1 00:00:06,158 --> 00:00:09,194 WE'RE ONLINE? OK 2 00:00:09,194 --> 00:00:13,031 SO THEN I CAN GREET EVERYONE WHO 3 00:00:13,031 --> 00:00:15,567 IS ONLINE AS WELL AS HERE FOR 4 00:00:15,567 --> 00:00:16,201 TODAY'S GRAND ROUNDS. 5 00:00:16,201 --> 00:00:18,170 I'M REALLY DELIGHTED TO BE HERE 6 00:00:18,170 --> 00:00:20,705 TO INTRODUCE OUR SPEAKER, 7 00:00:20,705 --> 00:00:22,874 MITCHELL HO. 8 00:00:22,874 --> 00:00:24,576 SO I'M SUSAN GOTTESMAN, CHIEF OF 9 00:00:24,576 --> 00:00:26,044 THE LABORATORY OF MOLECULAR 10 00:00:26,044 --> 00:00:29,548 BIOLOGY. 11 00:00:29,548 --> 00:00:31,750 IRA PASTAN WHO FORMED THE LAB 12 00:00:31,750 --> 00:00:33,151 AND HAS BEEN THE GUIDING FORCE 13 00:00:33,151 --> 00:00:35,454 BEHIND IT IS HERE WITH US AS 14 00:00:35,454 --> 00:00:37,322 WELL, AND MITCHELL FIRST CAME TO 15 00:00:37,322 --> 00:00:39,958 US TO WORK WITH -- SO A LITTLE 16 00:00:39,958 --> 00:00:40,826 ABOUT MITCHELL. 17 00:00:40,826 --> 00:00:42,227 HE DID HIS UNDERGRADUATE 18 00:00:42,227 --> 00:00:43,995 EDUCATION IN CHINA. 19 00:00:43,995 --> 00:00:45,630 HE CAME TO THE U.S. AS A 20 00:00:45,630 --> 00:00:46,531 POSTBAC, WHICH I DIDN'T KNOW 21 00:00:46,531 --> 00:00:51,102 UNTIL I READ YOUR CV, AT UCSF, 22 00:00:51,102 --> 00:00:53,271 SPENT SOME TIME IN CALIFORNIA AT 23 00:00:53,271 --> 00:00:56,241 SOME COMPANIES, AND THEN GOT HIS 24 00:00:56,241 --> 00:01:00,278 PH.D. IN IMMUNOLOGY AT ILLINOIS 25 00:01:00,278 --> 00:01:01,646 URBANA-CHAMPAIGN AND STARTED A 26 00:01:01,646 --> 00:01:03,882 POSTBAC WITH IRA IN THE 27 00:01:03,882 --> 00:01:05,116 LABORATORY OF MOLECULAR BIOLOGY, 28 00:01:05,116 --> 00:01:06,852 DID SOME BEAUTIFUL WORK, AND WE 29 00:01:06,852 --> 00:01:10,589 WERE ABLE TO DO A TENURE TRACK 30 00:01:10,589 --> 00:01:12,657 SEARCH AND FOUND MITCHELL IN 31 00:01:12,657 --> 00:01:15,293 2008, AND HE STARTED HIS OWN 32 00:01:15,293 --> 00:01:19,197 ANTIBODY THERAPY GROUP WITH LMB, 33 00:01:19,197 --> 00:01:20,866 HE'S SINCE A LONG TIME AGO NOW 34 00:01:20,866 --> 00:01:22,067 BEEN TENURED AND NOW IS DEPUTY 35 00:01:22,067 --> 00:01:23,168 CHIEF OF THE LABORATORY OF 36 00:01:23,168 --> 00:01:25,370 MOLECULAR BIOLOGY. 37 00:01:25,370 --> 00:01:27,739 IN ADDITION, A FEW YEARS AGO, HE 38 00:01:27,739 --> 00:01:30,609 STARTED THE ANTIBODY ENGINEERING 39 00:01:30,609 --> 00:01:32,010 PROGRAM, WHICH SOME OF YOU MAY 40 00:01:32,010 --> 00:01:34,746 HAVE TAKEN ADVANTAGE OF OVER THE 41 00:01:34,746 --> 00:01:36,715 YEARS, AND IS DIRECTOR OF THAT 42 00:01:36,715 --> 00:01:39,551 ALSO IN LMB. 43 00:01:39,551 --> 00:01:41,319 SO MITCHELL DOES A LOT OF THINGS 44 00:01:41,319 --> 00:01:42,854 AND HE DOES A LOT OF THEM WELL. 45 00:01:42,854 --> 00:01:46,558 HE'LL BE TELLING YOU ABOUT 46 00:01:46,558 --> 00:01:47,993 ASPECTS OF HIS RESEARCH IN A FEW 47 00:01:47,993 --> 00:01:49,194 MINUTES, BUT JUST A FEW OTHER 48 00:01:49,194 --> 00:01:50,495 THINGS, HE WAS THE LEAD 49 00:01:50,495 --> 00:01:53,565 INSTRUCTOR FOR THE FAES 50 00:01:53,565 --> 00:01:55,200 BIOCHEMISTRY COURSE FOR 14 51 00:01:55,200 --> 00:01:57,469 YEARS, AND NOW IS ON THE FAES 52 00:01:57,469 --> 00:01:57,903 BOARD OF DIRECTORS. 53 00:01:57,903 --> 00:02:00,338 I THINK THIS IS A PATTERN. 54 00:02:00,338 --> 00:02:02,541 HE GETS INVOLVED WITH THINGS, 55 00:02:02,541 --> 00:02:03,942 DOES THEM WELL AND THEN GETS 56 00:02:03,942 --> 00:02:04,943 DRAGGED INTO LEADERSHIP. 57 00:02:04,943 --> 00:02:09,447 SO HE'S ALSO DOING -- HE'S A 58 00:02:09,447 --> 00:02:10,248 LEADERSHIP IN THE ANTIBODY 59 00:02:10,248 --> 00:02:11,983 SOCIETY AND THE CHINESE ANTIBODY 60 00:02:11,983 --> 00:02:13,585 SOCIETY, HAS A NUMBER OF HONORS 61 00:02:13,585 --> 00:02:15,554 AND LOTS OF INVITATIONS AND WAS 62 00:02:15,554 --> 00:02:16,788 ELECTED AS A FELLOW IN THE 63 00:02:16,788 --> 00:02:17,556 AMERICAN INSTITUTE FOR MEDICAL 64 00:02:17,556 --> 00:02:24,396 AND BA BIOLOGICAL ENGINEERING IN 65 00:02:24,396 --> 00:02:25,096 2003? 66 00:02:25,096 --> 00:02:25,297 2023. 67 00:02:25,297 --> 00:02:27,032 I KNEW I TYPED IT WRONG. 68 00:02:27,032 --> 00:02:28,433 LAST YEAR. 69 00:02:28,433 --> 00:02:31,069 SO TODAY, HE'S GOING TO TELL YOU 70 00:02:31,069 --> 00:02:34,239 SOME ASPECT OF HIS VERY ACTIVE 71 00:02:34,239 --> 00:02:40,145 RESEARCH PROGRAM ABOUT GIEP GLIP 72 00:02:40,145 --> 00:02:42,881 CANS AS CANCER TARGETS FOR CAR-T 73 00:02:42,881 --> 00:02:43,648 IMMUNOTHERAPY, SO LOOKING 74 00:02:43,648 --> 00:02:44,115 FORWARD TO IT. 75 00:02:44,115 --> 00:02:49,854 [APPLAUSE] 76 00:02:49,854 --> 00:02:51,690 >> THANK YOU, SUSAN, FOR A VERY 77 00:02:51,690 --> 00:02:52,791 KIND INTRODUCTION. 78 00:02:52,791 --> 00:02:56,828 IT'S WONDERFUL TO SEE COLLEAGUES 79 00:02:56,828 --> 00:02:58,363 HERE. 80 00:02:58,363 --> 00:03:00,098 AS SUSAN INTRODUCED, I STARTED 81 00:03:00,098 --> 00:03:02,734 MY POSTDOC MORE THAN 20 YEARS 82 00:03:02,734 --> 00:03:08,440 AGO IN DR. IRA HAS TA PASTAN'S , 83 00:03:08,440 --> 00:03:11,376 GLAD THAT DR. PASTAN IS HERE 84 00:03:11,376 --> 00:03:12,811 TODAY, AND ACTUALLY JUST TO MAKE 85 00:03:12,811 --> 00:03:16,748 SURE I'M STILL DOING GOOD. 86 00:03:16,748 --> 00:03:18,817 OKAY. 87 00:03:18,817 --> 00:03:22,420 SO IN THE NEXT 40, 45 MINUTES, 88 00:03:22,420 --> 00:03:24,055 I'M GOING TO TALK ABOUT MY WORK 89 00:03:24,055 --> 00:03:27,158 ON THE GLYPICAN AS A CANCER 90 00:03:27,158 --> 00:03:27,525 TARGET. 91 00:03:27,525 --> 00:03:30,095 MANY OF YOU PROBABLY KNOW I'M 92 00:03:30,095 --> 00:03:33,031 WORKING ON GLYPICANS FOR A 93 00:03:33,031 --> 00:03:34,733 WHILE, WE STARTED CHEMISTRY, WE 94 00:03:34,733 --> 00:03:35,767 MADE ANTIBODIES, WE ACTUALLY 95 00:03:35,767 --> 00:03:39,270 TRIED TO DEVELOP A CELL THAT 96 00:03:39,270 --> 00:03:40,238 EVENTUALLY CAN BENEFIT PATIENTS 97 00:03:40,238 --> 00:03:41,773 AND IN RECENT YEARS, WE GET INTO 98 00:03:41,773 --> 00:03:45,410 THE FIELD OF CAR-T CELLS, TRY TO 99 00:03:45,410 --> 00:03:49,214 USE OUR ANTIBODY WE DEVELOPED TO 100 00:03:49,214 --> 00:03:50,649 MAKE CAR-T CELLS, HOPEFULLY WE 101 00:03:50,649 --> 00:03:52,817 CAN TREAT PATIENTS. 102 00:03:52,817 --> 00:03:55,553 IN FACT, WE HAVE ONE CLINICAL 103 00:03:55,553 --> 00:03:56,688 TRIAL ONGOING IN THE CLINICAL 104 00:03:56,688 --> 00:04:01,159 CENTER AND THREE UPCOMING NEXT 105 00:04:01,159 --> 00:04:03,228 YEAR, AND WE ARE VERY EXCITED. 106 00:04:03,228 --> 00:04:04,663 I THINK IT'S A GOOD TIME FOR ME 107 00:04:04,663 --> 00:04:05,864 TO SHARE SOME OF OUR WORK. 108 00:04:05,864 --> 00:04:08,600 THE WORK IS ABOUT 15 OR 16 109 00:04:08,600 --> 00:04:12,570 YEARS' WORK HERE WITH MY 110 00:04:12,570 --> 00:04:13,605 COLLEAGUES, AND WE'RE ALWAYS 111 00:04:13,605 --> 00:04:15,373 LOOKING FOR ADVICE AND 112 00:04:15,373 --> 00:04:18,710 COLLABORATIONS. 113 00:04:18,710 --> 00:04:22,113 SO THIS IS MY DISCLOSURE, JUST 114 00:04:22,113 --> 00:04:23,748 SIMPLY SAY I'M AN INVENTOR FOR 115 00:04:23,748 --> 00:04:26,418 MANY PATENTS THAT BELONG TO THE 116 00:04:26,418 --> 00:04:29,320 NIH ABOUT ANTIBODY THERAPIES. 117 00:04:29,320 --> 00:04:31,723 MY LAB FORTUNATELY GETS RESEARCH 118 00:04:31,723 --> 00:04:36,094 FUNDS OVER THE YEARS FROM -- AND 119 00:04:36,094 --> 00:04:36,661 PHARMACEUTICAL COMPANIES. 120 00:04:36,661 --> 00:04:37,996 THEY'RE NOT JUST PROVIDING 121 00:04:37,996 --> 00:04:40,699 USEFUL RESOURCE BUT ALSO EDUCATE 122 00:04:40,699 --> 00:04:43,668 US HOW TO MOVE FROM THE LAB TO 123 00:04:43,668 --> 00:04:45,303 THE CLINIC, ULTIMATELY BENEFIT 124 00:04:45,303 --> 00:04:48,173 THE PATIENTS. 125 00:04:48,173 --> 00:04:53,845 SO I WANT TO START MY TALK WITH 126 00:04:53,845 --> 00:04:56,247 AN OVERVIEW WHAT ANTIBODY CAN DO 127 00:04:56,247 --> 00:04:57,115 FOR CANCER THERAPY. 128 00:04:57,115 --> 00:04:59,517 SO ANTIBODY AS I SHOW HERE IN 129 00:04:59,517 --> 00:05:01,152 MOST RECENT REVIEW WE RAO 130 00:05:01,152 --> 00:05:04,322 WRITING, AND THAT IS IT'S A Y 131 00:05:04,322 --> 00:05:06,091 SHAPE OF PROTEINS AS SHOWN HERE. 132 00:05:06,091 --> 00:05:08,259 I DON'T HAVE POINTER BUT I TRY 133 00:05:08,259 --> 00:05:14,833 TO MAKE A DIGITAL POINTER. 134 00:05:14,833 --> 00:05:15,266 OKAY. 135 00:05:15,266 --> 00:05:19,104 SO THIS IS A Y SHAPE ANTIBODY, 136 00:05:19,104 --> 00:05:21,706 AND THE WAY ANTIBODY ATTACKS THE 137 00:05:21,706 --> 00:05:26,077 CANCER CELLS, THEY NORMALLY -- 138 00:05:26,077 --> 00:05:27,946 ADCC, ANTIBODY DEPENDENT 139 00:05:27,946 --> 00:05:29,948 CELLULAR TOXICITY, AND ENGAGE 140 00:05:29,948 --> 00:05:39,124 THE NK CELL MIKE PHAG MICROPHAGE 141 00:05:39,124 --> 00:05:39,758 ANTIBODY. 142 00:05:39,758 --> 00:05:43,595 CAN ALSO BLOCK THE CHECKPOINT, 143 00:05:43,595 --> 00:05:46,731 PD-1 -- INTERACTIONS. 144 00:05:46,731 --> 00:05:49,167 AND ANTIBODY COULD ACTUALLY 145 00:05:49,167 --> 00:05:50,401 ENGAGE THE T CELLS THAT'S 146 00:05:50,401 --> 00:05:51,369 RELATED TO WHAT I'M GOING TO 147 00:05:51,369 --> 00:05:53,004 TALK ABOUT, THEY ACTUALLY BRING 148 00:05:53,004 --> 00:05:55,874 THE T CELLS USING SO-CALLED -- 149 00:05:55,874 --> 00:05:57,308 ANTIBODY THE T-CELL ENGAGE TO 150 00:05:57,308 --> 00:06:00,211 HAVE ANOTHER ARM -- ON T CELLS, 151 00:06:00,211 --> 00:06:01,846 BRING THE T CELLS TO THE TUMORS, 152 00:06:01,846 --> 00:06:03,615 AND KILL IT. 153 00:06:03,615 --> 00:06:06,117 AND THE ANTIBODY COULD ALSO 154 00:06:06,117 --> 00:06:09,087 BRING OTHER IMMUNE CELLS LIKE NK 155 00:06:09,087 --> 00:06:10,388 CELLS, ATTACK TUMORS, BUT IN 156 00:06:10,388 --> 00:06:12,157 THIS CASE LIKE LUNG CANCER 157 00:06:12,157 --> 00:06:14,759 CELLS, THEY EXPRESS BOTH EGFR 158 00:06:14,759 --> 00:06:17,929 AND MET, SO ANTIBODY COULD HAVE 159 00:06:17,929 --> 00:06:20,131 BISPECIFIC TARGETED -- EGFR, 160 00:06:20,131 --> 00:06:22,634 BLOCK THE HGF BINDING AND EGF 161 00:06:22,634 --> 00:06:25,904 BINDING AND THE INHIBITOR CANCER 162 00:06:25,904 --> 00:06:26,471 SIGNALING ON THE OTHER HAND 163 00:06:26,471 --> 00:06:27,906 BRING THE NK CELLS TO THE TUMOR 164 00:06:27,906 --> 00:06:29,541 CELLS. 165 00:06:29,541 --> 00:06:32,043 AND THE OTHER THING THAT'S VERY 166 00:06:32,043 --> 00:06:33,244 INTERESTING AND STILL VERY 167 00:06:33,244 --> 00:06:35,146 ACTIVE FIELD IS THE ANTIBODY 168 00:06:35,146 --> 00:06:37,282 COULD BRING THE CYTOTOXIC DRUGS 169 00:06:37,282 --> 00:06:40,885 LIKE SMALL MOLECULES, ADC, AND 170 00:06:40,885 --> 00:06:44,622 IT CAN ALSO -- RADIO ISOTOPE, MY 171 00:06:44,622 --> 00:06:45,490 COLLABORATORS HERE, WE ARE 172 00:06:45,490 --> 00:06:46,491 WORKING ACTIVELY ON THIS, I 173 00:06:46,491 --> 00:06:47,792 DON'T HAVE TIME TO SHARE THE 174 00:06:47,792 --> 00:06:50,228 VERY BEAUTIFUL DATA WE HAVE NOW 175 00:06:50,228 --> 00:06:51,396 USING OUR ANTIBODY TO PUT THE 176 00:06:51,396 --> 00:06:52,831 RADIO ISOTOPE ON IT. 177 00:06:52,831 --> 00:06:55,767 AND THE OTHER THINGS, 178 00:06:55,767 --> 00:06:57,602 IMMUNOTOXIN BRING TO THE HOME, 179 00:06:57,602 --> 00:06:59,938 AND THAT IS DR. IRA PASTAN AND 180 00:06:59,938 --> 00:07:01,239 HIS TEAM IN LABORATORY OF 181 00:07:01,239 --> 00:07:03,341 MOLECULAR BIOLOGY OVER THE YEARS 182 00:07:03,341 --> 00:07:05,743 DEVELOPED AN IMMUNOTOXIN, AND 183 00:07:05,743 --> 00:07:07,579 THAT'S THE FIRST AND THE ONLY 184 00:07:07,579 --> 00:07:10,882 IMMUNOTOXIN APPROVED BY FDA 185 00:07:10,882 --> 00:07:13,051 TREATING -- LEUKEMIA, QUITE A 186 00:07:13,051 --> 00:07:20,258 MAZE HERE LEADING THE TRIALS. 187 00:07:20,258 --> 00:07:23,127 THEN WHEN WE LOOK AT THE CANCER 188 00:07:23,127 --> 00:07:26,831 FIELD, THESE ARE THE CANCER MOST 189 00:07:26,831 --> 00:07:29,200 FREQUENTLY KILLED PATIENTS IN 190 00:07:29,200 --> 00:07:30,668 THE UNITED STATES. 191 00:07:30,668 --> 00:07:32,971 NUMBER ONE IS LUNG CANCER 192 00:07:32,971 --> 00:07:35,840 FOLLOWED BY COLORECTAL CANCER, 193 00:07:35,840 --> 00:07:37,775 PANCREATIC CANCER, BREAST 194 00:07:37,775 --> 00:07:41,079 CANCER, PROSTATE, LIVER AND 195 00:07:41,079 --> 00:07:42,480 BILE -- THERE ARE REALLY NOT 196 00:07:42,480 --> 00:07:43,915 MANY TARGETS FOR THOSE TOP 197 00:07:43,915 --> 00:07:45,550 CANCERS. 