE GOOD AND THE BAD AND SO HOW DO PATIENTS RESPOND? RECENTLY, IF YOU SEQUENCE PATIENTS’ TOMBERED — TUMORED YOU LOOK AT THE GOOD TYPE IN YELLOW AND BAD TYPE AND THIS IS A PLOT AND THEY’RE GOOD FOR TELLING YOU WHAT WE SAY HOW DEEP IS THE RESPONSE. DOES IT TREAT THE TUMOR A LOT. WHEN I SAID A LOT YOU THINK THE Y AXIS GOES DOWN TO NEGATIVE 100% TO BE GONE BUT THIS ACCESS ONLY GOES DOWN TO NEGATIVE 40% BECAUSE THAT’S THE BEST WE CAN DO IN GENERAL WITH OUR CURRENT THERAPIES. COMPLETE RESPONSES ARE ALL THE TOMBERS GO AWAY ARE RARE. CAN SEE THE YELLOW IS ON THE WRONG SIGHT AND PURPLE IS IN THE RIGHT SIDE. AS PATIENTS ARE MORE INTERESTED IN AND ONCOLOGISTS AS WELL IS HOW LONG DO PATIENTS NEED TO GO BEFORE THEIR TUMOR STARTS TO GROW AND THEIR THERAPY ISN’T WORKING ANYMORE. THIS SAYS HOW DURABLE IS YOUR THERAPY. IF YOU HAVE THE BASAL LIKE KIND THE THEMO THERAPY IS NOT GOING TO WORK AS WELL. THIS IS GREAT BUT THE PROBLEM IS THAT WE DON’T HAVE ANYTHING ELSE WE KNOW WILL WORK IN THE PATIENTS WITH THE BASAL LIKE TYPE AND DOES WORK IN SOME PATIENTS. SO THESE PATIENTS CONTINUE TO GET THE THEMMO THERAPY WE HAVE — CHEMOTHERAPY BECAUSE WE HAVEN’T FOUND ANYTHING ELSE THAT WORKS FOR THIS SUBGROUP. WE’VE ALSO BEEN LOOKING AT CHROMOSOMAL STRUCTURE. FOR KINDS WERE IDENTIFIED. ONE CORRELATES WITH THE BRA MA AND — BRCA MUTATION AND THE SATELLITE AND STABLE AND THIS HAS BEEN LOOKED AT. IN ADDITION TO DEFINING OTHER TYPES THEY DEFINE STROMAL SUBTYPES. STRO MA CELLS ARE IN THE TUMOR BUT NOT IN THE CANCER CELLS AND THEY FOUND IF YOU CLASSIFIED THE EXPRESSION OF DIFFERENT GENES BY RNA SEQ OF THE STROMAL COMPONENTS YOU COULD CLASSIFIED TO A SURVIVAL STATUS. THERE’S GOOD AND BAD — PROGNOSIS. IF WE WANT TO MOVE ON HOW DO WE DO THAT? SO IF YOU LOOK AT THE GENOME OF PANCREAS CANCER AND HOW PATIENT’S TUMORS ARE MUTATED, THIS IS REPRESENTING THAT PHENOMENON SHOWING THE FREQUENCY OF MUTATION BY THE SIZE OF THE LOOKING AT.THIS POSTER YOU’RE ASK YOU CAN SEE MUTATION OF K RAS DOMINATES THE LANDSCAPE. OVER 90% OF PATIENTS HAVE KRAS MUTATION AND THIS IS CONSIDERED THE IMPORTANT LEISURE. 70% HAD P35 LOSS AND ANOTHER 30% TO 50% HAVE A LOSS OF CDK AND 2A. THERE ARE NO OTHER MUTATIONS MORE COMMON THAN 10% IN THE POPULATION AND THE ISSUE WITH PRECISION MEDICINE ALL FOUR OF THE BIG FOUR HAVE TRADITIONALLY BEEN CONSIDERED UNDRUGGABLE. THERE’S CHANGING FOR KRAS AND THERE’S AN INHIBITOR OF THE MUTANT AND UNFORTUNATELY ONLY 2% OF CANCER PATIENTS HAVE THE MUTATION. SO PATIENTS OF CRAN — PANCREAS HAVE G12D OR G12B MUTATION. AND WHAT’S BEING PURSUED IS A THERAPY IS TO DELIVER RNA AGAINST KRAS TO PANCREAS CANCER TUMORS. ONE STRATEGY IS TO PACKAGE IT INSIDE OF EXOSOMES OR ARTIFICIAL EXOSOMES. THE REASON IS BECAUSE EXOSOMES ARE MORE RESISTANT TO DIGESTION THAN IF YOU WERE TO PACK IN LIPOSOMES. AND THEY ACCUMULATE IN LIVER, PANCREAS AND LUNGS WHICH IS THE PLACES CANCER USUALLY GOES AND THE INCREASE IS MACROCYTOSIS AND EVEN IF OTHER CELLS TAKE IT UP THERE’S NO EFFECT ON THE KRAS WILD TYPE CELLED. THERE’S NO ACTIVITY IN MICE COMPARED TO THE MODELS AND THEY DO WELL WHEN THEY HAVE A PACKAGE IN EXO SYSTEMS. SO OTHERS HAVE SAID, WELL, LET’S GO FURTHER INTO THE PRECISION MEDICINE. THOUGH PATIENTS OF PANCREAS CANCER HAVE TARGETED MUTATIONS. WE CAN PERFORM WHAT WE CALL A BASKET STUDY WHERE WE EXEC PATIENTS TUMORS AND THEN LOOK TO SEE WHAT MUTATION THEY SPECIFICALLY HAVE AND GIVE THEM A DRUG WE ALREADY KNOW CAN BLOCK THAT PARTICULAR MUTATION. THIS STUDY CALLED KNOW YOUR TUMOR WAS SPONSORED BY THE PANCREAS CANCER INSTITUTE AND THEY WERE ABLE TO GET OVER 90% WHICH IS AN ACHIEVEMENT IN AND OF ITSELF BECAUSE AS I TOLD YOU IT’S HARD TO GET TUMOR SAMPLES FROM THE PATIENTS. 50% HAD ACTUAL MUTATIONS. TO 27% HIGHLY ACTIONABLE. MY DEFINITION IS DIFFERENT THAN THEIRS WOULD BE. I WOULD SAY I WOULD NOT GO WITH THOSE NUMBERS. WHAT THEY FOUND IS EXAMPLES WOULD BE DNA REPAIR GENES LIKE MUTATION, BRCA FOUND IN 8%. WE KNOW IF YOU GIVE THOSE PATIENTS A PLATINUM CHEMOTHERAPY THEY RESPOND BETTER AND IF YOU MATCH THEM TO THE TREATMENT WE EXPECT THEM TO DO BETTER. I THINK THAT’S TWO ENDS OF THE STRATEGY. BASICALLY THERE WERE 18 OF 320 WHO WERE ABLE TO GET A MATCH THERAPY. THE OVERALL SURVIVAL WAS MONTHS. THE PREVENTION INCREASE SURVIVAL. IT WAS NOT A HUGE BEN KNIT — BENEFIT IN THE OVERALL POPULATION BUT THERE WERE A COUPLE BRIGHT SPOTS. MTRAC IS ANOTHER EXAMPLE. LESS THAN 1% OF PATIENTS HAVE IT BUT IT STILL WORKS IN PANCREAS CANCER. MANY OTHERS LIKE CD4X INHIBITERS OR AGONISTS DON’T WORK EVEN WHEN THEY HAVE PATIENTS WITH THIS AND EVEN KRAS MUTATION IS MESSING EVERYTHING UP. THE BASKET STUDIES OF SINGLE AGENT IN GENERAL HAVE NOT BEEN SUCCESSFUL FOR THE LARGE MAJORITY OF PATIENTS WITH PANCREAS CANCER EVEN IF THEY HAVE ONE OF THESE ACTIONABLE MUTATIONS. THERE’S A LOT OF TALK THAT I THINK IS INTERESTING DRIVEN BY THE KRAS MUTATION AND THERE’S OTHER FACTORS INVOLVED AS WELL. THERE’S A CHANGE IN METABOLIC REPROGRAMMING. ANY CHANGE IN THE CELL IS SOMETHING YOU CAN POTENTIALLY TARGET WITH DRUGS. WE KNOW KRAS AND THEN SIGNALLING. WE HAVE DRUGS THAT BLOCK THEM AND SO LET’S SAY WE BLOCK USING A DRUG APPROVED FOR MELANOMA. MEN WHAT WAS RECENTLY FOUND IS WHEN YOU BLOCK THIS IT TURNS OUT THE DOWN STREAM MEDIA IN THE PATHWAY INHIBIT AUTOPHAGY. SO IF YOU INHIBIT THAT PATHWAY YOU GET MORE OUGHT — AUTOPHAGIC BLOCK BUT IF YOU BLOCK IT YOU GET RESULTS LIKE THIS. THIS IS A MODEL IN MICE WITH PANCREAS CANCER AND THE YELLOW IS WHAT HAPPENS WHEN YOU GIVE THIS WHEREAS THE BLUE LINE IS WHAT HAPPENS WHEN YOU GIVE STANDARD OF CARE CHEMOTHERAPY. YOU CAN SEE THE OTHER LINES OF THE DRUGS THAT DON’T DO MUCH. BECAUSE THEY’RE BOTH FDA APPROVED THEY CAN