1 00:00:07,866 --> 00:00:13,138 >> THANK YOU ALL FOR COMING, AND 2 00:00:13,138 --> 00:00:16,207 HAVING I THINK A REALLY EXCITING LECTURE. 3 00:00:16,207 --> 00:00:18,843 YOU'RE IN FOR A TREAT. 4 00:00:18,843 --> 00:00:21,880 I OF COURSE KNOW THIS INTIMATELY 5 00:00:21,880 --> 00:00:25,717 BECAUSE I'M INTRODUCING ONE OF 6 00:00:25,717 --> 00:00:31,189 MY BEST FRIENDS AND COLLEAGUES 7 00:00:31,189 --> 00:00:35,360 AT THE CCR NCI WYN WILSON. 8 00:00:35,360 --> 00:00:38,430 IT'S REALLY SPECIAL BECAUSE I 9 00:00:38,430 --> 00:00:40,799 THINK WYNDHAM IS SPECIAL AND 10 00:00:40,799 --> 00:00:42,801 EPITOMIZES WHAT WE SHOULD BE 11 00:00:42,801 --> 00:00:45,870 DOING AS A CLINICAL SCIENTIST, I 12 00:00:45,870 --> 00:00:46,871 WOULD SAY. 13 00:00:46,871 --> 00:00:50,475 YOU KNOW, NOTICE I DIDN'T 14 00:00:50,475 --> 00:00:52,711 JUST -- SO WE'RE -- WHAT WORKS 15 00:00:52,711 --> 00:00:58,149 VERY WELL IN THE TEAM IS THAT 16 00:00:58,149 --> 00:01:00,986 WYNDHAM BEGAN AS I DID AS AN 17 00:01:00,986 --> 00:01:04,489 MD/PHD AT STANFORD. 18 00:01:04,489 --> 00:01:09,761 I WAS AT PENN, AND DID, YOU 19 00:01:09,761 --> 00:01:11,730 KNOW, VERY SOLID 20 00:01:11,730 --> 00:01:13,264 LABORATORY-BASED WORK, AND HE 21 00:01:13,264 --> 00:01:17,168 THEN FOUND THAT HE GOT MORE 22 00:01:17,168 --> 00:01:20,038 GRATIFICATION OUT OF THINKING 23 00:01:20,038 --> 00:01:20,905 ABOUT CLINICAL PROBLEMS. 24 00:01:20,905 --> 00:01:24,175 I, ON THE OTHER HAND, RAN THE 25 00:01:24,175 --> 00:01:26,811 OPPOSITE DIRECTION AND AFTER A 26 00:01:26,811 --> 00:01:29,147 YEAR OF CLINIC, I HAD IT, I JUST 27 00:01:29,147 --> 00:01:30,782 HAD IT. 28 00:01:30,782 --> 00:01:35,053 BUT THE POINT IS I MET WYNDHAM, 29 00:01:35,053 --> 00:01:38,523 HE HAD BEEN HERE IN THE NCI FOR 30 00:01:38,523 --> 00:01:42,927 SOME TIME, HAD GREAT MENTORS, 31 00:01:42,927 --> 00:01:44,763 DAN LONGO, BRUCE CHADNER, BUT I 32 00:01:44,763 --> 00:01:47,732 MET HIM AT A P.I. RETREAT. 33 00:01:47,732 --> 00:01:50,568 SO ADVERTISEMENTS FOR THE P.I. 34 00:01:50,568 --> 00:01:52,237 RETREAT, AND SOMEBODY SAID YOU 35 00:01:52,237 --> 00:01:54,839 REALLY GOT TO MEET THIS GUY, 36 00:01:54,839 --> 00:01:59,444 WYNDHAM WILSON, AND I WAS JUST 37 00:01:59,444 --> 00:02:03,748 DEVELOPING SOME MOMENTUM ON 38 00:02:03,748 --> 00:02:07,085 STUDYING THE GENOMICS OF 39 00:02:07,085 --> 00:02:08,453 ESPECIALLY DIFFUSE LARGE B-CELL 40 00:02:08,453 --> 00:02:10,288 LYMPHOMA WHICH WYNDHAM WILL TALK 41 00:02:10,288 --> 00:02:10,722 ABOUT. 42 00:02:10,722 --> 00:02:13,224 THE REST IS HISTORY. 43 00:02:13,224 --> 00:02:16,327 THAT'S WELL OVER 23 YEARS OR SO 44 00:02:16,327 --> 00:02:19,297 THAT WE'VE WORKED TOGETHER. 45 00:02:19,297 --> 00:02:22,367 I WILL LET WYNDHAM TELL A LOT OF 46 00:02:22,367 --> 00:02:24,302 THE RECENT STORIES, BUT I DID 47 00:02:24,302 --> 00:02:25,670 WANT TO HIGHLIGHT SOME 48 00:02:25,670 --> 00:02:27,706 INTERESTING THINGS THAT TELL YOU 49 00:02:27,706 --> 00:02:29,441 ABOUT HIM. 50 00:02:29,441 --> 00:02:39,184 SO, ONE THING IS HIS VERY 51 00:02:39,184 --> 00:02:40,952 UNCONVENTIONAL AND INTEREST IN 52 00:02:40,952 --> 00:02:43,788 EXPLORING THE UNEXPLORED, I 53 00:02:43,788 --> 00:02:44,689 WOULD SAY. 54 00:02:44,689 --> 00:02:50,061 SO, HE WOULD DO THINGS -- HE 55 00:02:50,061 --> 00:02:53,198 WOULD HAVE RARE PATIENTS WITH 56 00:02:53,198 --> 00:02:59,204 LYMPHOMAS, SUCH AS THOSE WITH AN 57 00:02:59,204 --> 00:03:04,676 EBV-DRIVEN PROCESS CALLED 58 00:03:04,676 --> 00:03:05,477 LYMPHOMATOID GRANULOMATOSIS, 59 00:03:05,477 --> 00:03:07,946 THAT LED HIM TO DEVELOP OVER A 60 00:03:07,946 --> 00:03:14,285 VERY LONG TIME FRAME, 30 YEARS, 61 00:03:14,285 --> 00:03:17,122 A SUCCESSFUL TREATMENT THAT 62 00:03:17,122 --> 00:03:19,324 PREVENTED PATIENTS WITH SORT OF 63 00:03:19,324 --> 00:03:21,292 LOW-GRADE DISEASE FROM 64 00:03:21,292 --> 00:03:23,361 PROGRESSING TO HIGH-GRADE 65 00:03:23,361 --> 00:03:24,896 DISEASE THAT WOULD KILL, AND AT 66 00:03:24,896 --> 00:03:28,199 THAT TIME THAT WAS VERY 67 00:03:28,199 --> 00:03:28,800 EXPERIMENTAL. 68 00:03:28,800 --> 00:03:30,368 THAT WAS INTERFERON. 69 00:03:30,368 --> 00:03:35,740 AND HIS HYPOTHESIS WAS SIMPLY 70 00:03:35,740 --> 00:03:37,909 THIS IS AN IMMUNE-MEDIATE 71 00:03:37,909 --> 00:03:39,144 DEFICIT AND INTERFERON WOULD DO 72 00:03:39,144 --> 00:03:40,311 IT, AND IT DID. 73 00:03:40,311 --> 00:03:45,950 MIND YOU, THIS IS STARTING IN -- 74 00:03:45,950 --> 00:03:49,487 WHAT WAS IT, 1997? 75 00:03:49,487 --> 00:03:49,954 1990, YEAH. 76 00:03:49,954 --> 00:03:54,559 SO, THIS IS WELL BEFORE ALL THE 77 00:03:54,559 --> 00:03:55,994 BUZZ AROUND IMMUNOTHERAPY. 