198 00:07:45,550 --> 00:07:48,987 AND EVEN FOR LATE STAGE CLINICAL 199 00:07:48,987 --> 00:07:50,788 TRIALS, THERE ARE NOT MANY -- 200 00:07:50,788 --> 00:07:51,890 AVAILABLE FOR TREATING THOSE 201 00:07:51,890 --> 00:07:52,557 CANCERS. 202 00:07:52,557 --> 00:07:55,927 AND WHEN I STARTED MY CAREER 203 00:07:55,927 --> 00:07:59,764 HERE AND HAVE MY OWN LAB, I GET 204 00:07:59,764 --> 00:08:01,833 ADVICE SAYING WE SHOULD WORK ON 205 00:08:01,833 --> 00:08:03,268 LIVER CANCER BECAUSE THAT'S THE 206 00:08:03,268 --> 00:08:05,637 CANCER VERY POORLY UNDERSTOOD 207 00:08:05,637 --> 00:08:07,438 AND WE NEED THERAPY. 208 00:08:07,438 --> 00:08:10,475 SO THAT'S WHY I STARTED MY 209 00:08:10,475 --> 00:08:13,444 JOURNEY HERE, THE LAB WORKING ON 210 00:08:13,444 --> 00:08:15,947 THE GPC ON LIVER CANCER, THEN 211 00:08:15,947 --> 00:08:19,784 LATER ON IN MOST RECENT YEARS WE 212 00:08:19,784 --> 00:08:21,185 EXPRESS -- EXPAND OUR PROGRAM TO 213 00:08:21,185 --> 00:08:27,325 GAAP 2 IN NEED TRICK C PEDIATRID 214 00:08:27,325 --> 00:08:28,526 ALSO PANCREATIC CANCER SO I'M 215 00:08:28,526 --> 00:08:34,132 GOING TO TALK ABOUT THAT. 216 00:08:34,132 --> 00:08:35,900 SO CAR-T CELLS BASICALLY MEANS 217 00:08:35,900 --> 00:08:40,672 YOU HAVE TO REPROGRAM THE T 218 00:08:40,672 --> 00:08:42,974 CELLS, LEAD THE T CELLS TO THE 219 00:08:42,974 --> 00:08:44,442 TUMORS AND IT HAS TO RECOGNIZE 220 00:08:44,442 --> 00:08:46,678 THE TUMOR ENERGY. 221 00:08:46,678 --> 00:08:50,181 AS I SAID, TO BE ABLE TO CURE 222 00:08:50,181 --> 00:08:52,383 TUMOR CELLS, YOU REALLY NEED TO 223 00:08:52,383 --> 00:08:54,452 HAVE THE RIGHT ANTIGENS. 224 00:08:54,452 --> 00:08:56,854 AND WHEN CAR-T CELLS BE VERY 225 00:08:56,854 --> 00:09:00,458 SUCCESSFUL SO FAR TO KILL TUMOR 226 00:09:00,458 --> 00:09:03,528 CELLS, OUR NCI COLLEAGUE STEVE 227 00:09:03,528 --> 00:09:04,963 ROSENBERG, THEY ACTUALLY SHOWED 228 00:09:04,963 --> 00:09:07,231 THE CD19 CAR-T CELL COULD KILL 229 00:09:07,231 --> 00:09:09,434 THE LEUKEMIA CANCER CELLS, BUT 230 00:09:09,434 --> 00:09:11,302 WHEN YOU USE THE SAME APPROACH 231 00:09:11,302 --> 00:09:14,906 TO THE SOLID TUMOR, THEN WE ARE 232 00:09:14,906 --> 00:09:16,240 FACING MANY BARRIERS OF 233 00:09:16,240 --> 00:09:18,076 CHALLENGES HERE. 234 00:09:18,076 --> 00:09:19,444 SO THE CAR-T CELLS NEED TO GET 235 00:09:19,444 --> 00:09:21,713 INTO THE TUMOR MICROENVIRONMENT 236 00:09:21,713 --> 00:09:23,982 AND OVERCOME THE EXTRACELLULAR 237 00:09:23,982 --> 00:09:29,354 MATRIX, AND THEN HAS TO BE 238 00:09:29,354 --> 00:09:30,655 ENCOUNTERED WITH 239 00:09:30,655 --> 00:09:32,523 IMMUNOSUPPRESSIVE CELLS AND 240 00:09:32,523 --> 00:09:33,157 IMMUNOSUPPRESSIVE MOLECULES. 241 00:09:33,157 --> 00:09:36,027 AND IN THE END, WE REALLY NEED 242 00:09:36,027 --> 00:09:39,897 THE TUMOR ANTIGENS, AND EVEN 243 00:09:39,897 --> 00:09:41,699 FOR -- THOSE ARE HETEROGENEOUS 244 00:09:41,699 --> 00:09:43,034 MEANING THEIR EXPRESSION MAY BE 245 00:09:43,034 --> 00:09:44,235 VERY DIFFERENT FROM PATIENT TO 246 00:09:44,235 --> 00:09:46,070 PATIENT AND EVEN IN THE SAME 247 00:09:46,070 --> 00:09:47,605 PATIENT, FROM TUMOR CELLS TO THE 248 00:09:47,605 --> 00:09:50,141 OTHER TUMOR CELLS, THEY ARE VERY 249 00:09:50,141 --> 00:09:52,877 DIFFERENT. 250 00:09:52,877 --> 00:09:56,547 SO MY LAB HAS BEEN FOCUSED ON 251 00:09:56,547 --> 00:10:00,084 STUDIES OF GLYPICAN AS NEW 252 00:10:00,084 --> 00:10:00,618 TARGETS OVER THE YEARS. 253 00:10:00,618 --> 00:10:03,154 SO THERE ARE SIX MEMBERS IN THE 254 00:10:03,154 --> 00:10:03,688 GLYPICAN FAMILY. 255 00:10:03,688 --> 00:10:06,858 THEY ALL HAVE A CORE PROTEIN 256 00:10:06,858 --> 00:10:10,495 WITH THE HEPARAN -- THEY DISPLAY 257 00:10:10,495 --> 00:10:14,832 ON THE CELL SURFACE AS AT 258 00:10:14,832 --> 00:10:18,036 GLYCOLIPID, ALL OF THEM HAS 259 00:10:18,036 --> 00:10:20,738 THESE TWO -- THEY'RE CANONICAL, 260 00:10:20,738 --> 00:10:23,775 DOESN'T MATTER IN DROSOPHILA OR 261 00:10:23,775 --> 00:10:26,778 C. ELEGANS OR -- WHICH 262 00:10:26,778 --> 00:10:29,614 INDICATING THE EVOLUTIONARY 263 00:10:29,614 --> 00:10:30,648 SELECTION PRESSURE, THESE ARE 264 00:10:30,648 --> 00:10:32,784 IMPORTANT FOR THEIR FUNCTION. 265 00:10:32,784 --> 00:10:34,986 AND WE STARTED WITH AS I SAID 266 00:10:34,986 --> 00:10:37,321 THE GPC3 IN LIVER CANCER AND 267 00:10:37,321 --> 00:10:39,023 THEN WE GRADUALLY EXPAND OUR 268 00:10:39,023 --> 00:10:42,727 PROGRAM STARTING GPC -- WHERE WE 269 00:10:42,727 --> 00:10:52,904 STARTED GPC1 -- TO INDUCE WPT WT 270 00:10:52,904 --> 00:10:55,640 SIGNALING IN THE CANCER CELLS 271 00:10:55,640 --> 00:11:00,945 WHILE GPC 4, 5 AND 6 INHIBIT WNT 272 00:11:00,945 --> 00:11:01,446 SIGNALING SO OPPOSITE. 273 00:11:01,446 --> 00:11:05,817 SO THIS IS GPC3. 274 00:11:05,817 --> 00:11:12,490 AND WE STUDIED THE GPC3 WHEN -- 275 00:11:12,490 --> 00:11:18,396 SO WE STUDIED GPC3, WE FOCUS ON 276 00:11:18,396 --> 00:11:26,537 THE WNT FRIZZLED/GPC AS 277 00:11:26,537 --> 00:11:27,672 SIGNALING ACTIVATION COMPLEX ON 278 00:11:27,672 --> 00:11:32,276 THE CANCER CELL SURFACE. 279 00:11:32,276 --> 00:11:34,145 THERE'S QUITE CONFLICTING DATA 280 00:11:34,145 --> 00:11:36,214 FROM MY LAB AND OTHER LAB TO TRY 281 00:11:36,214 --> 00:11:42,787 TO UNDERSTAND HOW GPC3 -- WNT. 282 00:11:42,787 --> 00:11:44,255 WE NEED TO DO BIOCHEMISTRY. 283 00:11:44,255 --> 00:11:45,823 SO HERE IS THE MODEL WE HAVE. 284 00:11:45,823 --> 00:11:49,427 THE WNT ACTUALLY ATTRACTS THE 285 00:11:49,427 --> 00:11:56,567 GPC3 AS CON CONCENTRATEWITH FRL 286 00:11:56,567 --> 00:11:59,303 AND ULTIMATELY INDUCE THE BETA 287 00:11:59,303 --> 00:12:02,373 CAR-T SIGNALING AND UPREGULATE 288 00:12:02,373 --> 00:12:04,342 WNT TARGET GENES AND LEAD TO THE 289 00:12:04,342 --> 00:12:07,078 HCC LIVER CANCER CELL GROWTH. 290 00:12:07,078 --> 00:12:09,780 WHEN ONE OF MY FIRST POSTDOC 291 00:12:09,780 --> 00:12:11,782 CAME TO THE LAB, SHE WAS VERY 292 00:12:11,782 --> 00:12:13,117 INTERESTED IN CANCER SIGNALING. 293 00:12:13,117 --> 00:12:14,485 SO I SAID WELL, WHY DON'T YOU 294 00:12:14,485 --> 00:12:16,687 JUST TRY TO DO SOME BIOCHEMISTRY 295 00:12:16,687 --> 00:12:19,490 OF THE WNT AND THE GPC3 TO 296 00:12:19,490 --> 00:12:20,958 FIGURE OUT THE INTERACTION, AS I 297 00:12:20,958 --> 00:12:23,127 SAID FOR A WHILE, THIS KIND OF 298 00:12:23,127 --> 00:12:23,895 INTERACTION IS NOT CLEAR. 299 00:12:23,895 --> 00:12:25,796 SO THE BIOCHEMISTRY OF GPC3 IS 300 00:12:25,796 --> 00:12:26,531 NOT KNOWN. 301 00:12:26,531 --> 00:12:29,700 AND SO WE START TO MAP THE WNT 302 00:12:29,700 --> 00:12:33,804 BINDING DOMAIN ON THE GPC3 -- 303 00:12:33,804 --> 00:12:41,212 CHAIN AND LUCKILY WE HAVE A -- 304 00:12:41,212 --> 00:12:45,983 JIAN LIU -- WITH DEFINE THE 305 00:12:45,983 --> 00:12:46,751 RESIDUES. 306 00:12:46,751 --> 00:12:48,519 USING THOSE KIND OF TOOLS, WE 307 00:12:48,519 --> 00:12:50,688 SHOULD BE ABLE TO MAP THE -- 308 00:12:50,688 --> 00:12:53,124 EXACTLY THE BINDING MOTIF ON THE 309 00:12:53,124 --> 00:12:56,827 HEPARAN SULFATE GLYCATE CHAINS 310 00:12:56,827 --> 00:12:57,595 FOR THE WNT. 311 00:12:57,595 --> 00:12:59,363 THIS IS IMPORTANT FINDING 312 00:12:59,363 --> 00:13:00,531 BECAUSE IT DOES NOT SEEM LINE 313 00:13:00,531 --> 00:13:03,067 THE WNT BINDING TOTALLY RELIES 314 00:13:03,067 --> 00:13:03,834 ON THE NEGATIVE CHARGE BECAUSE 315 00:13:03,834 --> 00:13:07,772 WE HAVE MORE NEGATIVE CHARGES -- 316 00:13:07,772 --> 00:13:08,906 RESIDUES OR -- WOULD NOT DO THE 317 00:13:08,906 --> 00:13:10,841 WNT BINDING AND WOULD NOT 318 00:13:10,841 --> 00:13:11,809 FUNCTIONALLY INDUCE THE WNT 319 00:13:11,809 --> 00:13:12,376 SIGNALING. 320 00:13:12,376 --> 00:13:15,213 SO ULTIMATELY, YOU NEED A 321 00:13:15,213 --> 00:13:18,282 STRUCTURE OF MINIMUM SIX 322 00:13:18,282 --> 00:13:21,652 SACCHARIDE RESIDUES, YOU NEED A 323 00:13:21,652 --> 00:13:25,590 2-O AND 6-O SULFATIONS AND 324 00:13:25,590 --> 00:13:27,358 CONFIRM NATION -- NOT JUST 325 00:13:27,358 --> 00:13:30,061 NEGATIVE CHARGE AND KNEE 3-O 326 00:13:30,061 --> 00:13:31,195 SULFATION TO ENHANCE THE WNT 327 00:13:31,195 --> 00:13:31,929 SIGNALING. 328 00:13:31,929 --> 00:13:33,030 FURTHERMORE, WHEN WE LOOK AT THE 329 00:13:33,030 --> 00:13:38,169 WNT BINDING SIDE ON THE PROTEIN 330 00:13:38,169 --> 00:13:41,772 CORE AND ACTUALLY IT WAS WEI 331 00:13:41,772 --> 00:13:43,341 GAO'S IDEA, SHE CAME TO ME AND 332 00:13:43,341 --> 00:13:47,745 SAID HEY -- ON THE ENVELOPE OF 333 00:13:47,745 --> 00:13:48,679 GLYCAN 3 MIGHT BE INTERESTING TO 334 00:13:48,679 --> 00:13:51,182 LOOK BECAUSE IT'S SIMILAR LIKE A 335 00:13:51,182 --> 00:13:54,485 FRIZZ EL. 336 00:13:54,485 --> 00:14:00,291 SO I CONSULTED MY COLLEAGUE B.K. 337 00:14:00,291 --> 00:14:03,127 LEE AND B.K. ACTUALLY DESIGNED 338 00:14:03,127 --> 00:14:04,662 SUBMUTATION IN THIS REGION AND 339 00:14:04,662 --> 00:14:08,499 WEIGHTED ALL THE MUTATIONS. 340 00:14:08,499 --> 00:14:09,834 WE ALSO TESTED THE CELL IN A 341 00:14:09,834 --> 00:14:11,335 MOUSE MODEL, INDICATING, YES, 342 00:14:11,335 --> 00:14:13,371 THAT'S THE WNT BINDING SITE ON 343 00:14:13,371 --> 00:14:15,606 THE GPC3. 344 00:14:15,606 --> 00:14:17,908 AND MORE RECENTLY, BEFORE AND 345 00:14:17,908 --> 00:14:20,978 DURING THE PANDEMIC, I 346 00:14:20,978 --> 00:14:22,680 COLLABORATED WITH STANFORD TO 347 00:14:22,680 --> 00:14:26,784 TRY TO FIGURE OUT MORE ABOUT THE 348 00:14:26,784 --> 00:14:28,552 GLYPICAN, HOW GLYPICAN ACTIVATE 349 00:14:28,552 --> 00:14:29,186 WNT SIGNALING. 350 00:14:29,186 --> 00:14:31,022 SO THIS IS THE WNT WHERE IT'S 351 00:14:31,022 --> 00:14:34,325 NOT ACTIVATED. 352 00:14:34,325 --> 00:14:36,394 SO THERE'S NO GPC3 HERE. 353 00:14:36,394 --> 00:14:43,701 THERE'S A PROTEIN CALLED ZNRF3, 354 00:14:43,701 --> 00:14:47,872 RNF43, I USUALLY CALL IT ZNR, IT 355 00:14:47,872 --> 00:14:52,576 ACTUALLY DEGRADE FRIZZLE, IN LOW 356 00:14:52,576 --> 00:14:53,344 LEVELS. 357 00:14:53,344 --> 00:14:55,246 SO WHEN GLYPICAN COMES, THE 358 00:14:55,246 --> 00:14:56,847 GLYPICAN COULD BE ELEVATED IN 359 00:14:56,847 --> 00:15:02,520 THE CANCER LIKE IN LIVER CANCER, 360 00:15:02,520 --> 00:15:03,954 PROTEOGLYCAN IS A CORE RECEPTOR 361 00:15:03,954 --> 00:15:05,690 FOR HEPATITIS AND HEPATITIS B 362 00:15:05,690 --> 00:15:07,558 AND HEPATITIS C, EVEN IN THE 363 00:15:07,558 --> 00:15:10,428 COVID, THEY ARE ALSO CO-RECEPTOR 364 00:15:10,428 --> 00:15:12,496 AND ATTACHMENT FOR THE SARS COV. 365 00:15:12,496 --> 00:15:15,833 SO INCLUDING POTENTIALLY CHRONIC 366 00:15:15,833 --> 00:15:17,935 INFLAMMATION, AND THOSE 367 00:15:17,935 --> 00:15:19,470 RECEPTORS MAY BE ELEVATED IN THE 368 00:15:19,470 --> 00:15:21,772 LIVER CANCER, AND THEN ACTIVATE 369 00:15:21,772 --> 00:15:26,277 WNT SIGNALING BY INTACT WITH WNT 370 00:15:26,277 --> 00:15:28,346 AND FRIZZLE AS I JUST DESCRIBED, 371 00:15:28,346 --> 00:15:30,214 THEY HAVE VERY DEFINED 372 00:15:30,214 --> 00:15:31,182 BIOCHEMICAL INTERACTIONS. 373 00:15:31,182 --> 00:15:34,352 AND WHAT THE GLYPICAN COULD DO, 374 00:15:34,352 --> 00:15:37,755 SO I CALLED THE SECOND 375 00:15:37,755 --> 00:15:40,257 MECHANISM, ACTUALLY ANOTHER 376 00:15:40,257 --> 00:15:41,459 PROTEIN RELATIVELY NEW FOR THE 377 00:15:41,459 --> 00:15:46,630 WNT FIELD, AND IT SEEMS LIKE A 378 00:15:46,630 --> 00:15:49,900 BROAD CANONICAL RECEPTOR CALLED 379 00:15:49,900 --> 00:15:51,202 LGR456 TO THE CELL SURFACE AND 380 00:15:51,202 --> 00:15:53,704 THEY COULD ACTUALLY -- WITH THE 381 00:15:53,704 --> 00:15:58,442 ZNR PROTEIN AND CAUSE MAYBE ENDO 382 00:15:58,442 --> 00:16:00,511 CYTOSIS, SO THE FRIZZLE WILL NOT 383 00:16:00,511 --> 00:16:02,480 BE UBIQUITINNIZED ANYMORE. 384 00:16:02,480 --> 00:16:05,549 SO THAT WAY YOU CAN -- THE WNT 385 00:16:05,549 --> 00:16:05,850 SIGNALING. 386 00:16:05,850 --> 00:16:07,885 WHAT WE FIND HERE IS GLYPICAN 387 00:16:07,885 --> 00:16:09,687 COULD DO THE SAME THING, IT 388 00:16:09,687 --> 00:16:12,757 COULD BRING THE -- 40 TO THE 389 00:16:12,757 --> 00:16:13,958 CELL SURFACE. 