BE GIVEN BY BRAVE PHYSICIANS WE CALL OFF-LABEL AND DID THIS IN PATIENTS WITH NO OTHER TREATMENT LEFT AND TURNS OUT THEY HAD A RESPONSE THAT YOU CAN SEE IN THE CT SCAN. LOOK AT THE BOX. THIS IS THE LIVER IN THE CT SCAR AND EACH SHOWS A DARK SPOT WHICH SAY TUMOR. YOU CAN SEE THE DARK SPOTS HAVE LARGELY GONE AWAY. IT’S A DIFFERENT SLICE OF THE LIVER SHOWING THE SAME THING. WE’RE HOPING TO HAVE THE TRIAL OPEN SOON AT NCI. IT’S A NEW STRATEGY FOR ATTACKING KRAS MUTATION BY GOING DOWN STREAM OF KRAS IN THE PATHWAY. NOW, WHAT ABOUT IMMUNOTHERAPY? THIS STUDY WAS DONE HERE AND YOU CAN SEE THERE IS NO SIGNAL OF ANYONE RESPONDING AND THE SAME WITH ANTI-PD1 DRUGS. THERE WERE SOME PATIENTS TREATED WITH PANCREAS ADENOCARCINOMA AND THE MEDIAN SURVIVAL RATE OF 3.9 MONTHS. AND THE LIGHT IN THE TUNNEL IS OING BACK TO THE PRECISION ONCOLOGY IDEA THERE’S LESS THAN 1%, .6% OF PANCREATIC CANCER PATIENTS AND THIS BLUE IS PANCREAS CANCER AND THOSE WITH THE UNSTABLE TUMORS RESPOND TO THE ANTI-PD1 DRUG. THIS IS PART OF WHAT LED AND THIS IS THE STUDIO THAT SHOWED IT TO THE — STUDY THAT SHOWED THIS TYPE OF TRIAL REGARDLESS OF THEIR TUMOR TYPE. WE LIKE TO CHECK AND MAKE SURE PATIENTS DON’T HAVE THE MUTATION BECAUSE IT’S A GAME CHANGER. THERE’S A LOT OF RESEARCHERS DOING WORK AND I’LL GLOSS OVER THAT IN THE INTEREST OF TIME. THE FIRST IDEA IS TO MAKE A COLD TUMOR LIKE PANCREAS CANCER WHICH DOESN’T HAVE A LOT OF MUTATIONS AND DOESN’T HAVE A LOT OF T VERY WELL ACTIVATION TO MAKE IT TURN HOT AND BE SOMETHING TO RECOGNIZE BY COMBINING WITH AGENT THAT STIMULATE THE IMMUNE RESPONSE. RADIATION, CHEMO THERAPY AND COME IN AFTERWARDS WITH AN IMMUNE CHECKPOINT TO RELEASE THE IMMUNE SYSTEM TO ATTACK THE TUMOR. MANY OF THESE STUDIES ARE GOING — ONGOING AND THE ISSUE IS NOT THE T CELL ACTIVATION CENTER BUT THE PRIMARY PROBLEM IS THERE’S A TON OF MONOCYTES PREVENTING THE T CELLS HAVE STAYING ACTIVATED. THERE’S TECHNOLOGIES USING THE BLOCKERS TO TRY AND REPROGRAM OR REMOVE THESE IMMUNOSUPPRESSIVE MACROPHAGES FROM THE TUMOR ENVIRONMENT. AND THE ANTIGEN PRESENTING CELLS ARE GET BOOST AND THE AGONIST HAS BEEN PROMISING FOR THE DISEASE AND WE’LL SEE HOW IT CONTINUES TO GO. THERE’S TALK THE PD1 CHECK POINTS WHICH WERE WHAT WE WERE HEARING ABOUT AS CLINICIANS BECAUSE WE HAVE TUMOR TYPES ARE NOT THE RIGHT CHECKPINT FOR THIS DISEASE AND PERHAPS WE’RE BARKING UP THE WRONG TREE IN THINKING IT’S GOING TO GET T CELLS ACTIVATED IN THE PARTICULAR TUMOR TYPE. SO WHAT IS GOING ON WITH PANCREAS CANCER THAT MAKES IT SO DIFFICULT TO TREAT AND PROBLEMATIC. PANCREATIC CANCER HAS A HUGE AMOUNT OF BASICALLY SCAR TISSUE AROUND A SMALL AMOUNT OF CANCER CELLS. IT’S NOT MY FAVORITE SLIDE IN THE WORLD BUT BASICALLY THE AREAS LOOK TO ME LIKE SOMETHING ELSE AND YOU CAN SEE THERE’S HUGE AREAS WHERE THE LIGHT PINK IS WHERE WE’RE TALKING ABOUT MATRIX AND THERE’S FIBROBLASTS. AND PANCREAS CANCER HAS BEEN CALLED THE WOUND THAT DOES NOT HE’LL. YOU’RE LOOKING AT THE IMMUNE SYSTEM TO MAKE A RESPONSE. THIS SHOWS WHAT MEDIATORS ARE ABOUT TO BE INVOLVED AND THIS IS CONSIDERED TO BE A PRIMARY ISSUE IN PANCREATIC CANCER. THIS THIS IS COMPLEX WHERE YOU HAVE CANCER CELLS THAT CAUSE THIS RESPONSE MADE BY FIBROBLASTS SECRETED FROM CANCER CELLS TO IMMUNE SUPPRESSION AND OTHER EFFECTS AS WELL. AND WE’RE NOT JUST TALKING ABOUT ONE CELL BUT DIFFERENT KINDS. SO WORK FROM TWO GROUPS WAS RECENTLY PUBLISHED WHICH SHOWED, HEY, THERE’S DIFFERENT FIBROBLASTS IN THESE CANCER TUMORS AND THEY’RE IMPORTANT TO THE BETA SIGNALLING AND LAYING DOWN A BUNCH OF MATRIX AND THEY MAY BE GOOD BECAUSE THEY’RE RESTRAINING THE TUMOR AND IT’S KEEPING IT LOCKED IN SO IT CAN’T METASTASIZE AND THERE’S FIBROBLASTS WHICH ARE SENDING OUT MEDIATORS WHICH SUPPRESS THE IMMUNE SYSTEM AND HELP CANCER CELLS GROW. IF WE WANT TO TARGET THE STROMA WE HAVE TO BE ABLE TO DIFFERENTIATE BETWEEN THE FIBROBLASTS IN THE TUMOR. THE LAST THING I WAS GOING TALK ABOUT IS TARGETING STROMA WHICH IS A HUGE TOPIC IN PANCREAS CANCER. THERE’S A FANCY MOUSE MODEL IN INVENTED WHICH TRANSFORMED OUR ABILITY TO DO ALL KIND MUCH STUDIES BECAUSE THE OTHER MODELS HAVE NOT BEEN PREDICTIVE OF WHETHER DRUGS ARE EFFECTIVE IN PANCREAS CANCER. LARGELY WE THINK BECAUSE OF THE STRONG SMOKAL RESPONSE YOU DON’T SEE WHEN YOU USE THOSE — STRONG STROMAL RESPONSE YOU DON’T SEE WHEN YOU USE THOSE. AND THIS IS WHERE YOU END UP MUTATIONS OF KRAS AND P53 SPECIFICALLY IN THE PANCREAS. THEN YOU USE A PANCREAS SPECIFIC COMBINE MOUSE AND THAT ENDS UP CAUSING PANCREAS ADENOCARCINOMA SO YOU CAN DO EXPERIMENTS. THE LIMITATIONS OF THIS MODEL IS THE TUMORS RUN THROUGHOUT THE PANCREAS, MANY PRIMARY TUMORS. ALL OF THESE MICE GET METASTASES. IT’S NOT THE BEST STUDY FOR METASTASES AND PRIMARILY DIE OF METASTASES NOT THE PRIMARY DISEASE. IT’S GREAT TO LOOK AT HOW WELL YOUR DRUG CAN MAKE TUMORS GO AWAY. SO THE IDEA WITH THE ISSUE OF STROMA WAS STARTED AND THE IDEA IS THERE’S SO MUCH STROMA AND THE MATRIX IS SO DENSE AND THERE ARE MATRIX SUBSTANCES LIKE HYALURONIC ACID AND IT CREATES SUCH A PRESSURE IT SQUASHES DOWN BLOOD VESSELS AND THIS LEADS TO THE PRESSURE IN THE VESSELS BEING ARTERIAL AND THIS IS DIFFERENT THAN HOW WE THINK OF MOST CANCERS WHEN WE THINK OF THEM BEING HIGHLY VASCULAR WITH EXCELLENT BLOOD SUPPLIES. PANCREAS CANCER IS DIFFERENT AND WHEN WE DO C.T. SCANS AND GIVE PEOPLE CONTRAST WHICH GOES INTO THE VESSELS AND TYPICALLY THAT HIGHLIGHTS OTHER KINDS OF TUMORS, WHEN WE DO THAT FOR PANCREAS CANCER WE’RE LOOKING FOR THE DARK SPOT NOT THE BRIGHT SPOT BECAUSE THEY’RE HYPOVASCULAR. THE IDEA IS IF YOU COULD, FOR INSTANCE, BLOCK HYALURONIC ACID OR DEGRADE IT, IT WOULD OPEN UP THE VESSELS AND YOU WOULD GET MORE