78 00:03:55,994 --> 00:03:59,597 ANOTHER-- I WANT TO HIGHLIGHT 79 00:03:59,597 --> 00:04:03,535 THAT WYNDHAM'S WORK CHANGES 80 00:04:03,535 --> 00:04:06,838 PRACTICE, SO HE DEVELOPED A 81 00:04:06,838 --> 00:04:09,707 CONCEPT THAT YOU COULD GET A 82 00:04:09,707 --> 00:04:16,347 BETTER CELL KILL WITH 83 00:04:16,347 --> 00:04:17,248 CHEMOTHERAPY BY INFUSING THE 84 00:04:17,248 --> 00:04:19,217 CHEMOTHERAPY I.V., ESPECIALLY 85 00:04:19,217 --> 00:04:21,286 THE CONCEPT OF ESSENTIALLY IN 86 00:04:21,286 --> 00:04:22,520 VIVO PHARMACODYNAMICS. 87 00:04:22,520 --> 00:04:24,355 THAT IS, WITH EACH CYCLE OF 88 00:04:24,355 --> 00:04:28,226 CHEMOTHERAPY, YOU GO UP A NOTCH, 89 00:04:28,226 --> 00:04:33,898 AND YOUR MEASURE OF HITTING THE 90 00:04:33,898 --> 00:04:36,968 MARK IS NEUTROPENIA, SO BY DOING 91 00:04:36,968 --> 00:04:39,037 THIS YOU ESCALATE THE DOSES TO 92 00:04:39,037 --> 00:04:41,339 JUST WHAT THE PATIENT CAN 93 00:04:41,339 --> 00:04:44,509 TOLERATE, AND THAT IS CALLED 94 00:04:44,509 --> 00:04:47,045 DOSE ADJUSTMENT, AND THAT HAS 95 00:04:47,045 --> 00:04:53,251 BECOME A MAINSTAY IN LYMPHOMA 96 00:04:53,251 --> 00:04:54,419 THERAPY WORLDWIDE FOR THE 97 00:04:54,419 --> 00:05:00,291 TREATMENT OF ESPECIALLY THE MOST 98 00:05:00,291 --> 00:05:02,794 AGGRESSIVE SUBTYPES OF LYMPHOMA. 99 00:05:02,794 --> 00:05:05,964 AND THE FINAL ONE I WANT TO 100 00:05:05,964 --> 00:05:08,032 EMPHASIZE WHICH WILL BE A LITTLE 101 00:05:08,032 --> 00:05:11,336 BIT AT THE BEGINNING OF 102 00:05:11,336 --> 00:05:13,204 WYNDHAM'S TALK WILL BE STUDYING 103 00:05:13,204 --> 00:05:18,243 NEW DRUGS IN THE SPACE OF 104 00:05:18,243 --> 00:05:18,509 LYMPHOMA. 105 00:05:18,509 --> 00:05:21,946 AND I HAD BY CHANCE ENCOUNTER AT 106 00:05:21,946 --> 00:05:24,349 AN ACR MEETING BEEN APPROACHED 107 00:05:24,349 --> 00:05:29,954 BY A COMPANY WHO HAD A MOLECULE 108 00:05:29,954 --> 00:05:31,389 TARGETING BTK THAT THEY -- I 109 00:05:31,389 --> 00:05:41,232 FORGET WHAT THEY CALLED IT, PCI 110 00:05:41,232 --> 00:05:43,768 2765, I CAME BACK WYNDHAM HAD I 111 00:05:43,768 --> 00:05:45,937 WOULD SAY A HEALTHY SKEPTICISM 112 00:05:45,937 --> 00:05:47,372 BUT NOT THAT PREVENTED HIM FROM 113 00:05:47,372 --> 00:05:53,077 DOING THE EXPERIMENT, AND THAT 114 00:05:53,077 --> 00:05:59,951 IS IN UNBELIEVABLY SHORT TIME BY 115 00:05:59,951 --> 00:06:02,487 TODAY'S STANDARDS, MY EDITORIAL 116 00:06:02,487 --> 00:06:05,356 REMARK, BETWEEN 3 AND 6 MONTHS 117 00:06:05,356 --> 00:06:08,092 WYNDHAM WAS TREATING THE FIRST 118 00:06:08,092 --> 00:06:12,030 PATIENT WITH DIFFUSE LYMPHOMA 119 00:06:12,030 --> 00:06:13,564 EVER WITH ABRUTINIB MODEL 120 00:06:13,564 --> 00:06:14,132 THERAPY. 121 00:06:14,132 --> 00:06:16,501 AND THE PLAN WAS, WELL, LET'S 122 00:06:16,501 --> 00:06:18,836 JUST SEE IN 10 PATIENTS, AND WE 123 00:06:18,836 --> 00:06:20,004 GOT GOOD RESULTS IN 10 PATIENTS. 124 00:06:20,004 --> 00:06:22,674 AND THAT LED TO A NATIONAL 125 00:06:22,674 --> 00:06:24,175 STUDY, WYNDHAM WILL TELL YOU 126 00:06:24,175 --> 00:06:24,943 ABOUT THAT. 127 00:06:24,943 --> 00:06:27,245 SO I THINK IT'S THAT 128 00:06:27,245 --> 00:06:30,081 FEARLESSNESS THAT I'VE REALLY 129 00:06:30,081 --> 00:06:32,183 ENJOYED, HIS OPENNESS TO IDEAS. 130 00:06:32,183 --> 00:06:35,687 SO YOU'LL HEAR A LOT OF OTHER 131 00:06:35,687 --> 00:06:38,423 STUDIES THAT ARE EVEN FARTHER 132 00:06:38,423 --> 00:06:38,656 THERE. 133 00:06:38,656 --> 00:06:40,858 SO I WANT TO LEAVE SOME TIME, I 134 00:06:40,858 --> 00:06:42,694 DON'T WANT TO TAKE THE WHOLE 135 00:06:42,694 --> 00:06:42,894 TIME. 136 00:06:42,894 --> 00:06:44,362 YOU'VE DONE A LOT IN YOUR 137 00:06:44,362 --> 00:06:45,363 CAREER, MAN. 138 00:06:45,363 --> 00:06:49,200 SO MY PLEASURE TO INTRODUCE 139 00:06:49,200 --> 00:06:49,567 WYNDHAM WILSON. 140 00:06:49,567 --> 00:06:57,075 [APPLAUSE] 141 00:06:57,075 --> 00:06:58,176 >> WELL, I'M GLAD THE LIGHTS 142 00:06:58,176 --> 00:06:59,243 AREN'T TOO BRIGHT BECAUSE I 143 00:06:59,243 --> 00:07:01,379 DON'T WANT YOU TO SEE ALL MY 144 00:07:01,379 --> 00:07:02,780 REDNESS HERE. 145 00:07:02,780 --> 00:07:03,114 OKAY. 146 00:07:03,114 --> 00:07:06,084 SO, I'M GOING TO -- BECAUSE WE 147 00:07:06,084 --> 00:07:07,952 HAVE A VERY DIVERSE AUDIENCE -- 148 00:07:07,952 --> 00:07:11,222 TAKE YOU THROUGH A 24-YEAR 149 00:07:11,222 --> 00:07:13,324 JOURNEY FROM THE START OF WHEN 150 00:07:13,324 --> 00:07:16,494 LOU AND I FIRST STARTED TO WORK 151 00:07:16,494 --> 00:07:18,463 TOGETHER, ALL THE WAY THROUGH 152 00:07:18,463 --> 00:07:19,964 WHERE WE CURRENTLY ARE. 153 00:07:19,964 --> 00:07:22,533 AND THAT IS HOW LONG IT ACTUALLY 154 00:07:22,533 --> 00:07:24,502 TOOK TO GET US TO WHERE WE ARE 155 00:07:24,502 --> 00:07:24,669 NOW. 156 00:07:24,669 --> 00:07:27,538 BUT I THINK THERE ARE MANY, MANY 157 00:07:27,538 --> 00:07:31,175 LESSONS THAT WE CAN LEARN FROM 158 00:07:31,175 --> 00:07:33,344 GOING THROUGH THIS. 159 00:07:33,344 --> 00:07:34,779 SO, FOR THOSE THAT -- THOSE OF 160 00:07:34,779 --> 00:07:37,949 YOU WHO, YOU KNOW, JUST TO PUT 161 00:07:37,949 --> 00:07:40,451 LARGE CELL INTO PERSPECTIVE, 162 00:07:40,451 --> 00:07:42,353 IT'S THE FIFTH MOST COMMON -- 163 00:07:42,353 --> 00:07:47,258 NOT LARGE CELL BUT LYMPHOMA IS 164 00:07:47,258 --> 00:07:57,802 THE FIFTY MOST COMMON, LYMPHOMA 165 00:08:02,306 --> 00:08:02,940 THE LARGEST. 