390 00:16:13,958 --> 00:16:17,895 WE KNOCK OUT THE 456, COULD 391 00:16:17,895 --> 00:16:19,430 STILL BRING TO THE CELL SURFACE 392 00:16:19,430 --> 00:16:20,297 AND ACTIVATE WNT. 393 00:16:20,297 --> 00:16:21,599 MEANING THE GLYPICAN COULD DO 394 00:16:21,599 --> 00:16:22,066 BOTH THINGS. 395 00:16:22,066 --> 00:16:25,102 IT COULD ACTUALLY -- WNT, 396 00:16:25,102 --> 00:16:26,337 BROUGHT WNT TO THE CELL SURFACE 397 00:16:26,337 --> 00:16:28,639 WITH FRIZZLE TO ACTIVATE THE 398 00:16:28,639 --> 00:16:30,808 BETA CATENIN, IT COULD ALSO 399 00:16:30,808 --> 00:16:35,946 BRING THE R-SPONDIN TO THE CELL 400 00:16:35,946 --> 00:16:39,650 SURFACE AND UBIQUINATION BY R 401 00:16:39,650 --> 00:16:39,984 PROTEINS. 402 00:16:39,984 --> 00:16:42,720 SO BASED ON ALL THIS RESEARCH, 403 00:16:42,720 --> 00:16:44,922 WE THINK TARGETING WNT IS A 404 00:16:44,922 --> 00:16:47,525 REALLY GOOD IDEA BUT NOT 405 00:16:47,525 --> 00:16:49,627 SPECIFIC BECAUSE WNT AND FRIZZLE 406 00:16:49,627 --> 00:16:51,796 ALSO EXPRESS NORMAL TISSUES. 407 00:16:51,796 --> 00:16:53,764 AND INDEED ON A LOT OF LAB 408 00:16:53,764 --> 00:16:55,533 INCLUDING COMPANIES WORKING ON 409 00:16:55,533 --> 00:16:58,702 WNT AND FRIZZLE TRIED TO DEVELOP 410 00:16:58,702 --> 00:17:00,337 DRUGS BUT WE BELIEVE THE BETTER 411 00:17:00,337 --> 00:17:03,641 STRATEGY MAY BE JUST TARGET 412 00:17:03,641 --> 00:17:05,910 TARGETING -- GLYPICAN BECAUSE 413 00:17:05,910 --> 00:17:08,612 THEY ARE MORE TUMOR SPECIFIC 414 00:17:08,612 --> 00:17:09,680 ANTIGENS AND THE SAME COMPANY IN 415 00:17:09,680 --> 00:17:11,482 THE LAB ALSO TARGETED -- USING 416 00:17:11,482 --> 00:17:13,984 ANTIBODY BUT AGAIN IT ALSO CAN 417 00:17:13,984 --> 00:17:15,753 BE ON THE NORMAL TISSUES AND WE 418 00:17:15,753 --> 00:17:18,489 THINK GLYPICAN MIGHT BE A BETTER 419 00:17:18,489 --> 00:17:22,092 ANTIGEN. 420 00:17:22,092 --> 00:17:23,828 MANY YEARS AGO, WHEN I START TO 421 00:17:23,828 --> 00:17:27,031 MAKE GPC3 ANTIBODY, IT WAS VERY 422 00:17:27,031 --> 00:17:27,331 CHALLENGING. 423 00:17:27,331 --> 00:17:29,867 WE FAILED AT THREE -- NONE OF 424 00:17:29,867 --> 00:17:33,137 THEM WORKED, AND I JUST CAME 425 00:17:33,137 --> 00:17:34,872 BACK LAST WEEK, STILL SCIENTISTS 426 00:17:34,872 --> 00:17:36,874 CAME TO THE MEETING AND TOLD ME 427 00:17:36,874 --> 00:17:40,344 THEY TRIED TO MAKE ANTIGPC3 428 00:17:40,344 --> 00:17:42,680 ANTIBODY LIKE YP7 WE MADE, AND 429 00:17:42,680 --> 00:17:45,082 THEY EITHER FAILED OR THEY ONLY 430 00:17:45,082 --> 00:17:46,584 GET ANTIBODY WITH LOW AFFINITY. 431 00:17:46,584 --> 00:17:51,956 THE REASON IS THE GLYPICAN -- 432 00:17:51,956 --> 00:17:53,924 IT'S VERY HARD TO MAKE 433 00:17:53,924 --> 00:17:54,592 ANTIBODIES. 434 00:17:54,592 --> 00:17:56,861 THEY'RE EXPRESSED IN THE FETAL 435 00:17:56,861 --> 00:18:01,365 LIVER AND PLACENTA AND HIGH 436 00:18:01,365 --> 00:18:07,204 EXPRESSION OF -- THE WAY YOU 437 00:18:07,204 --> 00:18:12,643 MINIMIZE HCC, USING PEPTIDE WE 438 00:18:12,643 --> 00:18:14,078 SCREENED A LOT OF CELLS AND 439 00:18:14,078 --> 00:18:15,346 TISSUES AND MANY, MANY CLONES. 440 00:18:15,346 --> 00:18:17,548 TO DO THAT, REMEMBER WE HAVE A 441 00:18:17,548 --> 00:18:21,719 TH96 WELL FLOW CYTOMETRY IN THE 442 00:18:21,719 --> 00:18:24,221 LAB AND EACH PLATE, YOU HAVE TO 443 00:18:24,221 --> 00:18:24,655 RUN ONE HOUR. 444 00:18:24,655 --> 00:18:27,091 SO THAT MEANS MANY, MANY HOURS, 445 00:18:27,091 --> 00:18:32,530 WE STAYED OVERNIGHT TO SCREEN 446 00:18:32,530 --> 00:18:35,366 ALL THE CLONES AND TRY TO FIND A 447 00:18:35,366 --> 00:18:37,535 WP7. 448 00:18:37,535 --> 00:18:40,638 SO YEN PHUN GWAS A POSTBAC AT 449 00:18:40,638 --> 00:18:41,939 THAT TIME, DID ALL THIS WORK, 450 00:18:41,939 --> 00:18:43,807 SHE IS NOW AT HARVARD AS A 451 00:18:43,807 --> 00:18:45,543 RESIDENT AND DOING -- BEING A 452 00:18:45,543 --> 00:18:46,644 DOCTOR THERE IN THE SURGERY 453 00:18:46,644 --> 00:18:51,148 DEPARTMENT. 454 00:18:51,148 --> 00:18:58,222 SO NOW WE FIND Y 7 HAS NO BINDO 455 00:18:58,222 --> 00:19:00,658 BINDING ON ANY HUMAN O ORGAN AND 456 00:19:00,658 --> 00:19:05,029 THAT IS GREAT -- IN THE CART 457 00:19:05,029 --> 00:19:08,532 CELLS AT THE MOMENT. 458 00:19:08,532 --> 00:19:10,701 SO THEN IT COMES TO THE CAR-T. 459 00:19:10,701 --> 00:19:14,004 SO WE TRY TO MAKE CAR-T CELLS 460 00:19:14,004 --> 00:19:15,306 USING THE ANTIBODY WE DEVELOPED 461 00:19:15,306 --> 00:19:19,777 FOR THE GPC3. 462 00:19:19,777 --> 00:19:23,514 THEN A LOT OF PEOPLE CONFUSED 463 00:19:23,514 --> 00:19:26,684 WITH THEM BUT TO BE HONEST, BOTH 464 00:19:26,684 --> 00:19:29,954 LIs ARE REALLY IMPORTANT, THEY 465 00:19:29,954 --> 00:19:31,288 BOTH REALLY CONTRIBUTED EQUALLY 466 00:19:31,288 --> 00:19:33,357 TO MANY OF OUR PROJECTS. 467 00:19:33,357 --> 00:19:35,826 SO ACTUALLY WHEN DAN CAME TO THE 468 00:19:35,826 --> 00:19:40,364 LAB, SHE WAS A PH.D. STUDENT 469 00:19:40,364 --> 00:19:41,565 FROM PROGRAM FROM CHINA AND 470 00:19:41,565 --> 00:19:44,602 DECIDED TO STAY AS A POSTDOC, 471 00:19:44,602 --> 00:19:46,370 SHE JUST GOT OUTSTANDING AWARD 472 00:19:46,370 --> 00:19:48,639 YESTERDAY AND GAVE KEYNOTE IN 473 00:19:48,639 --> 00:19:50,474 THE FELLOW RETREAT. 474 00:19:50,474 --> 00:19:52,376 AND NAN CAME AS A POSTDOC IN THE 475 00:19:52,376 --> 00:19:54,144 LAB, AND EVENTUALLY PROMOTED AS 476 00:19:54,144 --> 00:19:56,180 A STAFF SCIENTIST BY DOING CAR-T 477 00:19:56,180 --> 00:19:58,415 CELLS AND LAST YEAR, SHE LEFT 478 00:19:58,415 --> 00:20:03,087 AND NOW LEADING CAR-T -- 479 00:20:03,087 --> 00:20:05,623 ALLOGENIC CAR-T ENGINEERING 480 00:20:05,623 --> 00:20:06,924 PROGRAM IN ASTRAZENECA. 481 00:20:06,924 --> 00:20:08,559 SO BOTH OF THEM ARE DOING 482 00:20:08,559 --> 00:20:09,760 IMPORTANT WORK HERE. 483 00:20:09,760 --> 00:20:13,063 SO WE ACTUALLY PUT THE ANTIBODY 484 00:20:13,063 --> 00:20:16,333 SINGLE CHAIN -- FUSED WITH CD8H 485 00:20:16,333 --> 00:20:20,371 AND THE H-1BB CD3 AS A CAR AND 486 00:20:20,371 --> 00:20:23,540 WE PUT HEGFR TRUNK BECAUSE WE 487 00:20:23,540 --> 00:20:25,209 WANT TO REMOVE IT, WE PUT OFF 488 00:20:25,209 --> 00:20:30,648 SWITCH ON IT SO IT CAN BE REM 489 00:20:30,648 --> 00:20:31,015 REMOVED. 490 00:20:31,015 --> 00:20:32,950 WE DON'T WANT TO GO VERY DETAIL 491 00:20:32,950 --> 00:20:37,354 BUT WE ACTUALLY COMPARE THE TWO 492 00:20:37,354 --> 00:20:41,525 ANTIBODY, ONE BIND -- TERMINAL, 493 00:20:41,525 --> 00:20:44,228 ONE THE C TERMINAL AND WE FIND 494 00:20:44,228 --> 00:20:46,730 THE ONE CAR-T DERIVED FROM THE 495 00:20:46,730 --> 00:20:48,699 HUMANIZED YP7 CLOSE TO THE 496 00:20:48,699 --> 00:20:50,801 MEMBRANE IS THE MOST POTENT AND 497 00:20:50,801 --> 00:20:53,070 ON DOSE DEPENDENT YOU CAN SEE 498 00:20:53,070 --> 00:20:53,837 IT'S ACTUALLY VERY EFFECTIVE 499 00:20:53,837 --> 00:20:57,474 WHEN IT'S A HIGH DOSE, ALL THE 500 00:20:57,474 --> 00:20:59,109 MICE RECOVER, WERE TUMOR-FREE. 501 00:20:59,109 --> 00:21:01,512 BUT WE ACTUALLY LIKE -- IT'S A 502 00:21:01,512 --> 00:21:02,479 SINGLE DOMAIN BODY. 503 00:21:02,479 --> 00:21:03,714 I'M GOING TO TALK ABOUT IT WHEN 504 00:21:03,714 --> 00:21:05,683 I MATCH THE GPC1 PROJECT. 505 00:21:05,683 --> 00:21:08,085 AND WE REALLY WANT TO -- 506 00:21:08,085 --> 00:21:10,054 EVENTUALLY WE THINK MAYBE WE CAN 507 00:21:10,054 --> 00:21:11,588 OPTIMIZE CAR-T CELL IN 508 00:21:11,588 --> 00:21:14,058 PARTICULAR FOR NANOBODY, BECAUSE 509 00:21:14,058 --> 00:21:19,697 THE CURRENT FORMAT CAR-T DOES 510 00:21:19,697 --> 00:21:20,964 NOT SEEM COMPATIBLE WITH 511 00:21:20,964 --> 00:21:22,866 ANTIBODY SO WE NEED TO DO MORE 512 00:21:22,866 --> 00:21:24,601 ENGINEERING TO MAKE IT WORK, TO 513 00:21:24,601 --> 00:21:26,870 FORM -- USING NANOBODY WITH 514 00:21:26,870 --> 00:21:27,204 CAR-T CELLS. 515 00:21:27,204 --> 00:21:29,339 BUT BECAUSE OF THIS WORK, WE ARE 516 00:21:29,339 --> 00:21:33,544 NOW RUNNING A CLINICAL TRIAL AT 517 00:21:33,544 --> 00:21:35,746 THE NIH. 518 00:21:35,746 --> 00:21:38,816 I THINK HE'S NOW IN LIVER CANCER 519 00:21:38,816 --> 00:21:40,784 MEETING AT SALT LAKE CITY, AND 520 00:21:40,784 --> 00:21:42,519 HE HAPPILY SHARED ME SOME OF THE 521 00:21:42,519 --> 00:21:45,689 MOST UPDATED CLINICAL DATA AND 522 00:21:45,689 --> 00:21:47,024 SO THE TRIAL IS STILL GOING ON. 523 00:21:47,024 --> 00:21:50,728 WE ARE ON THE SECOND DOSAGE, AND 524 00:21:50,728 --> 00:21:55,432 WE ALREADY PASS THE FIRST DOS 525 00:21:55,432 --> 00:21:56,967 DOSAGE, SECOND DOSAGE OF THE 526 00:21:56,967 --> 00:21:58,268 TRIAL SO WE'RE RECRUITING 527 00:21:58,268 --> 00:22:02,206 PATIENTS. 528 00:22:02,206 --> 00:22:03,907 AND AS A MOLECULAR BIOLOGIST, I 529 00:22:03,907 --> 00:22:05,809 ALWAYS WANT TO KNOW WHY, THE 530 00:22:05,809 --> 00:22:07,444 MECHANISMS, AND WHY CAR-T CELLS 531 00:22:07,444 --> 00:22:09,847 COULD WORK, SO WE ACTUALLY 532 00:22:09,847 --> 00:22:10,948 ISOLATED SINGLE CAR-T CELLS FROM 533 00:22:10,948 --> 00:22:12,583 MICE AND TRY TO STUDY THEM. 534 00:22:12,583 --> 00:22:14,918 SO ONE WAY WE DO IT, WE ACTUALLY 535 00:22:14,918 --> 00:22:17,521 ISOLATE CAR-T CELL FROM SPLEEN 536 00:22:17,521 --> 00:22:18,822 OR FROM THE MOUSE BLOOD AND 537 00:22:18,822 --> 00:22:20,624 EVENTUALLY IN THE PATIENTS, WE 538 00:22:20,624 --> 00:22:22,993 CAN COLLECT THE BLOOD FROM THE 539 00:22:22,993 --> 00:22:26,363 PATIENTS IN THE CLINICAL TRIAL. 540 00:22:26,363 --> 00:22:28,031 SO WE CO-CULTURE WITH TUMOR 541 00:22:28,031 --> 00:22:31,068 CELLS AND ANALYZE THEM. 542 00:22:31,068 --> 00:22:35,038 WE ANALYZE -- IT'S LIKE A 543 00:22:35,038 --> 00:22:43,113 NANOFNANOFLUIDIC CHAMBER, WE HA5 544 00:22:43,113 --> 00:22:44,548 CHEMOKINE CYTOKINE WHICH LISTED 545 00:22:44,548 --> 00:22:46,850 VERY SMALL HERE, SORRY FOR THAT, 546 00:22:46,850 --> 00:22:48,585 ALL THE CYTOKINE, CHEMOKINE AND 547 00:22:48,585 --> 00:22:50,120 WE CAN TRACK THEM AND WE CAN 548 00:22:50,120 --> 00:22:53,056 ANALYZE FROM EACH SINGLE CAR-T 549 00:22:53,056 --> 00:22:56,026 CELLS, WHAT CYTOKINE, CHEMOKINE, 550 00:22:56,026 --> 00:22:57,561 CYTOTOXIC EFFECT RELEASED 551 00:22:57,561 --> 00:22:57,995 SIMULTANEOUSLY. 552 00:22:57,995 --> 00:23:01,598 AND IN THIS MICROFLUIDIC 553 00:23:01,598 --> 00:23:03,567 CHAMBERS. 554 00:23:03,567 --> 00:23:07,504 TOTAL 500 -- CAR-T CELLS SO BY 555 00:23:07,504 --> 00:23:09,706 DOING THAT, WE ACTUALLY FIND -- 556 00:23:09,706 --> 00:23:10,474 LITTLE SURPRISING AT THAT TIME 557 00:23:10,474 --> 00:23:12,342 IS, WHEN WE CO-CULTURED WITH 558 00:23:12,342 --> 00:23:14,511 TUMOR CELLS OR KNOCKOUT CELLS 559 00:23:14,511 --> 00:23:17,915 OBVIOUSLY, THE CAR-T CELLS WILL 560 00:23:17,915 --> 00:23:19,383 RECOVER THE -- MICE. 561 00:23:19,383 --> 00:23:23,587 THOSE MUSE TREATED WITH CAR-T TE 562 00:23:23,587 --> 00:23:24,855 TREATED WITH CAR-T CELLS FOR 563 00:23:24,855 --> 00:23:27,191 MANY, MANY WEEKS, THEY ARE STILL 564 00:23:27,191 --> 00:23:29,827 SPECIFIC FOR THE ANTIGEN. 565 00:23:29,827 --> 00:23:31,895 SO IF IN CO-CULTURE WITH THE 566 00:23:31,895 --> 00:23:32,996 ANTIGEN POSITIVE TUMOR CELLS, 567 00:23:32,996 --> 00:23:34,398 YOU CAN SEE THEY RELEASE A LOT 568 00:23:34,398 --> 00:23:38,335 OF CYTOKINE OR CYTOTOXIC 569 00:23:38,335 --> 00:23:39,870 FACTORS, BUT IF YOU CO-CULTURE 570 00:23:39,870 --> 00:23:42,506 WITH KNOCKOUT TUMOR CELLS, THE 571 00:23:42,506 --> 00:23:44,374 SAME TUMOR CELLS, JUST KNOCK OUT 572 00:23:44,374 --> 00:23:46,977 THE GPC3, YOU HAVE MUCH LESS. 573 00:23:46,977 --> 00:23:48,412 SO THEY'RE PERSISTENT, THEY ARE 574 00:23:48,412 --> 00:23:51,715 IN MICE FOR MANY WEEKS, AND THEY 575 00:23:51,715 --> 00:23:54,518 ARE -- BUT VERY FEW CAR-T CELLS. 576 00:23:54,518 --> 00:23:56,687 ONLY .5 TO 1%. 577 00:23:56,687 --> 00:23:57,855 WE CALL IT POLYFUNCTIONAL 578 00:23:57,855 --> 00:24:00,757 BECAUSE THEY CAN PRODUCE -- 579 00:24:00,757 --> 00:24:04,061 GAMMA INTERFERON -- SO THAT'S A 580 00:24:04,061 --> 00:24:06,496 LITTLE SURPRISING TO US BUT IN 581 00:24:06,496 --> 00:24:07,998 THE BEGINNING WE THOUGHT MAYBE 582 00:24:07,998 --> 00:24:09,766 EVEN MORE THAN THAT, MAYBE 5%, 583 00:24:09,766 --> 00:24:11,168 10% BUT ACTUALLY IT'S ONLY LESS 584 00:24:11,168 --> 00:24:12,002 THAN 1%. 