DRUG TO THE TUMOR AND YOU’D BE ABLE TO KILL THE TUMOR CELLS BETTER. THIS IDEA HAS BEEN AROUND A DECADE AND A HALF THAT WE COULD GET BETTER DRUG DELIVERY. THIS IS WHAT THE RESULTS WERE IN MICE WHEN YOU GAVE THIS DRUG THAT DEGRADES HYALURONIC ACID AND THE METASTASIS WENT DOWN AND IT WENT TO A STUDY AND STAGE 2 STUDY WAS COMPLETED AND THEY RECEIVED ONE STANDARD OF CARE THERAPY REGIMENTS WITH OR WITHOUT PH20. THERE WAS NO DIFFERENCE IN THE SURVIVAL FOR THE WHOLE POPULATION. THIS WAS GIVEN WITH A DIFFERENT STANDARD CHEMO THERAPY AND THE PATIENTS THAT GOT THE PH20 DID WORSE. THEY HAD A WORSE SURVIVAL THAN THOSE THAT GOT THE OTHER ALONE. HOUR HOWEVER, IF YOU LOOKED AT THIS STUDY AND THE BLUE LINE ARE THE PATIENT GOT THIS AND THIS IS A SPECIFIC PROPORTION WITH HAVE THE DENSEST NASTIEST TUMORS. THERE’S AN ADVANTAGE TO GETTING THIS PARTICULAR DRUG IN THE PHASE 2 SETTING. IN THE PHASE 2 STUDY IT’S NOT STRONG ENOUGH EVIDENCE BECAUSE THERE’S NOT ENOUGH S AND THE STATISTICS AREN’T GOOD ENOUGH TO GET TO A DRUG APPROVAL. THIS WENT INTO A PHASE THREE STUDY FOR PATIENTS WITH HIGH STROMA TUMORS TO SEE IF THERE’S A SURVIVAL. AND DISAPPOINTED TO REPORT THEY JUST RELEASED A PRESS RELEASED AND IT WAS A NEGATIVE STUDY AND THE STRATEGY WAS NOT ABLE TO HELP PATIENTS WITH HIGH STROMAL TUMORS. BEFORE THE PEG PH20 STORY USING THE HEDGEHOG PATHWAY SIGNALLING THAT MAKES THE FIBROBLASTS AND ALL THAT STROMA. IF YOU GIVE A HEDGEHOG BLOCKER YOU CAB — IN IMPROVE SURVIVAL BUT WHEN I WAS TESTED THERE WAS NO DIFFERENCE WITH THOSE WHO GOT THE HEDGEHOG INHIBITOR OR THE OTHER AND WHEN THEY LOOK AT THE INITIAL DATA THEY FOUND IF YOU’RE GIVING THE DRUG AT A DIFFERENT TIME IT AFFECTS ME STAS TA SIS. THOUGH YOU CAN GET MORE DRUG IN THE TUMOR THE PROBLEM — THOUGH YOU CAN GET MORE DRUG IN THE TUMOR THE PROBLEM IS THAT WHEN YOU TAKE AWAY THE MATRIX YOU GET METASTASIS AND IT DIFFERENTIATES. WHEN YOU TALK ABOUT STROMA, IT’S NOT SO MUCH DESTROYING AND BLOCKING STROMA PEOPLE ARE TRYING TO DO WHEN THEY DESIGN DRUGS TO SIT — DRUG IS TO ELIMINATE THE STROMA ALTOGETHER. THAT’S THE IDEA. STROMAL TARGETING MAY NOT ALWAYS HAVE A SPECIAL THERAPEUTIC RESPONSE BECAUSE THE INTERACTION IS COMPLEX AND YOU NEED TO THINK THROUGH CAREFULLY WHAT IT IS YOU’RE ELIMINATING WHEN YOU TARGET STROMA. I WORK ON THESE TYPES OF TARGETED PROTEINS AND THERE’S A G.I. LINKED PROTEIN AND YOU CAN SEE THIS IS PANCREAS CANCER AND THESE ARE THE TUMOR CELLS AND THE BLOOD IS THE NOT-STROMAL CELLS. SO CRAN — PANCREATIC CELLS ARE LIMITED TO THE EPITHELIAL CELLS AND THIS IS PART OF THE PERINEUM. THERE’S A FIBROUS LAIR ON THE OUTSIDE — LAYER OUTSIDE OF THE HEART AND GENERALLY DISPENSABLE. DON’T NEED TO HAVE THEM TO LIVE. AND IF YOU KNOCK IT OUT IN MICE, NOTHING HORRIBLE HAPPENS, THEY LIVE NORMALLY. THIS GIVES YOU THE IDEA THAT TARGETING MESO THTHELLIN IS NOT EXPRESSED IN NORMAL CELLS. AND YOU GET LOW AMOUNTS OF DFFERENTIAL EXPRESSION ON CELLS THAT ARE NORMAL YOU DON’T WANT TO TARGET AND HIGH ENOUGH YOU DO WANT TO TARGET THE CANCER CELLS. SO HOW GOOD IS THE EXPRESSION IN PANCREAS CANCER. THERE’S 5% OF TUMORS NEGATIVE FOR MESOTHELIN AND 5% OR LESS OF THE TUMOR CELLS WERE EXPRESSED. AND BECAUSE OF THE DIFFERENTIAL EXPRESSION IN PANCREAS CANCER AND OTHER TUMOR TYPES. THERE’S BEEN QUITE A FEW DRUGS TARGETI TARGETING MESOTHELIN DRUGS AND YOU HAVE AN ANTIBODY WITH A CHEMO THERAPY DRUGS AND THOSE THAT TARGET MESOTHELIN AND WE’RE INTERESTED IN ANTIBODY BASED MOLECULES AND THE TOXIN IS THE MOST TOXIC SUBSTANCE. SO WE TAKE THE BINDING DOMAIN OF THE ANTIBODY AND FEES IT IN FRAME TO THE CATALYTIC DOMAIN AND THIS BLUE ONE HERE. THIS MAKES A SINGLE RECOMBINANT MOLECULE AND AS THE — AND THIS IS WHAT IT LOOKS LIKE. IT BINDS ON THE SURFACE OF THE CELL. AND THEN MOST WILL GO TO A PATHWAY WHERE IT’S DEGRADE LYSOSOMES BUT A SMALL PERCENTAGE WILL GO THROUGH THE RETRO GRADE PATHWAY THENS ESCAPES THROUGH AN UNKNOWN MECHANISM AND THEN GOES THROUGH ELONGATION FACTOR 2. IT’S A NON-REDUNDANT ENZYME CRITICAL FOR PROTEIN
SINYNTHESIS. THE BOTTOM LINE IS IT CAN’T MAKE OTHER PROTEINS AS WELL INCLUDING PROSURVIVAL FACTORS LIKE MCL1 THAT ARE SHORT LIVED AND LEADS TO APOPTOSIS. WHAT WE FOUND IN MY LAB IS IF WE COMBINED THEM CHIS — THIS IS WHAT THE TWO DO WHEN THEY ARE COMBINED. SO BASED ON THIS AND OTHER DATA WE HAD WE DECIDED TO BRING THIS COMBINATION TO CLINICAL TRIAL IN PATIENTS. THIS IS WHAT WE FOUND. THIS IS ANOTHER ONE OF THOSE WATER FALL PLOTS BUT HERE WE’RE ONLY LOOKING AT MAXIMUM CHANGE IN THE TUMOR AND WE CONSIDER IT STATISTICALLY SIGNIFICANT IF THERE’S A DECREASE OF 50% OR MORE. WE SAW THAT IN THE NUMBER OF PATIENTS ON THE STUDY. AND THE INTERESTING THING WE FOUND IS IF WE WORKED ON THE PERCENTAGE OF PATIENT ON THE STUDY, THE PATIENTS WITH THE BETTER RESPONSES YOU CAN SEE TENDED TO HAVE A HY — HIGHER PERCENTAGE OF CELLS. WE FOUND THE REGIMENT WAS TOO TOXIC THOUGH WE HAD A PATIENT WITH A POSITIVE TUMOR RESPONSE. WE CAN LEARN OTHER INFORMATION FROM THIS. ONE ISSUE WITH THE IMMUNOTOXIN DRUG, IF WE INJECT IT INTO THE BLOODSTREAM YOUR IMMUNE SYSTEM IS SMART ENOUGH TO KNOW AND RECOGNIZE THAT PROTEIN. IF THEY’RE CONTINUE TO GIVE THEM TO PATIENTS THEN IT MAKES NEURALING THE CORRECT SYSTEM. IF YOU LOOK HERE, THESE ARE THE DRUG LEVELS IN MY PATIENTS DURING CYCLE 1. YOU CAN SEE THE AVERAGE IS TYPICALLY UP HERE. THEN WE HAD FOUR PATIENTS THAT DIDN’T LIKE WE DIDN’T EVEN GIVE IT TO THEM. WHAT HAPPENS IS WE SEE A RISE IN THE ANTIBODIES. IF YOU PLOT THINGS THIS WAY THE MAXIMUM SERUM CONCENTRATION IN THE ORANGE HERE AND THE TIGHTER OF ANTI-DRUG ANTIBODIES IN THE PURPLE FOR EVERY SINGLE PATIENT, THESE TWO DOTS ARE ON THE OPPOSITE END OF THE SPECTRUM. IF YOU HAVE