166 00:08:02,940 --> 00:08:04,742 WHERE ARE WE IN TERMS OF THIS 167 00:08:04,742 --> 00:08:05,009 TUMOR? 168 00:08:05,009 --> 00:08:06,544 WE CAN ACTUALLY CURE THIS. 169 00:08:06,544 --> 00:08:08,946 AND WE'VE BEEN ABLE TO CURE 170 00:08:08,946 --> 00:08:11,916 LARGE CELL SINCE THE EARLY 171 00:08:11,916 --> 00:08:16,287 1970s USING JUST CHEMOTHERAPY 172 00:08:16,287 --> 00:08:17,055 ALONE. 173 00:08:17,055 --> 00:08:19,223 IN THE 1970s, ONLY AROUND 25 174 00:08:19,223 --> 00:08:22,960 TO 30% OF PEOPLE COULD BE CURED. 175 00:08:22,960 --> 00:08:26,898 BUT NOW WITH THE USE OF 176 00:08:26,898 --> 00:08:32,270 IMMUNOTHERAPY, IN THIS CASE IT'S 177 00:08:32,270 --> 00:08:33,371 RITUXIMAB, WE'RE CURING 178 00:08:33,371 --> 00:08:35,540 SOMEWHERE IN THE -- SOMEWHERE 179 00:08:35,540 --> 00:08:37,375 AROUND 60% OVERALL. 180 00:08:37,375 --> 00:08:39,377 THIS MEANS THAT 30 TO 40% ARE 181 00:08:39,377 --> 00:08:40,578 NOT CURED. 182 00:08:40,578 --> 00:08:43,781 SO, WE NEED BETTER THERAPY, BOTH 183 00:08:43,781 --> 00:08:47,618 FOR UP-FRONT THERAPY, BUT ALSO 184 00:08:47,618 --> 00:08:48,586 ONCE SOMEBODY RELAPSES, THE 185 00:08:48,586 --> 00:08:51,222 ABILITY TO CURE THEM IS VERY, 186 00:08:51,222 --> 00:08:54,725 VERY LOW. 187 00:08:54,725 --> 00:09:03,534 AND SHOWN HERE IS -- SO THIS IS 188 00:09:03,534 --> 00:09:06,404 SHOWING WHAT THE CURE RATE OF 189 00:09:06,404 --> 00:09:10,675 RELAPSE REFRACTORY LARGE CELL IS 190 00:09:10,675 --> 00:09:12,210 USING STANDARD THERAPY AND OFTEN 191 00:09:12,210 --> 00:09:13,311 BONE MARROW TRANSPLANT. 192 00:09:13,311 --> 00:09:16,380 YOU CAN SEE YOU'RE ONLY CURING 193 00:09:16,380 --> 00:09:20,017 IN THE RELAPSE STATE AROUND 12%. 194 00:09:20,017 --> 00:09:22,086 SO, THE STATE OF THE ARCH WAS 195 00:09:22,086 --> 00:09:22,954 VERY, VERY POOR. 196 00:09:22,954 --> 00:09:26,524 I THINK WE'VE ALL BEEN VERY 197 00:09:26,524 --> 00:09:28,526 EXCITED BY CAR T CELLS AND WE'RE 198 00:09:28,526 --> 00:09:31,863 NOW SEEING IT BEING USED 199 00:09:31,863 --> 00:09:32,163 EVERYWHERE. 200 00:09:32,163 --> 00:09:34,699 BUT THE REALITY IS THERE'S A LOT 201 00:09:34,699 --> 00:09:37,635 OF SELECTION GOING ON WHEN YOU 202 00:09:37,635 --> 00:09:40,605 BRING PEOPLE IN FOR CAR T CELL 203 00:09:40,605 --> 00:09:40,838 THERAPY. 204 00:09:40,838 --> 00:09:44,976 WE'RE NOW FINDING THAT THERE'S 205 00:09:44,976 --> 00:09:47,945 EMERGING LATE-TERM CHRONIC 206 00:09:47,945 --> 00:09:49,247 TOXICITY INCLUDING INSERTIONAL 207 00:09:49,247 --> 00:09:50,781 MUTAGENESIS, WHICH IS STILL RARE 208 00:09:50,781 --> 00:09:52,984 BUT DOES LEAD TO PEOPLE DYING, 209 00:09:52,984 --> 00:09:56,154 AND YOU CAN SEE THAT WE'RE ONLY 210 00:09:56,154 --> 00:09:58,022 CURING AROUND 32% OF PEOPLE 211 00:09:58,022 --> 00:09:59,657 USING CAR T CELLS. 212 00:09:59,657 --> 00:10:04,595 SO THAT'S CERTAINLY BETTER THAN 213 00:10:04,595 --> 00:10:08,232 12 BUT WE STILL HAVE A LONG WAY 214 00:10:08,232 --> 00:10:09,433 TO MOVE THE FIELD. 215 00:10:09,433 --> 00:10:12,803 NOW, I'M GOING TO TAKE US ALL 216 00:10:12,803 --> 00:10:14,438 THE WAY BACK TO 2000 WHEN LOU 217 00:10:14,438 --> 00:10:16,841 AND I FIRST STARTED TO WORK 218 00:10:16,841 --> 00:10:17,275 TOGETHER. 219 00:10:17,275 --> 00:10:20,344 AND THIS IS WHERE LOU LED THE 220 00:10:20,344 --> 00:10:24,515 FIELD IN TRYING TO UNDERSTAND 221 00:10:24,515 --> 00:10:26,217 WHAT THE MOLECULAR BASIS FOR 222 00:10:26,217 --> 00:10:29,120 LARGE CELL IS, UP TO THIS POINT 223 00:10:29,120 --> 00:10:33,491 LARGE CELL WAS SIMPLY DEFINED AS 224 00:10:33,491 --> 00:10:38,229 BEING A B CELL TUMOR THAT WAS 225 00:10:38,229 --> 00:10:40,598 RELATIVELY LARGE, AND IT GREW IN 226 00:10:40,598 --> 00:10:42,934 A DIFFUSE PATTERN. 227 00:10:42,934 --> 00:10:44,769 IT MOSTLY GREW WITHIN LYMPH 228 00:10:44,769 --> 00:10:49,941 NODES, ALTHOUGH IT ALSO COULD GO 229 00:10:49,941 --> 00:10:52,577 INTO OTHER SITES AS WELL. 230 00:10:52,577 --> 00:10:54,579 WHEN YOU SAY DLBCL, DIFFUSE 231 00:10:54,579 --> 00:10:57,048 LARGE CELL, I THINK IT DOESN'T 232 00:10:57,048 --> 00:10:59,917 TAKE A ROCKET SCIENTIST TO 233 00:10:59,917 --> 00:11:01,886 REALIZE THIS IS SO GENERAL THAT 234 00:11:01,886 --> 00:11:03,221 IT'S PROBABLY NOT A SINGLE 235 00:11:03,221 --> 00:11:03,454 DISEASE. 