585 00:24:12,002 --> 00:24:14,771 WHEN WE LOOK AT THE CAR-T CELLS, 586 00:24:14,771 --> 00:24:16,540 WE ACTUALLY LOOKED IN THE 587 00:24:16,540 --> 00:24:17,941 CLINICAL, WE FIND THIS NUMBER IS 588 00:24:17,941 --> 00:24:20,911 QUITE RIGHT FOR MOST OF THE 589 00:24:20,911 --> 00:24:22,012 CAR-T CELLS. 590 00:24:22,012 --> 00:24:24,948 SO WHEN WE LOOK AT THE GENOME, 591 00:24:24,948 --> 00:24:26,783 THE PHENOTYPE WE WANT TO LOOK AT 592 00:24:26,783 --> 00:24:27,484 THE GENOME TYPE. 593 00:24:27,484 --> 00:24:29,419 WE WANT TO SEE WHAT ARE THESE 594 00:24:29,419 --> 00:24:32,055 CAR-T CELLS, WHERE THE TRANS 595 00:24:32,055 --> 00:24:35,659 GENE GOES -- NORMALLY LAB USE TO 596 00:24:35,659 --> 00:24:37,961 SEQUENCE THE HIV VIRUS IN THE 597 00:24:37,961 --> 00:24:38,629 T-CELL GENOME. 598 00:24:38,629 --> 00:24:44,701 SO WE ACTUALLY PARTICULARLY 599 00:24:44,701 --> 00:24:46,703 INTEGRATION SITE IN THE T-CELL 600 00:24:46,703 --> 00:24:47,037 GENOME. 601 00:24:47,037 --> 00:24:49,106 WHEN WE LOOK AT THAT, WE FIND IN 602 00:24:49,106 --> 00:24:50,641 MULTIPLE MICE AFTER TREATMENT, 603 00:24:50,641 --> 00:24:52,342 LIKE THREE WEEKS, FIVE WEEKS OR 604 00:24:52,342 --> 00:24:53,810 SIX WEEKS IN DIFFERENT MICE, WE 605 00:24:53,810 --> 00:24:57,547 CAN SEE CLEARLY THEY CAN'T GO TO 606 00:24:57,547 --> 00:24:59,950 SO-CALLED HOT SPOT IN THE T-CELL 607 00:24:59,950 --> 00:25:00,284 GENOME. 608 00:25:00,284 --> 00:25:02,152 SO BEFORE THE TREATMENT, CAR 609 00:25:02,152 --> 00:25:03,153 COULD GO TO ANYWHERE IN THE 610 00:25:03,153 --> 00:25:03,587 GENOME. 611 00:25:03,587 --> 00:25:06,056 SO WE ACTUALLY SEE IT FROM THE 612 00:25:06,056 --> 00:25:08,058 CHROMOSOME 1 TO 22 AND THEN YOU 613 00:25:08,058 --> 00:25:09,559 SEE THE X CHROMOSOME. 614 00:25:09,559 --> 00:25:12,095 JUST NOT MANY IN THE Y 615 00:25:12,095 --> 00:25:13,163 CHROMOSOME BECAUSE Y CHROMOSOME 616 00:25:13,163 --> 00:25:16,900 IS VERY, VERY SMALL, AND 617 00:25:16,900 --> 00:25:18,335 ESPECIALLY -- IT'S -- YOU WILL 618 00:25:18,335 --> 00:25:20,737 LESS FREQUENTLY SEE THE CAR IN A 619 00:25:20,737 --> 00:25:21,538 Y CHROMOSOME BUT OTHER THAN 620 00:25:21,538 --> 00:25:22,873 THAT, YOU SEE IT EVERYWHERE. 621 00:25:22,873 --> 00:25:24,107 BUT THEN YOU'RE SELECTING THE 622 00:25:24,107 --> 00:25:25,442 MICE UNDER THE SELECTION 623 00:25:25,442 --> 00:25:27,277 PRESSURE FOR MANY WEEKS AND YOU 624 00:25:27,277 --> 00:25:29,646 RECOVER THOSE CAR-T CELLS, YOU 625 00:25:29,646 --> 00:25:31,548 RUN THE SINGLE CELL AND THEN 626 00:25:31,548 --> 00:25:33,517 SEND YOU TO THE GENOME SEQUENCE, 627 00:25:33,517 --> 00:25:38,789 YOU COULD FIND THAT THOSE 628 00:25:38,789 --> 00:25:40,958 GENES -- NUPL1 IS PROBABLY 629 00:25:40,958 --> 00:25:42,292 RELATED TO T-CELL SURVIVAL AND 630 00:25:42,292 --> 00:25:44,795 THEY ACTUALLY FREQUENTLY HAVE 631 00:25:44,795 --> 00:25:46,096 CAR INTEGRATED INTO THAT GENE 632 00:25:46,096 --> 00:25:47,397 AND SURVIVE AND BE VERY ACTIVE 633 00:25:47,397 --> 00:25:48,865 FOR MANY WEEKS. 634 00:25:48,865 --> 00:25:50,267 AND NOT ONLY FOR ONE SIDE, IT 635 00:25:50,267 --> 00:25:51,601 COULD BE MORE THAN ONE SIDE, IN 636 00:25:51,601 --> 00:25:53,203 THE SAME DIRECTION, MEANING THE 637 00:25:53,203 --> 00:25:54,104 SELECTION PRESSURE IS PRETTY 638 00:25:54,104 --> 00:25:58,342 HIGH. 639 00:25:58,342 --> 00:26:00,544 SO THAT'S KIND OF INTERESTING. 640 00:26:00,544 --> 00:26:02,846 WE KIND OF HYPOTHESIZED WE 641 00:26:02,846 --> 00:26:04,147 PROBABLY JUST NEED A FEW 642 00:26:04,147 --> 00:26:06,083 FUNCTIONAL CAR-T CELLS TO EXPAND 643 00:26:06,083 --> 00:26:08,418 AND KILL TUMOR CELLS IN MICE OR 644 00:26:08,418 --> 00:26:11,922 EVEN IN HUMANS. 645 00:26:11,922 --> 00:26:14,224 TO GO TO THE EXTREME WE PROBABLY 646 00:26:14,224 --> 00:26:15,425 NEED ONE CAR-T CELL TO BE ABLE 647 00:26:15,425 --> 00:26:16,059 TO WORK. 648 00:26:16,059 --> 00:26:16,960 SO THAT'S THE GOAL. 649 00:26:16,960 --> 00:26:19,029 SO MAYBE WE CAN ENGINEER JUST 650 00:26:19,029 --> 00:26:21,198 ONE CAR-T CELL TO MAKE IT 651 00:26:21,198 --> 00:26:22,532 POLYFUNCTIONAL AND PERSISTENT 652 00:26:22,532 --> 00:26:27,237 INSTEAD OF A POOL OF CAR-T 653 00:26:27,237 --> 00:26:27,671 CELLS. 654 00:26:27,671 --> 00:26:30,607 SO BESIDES THIS, WE ALSO DO 655 00:26:30,607 --> 00:26:32,476 SINGLE CELL RNA SEQ, WE SEPARATE 656 00:26:32,476 --> 00:26:34,378 THE HIGH AND LOW POLYFUNCTIONAL 657 00:26:34,378 --> 00:26:37,280 CAR-T CELLS, SO WE SEQUENCE A 658 00:26:37,280 --> 00:26:42,085 SUBSET OF HIGH POLYFUNCTIONAL 659 00:26:42,085 --> 00:26:43,754 CAR-T CELL AND LOW BASED ON THE 660 00:26:43,754 --> 00:26:45,489 PHENOTYPE I JUST DESCRIBED, THE 661 00:26:45,489 --> 00:26:47,357 CYTOKINE AND CHEMOKINE RELEASE. 662 00:26:47,357 --> 00:26:52,162 AND THEN -- SO THOSE ARE THE 663 00:26:52,162 --> 00:26:54,564 CYTOKINE, CHEMOKINE FACTOR WE 664 00:26:54,564 --> 00:26:56,099 USE TO SEPARATE THEM, THE HIGH 665 00:26:56,099 --> 00:26:58,502 OR LOW CAR-T CELLS, AND THEN WE 666 00:26:58,502 --> 00:27:00,704 DO THE SINGLE CELL RNA SEQ SO 667 00:27:00,704 --> 00:27:03,440 ALL OF THEM, AND THEN WE LIST 668 00:27:03,440 --> 00:27:04,741 ALL OF THE GENES THAT MAY BE 669 00:27:04,741 --> 00:27:07,144 RELATED TO THE HIGH AND THE LOW 670 00:27:07,144 --> 00:27:07,811 POLYFUNCTIONAL CAR-T CELLS. 671 00:27:07,811 --> 00:27:09,880 SO I THINK WHEN WE'RE DOING 672 00:27:09,880 --> 00:27:11,748 THAT, WE'RE KEEPING IN MIND 673 00:27:11,748 --> 00:27:13,617 MAYBE ONE DAY WE CAN BUILD A 674 00:27:13,617 --> 00:27:15,252 POLYFUNCTIONAL CAR-T CELLS, THEY 675 00:27:15,252 --> 00:27:17,654 ARE ALLOGENIC, AND THEY ARE -- 676 00:27:17,654 --> 00:27:21,691 SO WE CAN DO GENOME EDITING TO 677 00:27:21,691 --> 00:27:24,094 BUILD THE CAR-T CELLS. 678 00:27:24,094 --> 00:27:28,331 SO WHEN WE DO THE GPC3, WE START 679 00:27:28,331 --> 00:27:29,466 TO THINK ABOUT MAYBE WE SHOULD 680 00:27:29,466 --> 00:27:30,767 WORK ON OTHER GLYPICANS. 681 00:27:30,767 --> 00:27:32,636 I SAID IN THE BEGINNING 682 00:27:32,636 --> 00:27:33,970 PARTICULARLY GPC2 AND 1 BECAUSE 683 00:27:33,970 --> 00:27:35,505 THEY ALSO INDUCE THE WNT 684 00:27:35,505 --> 00:27:36,039 SIGNALING. 685 00:27:36,039 --> 00:27:39,843 AND WE LOOKED AT MICRO ARRAY 686 00:27:39,843 --> 00:27:41,378 DATABASE AND OTHERS, WE FIND 687 00:27:41,378 --> 00:27:44,648 GPC2 IS ACTUALLY ONE OF THE 688 00:27:44,648 --> 00:27:46,950 TRANSCRIPT, YOU CAN FIND IT 689 00:27:46,950 --> 00:27:48,385 PARTICULARLY IN PEDIATRIC 690 00:27:48,385 --> 00:27:50,454 CANCERS AND IN GLIOMA DATABASE. 691 00:27:50,454 --> 00:27:51,988 I THINK ONE OF THE DATABASE DONE 692 00:27:51,988 --> 00:27:56,159 HERE IN POB BY RIMA AND CHRIS' 693 00:27:56,159 --> 00:27:57,794 GROUP AND THEY ACTUALLY DID ALL 694 00:27:57,794 --> 00:28:01,832 THE MICRO ARRAY IN MANY 695 00:28:01,832 --> 00:28:04,701 PEDIATRIC CANCER TISSUES. 696 00:28:04,701 --> 00:28:06,970 SO GPC2, WE ACTUALLY VALIDATE 697 00:28:06,970 --> 00:28:07,404 THAT. 698 00:28:07,404 --> 00:28:09,940 IT'S THE ONLY ONE, THE PROTEIN 699 00:28:09,940 --> 00:28:11,975 EXPRESSION CAN BE ELEVATED IN 700 00:28:11,975 --> 00:28:12,542 THE NEUROBLASTOMA. 701 00:28:12,542 --> 00:28:14,544 SO WE FOCUS ON NEUROBLASTOMA, 702 00:28:14,544 --> 00:28:17,047 AND THEN WE ALSO LOOK AT THE 703 00:28:17,047 --> 00:28:20,550 DATABASE AND WE FIND THAT THE 704 00:28:20,550 --> 00:28:22,385 HIGH GPC2 IS ACTUALLY RELEVANT 705 00:28:22,385 --> 00:28:25,789 TO THE POOR SURVIVAL OF THESE 706 00:28:25,789 --> 00:28:30,260 NEUROBLASTOMA PATIENTS. 707 00:28:30,260 --> 00:28:34,664 JUST LIKE THE GPC3, WE STUDIED 708 00:28:34,664 --> 00:28:35,866 GPC2 TO ALSO LOOK AT THE WNT 709 00:28:35,866 --> 00:28:36,733 SIGNALING. 710 00:28:36,733 --> 00:28:37,834 WHAT WE'RE FINDING IS IF WE 711 00:28:37,834 --> 00:28:39,903 KNOCK DOWN OR KNOCK OUT THE GPC3 712 00:28:39,903 --> 00:28:42,539 IN THIS CASE, WE ACTUALLY COULD 713 00:28:42,539 --> 00:28:44,841 SEE ACTIVE BETA CATENIN ALSO 714 00:28:44,841 --> 00:28:45,709 DECREASE. 715 00:28:45,709 --> 00:28:47,744 AND THE OTHER PROTEIN WE ARE 716 00:28:47,744 --> 00:28:58,388 INTERESTED IN IS CALLED N MIBG., 717 00:29:00,090 --> 00:29:02,325 SO WHEN WE KNOCK DOWN GPC2, YOU 718 00:29:02,325 --> 00:29:07,797 CAN SEE THE THE N-MYC SIGNIFICY 719 00:29:07,797 --> 00:29:09,866 GOING DOWN IN THE NEUROBLASTOMA 720 00:29:09,866 --> 00:29:10,300 CELL LINES. 721 00:29:10,300 --> 00:29:13,403 WHEN WE REPEAT IT WITH KNOCKOUT, 722 00:29:13,403 --> 00:29:14,804 YOU SEE THE SAME THING, IN THE 723 00:29:14,804 --> 00:29:16,640 SAME CELL LINE, KNOCKDOWN AND 724 00:29:16,640 --> 00:29:18,074 THE KNOCKOUT, YOU WILL SEE 725 00:29:18,074 --> 00:29:21,044 DECREASE OF THE N-MYC IN THESE 726 00:29:21,044 --> 00:29:22,012 CELLS. 727 00:29:22,012 --> 00:29:25,182 SO INDICATING THE GPC2 KNOCKDOWN 728 00:29:25,182 --> 00:29:26,616 AND KNOCKOUT WERE ACTUALLY 729 00:29:26,616 --> 00:29:33,290 REDUCED EXPRESSION OF N-MYC. 730 00:29:33,290 --> 00:29:34,925 TO MAKE AN ANTIBODY AGAINST 731 00:29:34,925 --> 00:29:36,259 GPC2, WE DID THE SAME THING WE 732 00:29:36,259 --> 00:29:38,428 DID FOR GPC3, SINCE WE ALREADY 733 00:29:38,428 --> 00:29:40,497 KNOW HOW TO MAKE THIS ANTIBODY, 734 00:29:40,497 --> 00:29:43,567 AND WE LEARN A LOT FROM OUR 735 00:29:43,567 --> 00:29:46,436 PROJECT TO TRY TO MAKE A GPC3 736 00:29:46,436 --> 00:29:46,736 ANTIBODY. 737 00:29:46,736 --> 00:29:50,140 SO HERE WE KNOW GLYPICANS ARE 738 00:29:50,140 --> 00:29:52,442 NOT IMMUNOGENIC SO WE HAVE TO 739 00:29:52,442 --> 00:29:56,580 DESIGN A PEPTIDE TO BREAK THE 740 00:29:56,580 --> 00:30:01,618 IMMUNE TOLERANCE. 741 00:30:01,618 --> 00:30:04,254 EXON 10 SEQUENCE, THEN WE ALSO 742 00:30:04,254 --> 00:30:05,889 USE MEMBRANE-PROXIMAL EPITOPE 743 00:30:05,889 --> 00:30:07,090 BECAUSE WE THINK BASED ON OUR 744 00:30:07,090 --> 00:30:10,594 DATA AND OTHER PEOPLE'S DATA, IN 745 00:30:10,594 --> 00:30:13,530 SINGLE CHAIN BASED CAR-T CELLS 746 00:30:13,530 --> 00:30:15,198 SEEMS LIKE -- MEMBRANE WILL BE 747 00:30:15,198 --> 00:30:18,802 MORE POTENT MEMBRANE EP TOAD FOR 748 00:30:18,802 --> 00:30:19,436 THE CAR-Ts. 749 00:30:19,436 --> 00:30:21,438 SO WE ACTUALLY INJECT INTO THESE 750 00:30:21,438 --> 00:30:23,940 MICE AND SCREEN AS WE DID FOR 751 00:30:23,940 --> 00:30:27,110 GPC3, AND THEN WE SCREEN 752 00:30:27,110 --> 00:30:28,645 NEUROBLASTOMA CELLS, WE DO A LOT 753 00:30:28,645 --> 00:30:33,650 OF SINGLE CELL FACT TO ACTUALLY 754 00:30:33,650 --> 00:30:36,386 IDENTIFY THE ANTIBODY. 755 00:30:36,386 --> 00:30:40,123 SO NAN LI DID THIS WORK, 756 00:30:40,123 --> 00:30:46,129 SCREENED ALL THESE ANTIBODIES 757 00:30:46,129 --> 00:30:48,098 AND 3 IS THE MOST PROMISING ONE 758 00:30:48,098 --> 00:30:49,332 BECAUSE IT BINDS THE TISSUE 759 00:30:49,332 --> 00:30:49,633 LEAST. 760 00:30:49,633 --> 00:30:51,067 EVEN THOUGH WE USE THE SAME 761 00:30:51,067 --> 00:30:52,702 PEPTIDE TO IMMUNIZE MICE, WE 762 00:30:52,702 --> 00:30:55,639 WILL GET ANTIBODY EVEN WE SCREEN 763 00:30:55,639 --> 00:30:56,840 ON THE CELLS ALREADY, WE STILL 764 00:30:56,840 --> 00:30:59,509 GET ANTIBODY ON THE TISH EURL, 765 00:30:59,509 --> 00:31:00,777 SOME IMPACT ON THE LIVER, MAYBE 766 00:31:00,777 --> 00:31:02,646 ON THE STOMACH OR MAYBE ON 767 00:31:02,646 --> 00:31:04,347 PANCREAS, SO CT3 IS THE ONLY ONE 768 00:31:04,347 --> 00:31:06,416 THAT HAS THE MOST CLEAN 769 00:31:06,416 --> 00:31:06,716 BACKGROUND. 770 00:31:06,716 --> 00:31:11,855 SO THAT'S WHY WE PICKED THE CT3, 771 00:31:11,855 --> 00:31:12,856 JUST BECAUSE OF THE TISSUE 772 00:31:12,856 --> 00:31:14,491 STAINING. 773 00:31:14,491 --> 00:31:18,862 SO THEN WE HAVE A FLEX AWARD, I 774 00:31:18,862 --> 00:31:22,699 HAVE A NEW POSTDOC, RISHI CAME 775 00:31:22,699 --> 00:31:25,535 TO THE LAB AND WE ANALYZED THE 776 00:31:25,535 --> 00:31:26,970 ISOFORM OF THE GPC2 BECAUSE WE 777 00:31:26,970 --> 00:31:28,505 THINK ISOFORM PLAYS IMPORTANT 778 00:31:28,505 --> 00:31:31,341 ROLE IN CANCER, PARTICULARLY 779 00:31:31,341 --> 00:31:32,242 CANCER-SPECIFIC ISOFORM IS VERY 780 00:31:32,242 --> 00:31:32,976 INTERESTING TO US. 781 00:31:32,976 --> 00:31:35,478 SO WE LOOKED AT GPC2. 