HIGH ANTI-DRUG ANTIBODIES THE ORANGE DOT IS LOW BECAUSE WE HAVE NEUTRALIZING ANTIBODIES PREVENTING YOU FROM GET GOOD SERUM LEVEL. AND IF YOU HAVE YOUR ANTIBODY TIGHT — TIDER IS LOW YOU GET THIS AND THE QUESTION IS HOW DO YOU OVERCOME THAT? THEY USED THE COMPOUNDS THAT BLOCK THE T CELLS. WE WERE INTERESTED IN THIS PARTICULAR DRUG THE KINASE INHIBITOR THAT BLOCKS LYMPHOCYTES AND GOOD FOR COLITIS. AND WHAT MANY FOUND IS IT CAN ELIMINATE THE FORMATION OF ANTIBODIES AGAINST SOME AMINO TOX INS IN MICE AND IF YOU IMMUNIZE THEM REPEATEDLY AND THIS IS WHAT YOU GET WEN YOU LOOK AT THE ANTIBODY TIDER. IF YOU DON’T GET IT AND YOU GET HIGH DRUG ANTIBODIES AGAINST THIS WHERE WE CAN EXPRESS THIS. SO IN ADDITION, IT WAS FOUND THAT THE TREATMENT COULD REDUCE THE MACROPHAGE POPULATION TUMORS SO YOU’D END UP WITH UPTAKE OF OUR MOLECULE BY MACROPHAGES INSIDE THE TUMOR. THIS COULD LEAD TO INCREASED HALF LIFE OF THE DRUG AND INCREASED DELIVERY OF THE TUMOR SO THE COMBINATION IN PURPLE HAD BETTER ANTI-TUMOR ADVOCACY THEN THE SINGLE AGENT. SO BECAUSE OF THIS WE’RE TESTING THE COMBINATION AND WHEN YOU RUN CLINICAL TRIALS THE FIRST THING YOU HAVE TO FIGURE OUT WITH ANY NEW DRUG COMBINATION IS WHAT DOSE YOU CAN GIVE TO PEOPLE SAFELY. THEN WE GO TO GIVE EVERYONE WHAT WE THINK IS THE BEST DOSE AND SEE IF WE CAN PREVENT THIS ANTIBODY FORMATION SO PATIENTS CAN GET THE DRUG FOR LONGER AND HAVE IT EFFECTIVE FOR LONGER. THIS IS HOW WE’RE DOING IT. SINCE THE IDEA IS THAT WE’RE BLOCKING THE ANTI-DRUG, ANTIBODY AND GIVING THE TOFACITINIB IN BETWEEN AND LETTING THE LYMPHOCYTES DO WHAT THEY’RE SUPPOSED TO DO AND THAT’S THE IDEA BEHINDTHE STUDY. I THINK WE’RE OUT OF TIME ELEMENT BUT IF ANYONE HAS ANY QUESTIONS. [APPLAUSE] .- BUT IF ANYONE HAS ANY QUESTIONS. [APPLAUSE] .- BUT IF ANYONE HAS ANY QUESTIONS. [APPLAUSE] .>>ANY QUESTIONS? PERHAPS YOU CAN ELABORATE ON THE NEW KRAS INHIBITOR.>>ON THE INHIBITOR, I JUST SAW SOME OF THE FIRST DATA REPORTING ON THAT AT THE TARGETS MEETING. IT SEEMS THERE’S A CONSENSUS WITH THE DEFAULT TEAM FOR THE TUMOR TYPES THAT MAKE G12B LIKE LUNG CANCER THE BIG TARGET THERE. THERE’S THERE IS NOT CAUSING RESPONSES IN EVERY PATIENT WITH THE MUTATION THAT GETS IT. IT SEEMS MOST OF THE DRUG COMPANIES ARE NOW LOOKING TO COMBINE THAT DRUG WITH OTHER NEW AGENT THAT ARE INHIBITING THE RAS PATHWAY AS WELL. FOR INSTANCE, SHIP INHIBITORS ARE COMING ONLINE. THEY’RE PROTEINS THAT INTERACT WITH RAS THAT HELP THE GTP EXCHANGE PROCESS AND BY BLOCKING BOTH THEY’RE HOPING TO GET A BIGGER EFFECT. THOSE THE NEXT THINGS COMING ONLINE IS TO TRY AND DO THESE DOUBLE COMBINATIONS OF THE PATHWAY.>>WE’LL MOVE ON. THANK YOU. THE NEXT LECTURE IS MARINA DOBROVOLSKAIA AT THE NANOTECHNOLOGY CHARACTERIZATION LAB AND GOT HER Ph.D. IN RUSSIA AND AN MBA AT HOOD COLLEGE FREDERICK AND CO-DIRECTOR OF OPERATIONS HEAD OF THE IMMUNOLOGY SECTION. ENTITLED NANOTECHNOLOGY FOR APPLICATIONS AND THE CONCERNS AND EFFECTS ON THE IMMUNE SYSTEM. MARINA.>>THANK YOU. GOOD EVENING, EVERYONE. THIS IS AN OUTLINE OF MY PRESENTATION FOR OUR DISCUSSION TONIGHT. REAL QUICK HERE’S EXAMPLES OF NANO PARTICLES IN DAILY LIFE AND SOME OF THE ATTENTION WILL BE GIVEN TO NANO PARTICLES IN NANO APPLICATIONS AND LOOK AT TECHNOLOGY AND THE SURVIVAL IN TOXICITY AND THE INTERACTION WITH THE IMMUNE SYSTEM AND AT THEN I’LL TELL YOU ABOUT THE NANOTECHNOLOGY LAB AND WHAT THE LABORATORY’S DOING. SO WHAT NANO TECHNOLOGY? SUE YOU SEE — YOU SEE TWO DEFINITIONS DEFINING THEM AS OBJECTS WITH SIZE IN ONE DIMENSION IN 1 AND 100 NANO METERS. ACCORDING TO THE UNITED STATES IT’S LESS THAN ONE MICROMETER AND THERE’S DIFFERENT DIMENSIONS. AND THEY’LL TALK ABOUT NANO PARTICLES WE’RE TALKING ABOUT OBJECTS WITH THE SIZE IN THE RANGE WITHIN THE SIZE OF THE MOLECULE OF THE BACTERIAL CELL. HERE’S SOME EXAMPLES OF THE NANO PARTICLES. YOU SEE THE CAPSULES AND INORGANIC NANO CELLS. THIS IS A HANDFUL OF EXAMPLES. YOU SEE THE NANO PARTICLES AND THERE’S MORE EXAMPLES. WE HAVE MATERIALS IN OUR DAILY LIFE WITHOUT RECOGNIZING THEM AS NANO TECHNOLOGY. AND THEY’RE USED IN BIOMEDICAL APPLICATIONS. I WAS LISTENING TO THE PREVIOUS PRESENTATION AND I WAS THINKING IT WOULD BE NICE TO SEE THIS USED IN A NANO PARTICLE TO PREVENT IMMUNOGENICITY AND IT’S USED IN FOOD AND BIOTECHNOLOGY AND WE SEE EXAMPLES OF THE APPLICATIONS. THIS ARE PRODUCTS ONE CAN BUY IN THE SUPER MARKET CREAMS AND TOOTHPASTE AND SOAPS WILL CONTAIN NANO MATERIALS. AND I WAS PREPARING NOR PRESENTATION I OPENED THE AMAZON WEBSITE AND SEARCHED NANO PARTICLES AND I FOUND THEM AVAILABLE IN AMAZON ONE HERE IS THE NANO PARTICLES AVAILABLE IN DIFFERENT SIZES AT QUITE AN AFFORDABLE PRICE AND ACCORDING TO CUSTOMER RATING THE PRODUCT IS RATED VERY HIGHLY. THIS IS NOT REQUIRE FOR FDA APPROVAL. YOU MAY SEE THIS IN AMAZON AND OTHER INTERNET WEBSITES GIVEN THEY’RE PROMOTED TO BENEFIT HEALTH AND IMPROVE HEALTH AND MEDICINES. AND IN USE NANO TECHNOLOGIES IN THEIR PROCESSES. IF YOU WOULD LIKE TO KNOW ALL THE COMPANIES USING NANO TECHNOLOGY THEY ARE SUMMARIZED AND NANO PARTICLES ENTER THE ENVIRONMENT THROUGH THE SOILS AND THEY’RE USED AS FERTILIZERS IN EVERY CULTURE AND WASTE WATER TREATMENT AND SUCH IN WATER AND AIR AND SOIL AND THIS CREATES AN EXPOSURE TO NANO MATERIALS TO HUMANS. SO THERE ARE NANO PARTICLES INJECTION, INHALATION AND OTHER ROUTES. AND THEY IMPACT HUMAN HEALTH. YOU MAY READ SOME ARTICLES REPORTED IT’S USED IN ENGINE COMBUSTION AND CAN EXAGGERATE ASTHMA SYMPTOMS AND CONTRIBUTE TO DISEASES. THERE’S MANY REPORTS IN THE LITERATURE ABOUT TOXICITY OF THE NANO PARTICLES. AND SOME ARE SUMMARIZED IN THIS SLIDE SO THE PARTICLES MAY ENTER THE CELL AND TAKEN UP BY THE CELLS. INDUCE OXIDATIVE STRESS