236 00:11:03,454 --> 00:11:05,590 OF COURSE WE KNEW THAT 237 00:11:05,590 --> 00:11:06,591 CLINICALLY BECAUSE SOME PEOPLE 238 00:11:06,591 --> 00:11:08,326 WOULD DO VERY WELL, SOME PEOPLE 239 00:11:08,326 --> 00:11:09,727 WOULDN'T, AND WE DIDN'T 240 00:11:09,727 --> 00:11:12,163 UNDERSTAND WHY. 241 00:11:12,163 --> 00:11:14,565 SO LOU REALLY I -- I THINK THE 242 00:11:14,565 --> 00:11:17,501 FIRST MICROARRAY IN CANCER, 243 00:11:17,501 --> 00:11:21,372 CERTAINLY THE FIRST MICROARRAY 244 00:11:21,372 --> 00:11:24,875 IN LYMPHOID TUMORS, WHAT HE DID, 245 00:11:24,875 --> 00:11:26,611 HE ARRAYED SEVERAL HUNDRED LARGE 246 00:11:26,611 --> 00:11:31,549 CELLS AND ALSO ARRAYED NORMAL B 247 00:11:31,549 --> 00:11:33,251 CELLS, TONSILS, ET CETERA, TO BE 248 00:11:33,251 --> 00:11:35,253 ABLE TO ASK THE QUESTION WHETHER 249 00:11:35,253 --> 00:11:38,856 OR NOT YOU COULD DIVIDE LARGE 250 00:11:38,856 --> 00:11:40,191 CELL INTO DIFFERENT TUMORS, 251 00:11:40,191 --> 00:11:43,461 BASED ON THEIR STAGES OF 252 00:11:43,461 --> 00:11:46,197 DIFFERENTIATION WHERE YOU USED 253 00:11:46,197 --> 00:11:49,267 AS YOUR GOLD STANDARD THE NORMAL 254 00:11:49,267 --> 00:11:50,034 CELL. 255 00:11:50,034 --> 00:11:51,736 AND THIS ACTUALLY WAS THE WHOLE 256 00:11:51,736 --> 00:11:54,205 START OF THE FIELD OF TARGETED 257 00:11:54,205 --> 00:11:57,341 THERAPY IN LARGE CELL. 258 00:11:57,341 --> 00:12:00,645 AND THIS STUDY FROM "NATURE" WAS 259 00:12:00,645 --> 00:12:02,280 PUBLISHED BY LOU IN 2000. 260 00:12:02,280 --> 00:12:06,317 AND THE KEY HERE IS HE 261 00:12:06,317 --> 00:12:08,286 IDENTIFIED TWO MAJOR GROUPS, ONE 262 00:12:08,286 --> 00:12:10,788 WAS CALLED THE ABC, ACTIVATED B 263 00:12:10,788 --> 00:12:12,990 CELL, AND THIS IS A TUMOR THAT 264 00:12:12,990 --> 00:12:16,260 IS DERIVED FROM A POST-GERMINAL 265 00:12:16,260 --> 00:12:22,433 CENTER, B CELL, THE OTHER MAJOR 266 00:12:22,433 --> 00:12:25,670 GROUP IS GCB, GERMINAL CELL 267 00:12:25,670 --> 00:12:27,538 B-CELL TUMOR DERIVED FROM CELLS 268 00:12:27,538 --> 00:12:29,640 THAT STILL HAVE DIFFERENTIATION 269 00:12:29,640 --> 00:12:30,941 STATE, MORE OR LESS, OF THE 270 00:12:30,941 --> 00:12:31,542 GERMINAL CENTER. 271 00:12:31,542 --> 00:12:34,211 AND SOMETHING WE'RE NOT GOING TO 272 00:12:34,211 --> 00:12:37,481 BE DISCUSSING NOW IS ANOTHER 273 00:12:37,481 --> 00:12:39,684 TOPIC, PRIMARY MEDIASTINAL, THIS 274 00:12:39,684 --> 00:12:45,623 COMES FROM A THYMIC B CELL. 275 00:12:45,623 --> 00:12:47,391 SO, UNDERSTANDING NOW WE HAVE 276 00:12:47,391 --> 00:12:50,361 THESE TWO MAJOR GROUPS, ONE FROM 277 00:12:50,361 --> 00:12:51,862 THE POST-GERMINAL CENTER, AND 278 00:12:51,862 --> 00:12:55,066 ONE FROM A GERMINAL CENTER CELL. 279 00:12:55,066 --> 00:12:56,901 BUT IF YOU REALLY WANT TO HAVE 280 00:12:56,901 --> 00:12:59,103 TARGETED THERAPY, YOU WANT TO 281 00:12:59,103 --> 00:13:01,372 UNDERSTAND WHAT THE CRITICAL 282 00:13:01,372 --> 00:13:03,274 DRIVING SIGNALING OF PATHWAYS 283 00:13:03,274 --> 00:13:04,008 ARE. 284 00:13:04,008 --> 00:13:07,111 THE FIRST HINT OF THIS ALSO CAME 285 00:13:07,111 --> 00:13:11,716 FROM LOU'S WORK WHERE HE LOOKED 286 00:13:11,716 --> 00:13:12,917 AT EXPRESSION OF NF-kappaB 287 00:13:12,917 --> 00:13:20,358 TARGET GENES, AS YOU KNOW 288 00:13:20,358 --> 00:13:22,326 NF-kappaB IS A VERY POTENT 289 00:13:22,326 --> 00:13:24,829 SURVIVAL FACTOR, AND WHAT HE 290 00:13:24,829 --> 00:13:28,666 FOUND WAS THAT ABC HAD HIGH 291 00:13:28,666 --> 00:13:30,534 EXPRESSION OF THESE NF-kappaB 292 00:13:30,534 --> 00:13:33,270 TARGET GENES, WHEREAS GERMINAL 293 00:13:33,270 --> 00:13:35,873 CENTER DID NOT. 294 00:13:35,873 --> 00:13:39,076 SO, THIS THEN LED INTO 295 00:13:39,076 --> 00:13:41,245 UNDERSTANDING THE BEGINNING OF 296 00:13:41,245 --> 00:13:46,050 THE DISSECTION OF WHY IS 297 00:13:46,050 --> 00:13:47,618 NF-kappaB INCREASED IN ABC 298 00:13:47,618 --> 00:13:50,554 LARGE CELL, AND IT TURNS OUT 299 00:13:50,554 --> 00:13:55,393 THAT IT IS INCREASED BY 300 00:13:55,393 --> 00:13:56,360 CONSTITUATIVE B CELL RECEPTOR 301 00:13:56,360 --> 00:13:59,430 SIGNALING AND YOU CAN SEE THE 302 00:13:59,430 --> 00:14:00,965 CASCADE HERE. 303 00:14:00,965 --> 00:14:03,134 AND WHAT WAS EVENTUALLY WORKED 304 00:14:03,134 --> 00:14:06,737 OUT IN NUMBERS OF THESE CASES BY 305 00:14:06,737 --> 00:14:11,475 LOU WAS THAT YOU HAVE ACTUAL 306 00:14:11,475 --> 00:14:12,643 ACTIVATING MUTATIONS, HERE THIS 307 00:14:12,643 --> 00:14:16,280 IS THE B CELL RECEPTOR ITSELF, 308 00:14:16,280 --> 00:14:18,249 YOU HAVE ACTIVATING MUTATIONS 309 00:14:18,249 --> 00:14:22,520 WITHIN THE RECEPTOR ITSELF, AND 310 00:14:22,520 --> 00:14:29,326 THEN A COLLABORATING TOLL LIKE 311 00:14:29,326 --> 00:14:32,163 RECEPTOR, 88, CAR 11, NOW A 20, 312 00:14:32,163 --> 00:14:37,535 A TUMOR SUPPRESSOR, WHICH 313 00:14:37,535 --> 00:14:38,536 INHIBITS NF-kappaB. 314 00:14:38,536 --> 00:14:41,939 AND SO THIS WAS THE BEGINNING OF 315 00:14:41,939 --> 00:14:43,808 UNDERSTANDING ALL THESE 316 00:14:43,808 --> 00:14:44,675 MUTATIONS WERE ACCUMULATED 317 00:14:44,675 --> 00:14:46,977 WITHIN MANY OF THE ABC TUMOR 318 00:14:46,977 --> 00:14:51,048 CELLS, BECAUSE THEY WERE 319 00:14:51,048 --> 00:14:53,884 ENHANCING B CELL SIGNALING, 320 00:14:53,884 --> 00:14:55,119 ULTIMATELY NF-kappaB. 