782 00:31:35,478 --> 00:31:39,582 THEY HAVE TWO ISOFORM, 201 AND 783 00:31:39,582 --> 00:31:40,750 203. 784 00:31:40,750 --> 00:31:43,386 201 IS IN CANCER, 203 IN NORMAL 785 00:31:43,386 --> 00:31:43,620 TISSUE. 786 00:31:43,620 --> 00:31:47,223 BUT IN THE CANCER, 201 HAS EXTRA 787 00:31:47,223 --> 00:31:50,493 EXON 3 AND EXON 8, 9, 10 EXONS, 788 00:31:50,493 --> 00:31:52,462 INDICATING IF WE DEVELOP AN 789 00:31:52,462 --> 00:31:54,931 ANTIBODY AGAINST THE 3, 8, 9 #, 790 00:31:54,931 --> 00:31:58,802 10, 910,THAT WOULD BE MORE 791 00:31:58,802 --> 00:31:59,569 TUMOR-SPECIFIC THAN IF WE 792 00:31:59,569 --> 00:32:01,204 TARGETED OTHER EXONS. 793 00:32:01,204 --> 00:32:03,273 LUCKILY WE ALREADY HAVE ANTIBODY 794 00:32:03,273 --> 00:32:05,675 BIND ON EXON 10, THAT'S THE CT3, 795 00:32:05,675 --> 00:32:07,210 SO WE THINK WE SHOULD GET 796 00:32:07,210 --> 00:32:09,746 ANTIBODY AGAINST CT3. 797 00:32:09,746 --> 00:32:10,880 I MEAN EXON 3. 798 00:32:10,880 --> 00:32:14,884 THE REASON IS YOU CAN SEE HERE, 799 00:32:14,884 --> 00:32:17,921 EXON 3 IS VERY CLEAN, EXCEPT THE 800 00:32:17,921 --> 00:32:20,056 TESTES, DID NOT HAVE ANY IN ANY 801 00:32:20,056 --> 00:32:20,657 NORMAL TISSUE. 802 00:32:20,657 --> 00:32:23,193 SO WE THINK WE SHOULD HAVE 803 00:32:23,193 --> 00:32:30,066 ANTIBODY AGAINST EXON 3 AND I I 804 00:32:30,066 --> 00:32:31,935 ASSIGNED RUIXUE TO DESIGN 805 00:32:31,935 --> 00:32:33,236 PROPOSAL IN THE FLEX PROJECT. 806 00:32:33,236 --> 00:32:37,507 BUT THEN RUIXUE DILIGENTLY MADE 807 00:32:37,507 --> 00:32:39,142 THE PROTEIN AND ONE DAY CAME TO 808 00:32:39,142 --> 00:32:42,445 MY OFFICE AND SAID HEY, I THINK 809 00:32:42,445 --> 00:32:44,414 CT3 ALSO BINDS TO EXON 3 EVEN 810 00:32:44,414 --> 00:32:46,816 THOUGH WE MADE CT3 AGAINST EXON 811 00:32:46,816 --> 00:32:48,651 10 BUT ALSO BIND EXON 3. 812 00:32:48,651 --> 00:32:49,886 I DON'T BELIEVE IT. 813 00:32:49,886 --> 00:32:51,421 SO I SAID YOU HAVE TO REPEAT IT. 814 00:32:51,421 --> 00:32:52,922 SO WE REPEAT IT, NAN ALSO REPEAT 815 00:32:52,922 --> 00:32:53,156 IT. 816 00:32:53,156 --> 00:32:55,692 IT SHOWS LIKE, YES, EVEN THOUGH 817 00:32:55,692 --> 00:32:57,327 WE IMMUNIZED THE MICE WITH EXON 818 00:32:57,327 --> 00:32:59,295 10, THE ANTIBODY STILL BINDS TO 819 00:32:59,295 --> 00:32:59,662 EXON 3. 820 00:32:59,662 --> 00:33:01,164 AND WE PICKED THIS ONE BECAUSE 821 00:33:01,164 --> 00:33:04,100 THE LOWEST BACKGROUND IN THE 822 00:33:04,100 --> 00:33:07,170 TISSUE ARRAY, AS I TOLD YOU. 823 00:33:07,170 --> 00:33:09,372 SO THAT START TO MAKE SENSE, AND 824 00:33:09,372 --> 00:33:11,441 THEN WE SENT TO FREDERICK, WE 825 00:33:11,441 --> 00:33:15,378 HAVE A CCR CENTER FOR MOLECULAR 826 00:33:15,378 --> 00:33:17,447 MICROSCOPY DOING EM, AND WE 827 00:33:17,447 --> 00:33:20,950 ACTUALLY SEE THE CT3 -- ACTUALLY 828 00:33:20,950 --> 00:33:23,052 BIND EXON 3 AND EXON 10. 829 00:33:23,052 --> 00:33:25,321 OKAY, SO WE COULD VISUALIZE IT. 830 00:33:25,321 --> 00:33:26,423 SO THAT'S GREAT. 831 00:33:26,423 --> 00:33:29,492 AND THEN, WE LOOK AT THE 832 00:33:29,492 --> 00:33:30,894 CT3 ANTIBODY ON A NORMAL TISSUE, 833 00:33:30,894 --> 00:33:34,631 WE FIND THAT, YES, INDEED, THEY 834 00:33:34,631 --> 00:33:37,233 DON'T BIND TO PRETTY MUCH 835 00:33:37,233 --> 00:33:40,437 ANYTHING EXCEPT THE TESTIS, VERY 836 00:33:40,437 --> 00:33:41,504 HIGHLY TUMOR SPECIFIC ANTIBODY 837 00:33:41,504 --> 00:33:42,405 DEVELOPED. 838 00:33:42,405 --> 00:33:44,908 SO IN CONCLUSION, I THINK IT'S 839 00:33:44,908 --> 00:33:46,876 FEASIBLE TO GENERATE TUMOR 840 00:33:46,876 --> 00:33:49,846 SPECIFIC ANTIBODY BY TARGETING 841 00:33:49,846 --> 00:33:51,247 TUMOR ASSOCIATED ISOFORM OR 842 00:33:51,247 --> 00:33:56,519 EXONS AND THE TUMOR ASSOCIATED 843 00:33:56,519 --> 00:33:57,921 ISOFORM/EXON, I THINK THEY'RE 844 00:33:57,921 --> 00:34:00,123 MORE IN THE CANCER, AND WE NEED 845 00:34:00,123 --> 00:34:00,990 TO FIND THEM. 846 00:34:00,990 --> 00:34:03,827 AND THAT THE CURRENT, WE HAVE 847 00:34:03,827 --> 00:34:07,330 EXPERT HERE, AND DOING THE 848 00:34:07,330 --> 00:34:08,298 ANALYSIS DEEP SEQUENCING, I 849 00:34:08,298 --> 00:34:10,733 THINK THE CURRENT METHODOLOGY 850 00:34:10,733 --> 00:34:12,602 MIGHT NEED TO BE OPTIMIZED OR 851 00:34:12,602 --> 00:34:14,671 IMPROVED TO BE ABLE TO FIND MORE 852 00:34:14,671 --> 00:34:22,412 ISOFORM AND EXONS IN THE TUMORS. 853 00:34:22,412 --> 00:34:26,483 WE ALSO TEST THE CT3 ANTIBODY ON 854 00:34:26,483 --> 00:34:29,652 OTHER PEDIATRIC CANCER, THEY ARE 855 00:34:29,652 --> 00:34:31,821 ALL VERY POSITIVE IN THOSE 856 00:34:31,821 --> 00:34:32,989 PEDIATRIC CANCER, BUT NEGATIVE 857 00:34:32,989 --> 00:34:34,357 IN THE NORMAL TISSUES. 858 00:34:34,357 --> 00:34:36,092 SO POTENTIALLY WE CAN TREAT 859 00:34:36,092 --> 00:34:37,527 OTHER PEDIATRIC CANCER, NOT ONLY 860 00:34:37,527 --> 00:34:41,364 JUST NEUROBLASTOMA. 861 00:34:41,364 --> 00:34:44,434 SO LIKE WE DO FOR GPC3 WE 862 00:34:44,434 --> 00:34:45,869 ACTUALLY MADE CAR-T CELLS THAT'S 863 00:34:45,869 --> 00:34:46,836 THE SAME CONSTRUCT, I'M NOT 864 00:34:46,836 --> 00:34:48,238 GOING TO GO INTO DETAIL. 865 00:34:48,238 --> 00:34:53,710 AND THEN WE TEST THE GPC2 IN 866 00:34:53,710 --> 00:34:54,177 NEUROBLASTOMA. 867 00:34:54,177 --> 00:34:55,245 THIS IS A VERY COMPLICATED 868 00:34:55,245 --> 00:34:55,612 MODEL. 869 00:34:55,612 --> 00:34:58,114 WE EITHER INJECTED THE 870 00:34:58,114 --> 00:35:00,083 NEUROBLASTOMA FOR ABOUT A MONTH, 871 00:35:00,083 --> 00:35:01,718 28 TO 35 DAYS, DEPENDS ON WHAT 872 00:35:01,718 --> 00:35:05,455 THE EXPERIMENT WE ACTUALLY TAKE. 873 00:35:05,455 --> 00:35:11,027 SO USUALLY ABOUT A MONTH. 874 00:35:11,027 --> 00:35:13,396 YOU -- EVERYWHERE IN THE MICE, 875 00:35:13,396 --> 00:35:15,064 FROM THE SKULL TO ADRENAL GLAND 876 00:35:15,064 --> 00:35:16,199 TO THE LEG TO EVERYWHERE, AND 877 00:35:16,199 --> 00:35:17,800 THEN YOU START TO TREAT IT WITH 878 00:35:17,800 --> 00:35:21,204 CAR-T CELLS, AND THEN YOU CAN 879 00:35:21,204 --> 00:35:30,813 SEE WITH THE TREATMENT, IT JUST 880 00:35:30,813 --> 00:35:32,682 TOTALLY ELIMINATED AND ALL THE 881 00:35:32,682 --> 00:35:33,583 MICE SURVIVED. 882 00:35:33,583 --> 00:35:34,784 SO BECAUSE OF THIS DATA AND 883 00:35:34,784 --> 00:35:38,288 OTHER DATA, WE ALSO DO THE 884 00:35:38,288 --> 00:35:39,822 MODEL, BASICALLY MICRO INJECT IN 885 00:35:39,822 --> 00:35:42,225 THE SAME CELL LINE INTO THE 886 00:35:42,225 --> 00:35:43,426 ADRENAL GLAND AND WE SHOW 887 00:35:43,426 --> 00:35:46,062 SIMILAR DATA. 888 00:35:46,062 --> 00:35:47,497 SO BECAUSE OF THIS DATA, WE ARE 889 00:35:47,497 --> 00:35:49,232 NOW COLLABORATING WITH PEDIATRIC 890 00:35:49,232 --> 00:35:51,301 ONCOLOGY BRANCH HERE TO START A 891 00:35:51,301 --> 00:35:58,341 CLINICAL TRIAL IN 2025 ERK 2025T 892 00:35:58,341 --> 00:36:02,712 A CANCER MOONSHOT GRANT, 893 00:36:02,712 --> 00:36:05,114 DR. ROSA NGUYEN IS GOING TO LEAD 894 00:36:05,114 --> 00:36:05,982 THIS TRIAL. 895 00:36:05,982 --> 00:36:07,850 AT THE SIMILAR TIME AS I SAID WE 896 00:36:07,850 --> 00:36:09,619 WORK ON GPC2, WE ALSO WORK ON 897 00:36:09,619 --> 00:36:13,890 GPC1. 898 00:36:13,890 --> 00:36:15,725 AND IT'S THE SAME KIND OF 899 00:36:15,725 --> 00:36:17,393 REPORTER EVEN THOUGH IT'S QUITE 900 00:36:17,393 --> 00:36:18,027 CONTROVERSIAL, IT'S BEEN 901 00:36:18,027 --> 00:36:20,663 REPORTED THAT GPC1 IS SECRETED 902 00:36:20,663 --> 00:36:22,632 FROM PANCREATIC CANCER CELLS AS 903 00:36:22,632 --> 00:36:25,168 EXOSOME, EVEN THOUGH THAT THAT D 904 00:36:25,168 --> 00:36:26,703 OF ARGUMENT IS DEBATED IN MANY 905 00:36:26,703 --> 00:36:28,237 MEETINGS WHETHER IT'S TRUE OR 906 00:36:28,237 --> 00:36:29,539 NOT, BUT WE ACTUALLY START TO 907 00:36:29,539 --> 00:36:32,709 LOOK AT GPC1 TO SEE WHETHER IT'S 908 00:36:32,709 --> 00:36:35,144 TRULY EXPRESSED IN THE 909 00:36:35,144 --> 00:36:38,314 PANCREATIC CANCER, WE DO RNA AND 910 00:36:38,314 --> 00:36:42,151 THE PROTEIN LEVELS AND USED 911 00:36:42,151 --> 00:36:43,286 NORMAL PANCREATIC CELL LINES AS 912 00:36:43,286 --> 00:36:43,620 A CONTROL. 913 00:36:43,620 --> 00:36:45,688 YOU CAN SEE GPC1 INDEED IS 914 00:36:45,688 --> 00:36:47,223 HIGHLY ELEVATED IN PANCREATIC 915 00:36:47,223 --> 00:36:48,391 CANCER. 916 00:36:48,391 --> 00:36:50,827 BUT UNLIKE GPC2 AND GPC3, GPC1 917 00:36:50,827 --> 00:36:55,865 IS MORE LIKE A PANCANCER TARGET, 918 00:36:55,865 --> 00:36:57,400 EXPRESSED NOT ONLY IN PANCREATIC 919 00:36:57,400 --> 00:37:01,037 CANCER BUT IN OTHER CANCERS -- 920 00:37:01,037 --> 00:37:01,904 SOLID TUMORS. 921 00:37:01,904 --> 00:37:03,673 SO LIKE A GPC2, WE ALSO LOOK AT 922 00:37:03,673 --> 00:37:05,308 THE WNT IN THE PANCREATIC 923 00:37:05,308 --> 00:37:05,742 CANCER. 924 00:37:05,742 --> 00:37:08,344 WE ALSO DO THE REPORTER -- USE 925 00:37:08,344 --> 00:37:09,712 GPC3 AS A CONTROL. 926 00:37:09,712 --> 00:37:12,081 LIKE A GPC3, IF WE OVEREXPRESS 927 00:37:12,081 --> 00:37:14,717 GPC1, IT WILL ELEVATE THE BETA 928 00:37:14,717 --> 00:37:16,486 CATENIN SIGNALING AND THAT'S 929 00:37:16,486 --> 00:37:17,920 SIMILAR LIKE WHAT THE GPC3 DOES 930 00:37:17,920 --> 00:37:25,028 IN LIVER CANCER. 931 00:37:25,028 --> 00:37:27,430 JIAJIA PAN IS A PH.D. STUDENT IN 932 00:37:27,430 --> 00:37:27,997 THE LAB. 933 00:37:27,997 --> 00:37:34,804 SHE MADE A GP GPC1 KNOCKOUT, EVN 934 00:37:34,804 --> 00:37:36,673 THOUGH WE DO CRISPR, MEANING 935 00:37:36,673 --> 00:37:38,007 THEY ARE TOTALLY INDEPENDENT 936 00:37:38,007 --> 00:37:40,176 KNOCKOUT CLONE, AND WE SEE ALL 937 00:37:40,176 --> 00:37:42,712 THIS SINGLE INDEPENDENT KNOCKOUT 938 00:37:42,712 --> 00:37:45,982 GPC1 CLONE IN PANCREATIC CANCER 939 00:37:45,982 --> 00:37:48,918 CELLS, AND -- SIGNIFICANT 940 00:37:48,918 --> 00:37:49,385 DECREASE. 941 00:37:49,385 --> 00:37:51,020 IT'S AMAZING, THE DECREASE AND I 942 00:37:51,020 --> 00:37:53,656 THINK IT'S JUST BECAUSE THE GPC1 943 00:37:53,656 --> 00:37:56,392 IS TOTALLY -- THOSE PANCREATIC 944 00:37:56,392 --> 00:37:58,594 CANCERS ARE VERY ADDICTED TO THE 945 00:37:58,594 --> 00:38:00,897 GPC1 WHEN YOU KNOCK OUT THE BETA 946 00:38:00,897 --> 00:38:02,131 CATENIN LEVEL IT REALLY GOES TO 947 00:38:02,131 --> 00:38:07,036 VERY, VERY LOW. 948 00:38:07,036 --> 00:38:10,406 TO MAKE THE GPC1 ANTIBODY THIS 949 00:38:10,406 --> 00:38:11,874 TIME, IN ADDITION TO WHAT WE DID 950 00:38:11,874 --> 00:38:15,912 FOR GPC3 AND GPC3 951 00:38:15,912 --> 00:38:18,448 2 IMMUNIZATION, NOW WE HAVE -- 952 00:38:18,448 --> 00:38:18,681 LIBRARY. 953 00:38:18,681 --> 00:38:23,052 SO WE MADE -- FROM THE CAM 954 00:38:23,052 --> 00:38:23,352 1 SHOCK. 955 00:38:23,352 --> 00:38:24,987 THOSE ARE VERY SPECIAL ANIMALS. 956 00:38:24,987 --> 00:38:28,057 THEY ACTUALLY PRODUCE THE SO 957 00:38:28,057 --> 00:38:28,825 CALLED SINGLE-DOMAIN ANTIBODY 958 00:38:28,825 --> 00:38:30,927 WHICH IS HEAVY CHAIN WITHOUT THE 959 00:38:30,927 --> 00:38:32,428 LIGHT CHAIN AND THOSE ANTIBODIES 960 00:38:32,428 --> 00:38:35,498 ARE VERY SMALL, SO THEY ACTUALLY 961 00:38:35,498 --> 00:38:38,601 ONLY HAVE 12 OR 15 KILODALTON 962 00:38:38,601 --> 00:38:41,003 INSTEAD OF 150 KILODALTON 963 00:38:41,003 --> 00:38:41,771 ANTIBODY IGG I SHOW IN THE 964 00:38:41,771 --> 00:38:42,972 BEGINNING. 965 00:38:42,972 --> 00:38:45,274 IT BINDS TO THE -- FUNCTION SITE 966 00:38:45,274 --> 00:38:48,578 AND IT HAS A BETTER TRANSDUCTION 967 00:38:48,578 --> 00:38:50,646 EFFICIENCY BECAUSE THEY ARE 968 00:38:50,646 --> 00:38:53,049 SMALL, AND MAY BE IDEAL FOR 969 00:38:53,049 --> 00:38:54,050 ALLOGENIC CAR-T BECAUSE YOU CAN 970 00:38:54,050 --> 00:38:58,888 DO A A LOT OF ENGINEERING TO THE 971 00:38:58,888 --> 00:39:03,926 GENOME AND EASY TO EXPRESS AND 972 00:39:03,926 --> 00:39:06,863 ENGINEER AS BISPECIFIC OR 973 00:39:06,863 --> 00:39:08,498 MULTI-SPECIFIC. 