AND A CHANGE IN PROTEINS AND MIGHT — MITOCHONDRIAL MUTATION AND THESE TYPES OF INTERACTIONS IN ENVIRONMENTAL AND OCCUPATIONAL NANO MATERIALS ARE SUBJECT OF THE INVESTIGATION BECAUSE NOW WE HAVE BEEN DEVELOPED FOR HEALTH AND HUMAN MATERIALS. NANO TECHNOLOGY IN THAT ENGINEERED MATERIALS WILL BE DESIGNED AND PHYSICAL, CHEMICAL PROPERTIES COULD BE OPTIMIZED. LET’S SEE WHAT KIND OF PART KAZ ARE USED. — PARTICLES ARE USED. THESE ARE ATTRACTIVE FOR MEDICAL APPLICATIONS. NANO PARTICLES IMPROVE THE FUNCTIONAL ABILITY WHICH MEANS IT MAY HAVE A TARGETING AGENT THAT WOULD SPECIFICALLY INTERACT WITH A RECEPTOR OR PROTEIN EXPRESSED IN THE SURFACE OF THE CANCER CELLS. OR FROM THE IMMUNOVASCULATURE AND EXPRESSED IN NORMAL BLOOD VESSELS. ALSO THE PARTICLES MAY BE DESIGNED TO DELIVER A DRUG IN THE IMAGING AGENT AND THIS IS DESCRIBED AS MULTIFUNCTIONAL ABILITY AND THERE’S TISSUES AFFECTED BY DISEASE WITHOUT NORMAL HEALTHY TISSUES. FOR THESE REASONS NANO PARTICLES USE AND FIND APPLICATIONS IN THERAPY AND USES AND DEVICES AS WELL AS IN AGENT. IN THE NEXT FEW SLIDES I’LL TALK MORE ABOUT MEDICINES AND SHARE SOME OF THE DATA IN SOME OF THE APPLICATION. THERE’S A RECENT PUBLICATION FOR THE CENTER FOR THE DRUG ADMINISTRATION AND THE MATERIALS SUBMITTED TO THE FDA FOR APPROVAL THROUGH 2018 THE MATERIALS WERE FOLLOWED BY NANO CRYSTALS, EMULSIONS AND CELLS IN OTHER TYPES OF MATERIALS YOU CAN SEE LISTED IN THIS. THERE’S A PREDICTION FOR THE BIOMEDICAL MATERIALS IN THE NANO TECHNOLOGY MARKET WHICH IS ALWAYS EXCITING FOR PEOPLE WORKING IN THE NANO TECHNOLOGY FIELD AT THE SAME TIME IT NEED TO LOOK AT THE MATERIALS IN MEDS MEDICINES. MOST ARE INVENTED FOR CANCER THERAPY AND HAVE FREQUENTLY USED NANO MATERIALS IN MEDICAL APPLICATIONS ARE SIZE LESS THAN 300 NANO METERS. AND REMEMBER IN THE BEGINNING OF THE PRESENTATION WE TALKED ABOUT DEFINITIONS AND IT HAS A DEF FISSIDEF — DEFINITION FOR THE SIZE AND WE USE THIS WHEN WE SEE A DEFINITION PROPOSED BY THE USDA BECAUSE OF THE MATERIALS ARE SLIGHTLY LARGER THAN THE 100 NANO METERS. THIS IS TO AVOID SPECIFIC INTERACTION AND MEMBRANES AND MOST OF THE MATERIALS ARE TO IMPROVE THE SYSTEM. THIS IS AN EXAMPLE AND USED AGAINST HEPATITIS VIRUSES AND MEDICINES AND THERE’S A RECENTLY APPROVED PRODUCT AND I’LL TALK ABOUT IT IN THE PRESENTATION. THIS IS A FORMULATION AND A NANO PARTICLE USED TO TREAT IRON DEFICIENCY AND THERE’S A RIBOSOMAL MEDICINE AND THIS IS ALSO A TYPE OF THAT DRUG FOR THERAPY. LET’S REVIEW SOME PRODUCTS AND THE BENEFITS THEY CONTRIBUTE TO THE PATIENT AND MEDICAL APPLICATIONS. THE EARLY CANCER DRUG IS IMPOSING TOXICITY. THIS IS WAS SHOWN IN MANY CLINICAL DRUGS FROM THIS RECENT STUDY DEMONSTRATE IT’S LESS TOXIC. IN ANOTHER STUDY THAT WAS CONDUCTED IN NETHERLANDS THEY DEMONSTRATED THE IMMUNE THERAPY DRUG ALSO HAS THE POTENTIAL TO ACTIVATE THE IMMUNE SYSTEM AND BE USED FOR IMMUNOTHERAPY. WHAT THEY DID IS THEY USED MICE AND A MOUSE MODEL AND THIS DID NOT DEMONSTRATE A SIGNIFICANT DIFFERENCE HOWEVER, THESE WERE USED IN THE TREATMENT THEY ABSORBED. AND WA BROUGHT THE INVESTIGATORS TO COMBINE DROXIL WITH OTHER THERAPIES. AND YOU SEE THEY WERE COMPARED TO THE SINGLE TREATMENT. IT’S CONSIDERED AS A DRUG TO BENEFIT IMMUNOTHERAPY AND USED IN COMBINATION WITH THE CHECKPOINT INHIBITERS. ANOTHER ANTICANCER DRUG IS ALSO INVESTIGATED IN COMBINATION WITH THIS IN CLINICAL TRIALS FOR METASTATIC BREAST CANCER. IT’S NOT WELL UNDERSTOOD HOW THE FORMULATIONS CONTRIBUTED TO THE EFFICACY OF IMMUNOTHERAPIES BUT WE HOPE TO SEE MORE RESEARCH IN THE COMING YEARS. BEN FITS TO GENE THERAPY. SOME WERE DEMONSTRATED TO HAVE EFFICA EFFICACY IN VITRO. WHEN IT COMES TO IN VIVO APPLICATIONS DUE TO THE SYSTEMIC APPLICATION OF THE MATERIALS. THEY IMPROVE OF THE DELIVERY AND COMPENSATE FOR THE MATERIALS IN THE BIOLOGICAL MARKETS ONE WOULD HAVE TO DELIVER HIGH DOSES AND THEY’RE ASSOCIATED MORE AND THIS IS WHERE NANO MORT — PARTICLES HELP WITH THE STABILITY AND AN EXAMPLE TO CONSIDER IS AGAINST THE PROTEIN. THIS IS A PROTEIN PRODUCED IN THE LIVER AND EXCESSIVE PRODUCTION OF THIS PROTEIN IS ASSOCIATED WITH A DISORDER. SO THIS USES IT TO CONTROL TRE EXPRESSION OF THE PROTEIN — THE INVESTIGATION OF THE PROTEIN THE EXPRESSION OF THE PROTEIN. AND THIS MATERIAL WAS SHOWN TO HELP IN CELLS AND CYTOTOXICITY AND CREATE A RESPONSE. THEY USE THIS PLATFORM AGAINST HPV CANCERS OR IN COMBINATION WITH IMMUNOTHERAPY AND WITH OTHER THERAPIES. ONE OF THE WAYS OUR NANO PARTICLES WORK IS THE ABILITY TO TRAVEL FROM THE SYSTEM INTO THE LYMPH NODE AND THIS IS CONTROLLED. HERE YOU SEE AN EXAMPLE OF TE MATERIALS WITH TWO SIZES. PAR PA PARTICLES ARE SOMETIMES STAY AT THE SIGHT — SITE OF INJECTION. AND THIS BENEFITS EFFICACY BUT ALSO BENEFITS DELIVERY OF THE DRUGS AGAINST MICROBES SUCH AS VIRUSES OR BACTERIA. IT’S USED THERE. THIS IS AN EXAMPLE OF THE BENEFITS FOR IMAGE GUIDED AND THERE’S IMAGES FROM THE UNIVERSITY AND TECHNOLOGIES DEVELOPED. THEY USE TUMORS IN DYE. THIS IS WHAT THE CANCERS SEE IN PATIENTS WITH OVARIAN CANCER. SOME OF THE TUMORS AND SOME ARE LARGE ENOUGH SO IT CAN BE SEEN — [NO AUDIO] CANNOT BE SEEN BY THE NAKED EYE AND IF UNRECEPTIVE AFFECTS THE DISEASE. IT ACCUMULATES IN THE TUMOR CELLS AND DURING THE SURGERY THE TOMBERS ARE EXPOSED AND THE SURGEON CAN SEE ALL THE GREEN MASSES HERE REPRESENT CANCER OF CELLS. SOME ARE LARGE AND CAN BE SEEN BY NAKED EYE AND SOME ARE SMALL ENOUGH THEY WOULD MISS IT WITHOUT THE TECHNOLOGY. DESPITE ALL THE BENEFITS OF NANO TECHNOLOGY, ONE OF THE IMPORTANT POINT OF NANO PARTICLES THEY MAY ACCUMULATE IN DIFFERENT ORGANS. I’D LIKE TO USE THE EXAMPLE OF A SMALL MOLECULE THAT LEADS IN BONE MARROW AND HEART AND IT’S UNDESIRABLE TOXICITY