321 00:14:55,119 --> 00:15:04,395 SO, THIS ACTUALLY TAKES TO US 322 00:15:04,395 --> 00:15:05,496 WHERE LOU LED OFF THIS MORNING, 323 00:15:05,496 --> 00:15:08,466 THAT HE WENT TO A CONFERENCE 324 00:15:08,466 --> 00:15:15,239 WHERE THEY PRESENTED SOME DATA 325 00:15:15,239 --> 00:15:17,641 WITH IBRUTINIB THAT INHIBITED 326 00:15:17,641 --> 00:15:20,411 TYROSINE KINASE, BTK IS RIGHT 327 00:15:20,411 --> 00:15:28,185 HERE, LOU HYPOTHESIZED IF WE 328 00:15:28,185 --> 00:15:30,488 EXPOSED PATIENTS TO THIS DRUG, 329 00:15:30,488 --> 00:15:32,456 THAT WE WOULD SEE TUMOR 330 00:15:32,456 --> 00:15:34,091 REDUCTIONS IN ABC BECAUSE THAT'S 331 00:15:34,091 --> 00:15:39,763 THE GROUP THAT HAD THE 332 00:15:39,763 --> 00:15:40,865 NF-kappaB, CONSTITUATIVE BCR 333 00:15:40,865 --> 00:15:42,199 SIGNALING, WHEREAS WE WOULDN'T 334 00:15:42,199 --> 00:15:44,034 SEE IT WITHIN THE GERMINAL 335 00:15:44,034 --> 00:15:44,502 CENTER. 336 00:15:44,502 --> 00:15:46,237 I SAID, OH, YEAH, RIGHT, RIGHT, 337 00:15:46,237 --> 00:15:46,637 RIGHT. 338 00:15:46,637 --> 00:15:51,475 I MEAN, I HAD ALREADY TESTED 339 00:15:51,475 --> 00:15:57,414 MANY, MANY DRUGS BEFOREHAND, 340 00:15:57,414 --> 00:15:58,382 CAMTOTHECINS, TAXOL, SO MANY 341 00:15:58,382 --> 00:15:59,016 NEVER PANDEMIC OUT. 342 00:15:59,016 --> 00:16:02,186 THIS WAS ONE OF THE FIRST 343 00:16:02,186 --> 00:16:03,320 TARGETED AGENTS I HAD EVER 344 00:16:03,320 --> 00:16:04,188 WORKED WITH. 345 00:16:04,188 --> 00:16:07,091 SO I SET UP A CLINICAL TRIAL 346 00:16:07,091 --> 00:16:09,660 WITH LOU. 347 00:16:09,660 --> 00:16:13,030 IT WAS A SMALL PILOT STUDY WHERE 348 00:16:13,030 --> 00:16:16,000 WE BROUGHT IN RELAPSED 349 00:16:16,000 --> 00:16:19,303 REFRACTORY LARGE CELL AND WE 350 00:16:19,303 --> 00:16:21,705 EXPOSED THEM TO IBRUTINIB AND 351 00:16:21,705 --> 00:16:22,573 THEN WE'RE CHARACTERIZED WHETHER 352 00:16:22,573 --> 00:16:26,610 OR NOT THEY WERE OF THE ABC OR 353 00:16:26,610 --> 00:16:27,578 GERMINAL CENTER TYPE. 354 00:16:27,578 --> 00:16:30,314 AND THIS IS WHAT WE FOUND. 355 00:16:30,314 --> 00:16:34,485 THIS IS WHAT'S CALLED A 356 00:16:34,485 --> 00:16:36,654 WATERFALL PLOT, PERCENT CHANGE 357 00:16:36,654 --> 00:16:38,956 IN TUMOR SIZE, AND ANYTHING 358 00:16:38,956 --> 00:16:41,692 BELOW THIS LINE MEANS TUMOR 359 00:16:41,692 --> 00:16:45,095 SHRINKS, DOWN 50% IS HERE, DOWN 360 00:16:45,095 --> 00:16:45,963 100% HERE. 361 00:16:45,963 --> 00:16:47,598 WHEREAS THIS MEANS THE TUMOR 362 00:16:47,598 --> 00:16:47,965 GROWS. 363 00:16:47,965 --> 00:16:50,134 AND I DON'T KNOW IF YOU CAN 364 00:16:50,134 --> 00:16:53,203 APPRECIATE THAT, BUT IN GENERAL, 365 00:16:53,203 --> 00:16:55,606 THERE WERE CERTAINLY FEWER OF 366 00:16:55,606 --> 00:16:57,975 THESE GERMINAL CENTER TYPES THAT 367 00:16:57,975 --> 00:17:02,746 SHRANK WELL ACTIVE TO THE ABC 368 00:17:02,746 --> 00:17:03,847 TYPE. 369 00:17:03,847 --> 00:17:06,150 BUT WHEN WE ACTUALLY GO TO 370 00:17:06,150 --> 00:17:07,251 IDENTIFY WHETHER OR NOT WE 371 00:17:07,251 --> 00:17:10,321 CONSIDER IT TO BE A CLINICALLY 372 00:17:10,321 --> 00:17:11,188 MEANINGFUL CHANGE, WE REQUIRE IT 373 00:17:11,188 --> 00:17:14,925 TO BE AT LEAST A 50% OF 374 00:17:14,925 --> 00:17:16,760 REDUCTION IN TUMOR SIZE. 375 00:17:16,760 --> 00:17:19,930 SO WHEN WE USE THAT CRITERIA, 376 00:17:19,930 --> 00:17:24,702 WHAT WE FOUND WAS THAT THE ABC 377 00:17:24,702 --> 00:17:27,071 TYPE HAD 15 OUT OF 39 PATIENTS 378 00:17:27,071 --> 00:17:30,341 HAVE AT LEAST A 50% SHRINKAGE 379 00:17:30,341 --> 00:17:33,744 AND ALMOST HALF OF THOSE HAD A 380 00:17:33,744 --> 00:17:36,046 COMPLETE RESOLUTION OF THEIR 381 00:17:36,046 --> 00:17:37,014 TUMOR. 382 00:17:37,014 --> 00:17:38,549 WHEREAS IN THE GERMINAL CENTER 383 00:17:38,549 --> 00:17:41,485 TYPE, THERE WAS ONLY ONE OUT OF 384 00:17:41,485 --> 00:17:45,022 20, SO THIS REALLY WAS THE FIRST 385 00:17:45,022 --> 00:17:47,291 VALIDATION CLINICALLY THAT THIS 386 00:17:47,291 --> 00:17:49,827 DRUG MIGHT BE PREFERENTIALLY 387 00:17:49,827 --> 00:17:54,298 USEFUL WITHIN THE ABC TYPE. 388 00:17:54,298 --> 00:17:57,468 NOW, LOU AND I WENT ON FURTHER 389 00:17:57,468 --> 00:17:59,169 AND ASKED THE QUESTION AS TO 390 00:17:59,169 --> 00:18:01,972 WHETHER OR NOT THERE WERE 391 00:18:01,972 --> 00:18:04,041 CERTAIN TYPES OF ABCs THAT 392 00:18:04,041 --> 00:18:07,645 MIGHT BE MORE OR LESS SENSITIVE 393 00:18:07,645 --> 00:18:09,980 TO THIS DRUG, AND WE KNEW THAT 394 00:18:09,980 --> 00:18:12,149 THERE WERE ALL THESE MUTATIONS 395 00:18:12,149 --> 00:18:21,659 THAT I'VE ALREADY POINTED OUT, 396 00:18:21,659 --> 00:18:24,061 MYD88, AND THE BCR RECEPTOR, AND 397 00:18:24,061 --> 00:18:26,063 WE FELT THAT IF A TUMOR IN FACT 398 00:18:26,063 --> 00:18:28,999 HAD BOTH OF THESE THEY WOULD 399 00:18:28,999 --> 00:18:32,403 HAVE BEEN HYPER-ADDICTED TO B 400 00:18:32,403 --> 00:18:33,270 CELL RECEPTOR SIGNALING. 