974 00:39:08,498 --> 00:39:09,766 IT'S LIKE A KEY IN THE HOLE, AS 975 00:39:09,766 --> 00:39:11,267 LONG AS THE HOLE IS THE SAME 976 00:39:11,267 --> 00:39:12,335 SIZE, SAME SHAPE, THEY ALWAYS 977 00:39:12,335 --> 00:39:13,770 CAN GET IN. 978 00:39:13,770 --> 00:39:16,072 SO THE NANOBODY REALLY CROSSES A 979 00:39:16,072 --> 00:39:17,073 LOT OF SPECIES. 980 00:39:17,073 --> 00:39:19,509 AND WE ALSO DO LIKE WE GO IN 981 00:39:19,509 --> 00:39:20,977 GPC2, WE DO THE EM TO TRY TO 982 00:39:20,977 --> 00:39:21,778 FIGURE OUT THE EPITOPE. 983 00:39:21,778 --> 00:39:24,213 THIS IS THE EM COMPLEX -- SO WE 984 00:39:24,213 --> 00:39:27,383 CAN SEE THE D4, THE NANOBODY 985 00:39:27,383 --> 00:39:29,485 ACTUALLY BINDS TO THE END OF THE 986 00:39:29,485 --> 00:39:32,321 GPC1, AND HM2 FAB ACTUALLY BINDS 987 00:39:32,321 --> 00:39:34,524 TO C TERMINAL OF THE -- CLOSE TO 988 00:39:34,524 --> 00:39:40,563 THE CELL SURFACE. 989 00:39:40,563 --> 00:39:41,998 SO AS I JUST DESCRIBED, THIS 990 00:39:41,998 --> 00:39:43,833 WILL SHOW YOU ONE EXAMPLE. 991 00:39:43,833 --> 00:39:45,902 THE WHOLE IGG WHICH IS HEAVY IN 992 00:39:45,902 --> 00:39:47,703 THE LIGHTER CHAIN BUT INTERFACE 993 00:39:47,703 --> 00:39:49,772 WITH THE ANTIGEN, PROTEIN 994 00:39:49,772 --> 00:39:50,873 ANTIGEN, ARE RELATIVELY FLAT, 995 00:39:50,873 --> 00:39:54,677 BUT IF WE USE THE NANOBODY, 996 00:39:54,677 --> 00:39:55,678 BECAUSE THE LOOP IS VERY LONG 997 00:39:55,678 --> 00:39:57,880 SOMETIMES THEY HAVE -- BOND TO 998 00:39:57,880 --> 00:39:59,315 STABILIZE IT, THEY COULD GO VERY 999 00:39:59,315 --> 00:40:02,819 DEEP TO THE VA CAVITY OF THE 1000 00:40:02,819 --> 00:40:05,454 PROTEIN, THAT WE THEY ACTUALLY 1001 00:40:05,454 --> 00:40:06,322 PROTRUDE INTO THE BACK POCKET 1002 00:40:06,322 --> 00:40:07,757 BECAUSE THIS IS ENZYME POCKET. 1003 00:40:07,757 --> 00:40:10,593 AND SO THIS IS SHARK BUT THE 1004 00:40:10,593 --> 00:40:11,928 CAMEL NANOBODY COULD DO THE SAME 1005 00:40:11,928 --> 00:40:12,128 THING. 1006 00:40:12,128 --> 00:40:14,564 I JUST WANT TO SHOW HERE, WE 1007 00:40:14,564 --> 00:40:17,500 HAVE A CAMEL NANOBODY -- THAT 1008 00:40:17,500 --> 00:40:21,470 CAN BE USED FOR -- DISCOVERY FOR 1009 00:40:21,470 --> 00:40:24,540 NOT ONLY CANCER BUT ALSO FOR 1010 00:40:24,540 --> 00:40:31,247 VIRUS, AND SCIENT SCIENTIST IN , 1011 00:40:31,247 --> 00:40:33,449 HUA AND JESSICA BOTH SPEND ONE 1012 00:40:33,449 --> 00:40:35,384 OR TWO YEARS FULL TIME WORKING 1013 00:40:35,384 --> 00:40:37,687 ON THIS AND GENERATED THOSE 1014 00:40:37,687 --> 00:40:38,487 CAMEL LIBRARY. 1015 00:40:38,487 --> 00:40:40,456 THIS LIBRARY, WE MADE EACH CAMEL 1016 00:40:40,456 --> 00:40:42,558 A LIBRARY SO TOTAL WE HAVE 20 1017 00:40:42,558 --> 00:40:45,027 LIBRARY, VERY BIG LIBRARY, AND 1018 00:40:45,027 --> 00:40:46,896 USING THOSE LIBRARY, JESSICA 1019 00:40:46,896 --> 00:40:48,364 HONG, BIOLOGIST IN MY LAB 1020 00:40:48,364 --> 00:40:51,868 ACTUALLY ISOLATED THE SARS CROW 1021 00:40:51,868 --> 00:40:53,402 V ANTIBODY DURING THE PANDEMIC 1022 00:40:53,402 --> 00:40:56,272 AND SHOW THEY ARE VERY BROADLY 1023 00:40:56,272 --> 00:40:58,174 NEUTRALIZING THE COV VARIANTS 1024 00:40:58,174 --> 00:40:59,876 AND THAT'S PRETTY EXCITING WORK 1025 00:40:59,876 --> 00:41:00,743 DURING THE PANDEMIC. 1026 00:41:00,743 --> 00:41:02,778 IT SHOWS THE NANOBODY COULD WORK 1027 00:41:02,778 --> 00:41:04,380 BOTH FOR CANCER AND VIRUS 1028 00:41:04,380 --> 00:41:06,115 ANTIGENS. 1029 00:41:06,115 --> 00:41:09,218 AND BACK TO GPC1. 1030 00:41:09,218 --> 00:41:11,087 SO NAN ACTUALLY FOUND AN 1031 00:41:11,087 --> 00:41:12,154 ANTIBODY CALLED D4. 1032 00:41:12,154 --> 00:41:13,456 IT ACTUALLY HAS A VERY HIGH 1033 00:41:13,456 --> 00:41:15,024 AFFINITY FOR MOUSE AND HUMAN 1034 00:41:15,024 --> 00:41:15,358 GPC1. 1035 00:41:15,358 --> 00:41:18,861 THAT MEANS YOU CAN START IN 1036 00:41:18,861 --> 00:41:20,396 MOUSE PANCREATIC CANCER MODELS 1037 00:41:20,396 --> 00:41:21,831 USING THIS NANOBODY. 1038 00:41:21,831 --> 00:41:27,069 AND ACTUALLY, AFFINITY IS A 1039 00:41:27,069 --> 00:41:27,970 SUBNANOMOLAR AFFINITY, EVEN 1040 00:41:27,970 --> 00:41:29,639 THOUGH IT'S SMALL, .7, IT'S NOT 1041 00:41:29,639 --> 00:41:32,041 LIKE A PEPTIDE, VERY HIGH 1042 00:41:32,041 --> 00:41:34,877 AFFINITY, SO -- MATURATION OR 1043 00:41:34,877 --> 00:41:35,912 DIRECTED EVOLUTION TO IMPROVE 1044 00:41:35,912 --> 00:41:40,249 THE AFFINITY BECAUSE IT'S -- THE 1045 00:41:40,249 --> 00:41:42,318 AFFINITY IS ALREADY WITHIN THE 1046 00:41:42,318 --> 00:41:47,790 THERAPEUTIC ANTIBODY WINDOWS. 1047 00:41:47,790 --> 00:41:49,992 SO WE ACTUALLY MAKE THE CAR-T 1048 00:41:49,992 --> 00:41:52,194 CELLS USING THIS NANOBODY. 1049 00:41:52,194 --> 00:41:53,729 WE FIND IF WE USE DIFFERENT -- 1050 00:41:53,729 --> 00:41:55,298 IT WILL HAVE DIFFERENT IMPACT. 1051 00:41:55,298 --> 00:41:57,934 I WILL NOT GO INTO DETAIL 1052 00:41:57,934 --> 00:41:59,135 BECAUSE WE MADE A LOT OF 1053 00:41:59,135 --> 00:42:00,870 DIFFERENT BUT I ONLY WANT TO 1054 00:42:00,870 --> 00:42:03,005 SHOW TWO HERE. 1055 00:42:03,005 --> 00:42:08,678 THE CD8 IN THE GPC3 AND 1056 00:42:08,678 --> 00:42:09,779 2 PROJECT. 1057 00:42:09,779 --> 00:42:15,284 IGG 4 HINGE IS SHORT, CD8 HINGE 1058 00:42:15,284 --> 00:42:18,988 IS 45 ACID SO WHEN WE SWITCH TO 1059 00:42:18,988 --> 00:42:21,290 THE SHORT HINGE, IGG 4 HINGE, 1060 00:42:21,290 --> 00:42:22,725 THEY'RE CLOSE TO EACH OTHER AND 1061 00:42:22,725 --> 00:42:26,329 THEY FORM PROBABLY BETTER DIMERS 1062 00:42:26,329 --> 00:42:28,030 AND EVEN INTRACELLULAR PART OF 1063 00:42:28,030 --> 00:42:33,002 THE MOLECULE CD3 DATA IS MORE 1064 00:42:33,002 --> 00:42:35,104 STRUCTURED THAN THE CD8 HINGE SO 1065 00:42:35,104 --> 00:42:37,606 THAT MEANS POTENTIALLY MAKES IT 1066 00:42:37,606 --> 00:42:38,074 MORE ACTUALLY ACTIVE. 1067 00:42:38,074 --> 00:42:44,413 SO INDEED, ACTUALLY SHOW USING 1068 00:42:44,413 --> 00:42:46,949 NANOBODY T CELLS WITH IGG HINGE 1069 00:42:46,949 --> 00:42:48,718 AND IT SHOWS MUCH BETTER KILLING 1070 00:42:48,718 --> 00:42:52,421 EFFECT THAN THE ORIGINAL 1071 00:42:52,421 --> 00:42:53,756 CD8 HINGE. 1072 00:42:53,756 --> 00:43:00,963 ANOTHER PH.D. STUDENT CAME AT 1073 00:43:00,963 --> 00:43:02,064 PH.D. PROGRAM FROM MAYO AND SHE 1074 00:43:02,064 --> 00:43:05,601 DID A SIMILAR EXPERIMENT USING 1075 00:43:05,601 --> 00:43:06,002 ANTIGPC3 NANOBODY. 1076 00:43:06,002 --> 00:43:07,336 AS YOU CAN SEE HERE, WHEN SHE 1077 00:43:07,336 --> 00:43:12,608 SWITCHED TO IGG 4 HINGE, THE 1078 00:43:12,608 --> 00:43:14,176 ANTIGPC NANOBODY CAR-T-CELL IS 1079 00:43:14,176 --> 00:43:16,445 VERY POTENT, EVEN MORE POTENT 1080 00:43:16,445 --> 00:43:19,849 THAN THE ONE I TALK ABOUT, 1081 00:43:19,849 --> 00:43:22,518 SINGLE CHAIN TARGETED IN GPC3 SO 1082 00:43:22,518 --> 00:43:24,053 WE'RE VERY EXCITED ABOUT THIS, 1083 00:43:24,053 --> 00:43:28,024 INDICATING IGG 4 IS PROBABLY THE 1084 00:43:28,024 --> 00:43:29,959 RIGHT HINGE FOR THE NANOBODY 1085 00:43:29,959 --> 00:43:31,293 CAR-T CELLS. 1086 00:43:31,293 --> 00:43:32,728 SO NOW IN THE LAST FEW MINUTE, 1087 00:43:32,728 --> 00:43:35,164 I'M GOING TO TALK ABOUT HOW CAN 1088 00:43:35,164 --> 00:43:36,899 WE MAKE EVEN MORE ACTIVE CAR-T 1089 00:43:36,899 --> 00:43:41,037 CELLS. 1090 00:43:41,037 --> 00:43:43,072 SO TUMOR ANTIGEN AS I SAID IN 1091 00:43:43,072 --> 00:43:46,342 THE BEGINNING IS HETEROJEAN US, 1092 00:43:46,342 --> 00:43:50,813 HETEROGENEOUSMOST ARE VERY LOW. 1093 00:43:50,813 --> 00:43:57,420 FOR HIGH TUMOR -- LIKE GPC2 AND 1094 00:43:57,420 --> 00:43:58,621 GPC3 SINCE WE HAVE A GOOD 1095 00:43:58,621 --> 00:44:00,389 ANTIBODY BUT ONLY TUMOR, NOT ANY 1096 00:44:00,389 --> 00:44:01,590 NORMAL TISSUES, WE COULD 1097 00:44:01,590 --> 00:44:04,560 PROBABLY AFFORD TO IMPROVE THE 1098 00:44:04,560 --> 00:44:06,195 ACTIVE -- OF THE CAR-T CELLS 1099 00:44:06,195 --> 00:44:08,731 WITH RESULT ON TARGET OF OFF 1100 00:44:08,731 --> 00:44:10,066 TUMOR TOXICITY BECAUSE THEY ARE 1101 00:44:10,066 --> 00:44:12,001 VERY TUMOR SPECIFIC. 1102 00:44:12,001 --> 00:44:14,437 SO KEEPING THAT IN MIND, WE 1103 00:44:14,437 --> 00:44:15,905 ACTUALLY COLLABORATEED WITH A 1104 00:44:15,905 --> 00:44:19,175 COMPANY SINCE 2018, SO WE 1105 00:44:19,175 --> 00:44:22,011 ACTUALLY COULD DEVELOP KIND OF 1106 00:44:22,011 --> 00:44:27,283 THE CONSTRUCT WHICH HAS A 1107 00:44:27,283 --> 00:44:33,289 GAMMA-DELTA CONSTRUCT WITH VLB 1108 00:44:33,289 --> 00:44:34,290 FAB, WITH TCR. 1109 00:44:34,290 --> 00:44:35,324 THE DIFFERENCE FROM THIS TO THE 1110 00:44:35,324 --> 00:44:39,128 CAR IS YOU CAN SEE THE CD3 PART 1111 00:44:39,128 --> 00:44:43,532 OF THE ACTIVATION PART C D3, 1112 00:44:43,532 --> 00:44:46,168 ANOTHER COVALENT BOND WITH THIS 1113 00:44:46,168 --> 00:44:49,872 CONSTRUCT, AND CD3 WITH PEPTIDE 1114 00:44:49,872 --> 00:44:50,439 BOND. 1115 00:44:50,439 --> 00:44:53,976 HERE WE DON'T USE ANY -- THEY 1116 00:44:53,976 --> 00:44:59,448 ACTUALLY RECRUIT CT3 JUST LIKE A 1117 00:44:59,448 --> 00:45:01,650 NATIVE TCR TO GET INTO THE 1118 00:45:01,650 --> 00:45:03,819 ACTIVATION COMPLEX. 1119 00:45:03,819 --> 00:45:07,756 SO WE ALSO SPLIT THE -- FACTOR 1120 00:45:07,756 --> 00:45:10,526 INTO A DIFFERENT MOLECULES AND 1121 00:45:10,526 --> 00:45:12,394 NOT COVALENT BOND WITH OUR CAR. 1122 00:45:12,394 --> 00:45:15,131 SO IN THAT WAY, WE ACTUALLY KEEP 1123 00:45:15,131 --> 00:45:19,168 EVERYTHING MORE LIKE A NATIVE 1124 00:45:19,168 --> 00:45:20,236 TCR EXCEPT THE VARIABLE REGION 1125 00:45:20,236 --> 00:45:21,837 OF THE TCR WE CHANGE IT WITH THE 1126 00:45:21,837 --> 00:45:24,874 FACT. 1127 00:45:24,874 --> 00:45:27,743 OBVIOUSLY WE WANT TO ASK WHETHER 1128 00:45:27,743 --> 00:45:30,279 THIS F TCR COULD REQUEST LOW 1129 00:45:30,279 --> 00:45:31,580 ANTIGEN DENSITY BECAUSE AS I 1130 00:45:31,580 --> 00:45:34,650 SHOW HERE, THIS IS VERY 1131 00:45:34,650 --> 00:45:37,953 IMPORTANT BECAUSE THIS IS THE 1132 00:45:37,953 --> 00:45:39,955 ANTIGEN SIZE PER CELL. 1133 00:45:39,955 --> 00:45:42,491 FOR MANY ANTIBODY THERAPY, WE'RE 1134 00:45:42,491 --> 00:45:46,929 TALKING ABOUT 100 SIZE PER CELL. 1135 00:45:46,929 --> 00:45:47,830 FOR CAR-T THERAPY IN GENERAL 1136 00:45:47,830 --> 00:45:49,965 WE'RE TALKING ABOUT MAYBE 1,000, 1137 00:45:49,965 --> 00:45:52,134 2,000 SIZE PER CELL AT THE 1138 00:45:52,134 --> 00:45:57,806 LOWEST CUTOFF YOU CAN KILL THE 1139 00:45:57,806 --> 00:45:58,707 TUMOR CELLS ACTUALLY 1140 00:45:58,707 --> 00:45:59,041 EFFICIENTLY. 1141 00:45:59,041 --> 00:46:01,043 TO GO DOWN TO SOMETHING LIKE 1142 00:46:01,043 --> 00:46:03,212 THIS, ONLY 500, EVEN LESS 1143 00:46:03,212 --> 00:46:04,947 BECAUSE WITH CONTROL IT'S HERE, 1144 00:46:04,947 --> 00:46:07,583 THE BACKGROUND, EVEN LESS, A 1145 00:46:07,583 --> 00:46:09,118 COUPLE OF HUNDRED SIZE PER CELL 1146 00:46:09,118 --> 00:46:10,519 IS ALMOST IMPOSSIBLE. 1147 00:46:10,519 --> 00:46:13,189 IF YOU USE ANY ANTIBODY 1148 00:46:13,189 --> 00:46:16,592 THERAPEUTIC DRUGS, OR EVEN 1149 00:46:16,592 --> 00:46:18,327 THE -- CAR-T CELLS AND USUALLY 1150 00:46:18,327 --> 00:46:20,429 THAT'S THE THRESHOLD, PROBABLY 1151 00:46:20,429 --> 00:46:21,330 1,000, 2,000 SIZE PER CELL. 1152 00:46:21,330 --> 00:46:23,832 AND THEN AMAZINGLY, WE ACTUALLY 1153 00:46:23,832 --> 00:46:27,703 USE THIS LAN1, INOCULATE TO MICE 1154 00:46:27,703 --> 00:46:29,538 TO MAKE SUBCUTANEOUS TUMOR, WE 1155 00:46:29,538 --> 00:46:33,075 START TO SEE THE F TCR ACTUALLY 1156 00:46:33,075 --> 00:46:35,044 SHRINK THE TUMORS, WE STARTED 1157 00:46:35,044 --> 00:46:39,114 ABOUT 110 TO 140 SIZE, AND THEN 1158 00:46:39,114 --> 00:46:41,650 THEY ACTUALLY GO TO ZERO. 1159 00:46:41,650 --> 00:46:43,419 OR TUMOR REMISSIONS. 1160 00:46:43,419 --> 00:46:44,520 VERY INTERESTING, WE ARE STILL 1161 00:46:44,520 --> 00:46:48,591 TRYING TO UNDERSTAND THAT, IS 1162 00:46:48,591 --> 00:46:50,659 THE HUMANIZED IS MORE POTENT 1163 00:46:50,659 --> 00:46:54,930 THAN MOUSE CT3 AB TCR. 1164 00:46:54,930 --> 00:46:57,032 EVEN THOUGH THE MOUSE STILL IS 1165 00:46:57,032 --> 00:46:59,602 HIGH, MORE ACTIVE THAN CAR, BUT 1166 00:46:59,602 --> 00:47:05,608 THE HUMANIZED VERSION OF CT3 1167 00:47:05,608 --> 00:47:07,142 ABTCR IS THE MOST POTENT. 