AS A SIDE EFFECT FOR MYO EXPRESSION AND TARGET TOXICITY. THIS DRUG WAS PART OF THE TOXICITY WAS AVOIDED. HOWEVER, IT’S ACCUMULATED IN THE CELLS OF THE SKIN AND THIS RESULTS IN INFLAMMATORY RESPONSE WE SEE IN THE PICTURE AND THERE’S EFFORTS TO UNDERSTAND TO VOID BOTH TARGET TOXICITY AND SIDE EFFECT. SEVERAL ATTEMPTS HAVE BEEN MADE. I’M SHOWING ONE OF THE EXAMPLES. DOXIL WAS FORMULATED WITH NANO PORT — PARTICLES. THE SIZE OF THE TERMS ACCUMULATED IN THE KIDNEY AND THE TOXICITY OF THE DRUG DEPENDED DISTRIBUTION OF THE NANO PARTICLE OF THE AREA. NOW LET’S TALK ABOUT NANO PARTICLE INTERACTION WITH THE IMMUNE SYSTEM. BEFORE WE TALK ABOUT THE RECOGNITION OF THE SITE I’D LIKE TO TALK ABOUT TERMINOLOGY. THERE’S PRODUCT TREATED WITH SPECIFIC MOLECULES. THE IMMUNE SYSTEM CAN RECOGNIZE ENDOGENOUS MOLECULES PRODUCED BY THE CELLS AND THESE SUBSTANCES FOR A VARIETY OF RECEPTORS EXPRESSED IN THE IMMUNE CELLS, THE RECEPTORS ARE CALLED RECOGNITION RECEPTORS AND IN THE LITERATURE YOU MAY SEE ADDITIONAL TERMINOLOGY SUCH AS NANO PARTICLES AND OTHER PATTERNS. SO NANO PARTICLES COULD BE PERCEIVED AND THERE’S PROPERTIES THAT ARE DANGEROUS SUCH AS OTHER MATERIALS AND NANO PARTICLES THAT MAY CAUSE RELEASE OF PARTICLES. NANO PARTICLES CAN BE TARGETED WITH PATHOGEN ASSOCIATED PATTERNS AND YOU CAN USE IT TO BENEFIT THERAPY AND CAN ALSO POSE TOXICITY. THERE’S A BALANCE BETWEEN THE NANO MATERIALS WITHIN THE TOXIC EFFECTS AND BENEFICIAL EFFECTS. NANO PARTICLES MAY HAVE STRUCTURES AND THOSE ARE CONSIDERED DANGEROUS AND MAY CARRY PROTEINS AND MAY BE RECOGNIZED AS STRANGERS. NANO MATERIALS COULD BE ENGINEERED TO PROVIDE BENEFICIAL INTERACTIONS. THEY’RE USED TO IMPROVE THERAPY IN INFECTIOUS DISEASE AND THEY CAN ALSO CAUSE UNDESIRABLE EFFECT AND THERE’S PARTICLES AND HOUR THE NANO PARTICLES ARE ENGINEERED FOR APPLICATIONS AND THERE’S UNDESIRABLE SIDE EFFECT. WHAT NANO TECHNOLOGY WANTS TO CHIEF IS FOR THE PATIENT AND WE TRIED BY USING THE MATERIAL TO NOT CREATE ADDITIONAL TOXICITY FOR UNDESIRABLE SIDESQUES THROUGH THE INTER — SIDE EFFECTS THROUGH INTERACTION. THE NANO PARTICLES WITH THE IMMUNE SYSTEM DEPENDS ON THE PHYSICAL PROPERTIES. AND THERE’S WORK IN THE LITERATURE AND WE FOUND IT IN OUR LABORATORY I SUMMARIZED HERE. NANO PARTICLES INDUCE CYTOKINES AND THEY ARE INVOLVED IN CALCULATION AND IF SOME COMPONENT OF THE PARTICLE IS INVOLVED THEY CAN CAUSE A PROFILE AND THEY CAN LOOK AT THE INFLAMMATION AND WE’LL TALK ABOUT SOME MOL EC — MOLECULES IN THE NEXT COUPLE OF SLIDES. COMPONENTS OF THE NANO PARTICLES ARE RECOMBINANT AND THERE’S AN INVESTIGATION OF THE MATERIALS FOR CLINICAL TRIALS AND THEY MAY RESULT IN OTHER INFLAMMATORY REACTION IN THE MATERIAL COMPONENTS. NANO FORMULATIONS MAY CONTAIN MANY PARTICLES AND THEY INHIBIT PLASMA CALCULATION TIME. AND WE’LL TALK ABOUT THE REACTIONS OF ACTIVATION LATER IN THE PRESENTATION. PARTICLES WITH 300 NANOMETERS AND SOME HAVE A SIZE OF 200 AND DEPENDING ON THE COMPOSITION THEY MAY POSE INFLAMMATION AND MAY DAMAGE OTHER SITES. THE FORM LAYINGS INDUCE OXIDATIVE STRESS AND IN THE PROPERTY OF THESE MATERIALS HAVE ONE HERE. AND IT HELPS TO IMPROVE PROPERTIES OF NANO PARTICLES HOWEVER, IF IT’S UNSTABLE THE CELLS HAVE TOXICITY. AND THIS WAS SHOWN TO INDUCE CHROMOSOME ACTIVATION AND THE BIOMARKER IS CYTOKINE INTERLEUKIN AND I’D LIKE TO SHOW HOW THEY INTERACT WITH PROTEINS AND VARY BY DISTRIBUTION AND I’LL SHOW THE LEUKOCYTES AND WE’LL TALK ABOUT THE TWO UNDERLYING MECHANISMS OF CYTOKINES AND TALK ABOUT THE IMMUNOSUPPRESSIVE PROPERTIES. THEY ARE COMPOSED OF THE BLOOD CELLS AND PROTEINS AND PLASMA. AND THE INTERACTION BETWEEN THE PARTICLES IN THE PLASMA PROTEINS IS BIDIRECTIONAL PROTEINS. THEY MAY HAVE PROTEINS THAT CHANGE ACTIVITY AND AS A RESULT NEW EPI TOPES MAY BE EXPOSED WHICH WOULD OTHERWISE NOT BE EXPOSED THROUGH AIN’T ACTION THEN PARTICLE BINDS TO THE PROTEINS AND MAY HAVE TARGETED-
ACTION THEN PARTICLE BINDS TO THE PROTEINS AND MAY HAVE TARGETED-
ACTION THEN PARTICLE BINDS TO THE PROTEINS AND MAY HAVE TARGETED MATERIALS. AND PROTEINS MAY INFLUENCE PARTICLE DISTRIBUTION AND APPEARANCE THIS IS FROM THE COMPUTATIONAL STUDY AND IT STEM STRAITS THE NANO PARTICLES SHOWN HERE IN DIFFERENT SIZES AND TWO PLASMA PROTEINS AND PROTEINS SHOWN IN YELLOW AND TO THE INTERACTION DEPENDS ON THE PARTICLE SIZE. THIS IS THE DATA THE STUDY CONDUCTED IN OUR LAB THAT SHOWS HOW PROTEIN BINDING EFFECTS THE PARTICLE. AND BEFORE THE PLASMA PROTEINS IT’S MEASURED BUT THE PARTICLES WERE INTUBATED WITH PLASMA THEY HAD CHANGES TO 96 NANOMETERS AND THAT’S DUE TO THE FORMATION OF THE PROTEIN. THE REASON WHY THIS IS IMPORTANT IS BECAUSE OUR IMMUNE SYSTEM AND ALL THE CELLS RECOGNIZE THE PARTICLE NOT AS A MATERIAL WITH THE SIZE BUT AS A MATERIAL WITH THE SIZE OF 76 CENTIMETERS. AND HERE YOU SEE THE DISTRIBUTION. THIS IS PARTICLES AND THIS IS PARTICLES OF THE SAME SIZE BUT NOT THE SAME AND THEY HAVE PROTECTIVE PROTEINS WE CAN SEE THE PARTICLES ARE TAKEN UP BY MACROPHAGES AND ELIMINATED AND YOU CAN SEE THIS IS BECAUSE THE WHOLE PARTICLES AND THEY’RE ABROGATED AND AGGREGATE. THEY ARE NOT TAKEN UP BY MACROPHAGES AND NOT CLEARED EFFICIENTLY BY THE LIVER. THAT’S IN VIVO. THERE’S TWO THEORIES ABOUT NANO PARTICLE DISTRIBUTION AND THESE MODELS WERE PROPOSED FROM THE UNIVERSITY OF NORTH CAROLINA. THERE’S MODELS FOR CAPTURE AND THE OTHER IS DIFFERENT. AND THEY ARE TAKEN UP BY THE CELLS THAT PRESIDE IN THE ORGANS SUCH AS TUMOR-ASSOCIATED MACROPHAGES OR MACROPHAGES OF THE SPLEEN. ACCORDING TO TO THE MODEL THEY’RE TAKEN UP BY MONOCYTES AND THEY DELIVER THE MATERIALS TO TISSUES SUCH AS LIVER AND SPLEEN. THERE’S TWO TYPES OF MACROPHAGES BASED ON THE PHENOTYPE. THE CLASSIC