401 00:18:33,270 --> 00:18:36,240 AND SO WHEN WE ACTUALLY LOOKED 402 00:18:36,240 --> 00:18:37,107 AT -- THESE WERE RELATIVELY 403 00:18:37,107 --> 00:18:39,410 SMALL NUMBERS BUT YOU CAN SEE 404 00:18:39,410 --> 00:18:41,278 AMONG THOSE TUMORS FIVE CASES 405 00:18:41,278 --> 00:18:44,248 THAT HAD BOTH A MUTATION WITHIN 406 00:18:44,248 --> 00:18:47,651 THE BCR RECEPTOR ITSELF AS WELL 407 00:18:47,651 --> 00:18:49,286 AS MyD88, THE RESPONSE RATE 408 00:18:49,286 --> 00:18:52,156 WAS 4 OUT OF 5. 409 00:18:52,156 --> 00:18:57,895 WE ALSO FOUND THAT IF IT WAS 410 00:18:57,895 --> 00:19:00,030 ONLY MyD88 ALONE, OR A WILD 411 00:19:00,030 --> 00:19:03,567 TYPE, THAT THEY ALSO RESPONDED 412 00:19:03,567 --> 00:19:06,503 BUT AGAIN NOT AS VIGOROUSLY AS 413 00:19:06,503 --> 00:19:09,673 IF THEY HAD BOTH OF THESE. 414 00:19:09,673 --> 00:19:12,543 SO WE IDENTIFIED THIS GROUP AS A 415 00:19:12,543 --> 00:19:19,983 GROUP THAT WAS HYPERADDICTED TO 416 00:19:19,983 --> 00:19:20,918 B CELL RECEPTOR SIGNALING. 417 00:19:20,918 --> 00:19:23,454 ONE THING I WANT TO POINT OUT, 418 00:19:23,454 --> 00:19:25,289 AND THIS IS CRITICAL, WHEN 419 00:19:25,289 --> 00:19:29,593 YOU'RE DEALING WITH TUMORS THAT 420 00:19:29,593 --> 00:19:30,594 HAVE MULTIPLE DIFFERENT 421 00:19:30,594 --> 00:19:32,329 MUTATIONS, LIKE LARGE CELL DOES, 422 00:19:32,329 --> 00:19:35,933 AND EVEN THOSE THAT ARE OF THE 423 00:19:35,933 --> 00:19:39,670 SINGLE TYPE SUCH AS ABC, THERE 424 00:19:39,670 --> 00:19:41,305 ARE MULTIPLE POINTS THAT THE 425 00:19:41,305 --> 00:19:45,442 TUMOR IS ABLE TO HIT IN ORDER TO 426 00:19:45,442 --> 00:19:46,643 INCREASE NF-kappaB AND SO IF 427 00:19:46,643 --> 00:19:50,080 YOU HAVE A SINGLE DRUG THERE'S 428 00:19:50,080 --> 00:19:54,852 LIKELY TO BE A WORKAROUND BY THE 429 00:19:54,852 --> 00:19:57,054 TUMOR CELLS, MEANING IF WE 430 00:19:57,054 --> 00:19:58,989 SIMPLY LOOK AT A KAPLAN-MEIER 431 00:19:58,989 --> 00:20:05,496 CURVE, WHETHER OR NOT WE HAVE 432 00:20:05,496 --> 00:20:07,765 DURABLE RESPONSES TO THESE 433 00:20:07,765 --> 00:20:11,969 DRUGS, YOU CAN SEE AS A SINGLE 434 00:20:11,969 --> 00:20:15,773 AGENT, ALTHOUGH IBRUTINIB MADE 435 00:20:15,773 --> 00:20:17,541 THE TUMOR SHRINK IN 40% OF ABC 436 00:20:17,541 --> 00:20:19,276 TYPES, THESE WERE NOT DURABLE. 437 00:20:19,276 --> 00:20:21,044 A SINGLE AGENT WAS NOT CURATIVE. 438 00:20:21,044 --> 00:20:23,781 I WILL SAY THERE WAS LIKE ONE OR 439 00:20:23,781 --> 00:20:27,050 TWO PATIENTS THAT WENT ON TO 440 00:20:27,050 --> 00:20:29,219 STAY IN REMISSION FOR YEARS AND 441 00:20:29,219 --> 00:20:31,755 YEARS, BUT THAT WAS BY FAR A 442 00:20:31,755 --> 00:20:32,956 VERY RARE EVENT. 443 00:20:32,956 --> 00:20:40,097 IF WE LOOK AT THE GCB TYPE, WE 444 00:20:40,097 --> 00:20:40,864 SEE NONE. 445 00:20:40,864 --> 00:20:47,738 I'M GOING TO NOW JUMP AHEAD TO 446 00:20:47,738 --> 00:20:53,443 ANOTHER CLASSIC PAPER THAT LOU 447 00:20:53,443 --> 00:20:59,483 PUBLISHED IN 2018 WHERE HE THEN 448 00:20:59,483 --> 00:21:03,420 FURTHER SUBDIVIDED LARGE CELLS 449 00:21:03,420 --> 00:21:06,924 INTO GENETIC TYPE BASED ON 450 00:21:06,924 --> 00:21:09,092 PROFILE. 451 00:21:09,092 --> 00:21:12,162 IT TURNS OUT ABC TYPE CAN BE 452 00:21:12,162 --> 00:21:14,498 DIVIDED INTO MULTIPLE TYPES, AND 453 00:21:14,498 --> 00:21:17,534 THE GERMINAL CENTER TYPE 454 00:21:17,534 --> 00:21:17,801 SIMILARLY. 455 00:21:17,801 --> 00:21:21,138 WHAT I WANT TO POINT OUT IS THAT 456 00:21:21,138 --> 00:21:23,774 THE MCD TYPE, THIS ONE UP HERE, 457 00:21:23,774 --> 00:21:28,745 IS CHARACTERIZED BY HAVING THESE 458 00:21:28,745 --> 00:21:30,013 MUTATIONS WITHIN MyD88 AND 459 00:21:30,013 --> 00:21:32,316 CD79B, SO THIS IS WHAT WE 460 00:21:32,316 --> 00:21:37,888 CONSIDER TO BE THE POSTER CHILD 461 00:21:37,888 --> 00:21:41,992 FOR FOR HYPERADDICTED LARGE 462 00:21:41,992 --> 00:21:45,696 CELLS TO B CELL RECEPTOR 463 00:21:45,696 --> 00:21:46,129 SIGNALING. 464 00:21:46,129 --> 00:21:50,500 SO, HOW COULD WE FURTHER TEST 465 00:21:50,500 --> 00:21:53,670 THIS IDEA THAT INHIBITING BTK 466 00:21:53,670 --> 00:21:54,771 COULD BE ESPECIALLY ACTIVE 467 00:21:54,771 --> 00:21:58,375 WITHIN THAT GROUP? 468 00:21:58,375 --> 00:21:59,610 WELL, TURNS OUT THERE IS A TYPE 469 00:21:59,610 --> 00:22:05,482 OF TUMOR WHERE THE CHANCE OF 470 00:22:05,482 --> 00:22:07,384 HAVING BOTH MyD88 AND CD79B IS 471 00:22:07,384 --> 00:22:08,252 VERY, VERY HIGH. 472 00:22:08,252 --> 00:22:12,723 IF YOU LOOK ACROSS YOUR 473 00:22:12,723 --> 00:22:16,360 CONVENTIONAL ABCs, AND AGAIN 474 00:22:16,360 --> 00:22:18,128 MOST TUMORS, LARGE CELL, GROW 475 00:22:18,128 --> 00:22:21,298 WITHIN NODES THAT YOU CAN SEE 476 00:22:21,298 --> 00:22:23,901 THAT AMONG SO-CALLED NODAL LARGE 477 00:22:23,901 --> 00:22:25,903 CELL, THAT'S ABC TYPE, HAVING 478 00:22:25,903 --> 00:22:26,970 BOTH IS RELATIVELY RARE. 479 00:22:26,970 --> 00:22:34,311 BUT IT TURNS OUT THAT IF YOU 480 00:22:34,311 --> 00:22:37,047 LOOK AT EXTRA-NODAL TUMORS, 481 00:22:37,047 --> 00:22:39,683 FOCUSING ON PRIMARY CNS, 37% OF 482 00:22:39,683 --> 00:22:42,519 THESE TUMORS HAVE BOTH OF THESE, 483 00:22:42,519 --> 00:22:45,489 AND THIS TUMOR TYPE IS HIGHLY 484 00:22:45,489 --> 00:22:47,190 ENRICHED FOR MCD TYPE. 485 00:22:47,190 --> 00:22:49,726 SO, WE ASKED THE QUESTION, OKAY, 486 00:22:49,726 --> 00:22:51,929 WE THINK THIS DRUG SHOULD WORK 487 00:22:51,929 --> 00:22:54,331 REALLY, REALLY WELL THERE, BUT 488 00:22:54,331 --> 00:22:57,601 NOBODY HAD EVER TESTED IT. 489 00:22:57,601 --> 00:23:00,003 SO, WE WENT AHEAD AND DID 490 00:23:00,003 --> 00:23:02,072 ANOTHER CLINICAL TRIAL. 