1168 00:47:07,142 --> 00:47:09,311 SO LAURA HUTCHINS, SHE'S A 1169 00:47:09,311 --> 00:47:10,546 POSTBAC IN THE LAB WORKING WITH 1170 00:47:10,546 --> 00:47:13,849 DAN ON THIS PROJECT, AND IT'S 1171 00:47:13,849 --> 00:47:15,918 VERY SURPRISING TO US IN THE 1172 00:47:15,918 --> 00:47:18,654 BEGINNING, THAT FACT. 1173 00:47:18,654 --> 00:47:20,022 REGARDLESS OF THAT, BECAUSE OF 1174 00:47:20,022 --> 00:47:22,391 THIS BEAUTIFUL DATA, AND THE 1175 00:47:22,391 --> 00:47:24,593 RESULT WE HAVE, THE COMPANY 1176 00:47:24,593 --> 00:47:28,330 DECIDE TO LICENSE OUR C 1177 00:47:28,330 --> 00:47:29,431 CT3 ANTIBODY AND ARE GOING TO 1178 00:47:29,431 --> 00:47:32,468 SPONSOR A CLINICAL TRIAL IN 1179 00:47:32,468 --> 00:47:33,502 2025, WE ALREADY SIGNED THE 1180 00:47:33,502 --> 00:47:35,537 CONTRACT AND GOING TO WORK IN 1181 00:47:35,537 --> 00:47:38,641 THE POB TO LEAD THE TRIAL HERE. 1182 00:47:38,641 --> 00:47:40,009 SO WE'RE GOING TO SEE MORE IN 1183 00:47:40,009 --> 00:47:41,710 THE CLINIC. 1184 00:47:41,710 --> 00:47:42,911 SO AGAIN, WE WANT TO UNDERSTAND 1185 00:47:42,911 --> 00:47:44,680 THE MECHANISM. 1186 00:47:44,680 --> 00:47:47,850 SO WHY THE F TCR IS MORE ACTIVE 1187 00:47:47,850 --> 00:47:49,051 THAN CAR, WE DON'T KNOW, THE 1188 00:47:49,051 --> 00:47:50,486 SHORT ANSWER IS WE DON'T KNOW. 1189 00:47:50,486 --> 00:47:53,022 MAYBE IT'S HUMANIZED CT3 FAB 1190 00:47:53,022 --> 00:47:55,658 SEQUENCE OF THE MICE FLOATING 1191 00:47:55,658 --> 00:47:57,860 WITH HUMAN SCAFFOLD BECAUSE THE 1192 00:47:57,860 --> 00:47:59,928 MOUSE WON'T WORK AS GOOD AS 1193 00:47:59,928 --> 00:48:01,697 HUMANIZED ONE, OR MAYBE NATIVE 1194 00:48:01,697 --> 00:48:05,434 TCR SIGNALING IS MORE REG 1195 00:48:05,434 --> 00:48:07,403 LATIVE, LESS EXHAUSTED, MORE 1196 00:48:07,403 --> 00:48:08,637 PERSISTENT, MORE TUMOR 1197 00:48:08,637 --> 00:48:10,072 INFILTRATION, SO WE CAN NAME ANY 1198 00:48:10,072 --> 00:48:12,908 OF THEM POTENTIALLY WHY IT'S 1199 00:48:12,908 --> 00:48:13,275 WORKING BETTER. 1200 00:48:13,275 --> 00:48:15,344 SO I JUST WANT TO SHOW ONE 1201 00:48:15,344 --> 00:48:17,212 PRELIMINARY DATA DONE BY ALEX 1202 00:48:17,212 --> 00:48:18,514 TRAN, ANOTHER POSTBAC IN THE 1203 00:48:18,514 --> 00:48:22,351 LAB, AND WE ACTUALLY TAKE THOSE 1204 00:48:22,351 --> 00:48:24,453 T CELLS, RECOVER THEM FROM THE 1205 00:48:24,453 --> 00:48:26,689 MICE, TREAT THEM WITH F TCR AND 1206 00:48:26,689 --> 00:48:27,656 COMPARE TO THE CAR. 1207 00:48:27,656 --> 00:48:29,491 FROM WEEK TWO TO WEEK FOUR. 1208 00:48:29,491 --> 00:48:31,260 WHICH IS VERY STRIKING. 1209 00:48:31,260 --> 00:48:37,333 IF YOU LOOK AT THE TSCM IS A 1210 00:48:37,333 --> 00:48:38,634 T-CELL LIKE MEMORY T CELLS. 1211 00:48:38,634 --> 00:48:42,905 IT SHOWS THE STEMNESS OF THE T 1212 00:48:42,905 --> 00:48:43,539 CELLS. 1213 00:48:43,539 --> 00:48:46,008 FROM WEEK TWO TO WEEK FOUR, 1214 00:48:46,008 --> 00:48:48,010 BASICALLY WE KEEP MORE OF THEM 1215 00:48:48,010 --> 00:48:51,513 40% STEMNESS, THE TSCM 1216 00:48:51,513 --> 00:48:51,980 POPULATION. 1217 00:48:51,980 --> 00:48:53,115 THAT MEANS IT'S VERY HIGH 1218 00:48:53,115 --> 00:48:57,686 STEMNESS OF THIS HUMANIZED AB 1219 00:48:57,686 --> 00:48:58,020 TCR. 1220 00:48:58,020 --> 00:49:01,890 MOST IS ONLY 20%, 30%, BUT MUCH 1221 00:49:01,890 --> 00:49:04,293 LESS IN THE CT3 CAR. 1222 00:49:04,293 --> 00:49:05,260 IT ONLY 8%. 1223 00:49:05,260 --> 00:49:10,332 SO THAT MEANS AB TCR IN GENERAL 1224 00:49:10,332 --> 00:49:12,534 HAS MORE MEMORY MARKERS, HAS 1225 00:49:12,534 --> 00:49:14,503 MORE STEMNESS THAN THE CAR. 1226 00:49:14,503 --> 00:49:17,706 AND THE HUMANIZED AB TCR EVEN 1227 00:49:17,706 --> 00:49:19,241 HAS MORE STEMNESS AND ENRICHED 1228 00:49:19,241 --> 00:49:22,945 MORE MEMORY MARKERS THAN THE 1229 00:49:22,945 --> 00:49:25,180 MOUSE CT3 AB TCR. 1230 00:49:25,180 --> 00:49:26,448 SO WE'RE STILL LEARNING IT AND 1231 00:49:26,448 --> 00:49:30,419 WHY THIS IS THE MECHANISM OF THE 1232 00:49:30,419 --> 00:49:34,256 EFFECT. 1233 00:49:34,256 --> 00:49:38,327 SO CONCLUSION, WE ACTUALLY SHOW 1234 00:49:38,327 --> 00:49:39,661 GPC123 TARGET FOR TREATING 1235 00:49:39,661 --> 00:49:40,996 PANCREATIC CANCER, PEDIATRIC 1236 00:49:40,996 --> 00:49:43,399 CANCER, LIVER CANCER. 1237 00:49:43,399 --> 00:49:45,501 UPCOMING CLINICAL TRIAL WILL -- 1238 00:49:45,501 --> 00:49:47,636 AS A TUMOR TARGET IN HUMANS, 1239 00:49:47,636 --> 00:49:49,138 NANOBODY CAN BE ENGINEERED AS A 1240 00:49:49,138 --> 00:49:53,842 BUILDING BLOCK FOR CAR-T AND 1241 00:49:53,842 --> 00:49:55,411 ENGINEER -- MIGHT BE MORE ACTIVE 1242 00:49:55,411 --> 00:49:56,945 PARTICULARLY IN LOW ANTIGEN 1243 00:49:56,945 --> 00:49:58,781 DENSITY TUMORS. 1244 00:49:58,781 --> 00:50:00,816 AND FOR NANOBODY, WE NEED TO 1245 00:50:00,816 --> 00:50:02,351 ENGINEER THE HINGE SO WE USE THE 1246 00:50:02,351 --> 00:50:04,420 SHORT IGG 4 HINGE FOR 1247 00:50:04,420 --> 00:50:05,821 NANOBODIES. 1248 00:50:05,821 --> 00:50:08,390 AND FOR FUTURE OF CAR 1249 00:50:08,390 --> 00:50:09,691 ENGINEERING I THINK WE NEED A 1250 00:50:09,691 --> 00:50:15,497 MORE TARGETED CAR, BY TARGET 1251 00:50:15,497 --> 00:50:18,700 TARGETING -- LIKE B7 -- 3 PLUS 1252 00:50:18,700 --> 00:50:22,438 GPC2 WHICH IS -- AND WE ARE 1253 00:50:22,438 --> 00:50:26,275 WORKING WITH DR. -- IN 1254 00:50:26,275 --> 00:50:27,943 PANCREATIC CANCER AND WE STILL 1255 00:50:27,943 --> 00:50:30,679 NEED TO LOOK AT THE OFF THE 1256 00:50:30,679 --> 00:50:32,881 SHELF ALLOGENIC CAR, NOT ONLY T 1257 00:50:32,881 --> 00:50:36,318 CELLS, MAYBE MICROPHAGE, 1258 00:50:36,318 --> 00:50:38,587 NEUTROPHIL, NK CELLS, EVEN 1259 00:50:38,587 --> 00:50:39,321 GAMMA-DELTA T CELLS MAY BE THE 1260 00:50:39,321 --> 00:50:41,590 ONE WE WANT TO FOCUS ON TO 1261 00:50:41,590 --> 00:50:43,459 SELECT AND TO BE ABLE TO 1262 00:50:43,459 --> 00:50:46,195 ENGINEER THEM. 1263 00:50:46,195 --> 00:50:50,732 SO WITH THAT, I THI THANK MANY 1264 00:50:50,732 --> 00:50:52,367 MEMBERS AND COLLEAGUES THAT HAVE 1265 00:50:52,367 --> 00:50:53,268 HELPED ON THE PROJECT. 1266 00:50:53,268 --> 00:50:56,238 I THINK WITHOUT THOSE VERY 1267 00:50:56,238 --> 00:50:57,773 TALENTED POSTDOC PH.D. STUDENT 1268 00:50:57,773 --> 00:50:59,575 AND POSTBACS, MEDICAL STUDENTS, 1269 00:50:59,575 --> 00:51:01,710 NOTHING CAN BE DONE HERE IN THE 1270 00:51:01,710 --> 00:51:04,279 LAST 15, 16 YEARS. 1271 00:51:04,279 --> 00:51:07,783 I THINK WE OWE THEM BIG THANKS, 1272 00:51:07,783 --> 00:51:09,418 AND THE COLLABORATORS, WE HAVE 1273 00:51:09,418 --> 00:51:11,887 TIM GRETEN IS LEADING THE LIVER 1274 00:51:11,887 --> 00:51:16,925 CANCER TRIAL AND POB IS -- THE 1275 00:51:16,925 --> 00:51:17,993 CANCER TRIAL NEXT YEAR WITH 1276 00:51:17,993 --> 00:51:19,361 THAT, AND ALSO WE HAVE A LOT OF 1277 00:51:19,361 --> 00:51:21,163 FUNDING FROM MOONSHOT, AND 1278 00:51:21,163 --> 00:51:22,764 SUPPORTED BY LIVER CANCER 1279 00:51:22,764 --> 00:51:26,535 PROGRAM, MANY OTHER PROGRAMS, 1280 00:51:26,535 --> 00:51:28,303 PEOPLE ALWAYS HELP TO BRING THE 1281 00:51:28,303 --> 00:51:29,771 CRADA AND THE LICENSING 1282 00:51:29,771 --> 00:51:30,806 OPPORTUNITY TO US. 1283 00:51:30,806 --> 00:51:31,840 WITH THAT, THANK YOU VERY MUCH. 1284 00:51:31,840 --> 00:51:42,017 [APPLAUSE] 1285 00:51:45,721 --> 00:51:47,055 >> THAT WAS A GREAT TALK, 1286 00:51:47,055 --> 00:51:47,756 MITCHELL. 1287 00:51:47,756 --> 00:51:49,892 ONE QUESTION I WANT TO SORT OF 1288 00:51:49,892 --> 00:51:53,996 POSE, AND MAYBE SHIN WEI CAN 1289 00:51:53,996 --> 00:51:54,630 COMMENT IN ADDITION TO THIS. 1290 00:51:54,630 --> 00:51:57,900 YOU MENTIONED THE IMPORTANCE OF 1291 00:51:57,900 --> 00:51:59,234 TARGET IDENTIFICATION AND 1292 00:51:59,234 --> 00:52:00,569 FINDING SPECIFIC ISOFORMS THAT 1293 00:52:00,569 --> 00:52:02,337 ARE TUMOR-SPECIFIC VERSUS ONES 1294 00:52:02,337 --> 00:52:03,972 THAT MIGHT BE EXPRESSED IN 1295 00:52:03,972 --> 00:52:04,606 NORMAL TISSUES. 1296 00:52:04,606 --> 00:52:06,008 DO YOU HAVE ANY COMMENTS AS TO 1297 00:52:06,008 --> 00:52:07,976 HOW WE GO ABOUT DOING THAT, 1298 00:52:07,976 --> 00:52:09,077 USING NEXT GENERATION 1299 00:52:09,077 --> 00:52:11,213 SEQUENCING, TISSUE MICRO ARRAYS, 1300 00:52:11,213 --> 00:52:11,480 ET CETERA? 1301 00:52:11,480 --> 00:52:11,847 THANK YOU. 1302 00:52:11,847 --> 00:52:14,149 >> I THINK THIS IS A QUESTION 1303 00:52:14,149 --> 00:52:15,384 PROBABLY FOR SHIN WEI. 1304 00:52:15,384 --> 00:52:18,220 SO I THINK IN GENERAL, AS FAR AS 1305 00:52:18,220 --> 00:52:22,291 I KNOW, I HAVE VERY LIMITED 1306 00:52:22,291 --> 00:52:22,558 KNOWLEDGE. 1307 00:52:22,558 --> 00:52:24,226 THEY ARE THE EXPERTS. 1308 00:52:24,226 --> 00:52:29,031 SO I THINK LIMITED KNOWLEDGE, 1309 00:52:29,031 --> 00:52:30,766 CURRENT TCGA AND MANY OTHER 1310 00:52:30,766 --> 00:52:32,067 DATABASE, IT'S VERY DIFFICULT TO 1311 00:52:32,067 --> 00:52:34,870 DIG IN TO THE ISOFORM AND IT'S 1312 00:52:34,870 --> 00:52:35,837 NOT SET FOR THAT PURPOSE. 1313 00:52:35,837 --> 00:52:37,406 I THINK WITH MORE COMPUTATIONAL 1314 00:52:37,406 --> 00:52:41,043 SKILLS AND MORE DEEP SEQUENCING 1315 00:52:41,043 --> 00:52:42,911 AND IMPROVEMENT, WE'LL GET MORE 1316 00:52:42,911 --> 00:52:44,746 AND MORE DATA AND I THINK THE 1317 00:52:44,746 --> 00:52:46,882 ISOFORM OF THE ANTIGEN LIKE THIS 1318 00:52:46,882 --> 00:52:52,487 WILL BETHIS, WE'LL BE ABLE TO FE 1319 00:52:52,487 --> 00:52:52,754 AND MORE. 1320 00:52:52,754 --> 00:52:54,256 >> THANK YOU SO MUCH. 1321 00:52:54,256 --> 00:52:56,992 I ECHO WHAT FREDDIE SAID. 1322 00:52:56,992 --> 00:52:57,993 FANTASTIC TALK. 1323 00:52:57,993 --> 00:53:00,562 REALLY EXCITING STUDY. 1324 00:53:00,562 --> 00:53:02,164 SO I WAS ACTUALLY THINKING WHILE 1325 00:53:02,164 --> 00:53:03,732 YOU WERE PRESENTING THE STUDY, 1326 00:53:03,732 --> 00:53:05,300 ONE OF -- ACTUALLY THIS IS NOT 1327 00:53:05,300 --> 00:53:11,640 DIRECTED TO YOUR WORK, THE CAR-T 1328 00:53:11,640 --> 00:53:13,041 THERAPY OFTEN -- THE MAJOR 1329 00:53:13,041 --> 00:53:15,911 PROBLEM IS THAT THE ANTIGEN 1330 00:53:15,911 --> 00:53:18,347 OFTEN BECOMES DIMINISHED IN 1331 00:53:18,347 --> 00:53:20,215 TUMOR THAT AS A RESULT, YOU GET 1332 00:53:20,215 --> 00:53:22,384 CONSTANTLY RELAPSE, RIGHT? 1333 00:53:22,384 --> 00:53:24,753 BUT I ASSUME -- I LIKE TO SEE 1334 00:53:24,753 --> 00:53:29,891 YOU HAVE THE NEW APPROACH, AB 1335 00:53:29,891 --> 00:53:30,325 TCR. 1336 00:53:30,325 --> 00:53:32,060 DO YOU THINK YOU CAN DESIGN A 1337 00:53:32,060 --> 00:53:34,096 STUDY TO TITRATE DIFFERENT 1338 00:53:34,096 --> 00:53:35,297 ANTIGEN LEVEL IN CELLS WITH 1339 00:53:35,297 --> 00:53:38,233 DOING SORT OF MIXTURES OF CELL 1340 00:53:38,233 --> 00:53:40,369 AND THEN TESTING WHETHER THIS IS 1341 00:53:40,369 --> 00:53:42,337 POTENTIALLY WOULD BE ABLE TO 1342 00:53:42,337 --> 00:53:43,205 ACTUALLY ELIMINATE THOSE 1343 00:53:43,205 --> 00:53:45,540 PROBLEMS? 1344 00:53:45,540 --> 00:53:48,176 >> THE AB TCR WILL KILL THE 1345 00:53:48,176 --> 00:53:49,511 CELLS BECAUSE THEY'RE VERY LOW 1346 00:53:49,511 --> 00:53:53,015 DENSITY, SO WE DO N THEY DO NOTE 1347 00:53:53,015 --> 00:53:54,683 A CLANS TO ESCAPE, IS THAT WHAT 1348 00:53:54,683 --> 00:53:55,017 YOU'RE ASKING? 1349 00:53:55,017 --> 00:53:55,417 >> YEAH. 1350 00:53:55,417 --> 00:53:56,752 >> WE COULD CERTAINLY DO THAT, 1351 00:53:56,752 --> 00:54:00,656 AND WE ACTUALLY NEED TO DO MORE 1352 00:54:00,656 --> 00:54:01,857 SINGLE CELL-BASED STUDY TO SEE 1353 00:54:01,857 --> 00:54:06,328 WHETHER WE HAVE THIS ESCAPE. 1354 00:54:06,328 --> 00:54:10,532 I THINK IN GENERAL, YOU WILL SEE 1355 00:54:10,532 --> 00:54:13,602 THE ANTIGEN ESCAPED IN THE 1356 00:54:13,602 --> 00:54:15,370 CLINICAL -- EVEN IN THE MICE, 1357 00:54:15,370 --> 00:54:18,073 AND SO I THINK THOSE KIND OF 1358 00:54:18,073 --> 00:54:21,343 THINGS WILL HAPPEN EVENTUALLY IN 1359 00:54:21,343 --> 00:54:25,414 CERTAIN PERCENTAGE WITH AB TCR 1360 00:54:25,414 --> 00:54:26,648 COULD ACTUALLY BE ABLE TO KILL 1361 00:54:26,648 --> 00:54:27,616 THEM BEFORE THEY ACTUALLY 1362 00:54:27,616 --> 00:54:27,949 ESCAPED. 