MACROPHAGE IS EFFICIENT BUT THE MACROPHAGE AND DEBA DEBATING ON DIFFERENT MACROPHAGES THEY COULD BE IN TWO OR ONE MACROPHAGE. IN THE CANCER IMMUNOTHERAPY, THE IMMUNOSUPPRESSIVE ENVIRONMENT OF THE TUMOR IS CREATED BY M2 MACROPHAGES. AND THEY’RE USED TO CHANGE THE TUMOR ENVIRONMENT AND PROVIDE M2 TO M1 AND YOU SEE THE DATA FROM THE RECENT ARTICLE THAT SHOWS PARTICLES AND COMPOSITIONS AND THEY CAN IMPROVE MACROPHAGES. AND THIS IS INVOLVED WITH THOR EITHER — THESE CELLS AND WE USED THEM WITH DIFFERENT SITES. AND WE FOUND PARTICLES HAVE DIFFERENT IN SIZE AND THE SURFACE IS ALSO IMPORTANT BECAUSE HERE WE’RE USING NANO PARTICLES OF THE SAME SIZE. WE SEE THE DAMAGE WHILE WE LOOKED AT THESE. AND NANO PARTICLES WOULD BE ENGINEERED TO EITHER SPECIFICALLY INTERACTION WITH DIFFERENT SYSTEMS OR TO AVOID IT AND RESTORING AND MAINTAINING THE BALANCE IS IMPORTANT FOR MAINTAINING HEMOSTASIS. THERE’S TOXICITIES. AND THE PROFILE ACTIVATION RESULTS IN ACTIVITY AND YOU SEE THE PARTICLES. IT MAY ALSO BIND. AND THEY MAY INTERACT WITH PLATELETS AND/OR MAY INFLUENCE AGONIST INDUCED ACTIVATION AND MAY CAUSE INTERACTIONS. THEY ALSO HAVE EFFECTS ON ENDOU ENDOUGH — ENDOTHELIAL CELLS AND THE NEXT SLIDES WILL GIVE YOU SOME EXAMPLES. THESE ARE HUMAN PLATELETS AND THESE ARE HUMAN PLATELETS ACTIVATED WITH THIS. THEY GO ACROSS. WE ARE USING GENERATION FIVE WE SEE THEY HAVE THE MATERIALS IS A CONTROL. AND HOWEVER, WE START MASKING THE PARTICLE SURFACE AND WE INDUCE THE ABROGATION. AND HERE I’M SHOWING YOU RESULTS OF THE RESEARCH CONDUCTED AND WE USED TWO DIFFERENT GENERATION SMALL PARTICLE AND THE LARGER PARTICLES GENERATION 7. AND WE SEE THE LARGER PARTICLES ARE MORE REACTIVE THAN SMALLER PAR PARTICLES HOWEVER, IF WE COMPARE THE MATERIALS WE SEE THESE ARE LESS REACTIVE. THIS IS BECAUSE IT’S LESS THAN IN THE PANEL. NANO PARTICLES MAY INTERACT WITH THE CELLS AND IMPOSE CYTOTOXICITY OR MAY INTERACT BY ACTIVATING PLATELETS OR LEUKOCYTES AND ACTIVATE A COMPLIMENT THE CALCULATION SYSTEM. AND THEY OCCUR REGARDLESS WHETHER THEY’RE RELATED TO THE ENDOTHELIAL CELL DYSFUNCTION AND CAN RESULT IN CELL DEATH. COMPLIMENT SYSTEM. IT’S A GROUP OF PROTEINS PRODUCED BY THE LIVER AND PRESENT IN PLASMA. THERE’S AN EXCESSIVE COMPLEMENT PROTEINS AND THEY HAVE CELL RESPONSES AND THEY PROMOTE ACTIVATIONAL T CELLS AND IT’S IMPORTANT FOR CELL REMOVAL RESPONSE. THERE’S RECENT DATA THAT SUGGESTS BESIDES THE PLASMA COMPLIMENT PROTEINS ARE AFFECTED BY IMMUNE CELLS AND THE COMPLIMENT PARTICIPATES IN THE CELLS AND WE LOOK AT NANO MATERIALS IN RESEARCH FROM STUDIES FROM DIFFERENT RESEARCH LABS WORLDWIDE AND THIS IS UNLIARABLE BECAUSE IT’S ASSOCIATED WITH HYPERSENSITIVITY REACTION AND THEN THEY MAY BENEFIT EFFICACY. YOU SEE THERE’S NOTHING PARTICULARLY GOOD OR BAD I’M JUST PRESENTING THERE’S APPLICATIONS AND WITH RESEARCH THEY’RE TRYING TO ACHIEVE AND ENHANCE BENEFIT FROM THE POSITIVE EFFECTS OF THE MATERIALS AND MINIMIZE THE MATERIALS. LET’S LOOK AT CYTOKINE REDUCTION. AND NANO PART CALS HAVE THE ABILITY TO INTRODUCE CYTOKINES OR MAY EFFECT THEM AND IN THIS CASE I’M USING A PUB LISHGD STUDY THAT — PUBLISHED STUDY AND THEY USED THE PARTICLES AND USED MATERIALS AND THEY’RE DIFFERENT IN LEFT. AND IF THE CELLS ARE TREATED WITH LOW CONCENTRATION WE SEE A LOW LEVEL OF CYTOKINES. AND THEN THE TREATMENT IS COMBINED WITH TITANIUM OXIDE AND THERE’S NO DIFFERENCE FROM THE TEMPORAL CELL. HOWEVER, WHEN COMBINED WITH THE MATERIALS WE SEE THE INCREASE IN THE CYTOKINE AND IT’S UFT IN COMPARISON TO THE — USED IN COMPARISON. SO WHAT’S THE MECHANISM OF THIS ACTIVITY. THE MECHANISM IS VERY INTERESTING. AND YOU HAVE MATERIALS TAKEN UP BY THE CELLS FROM THE ENDO SOMAL USES AND THE EXCESS PROTEOMES AND THE RIBOSOME IS CONCENTRATED AND IT’S RESULTS IN THE INCREASE IN THE LYSOSOME SIZE AND IN THE OTHER MATERIALS THEY INCREASE IT AND THIS IS REQUIRED WHICH IS IMPORTANT IN MATURATION OF THE LEUKEN 1. AND THIS IS CREATED AND THERE ARE THERE’S A SIGNAL FOR POTENTIAL DNA INTRODUCTION OF GENE EXPRESSION IN CYTOKINES. LIPOSOMES ARE MADE OF DIFFERENT KINDS AND WE USE THEY USE CYTOKINES. AND WHILE THEY’RE NEEDED THEY HAVE EXCESSIVE SECRETION OF TNF AT THE SITE OF INJECTION AND THEREFORE SHOULD AB VOIDED. AND THE — BE AVOIDED AND THERE’S OXIDATIVE STRESS. AND LEUKOSOMES HOUR CAN INDUCE — HOWEVER, CAN INDUCE CYTOKINES AND THEY DO THIS WITHOUT INFLAMMATORY CYTOKINES AND THE LIPOSOMES ARE ALSO INCREASE PRODUCTION OF SOME TYPE OF CELLS AND NOW LET’S TALK ABOUT ANOTHER TYPE OF NANO PARTICLES. THEY’RE MADE OF MOSTLY ACIDS. AND TOGETHER THEY FORM NANO PARTICLES WITH DIFFERENT SHAPES AND SIZES. WE FOUND THESE NANO MATERIALS ARE VERY GOOD IN INDUCING TYPE 1 AND HERE WE SHOW FOR EXAMPLE NANO PARTICLES MADE OF RNA ARE INDUCERS AND NANO PARTICLES WITH THE SAME SIZE AND SHAPE MADE OF DNA AND MATERIALS ARE MORE POTENT THAN THE OTHER MATERIALS LIKE RNA RINGS WHICH ARE MORE POTENT THAN RNA FIBERS. THEY’RE MADE OF THE SAME TYPE OF MATERIAL JUST DIFFERENT SHAPE. AND THE SIZE IS ALSO CONTRIBUTING HOWEVER, THE DIFFERENCE BETWEEN CERTAIN SIZES ARE SHOWING INDUCIBLE LEVELS. AND WHAT IS THE MECHANISM UNDERLYING INDUCTION OF THIS ACID NANO PARTICLES. THIS MATERIAL IS INTERESTING. WE TAKE NORMAL BACTERIAL DNA THEN IT DOES NOT REQUIRE AN INDICATOR. IT CAN BE CAPTURED AND INTERNALIZED AND ACTIVATED AN IMMUNE RESPONSE. THESE NANO PARTICLES ARE INVISIBLE TO THE IMMUNE SYSTEM UNLESS THERE’S SOME INDICATOR. AND IN THIS EXAMPLE I’M USING THE COMPLEX MATERIALS THAT ARE INTERNALIZED AND THE RECEPTOR IS INVOLVED IN THIS INTERNALIZATION. WE CAN SUPPRESS THE MATERIALS WITH RECEPTORS AND THIS INHIBITION IS INVOLVED IN THE PROCESS AND THIS IS PRODUCTION BY THESE AND IT