491 00:23:02,072 --> 00:23:03,840 THIS IS A LITTLE DIFFERENT 492 00:23:03,840 --> 00:23:04,041 STUDY. 493 00:23:04,041 --> 00:23:07,978 IN THIS CASE WE ALSO TOOK 494 00:23:07,978 --> 00:23:08,679 RELAPSED REFRACTORY TUMORS, THEY 495 00:23:08,679 --> 00:23:11,815 WERE ALL OF THESE PRIMARY CNS 496 00:23:11,815 --> 00:23:15,986 TYPES, AND WE DID A WINDOW USING 497 00:23:15,986 --> 00:23:18,488 IBRUTINIB ALONE FOR A TWO-WEEK 498 00:23:18,488 --> 00:23:20,457 PERIOD AND ADDED THAT TO 499 00:23:20,457 --> 00:23:20,791 CHEMOTHERAPY. 500 00:23:20,791 --> 00:23:22,759 THE REASON WE DID THAT IS 501 00:23:22,759 --> 00:23:26,029 BECAUSE THESE ARE HIGHLY LETHAL 502 00:23:26,029 --> 00:23:26,396 TUMORS. 503 00:23:26,396 --> 00:23:28,365 ONCE YOU RECUR, THE CHANCE OF 504 00:23:28,365 --> 00:23:31,201 DYING FROM THEM IS ESSENTIALLY 505 00:23:31,201 --> 00:23:31,635 100%. 506 00:23:31,635 --> 00:23:34,604 AND SO WE FELT THAT GIVEN THE 507 00:23:34,604 --> 00:23:41,144 WORK WE HAD DONE WITH IBRUTINIB 508 00:23:41,144 --> 00:23:43,447 WE WERE HOPING THE IBRUTINIB 509 00:23:43,447 --> 00:23:47,684 WOULD SHRINK TUMORS DOWN BUT 510 00:23:47,684 --> 00:23:48,819 DIDN'T THINK IT WOULD ERADICATE 511 00:23:48,819 --> 00:23:49,586 THEM. 512 00:23:49,586 --> 00:23:52,322 I WON'T GO INTO THE ENTIRE 513 00:23:52,322 --> 00:23:55,926 CLINICAL TRIAL. 514 00:23:55,926 --> 00:23:58,662 THE THERAPY IS CALLED TEDDY-OR, 515 00:23:58,662 --> 00:24:01,298 A PROGRAM MARK IS LEADING BUT 516 00:24:01,298 --> 00:24:08,872 I'M SHOWING THE WATER FALL PLOT 517 00:24:08,872 --> 00:24:10,707 FROM THIS TWO-WEEK WINDOW. 518 00:24:10,707 --> 00:24:12,376 EVERY PATIENT BUT ONE HAD 519 00:24:12,376 --> 00:24:14,644 SIGNIFICANT SHRINKAGE OF TUMOR. 520 00:24:14,644 --> 00:24:19,182 TWO IN FACT ACHIEVED A COMPLETE 521 00:24:19,182 --> 00:24:21,218 REMISSION WITH THIS DRUG. 522 00:24:21,218 --> 00:24:26,490 SO THIS REALLY WAS A VERY 523 00:24:26,490 --> 00:24:28,759 EXCITING FINDING THAT 524 00:24:28,759 --> 00:24:32,362 HYPERADDICTED ABC TUMORS WOULD 525 00:24:32,362 --> 00:24:38,068 BE HYPERSENSITIVE TO INHIBITING 526 00:24:38,068 --> 00:24:41,872 ABRUTINIB TYROSINE KINASE. 527 00:24:41,872 --> 00:24:49,346 WE DID A LARGE INTERNATIONAL 528 00:24:49,346 --> 00:24:58,288 PHASE 3 TRIAL ADDING IBRUTINIB 529 00:24:58,288 --> 00:25:01,058 IN PATIENTS WITH NON-GCB LARGE 530 00:25:01,058 --> 00:25:01,491 CELL. 531 00:25:01,491 --> 00:25:04,294 THIS WAS UNTREATED, RANDOMIZED 532 00:25:04,294 --> 00:25:05,529 STUDY, PATIENTS WERE RANDOMIZED 533 00:25:05,529 --> 00:25:08,598 IN A BLINDED FASHION TO GET 534 00:25:08,598 --> 00:25:11,968 R-CHOP STANDARD OF CARE PLUS OR 535 00:25:11,968 --> 00:25:12,969 MINUS IBRUTINIB THERAPY. 536 00:25:12,969 --> 00:25:14,938 I'M NOT GOING INTO WHY WE HAVE 537 00:25:14,938 --> 00:25:19,409 THIS BASED ON AGE BUT TURNED OUT 538 00:25:19,409 --> 00:25:21,311 IBRUTINIB IS TOXIC IN PEOPLE 539 00:25:21,311 --> 00:25:26,016 THAT ARE OLDER BUT YOU CAN SEE 540 00:25:26,016 --> 00:25:30,387 THOSE PATIENTS WITH ABC TYPE AND 541 00:25:30,387 --> 00:25:35,092 PATIENTS UNDER 60 ALL HAD 542 00:25:35,092 --> 00:25:36,726 SIGNIFICANT CLINICAL BENEFIT AND 543 00:25:36,726 --> 00:25:45,168 INCREASED CURE WHEN EYE 544 00:25:45,168 --> 00:25:49,785 IBRUTINIB WAS ADDED TO R-CHOP. 545 00:25:49,785 --> 00:25:56,926 MCD IS HYPERADDICTED, AND 100% OF THOSE PATIENTS THAT RECEIVED 546 00:25:56,926 --> 00:26:00,329 R-CHOP PLUS IBRUTINIB ARE CURED 547 00:26:00,329 --> 00:26:03,399 VERSUS ABOUT 40% OF THOSE WHO 548 00:26:03,399 --> 00:26:05,134 RECEIVE R-CHOP ALONE. 549 00:26:05,134 --> 00:26:08,204 SO, THIS IS ALL BUILDING ON THIS 550 00:26:08,204 --> 00:26:10,106 IDEA THAT THE BCR RECEPTOR 551 00:26:10,106 --> 00:26:13,676 SIGNALING CASCADE IS SOMETHING 552 00:26:13,676 --> 00:26:18,047 THAT WE SHOULD BE FOCUSING ON TO 553 00:26:18,047 --> 00:26:20,116 DEVELOP A TARGETED THERAPY. 554 00:26:20,116 --> 00:26:22,451 SO, JUST TO KIND OF BRING US ALL 555 00:26:22,451 --> 00:26:26,289 AT THE SAME POINT HERE, WE'VE 556 00:26:26,289 --> 00:26:28,491 SEEN THAT LARGE CELL IS NOT A 557 00:26:28,491 --> 00:26:30,326 SINGLE DISEASE TYPE. 558 00:26:30,326 --> 00:26:32,862 IT IS A VERY COMPLEX DISEASE 559 00:26:32,862 --> 00:26:35,798 TYPE WITH MANY DIFFERENT TYPES. 