1363 00:54:27,949 --> 00:54:30,786 SO I THINK THAT'S SOMETHING -- 1364 00:54:30,786 --> 00:54:33,488 WE DEFINITELY SHOULD LOOK. 1365 00:54:33,488 --> 00:54:38,326 >> FIRST OF ALL I WOULD -- 1366 00:54:38,326 --> 00:54:39,628 FANTASTIC TALK AND I HAVE 1367 00:54:39,628 --> 00:54:40,962 LEARNED A LOT. 1368 00:54:40,962 --> 00:54:44,266 MY QUESTION IS THAT BECAUSE GPC3 1369 00:54:44,266 --> 00:54:48,970 AND OTHER GPCs MAY BE 1370 00:54:48,970 --> 00:54:49,838 HETEROGENEOUS -- IN TUMOR CELLS, 1371 00:54:49,838 --> 00:54:51,973 IS THERE A CORRELATION BETWEEN 1372 00:54:51,973 --> 00:54:53,709 THE IMPRESSION OF THE CELLS AND 1373 00:54:53,709 --> 00:54:57,446 THE EFFICIENCY FOR THE 1374 00:54:57,446 --> 00:54:58,413 THERAPEUTIC AND WHETHER THERE 1375 00:54:58,413 --> 00:55:01,416 ARE CERTAIN MARKERS EXCEPT FOR 1376 00:55:01,416 --> 00:55:02,617 GPC3 THAT CAN BE PREDICTIVE 1377 00:55:02,617 --> 00:55:04,586 MARKERS FOR THE EITHER PATIENTS 1378 00:55:04,586 --> 00:55:06,488 OR THE MICE BENEFIT FROM THE 1379 00:55:06,488 --> 00:55:06,722 THERAPY? 1380 00:55:06,722 --> 00:55:09,024 THANK YOU. 1381 00:55:09,024 --> 00:55:11,760 >> VERY GOOD QUESTIONS. 1382 00:55:11,760 --> 00:55:13,195 I THINK YOUR FIRST QUESTION IS 1383 00:55:13,195 --> 00:55:17,699 KIND OF RELATED TO WHAT SHIN WEI 1384 00:55:17,699 --> 00:55:22,304 ASKING, BASICALLY IF YOU KILL 1385 00:55:22,304 --> 00:55:23,939 QUICKLY, THEY MAY NOT HAVE 1386 00:55:23,939 --> 00:55:25,407 CHANCE FOR SELECTION, AND THAT'S 1387 00:55:25,407 --> 00:55:28,810 WHAT AB TCR MIGHT BE DOING. 1388 00:55:28,810 --> 00:55:32,447 SO WHETHER YOU'RE ASKING WHETHER 1389 00:55:32,447 --> 00:55:34,416 THERE'S SOME PREDICTION, HIGH OR 1390 00:55:34,416 --> 00:55:35,851 LOW GPC, SO FIRST OF ALL HIGH OR 1391 00:55:35,851 --> 00:55:37,252 LOW GPC CORRELATE WITH 1392 00:55:37,252 --> 00:55:38,453 EFFICIENCY, I WOULD SAY WE DON'T 1393 00:55:38,453 --> 00:55:39,187 KNOW. 1394 00:55:39,187 --> 00:55:41,723 SO THAT'S WHY IN THE CLINICAL 1395 00:55:41,723 --> 00:55:43,992 TRIAL, WE SET THE -- VERY LOW, 1396 00:55:43,992 --> 00:55:47,562 25%, SO ANY PATIENT HAVE 25% 1397 00:55:47,562 --> 00:55:49,531 POSITIVITY FOR GPC3, WE WILL 1398 00:55:49,531 --> 00:55:50,398 RECRUIT THEM. 1399 00:55:50,398 --> 00:55:52,901 SO DOESN'T MATTER THEY HAVE 1400 00:55:52,901 --> 00:55:53,702 CHEMOTHERAPY, CHECKPOINT 1401 00:55:53,702 --> 00:55:54,636 THERAPY, WHATEVER, SO WE DON'T 1402 00:55:54,636 --> 00:55:55,370 CARE. 1403 00:55:55,370 --> 00:55:57,038 SO BECAUSE WE DON'T KNOW MUCH 1404 00:55:57,038 --> 00:56:01,176 ABOUT, YOU KNOW, WHAT ARE YOU 1405 00:56:01,176 --> 00:56:03,745 ASKING, WHAT IS THE BIOMARKER 1406 00:56:03,745 --> 00:56:04,513 FOR RESPONSE. 1407 00:56:04,513 --> 00:56:07,082 SO BASICALLY IN PHASE ONE 1408 00:56:07,082 --> 00:56:07,883 CLINICAL TRIAL WE INCLUDE 1409 00:56:07,883 --> 00:56:08,283 ANTIBODY. 1410 00:56:08,283 --> 00:56:10,051 AS LONG AS THEY HAVE 25% 1411 00:56:10,051 --> 00:56:10,919 POSITIVE, WE INCLUDE THEM. 1412 00:56:10,919 --> 00:56:12,154 WE DON'T CARE THEIR MEDICAL 1413 00:56:12,154 --> 00:56:13,155 HISTORY AND WHAT KIND OF 1414 00:56:13,155 --> 00:56:14,689 TREATMENT THEY HAVE. 1415 00:56:14,689 --> 00:56:16,324 SO WE LEARN THAT FROM THE PHASE 1416 00:56:16,324 --> 00:56:19,060 ONE CLINICAL TRIAL AND PROBABLY 1417 00:56:19,060 --> 00:56:21,496 YOU AND SHEN WEI EVENTUALLY 1418 00:56:21,496 --> 00:56:22,497 INVOLVED TO ANALYZE THOSE THINGS 1419 00:56:22,497 --> 00:56:25,433 TO BE ABLE TO HELP US TO 1420 00:56:25,433 --> 00:56:28,503 UNDERSTAND WHY SOME PATIENTS 1421 00:56:28,503 --> 00:56:29,538 RESPOND, SOME PATIENTS MAY NOT 1422 00:56:29,538 --> 00:56:30,539 RESPOND. 1423 00:56:30,539 --> 00:56:31,973 THESE ARE VERY COMPLICATED 1424 00:56:31,973 --> 00:56:33,074 THINGS I DON'T THINK WE KNOW 1425 00:56:33,074 --> 00:56:37,112 NOW. 1426 00:56:37,112 --> 00:56:38,580 >> ECHOING EVERYONE ELSE, THANK 1427 00:56:38,580 --> 00:56:40,215 YOU FOR THAT WONDERFUL TALK. 1428 00:56:40,215 --> 00:56:41,216 I APOLOGIZE BECAUSE I MIGHT HAVE 1429 00:56:41,216 --> 00:56:44,519 MISSED IT, BUT IN YOUR F TCR 1430 00:56:44,519 --> 00:56:45,520 CONSTRUCTS, IS THERE ANY 1431 00:56:45,520 --> 00:56:47,055 EVIDENCE OF WHETHER IT PAIRS 1432 00:56:47,055 --> 00:56:48,623 WITH ENDOGENOUS TCR CHAINS OR 1433 00:56:48,623 --> 00:56:53,328 NOT? 1434 00:56:53,328 --> 00:56:55,297 WITH YOUR F TCR CONSTRUCTS, IS 1435 00:56:55,297 --> 00:56:57,132 THERE ANY EVIDENCE OF WHETHER 1436 00:56:57,132 --> 00:56:58,767 ENDOGENOUS TCR LIKE ALPHA OR 1437 00:56:58,767 --> 00:57:02,137 BETA OR EVEN GAMMA-DELTA 1438 00:57:02,137 --> 00:57:02,370 COMPARE? 1439 00:57:02,370 --> 00:57:02,904 >> YES, YES. 1440 00:57:02,904 --> 00:57:04,172 THANK YOU FOR THE QUESTION. 1441 00:57:04,172 --> 00:57:07,676 YES, THE REASON WE DEVELOP 1442 00:57:07,676 --> 00:57:10,045 GAMMA-DELTA IS -- ALPHA BETA IS 1443 00:57:10,045 --> 00:57:12,414 TO TRY TO AVOID A MISMATCH WITH 1444 00:57:12,414 --> 00:57:17,118 ALPHA BETA BECAUSE GAMMA DELTA 1445 00:57:17,118 --> 00:57:18,820 PCR VERY LOW PERCENTAGE IN 1446 00:57:18,820 --> 00:57:19,788 SEPARATING T CELLS. 1447 00:57:19,788 --> 00:57:23,959 SO GAMMA DATA TCR IN GENERAL, IN 1448 00:57:23,959 --> 00:57:25,760 HUMANS IS TUCKED IN VIRUS, SO 1449 00:57:25,760 --> 00:57:28,163 THEY ARE PROTECTED FROM THE 1450 00:57:28,163 --> 00:57:31,233 VIRAL INFORECASTS. 1451 00:57:31,233 --> 00:57:34,169 SO THEY DON'T NEED TO HAVE A 1452 00:57:34,169 --> 00:57:36,438 LOT -- SO VERY SMALL NUMBER. 1453 00:57:36,438 --> 00:57:39,941 SO USING GAMMA BETA TCR WE WOULD 1454 00:57:39,941 --> 00:57:41,409 NOT HAVE A CHANCE TO MISMATCH 1455 00:57:41,409 --> 00:57:43,178 WITH ALPHA BETA BECAUSE MOST OF 1456 00:57:43,178 --> 00:57:45,680 THE T CELLS ARE ALPHA BETA. 1457 00:57:45,680 --> 00:57:47,015 AND IN TERMS OF WHETHER THEY 1458 00:57:47,015 --> 00:57:48,917 WERE MISMATCHED WITH THEIR OWN 1459 00:57:48,917 --> 00:57:52,520 NATIVE GAMMA-DELTA, SO WE DON'T 1460 00:57:52,520 --> 00:57:54,089 KNOW, AND SINCE THE NUMBER OF 1461 00:57:54,089 --> 00:57:56,391 THE GHANA DELTA TCR IN THE TOTAL 1462 00:57:56,391 --> 00:57:57,392 T-CELL POPULATION IS VERY, VERY 1463 00:57:57,392 --> 00:57:57,893 LOW. 1464 00:57:57,893 --> 00:58:01,830 MY FEELING IS NO, BECAUSE 1465 00:58:01,830 --> 00:58:03,365 SOMEBODY TOLD ME, I DID NOT DO 1466 00:58:03,365 --> 00:58:06,568 THIS IN MY LAB, BECAUSE 1467 00:58:06,568 --> 00:58:07,969 GAMMA-DELTA TCRs ARE DESIGNED 1468 00:58:07,969 --> 00:58:12,741 OR SELECTED DURING THE EVOLUTION 1469 00:58:12,741 --> 00:58:14,142 TO ATTACK THE VIRAL INFECTIONS 1470 00:58:14,142 --> 00:58:17,612 SO THEY DON'T LIKE VIRUS, AND WE 1471 00:58:17,612 --> 00:58:18,914 USE LENTIVIRUS TO INDUCE THE T 1472 00:58:18,914 --> 00:58:20,215 CELLS AND THEY USUALLY DON'T 1473 00:58:20,215 --> 00:58:20,882 LIKE IT. 1474 00:58:20,882 --> 00:58:23,451 SO IN FACT, YOU'RE VERY LESS 1475 00:58:23,451 --> 00:58:25,320 LIKELY TO INFECT OUR GAMMA-DELTA 1476 00:58:25,320 --> 00:58:27,088 TCR IN THE GAMMA-DELTA T CELLS 1477 00:58:27,088 --> 00:58:28,790 BECAUSE WE USE LENTIVIRUS. 1478 00:58:28,790 --> 00:58:30,091 THEY USUALLY KICK THEM OUT. 1479 00:58:30,091 --> 00:58:31,526 SO THEY DON'T LIKE ANY VIRUS. 1480 00:58:31,526 --> 00:58:34,863 IN FACT, MOST OF THE T CELLS WE 1481 00:58:34,863 --> 00:58:36,498 INFECT MIGHT BE ACTUALLY ALPHA 1482 00:58:36,498 --> 00:58:38,133 BETA, NOT GAMMA-DELTA, SO THERE 1483 00:58:38,133 --> 00:58:39,167 IS NO CHANCE TO MISMATCH WITH 1484 00:58:39,167 --> 00:58:39,534 OURS. 1485 00:58:39,534 --> 00:58:40,835 >> I SEE. 1486 00:58:40,835 --> 00:58:42,671 SO YOU JUST HAVE NEVER ASSESSED 1487 00:58:42,671 --> 00:58:43,271 IT, THOUGH -- 1488 00:58:43,271 --> 00:58:46,007 >> SO WE DON'T KNOW -- BUT THE 1489 00:58:46,007 --> 00:58:47,208 COMPANY ACTUALLY WORKING ON 1490 00:58:47,208 --> 00:58:50,845 THAT, THEY ACTUALLY PRESENTED AT 1491 00:58:50,845 --> 00:58:53,214 ACR MEETING -- IN VITRO, TRY TO 1492 00:58:53,214 --> 00:58:54,616 SELECT AND GROW THEM, BUT IT'S 1493 00:58:54,616 --> 00:58:57,218 VERY HARD TO PUT THE -- BECAUSE 1494 00:58:57,218 --> 00:58:59,387 THEY DON'T LIKE THE CAR. 1495 00:58:59,387 --> 00:59:01,790 CAR USE LENTIVIRUS NEUTRALIZE 1496 00:59:01,790 --> 00:59:03,091 DOESN'T MATTER WHAT VIRUS YOU 1497 00:59:03,091 --> 00:59:04,693 USE UNLESS YOU USE -- 1498 00:59:04,693 --> 00:59:06,661 JENNIFER -- TALK ABOUT THE -- 1499 00:59:06,661 --> 00:59:08,630 SELECTING, THE VECTOR OR 1500 00:59:08,630 --> 00:59:10,332 VEHICLES, MAY BE SOMETHING ELSE, 1501 00:59:10,332 --> 00:59:12,100 BUT I DON'T KNOW THAT, BUT IF 1502 00:59:12,100 --> 00:59:15,270 YOU USE THE VIRUS TO DELIVER THE 1503 00:59:15,270 --> 00:59:18,173 CAR, MAYBE GAMMA-DELTA TCR IS 1504 00:59:18,173 --> 00:59:18,807 VERY DIFFICULT TO DO. 1505 00:59:18,807 --> 00:59:19,874 >> VERY INTERESTING BIOLOGY. 1506 00:59:19,874 --> 00:59:27,382 THANK YOU. 1507 00:59:27,382 --> 00:59:32,620 >> WE'LL DO A CAST QUESTION ANDD 1508 00:59:32,620 --> 00:59:33,755 THANK YOU ON BEHALF OF EVERYONE. 1509 00:59:33,755 --> 00:59:35,457 SO I WAS FASCINATED WHERE YOU 1510 00:59:35,457 --> 00:59:36,891 LOOKED AT INTEGRATION OF CAR-T. 1511 00:59:36,891 --> 00:59:41,229 SO DO YOU THINK THAT SOME OR ARE 1512 00:59:41,229 --> 00:59:42,430 MORE ACTIVE BECAUSE THEY'RE ALSO 1513 00:59:42,430 --> 00:59:43,832 KNOCKING OUT SOMETHING ELSE? 1514 00:59:43,832 --> 00:59:44,699 >> ABSOLUTELY. 1515 00:59:44,699 --> 00:59:46,901 YEAH. 1516 00:59:46,901 --> 00:59:48,937 WE THINK IT COULD BE KNOCKOUT, 1517 00:59:48,937 --> 00:59:52,474 COULD BE DOMINANT NEGATIVE. 1518 00:59:52,474 --> 00:59:54,376 >> I GUESS THE QUESTION IS -- 1519 00:59:54,376 --> 00:59:56,845 >> SO WE DON'T KNOW MUCH ABOUT 1520 00:59:56,845 --> 00:59:57,746 THE BIOLOGY OF THAT. 1521 00:59:57,746 --> 01:00:00,281 WE HAVE TO DO THE FUNCTION ASSAY 1522 01:00:00,281 --> 01:00:00,482 TO -- 1523 01:00:00,482 --> 01:00:03,184 >> SO SEPARATE THEM OUT, AND 1524 01:00:03,184 --> 01:00:04,352 THEN SO THAT WOULD PREDICT MAYBE 1525 01:00:04,352 --> 01:00:06,654 IF YOU KNOCKED THAT GENE FIRST, 1526 01:00:06,654 --> 01:00:10,158 ALL OF YOUR CAR-T WOULD BE 1527 01:00:10,158 --> 01:00:10,458 HYPERACTIVE. 1528 01:00:10,458 --> 01:00:11,259 >> RIGHT. 1529 01:00:11,259 --> 01:00:16,498 SO WE TRY TO DEVELOP THE SO-C 1530 01:00:16,498 --> 01:00:19,667 SO-CALLED NON-VIRAL -- METHOD 1531 01:00:19,667 --> 01:00:21,703 TO -- AND THEN TO STUDY THEM. 1532 01:00:21,703 --> 01:00:23,905 SO WE TRY TO AVOID THE VIRUS 1533 01:00:23,905 --> 01:00:25,540 BECAUSE VIRUS TEND TO BRING 1534 01:00:25,540 --> 01:00:26,141 EXTRA THINGS. 1535 01:00:26,141 --> 01:00:26,641 >> OTHER THINGS. 1536 01:00:26,641 --> 01:00:31,846 >> YEAH, SO WE TRY TO USE KNOWNO 1537 01:00:31,846 --> 01:00:36,217 VIRUSES IN THE LAB -- SEVERAL 1538 01:00:36,217 --> 01:00:38,153 MONTHS AGO, JUST FOCUS ON THAT, 1539 01:00:38,153 --> 01:00:42,490 AND JUST TRY TO MAKE A MESSAGE 1540 01:00:42,490 --> 01:00:44,125 WITH OTHER VIRUS AND BE ABLE TO 1541 01:00:44,125 --> 01:00:47,262 USE THE GENOME EDITING TO EDIT 1542 01:00:47,262 --> 01:00:48,897 THE T CELLS' GENOME SO WE CAN 1543 01:00:48,897 --> 01:00:50,432 PUT THE CAR IN THE SPECIFIC SITE 1544 01:00:50,432 --> 01:00:50,932 WE WANT. 1545 01:00:50,932 --> 01:00:51,199 >> GREAT. 1546 01:00:51,199 --> 01:00:53,034 SO WE'LL LOOK FORWARD TO THE 1547 01:00:53,034 --> 01:00:54,469 NEXT CHAPTER OR MANY CHAPTERS 1548 01:00:54,469 --> 01:00:56,104 AND THE RESULTS OF THE CLINICAL 1549 01:00:56,104 --> 01:00:58,273 TRIALS, AND I'LL THANK YOU FOR A 1550 01:00:58,273 --> 01:01:00,542 WONDERFUL TALK, AND BEAUTIFUL 1551 01:01:00,542 --> 01:01:02,444 WORK AND THANK THE AUDIENCE FOR 1552 01:01:02,444 --> 01:01:03,278 GREAT QUESTIONS. 1553 01:01:03,278 --> 01:01:13,455 [APPLAUSE]