DECREASE THE UPTAKE OF THIS MATERIAL AND EXPRESS THE REPRESENTATION AND HERE WE SHOWED WE DO NOT HAVE A RESPONSE USED A REPORT IN THE CELL LINE AND WE SHOWED IN TLR7 THEY’RE RECOGNIZED. THIS IS ANOTHER INTERESTING FINDING LINKING THE PARTICLES TO THE ACIDS. SO WHY IS THIS IMPORTANT? SO IN THE PREVIOUS EXAMPLES WE SAW NANO PARTICLES DEPENDING ON THEIR SIZE MAY ACTIVATE CYTOKINES OR CONTRIBUTE TO THE CYTOKINE PRODUCTION IN OTHER MATERIALS. IF NANO PARTICLES INDUCE CYTOKINES IT MAY CONTRIBUTE TO THE INFLAMMATORY RESPONSES TO THE NANO TECHNOLOGY. HERE I’D LIKE TO REVIEW A CASE STUDY WHERE THE NUKE — NUCLEOTYPE WAS USED TO SHOW A RESPONSE. THESE COMPONENTS WERE COMBINED TOGETHER AND BOTH INTERFERON AND CYTOKINE PRODUCTION WAS USED. HERE THE DRUG INDUCES AND THE FINAL PRODUCT PRODUCES INTERFERON AND THE FINALLY PRODUCT INDUCES THE CYTOKINE AS WELL. SO WHY DO WE NEED TO KNOW ALL THIS, IT’S HAVE IMPORTANT TO INTEREST IMMUNOLOGICAL PROPERTIES AND IF THEY OVERLAP AND THEN WE NEED TO CONSIDER WHAT ARE THE APPLICATIONS OF THESE MATERIALS. IF THE FORMULATION IS INTENDED FOR SYSTEMIC DEMONSTRATION THEY MAY CREATE A SAFETY CONCERN. HOWEVER, IF THIS PROPERTIES ARE BENEFICIAL, IF THE FORMULATION IS COMBINED WITH THERAPIES AND VACCINES THEN IT IS OKAY TO PROCEED. THE TAKE HOME MESSAGE IS WE SHOULD USE OUR SIMULATIONS TO AVOID IN DESIRABLE ACTIVITY. I’D LIKE TO TALK ABOUT MORE COMPLEX INTERACTIONS IN TOXICITIES DUE TO THE NANO PARTICLES ABILITY TO ACTIVATE MULTIPLE MECHANISMS. AND INTERACTIONS. [AUDIO DIFFICULTIES] AND THERE’S THE ABILITY OF THE REACTION. IT’S MEDIATED AND IN THE CASE OF THE LIPOSOMES THE TRIGGER IS A COMPLIMENT TO THE ACTIVITY. [AUDIO DIFFICULTIES] AND INDUCTION OFCY CYTOKINES AND HERE YOU SEE THE COMPLEX INTERACTION WITHIN THE CELLS AND THE COMPLIMENTS. SO THE LIPOSOMES COMPLEMENT AND THERE’S THE IMMUNE CELLS. AS A RESULT THERE’S TOXICITY. HERE YOU SEE THE DATA FROM THE CLINIC STUDY SHOWING THE COMPLIMENT OF THE BLOOD OF PATIENTS 10 MINUTES OF THE COMPLEMENT. THEY WANTED TO OVERCOME THE LIPOSOMES AND IT STARTED WITH THE COLLABORATION AND THESE CYTOKINES ARE MORE POTENT. AND THERE IS NO DATA ABOUT THE NANO PARTICLE HYPERSENSITIVITY REACTION BUT THERE IS ONE REPORT ABOUT THE REACTION AND IT’S AN INTERESTING CASE A STUDENT WORKED IN THE LAB AND DISCOVERED THIS AND WAS ADMITTED TO THE HOSPITAL AND TREATED WITH STEROIDS AND RECOVERED AND CAME BACK TO WORK AND A FEW DAYS LATER HAD THE SAME SYMPTOMS. THEY TRIED TO INVESTIGATE BUT COULDN’T FIND ANY EXPLANATION. THE TREATMENT IS IMPORTANT. AND WHAT IS IMMUNOGENICITY IS COMPLETE AND IMMUNE RESPONSE WHICH COORDINATING WITH PRODUCTION OF IMMUNE RESPONSE AND IMMUNOGENICITY IS REFERRED AND ARE NANO PARTICLES ARE THEY — AND THERE’S LIPOSOMES AND ANTIBODIES TO THESE MATERIALS COULD BE UP TAKED. HOWEVER, ALL THE MANO MATERIALS APPROVED FOR CLINICAL USE, MOREOVER THERE’S DATA SHOWING I’VE SHOWN YOU SOME OF THOSE HERE. AND THERE’S NANO PARTICLES THAT WERE SHOWN TO CONTRIBUTE TO THE PROTEINS AND SILICON OIL. THESE MATERIALS ARE NOT ENGINEERED. THEY’RE ACCIDENTAL. SO THE TAKE HOME MESSAGE IS NANO PARTICLES CAN BE ENGINEERED BUT THIS ACCIDENTAL MATERIALS ARE NOT THE SAME. WE HAVE TO CONSIDER IT. AND POLY ETHYLENE GLYCOL IS USED FOR THE HYDRO PHILIC PROPERTIES AND PROTECT THEM. HOWEVER, STUDIES ARE REPORTED THERE’S INFUSION REACTIONS TO THIS. WE KNOW THE ANTIBODIES ARE PREDOMINANTLY FOUND IN FEMALES THAN MALES AND USED IN COSMETICS. AND HOWEVER, WE TRIED TO CALCULATE THE LEVEL OF THE ANTIBODIES WITH BIOLOGICAL RESPONSES THAT COMPLEMENT ACTIVATION. AND THEREFORE THE FUNCTION OF THE ANTIBODY STILL REQUIRES ADDITIONAL INVESTIGATION. SO FAR WE TALKED ABOUT IMMUNOSTIMULATIVE PROPERTIES BUT THEY COULD BE IMMUNOSUPPRESSIVE AND ANTI-INFLAMMATORY. THIS CAN BE MEDIATED WITH INTERACTION WITHIN THE PARTICLES AND CELLS AND USED TO GIVE YOU EXPRESSIVE DRUGS. AND I WOULD LIKE TO USE ONE EXAMPLE TO SHOW THAN — THE NANO MATERIALS AND THIS DECREASES ACTIVATION BY THE ANTIGENS AND THE MECHANISM THE CHANGE IN THE MITOCHONDRIAL FUNCTION. AND IF THIS HAPPENS IF THIS EXPOSURE INTO AN ANTIGEN THEN WE WOULD EXPECT A DECREASED RESPONSE TO IT AND IN FACT THERE ARE REPORTS IN THE LITERATURE DEMONSTRATING DECREASED RESPONSE TO AN ANTIGEN. HOWEVER, HERE WE DEMONSTRATED THE TREATMENT IS ALMOST AS EFFICIENT AS HYDRO CORTIZONE IN REDUCING DEVELOPMENT OF SKIN LESION IN THE MOUSE MODEL OF INFLAMMATO INFLAMMATORY CONDITIONS. AND IT DEPENDS WHETHER IT’S DESIRABLE OR UNDESIRABLE. PARTICLES CAN BE USED TO IMPROVE ORDER S AND IT CAN INFORM CREATION OF SAFE AND EFFECTIVE DRUG TECHNOLOGY. WE PROVIDE SCREENING AND USE OUR SAFE ESCAPE USING PHYSICAL METHODS AND WE’VE BEEN DOING IT SUCCESSFULLY THE LAST 15 YEARS. THIS IS OUR TEAM. I SHOWED SOME OF THE DATA IN MY PRESENTATION THEY GENERATED AND I’M ALSO THANKFUL TO MY COLLEAGUES AND ALUMNI AND THANK YOU VERY MUCH.>>ANY QUESTIONS? SO IF YOU USE BIODEGRADABLE NANO PARTICLES DO YOU GET AWAY WITH A LOT OF THE CYTOTOXICITY?>>GOOD QUESTION. SO BIODEGRADEABLE NANO PARTICLES IS MORE WELCOME IN MEDICAL APPLICATION BECAUSE THEY DO NOT ACCUMULATE. THEY DO THEIR JOB AND DEGRADE AND CLEAR. AND NON DEGRADABLE PART CALLED THEY CAN — PARTICLES THEY CAN DO THE WORK FOR A LONG PERIOD. SOME OF THE NON-BIODEGRADABLE MATERIALS HAVE NO TOXIC EFFECT AND EXPOSURE. SOME BIODEGRADABLE MATERIALS COULD BE CYTOTOXIC. IT DEPENDS ON THE PROPERTIES AND DRUGS THEY CARRY.>>THAT WILL DO IT. I’D LIKE TO THANK ALL THE SPEAKERS FOR THEIR EXCELLENT LECTURES AND THEY VOLUNTEERED THEIR TIME TO HELP EDUCATE THE NIH COMMUNITY AND THIS CONCLUDES THE TRACO LECTURES FOR 2019. THANK YOU.

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