560 00:26:35,798 --> 00:26:39,101 IT'S SIMPLY DEFINED BY BEING 561 00:26:39,101 --> 00:26:44,440 LARGE, B, AND GROWING IN A 562 00:26:44,440 --> 00:26:47,009 DIFFUSE WAY. 563 00:26:47,009 --> 00:26:49,045 AND THAT HITTING THE BCR 564 00:26:49,045 --> 00:26:50,212 SIGNALING IS EFFECTIVE, 565 00:26:50,212 --> 00:26:53,883 ESPECIALLY IN THOSE THAT ARE 566 00:26:53,883 --> 00:26:56,819 HYPERADDICTED TO IT, AND THAT 567 00:26:56,819 --> 00:26:59,121 THERE ARE MULTIPLE MUTATIONS 568 00:26:59,121 --> 00:27:04,593 ALONG THE BCR SIGNALING THAT ARE 569 00:27:04,593 --> 00:27:05,895 ENHANCING NF-kappaB. 570 00:27:05,895 --> 00:27:09,398 SO, HOW DO WE THINK ABOUT THIS 571 00:27:09,398 --> 00:27:13,035 IN TERMS OF TRYING TO COME UP 572 00:27:13,035 --> 00:27:18,841 WITH A WAY TO HIT MULTIPLE 573 00:27:18,841 --> 00:27:21,210 POINTS IN THIS CASCADE AND TO 574 00:27:21,210 --> 00:27:23,512 CURE PEOPLE WITH THIS TUMOR? 575 00:27:23,512 --> 00:27:27,650 AND SO, AGAIN, I GO BACK TO THIS 576 00:27:27,650 --> 00:27:32,655 HERE, AND YOU CAN SEE AGAIN ALL 577 00:27:32,655 --> 00:27:35,124 THE DIFFERENT MUTATIONS, AND SO 578 00:27:35,124 --> 00:27:39,395 THIS IS WHERE WE WERE WHEN LOU 579 00:27:39,395 --> 00:27:41,897 AND I AND THE TEAM BEGAN TO 580 00:27:41,897 --> 00:27:45,301 THINK ABOUT HOW DO WE COME UP 581 00:27:45,301 --> 00:27:48,704 WITH A BETTER THERAPY, BETTER 582 00:27:48,704 --> 00:27:50,606 TARGETED THERAPY. 583 00:27:50,606 --> 00:27:53,609 FIRST OFF, THE STATE OF THE ART 584 00:27:53,609 --> 00:27:57,013 WAS THAT TARGETED THERAPIES WERE 585 00:27:57,013 --> 00:27:59,415 CONVENTIONALLY GIVEN AS SINGLE 586 00:27:59,415 --> 00:28:00,950 AGENTS, WE ACTUALLY STARTED SOME 587 00:28:00,950 --> 00:28:03,352 OF THAT BY HAVING GIVEN 588 00:28:03,352 --> 00:28:07,523 IBRUTINIB AS A SINGLE AGENT. 589 00:28:07,523 --> 00:28:10,359 AND THEY WERE GIVEN CHRONICALLY 590 00:28:10,359 --> 00:28:13,562 AND ONLY GIVEN AS A SINGLE OR A 591 00:28:13,562 --> 00:28:16,065 DOUBLET BECAUSE IF YOU TRIED TO 592 00:28:16,065 --> 00:28:19,235 GIVE THESE KINDS OF AGENT, 593 00:28:19,235 --> 00:28:19,902 MULTIPLE AGENTS CHRONICALLY, YOU 594 00:28:19,902 --> 00:28:21,637 SIMPLY CAN'T DO IT. 595 00:28:21,637 --> 00:28:24,373 RUN INTO INTO MANY SIDE EFFECTS 596 00:28:24,373 --> 00:28:27,476 THAT LIMIT YOUR ABILITY TO KEEP 597 00:28:27,476 --> 00:28:30,046 GIVING THEM, ET CETERA. 598 00:28:30,046 --> 00:28:34,016 AND THIS APPROACH IS SIMPLY NOT 599 00:28:34,016 --> 00:28:36,886 CURATIVE IN LARGE CELL. 600 00:28:36,886 --> 00:28:40,156 SO, WE KNEW FROM LOOKING AT ALL 601 00:28:40,156 --> 00:28:43,125 THE MUTATIONS THAT WE WOULD HAVE 602 00:28:43,125 --> 00:28:45,528 TO HIT MULTIPLE POINTS IN ORDER 603 00:28:45,528 --> 00:28:50,566 TO COME UP WITH A THERAPY THAT 604 00:28:50,566 --> 00:28:52,101 WOULD BE CURATIVE. 605 00:28:52,101 --> 00:28:54,603 AND SO THE PRINCIPLES WE HAVE TO 606 00:28:54,603 --> 00:28:57,573 THINK OF HERE IS THAT 607 00:28:57,573 --> 00:29:03,579 COMBINATIONS OF DRUGS IDEALLY 608 00:29:03,579 --> 00:29:08,918 SHOULDN'T JUST BE ADDITIVE BUT 609 00:29:08,918 --> 00:29:09,852 SYNERGISTIC, ESPECIALLY IF 610 00:29:09,852 --> 00:29:10,786 YOU'RE HITTING MULTIPLE POINTS 611 00:29:10,786 --> 00:29:14,423 IN A CASCADE YOU CAN IMAGINE 612 00:29:14,423 --> 00:29:21,430 FROM A FIRST PRINCIPLE POINT OF 613 00:29:21,430 --> 00:29:23,399 VIEW EXPECT MORE THAN EACH ONE 614 00:29:23,399 --> 00:29:23,966 ALONE. 615 00:29:23,966 --> 00:29:28,671 YOU WANT YOUR COMBINATIONS TO BE 616 00:29:28,671 --> 00:29:28,971 SYNERGISTIC. 617 00:29:28,971 --> 00:29:30,506 BUT IN ORDER TO DO THAT, YOU 618 00:29:30,506 --> 00:29:34,477 HAVE TO GIVE ALL THE DRUGS AT 619 00:29:34,477 --> 00:29:35,444 THE SAME TIME. 620 00:29:35,444 --> 00:29:37,313 AND YOU ALSO WANT TO MAKE SURE 621 00:29:37,313 --> 00:29:40,816 THAT YOU GIVE AS HIGH A DOSE AS 622 00:29:40,816 --> 00:29:43,686 YOU CAN, BECAUSE IF YOU GIVE TOO 623 00:29:43,686 --> 00:29:46,188 LOW A DOSE RESISTANCE COMES UP, 624 00:29:46,188 --> 00:29:48,157 OR YOU'RE SIMPLY NOT AT ADEQUATE 625 00:29:48,157 --> 00:29:52,862 DOSE IN ORDER TO ACTUALLY 626 00:29:52,862 --> 00:29:53,629 INHIBIT YOUR TARGET. 627 00:29:53,629 --> 00:29:55,598 AND YOU NEED TO COME UP WITH 628 00:29:55,598 --> 00:30:01,270 DRUGS THAT HAVE WHAT ARE CALLED 629 00:30:01,270 --> 00:30:02,972 NON-OVERLAPPING SERIOUS 630 00:30:02,972 --> 00:30:03,239 TOXICITY. 631 00:30:03,239 --> 00:30:04,773 IF YOU COMBINE A BUNCH OF DRUGS 632 00:30:04,773 --> 00:30:07,643 THAT ALL HIT THE MARROW, THEN 633 00:30:07,643 --> 00:30:09,478 YOU'RE LIMITING YOUR ABILITY TO 634 00:30:09,478 --> 00:30:11,247 GIVE THEM BECAUSE YOU'RE SIMPLY 635 00:30:11,247 --> 00:30:12,781 WIPING OUT MARROW FUNCTION, AND 636 00:30:12,781 --> 00:30:14,850 WE ALL KNOW THAT WHEN YOU GET 637 00:30:14,850 --> 00:30:16,952 DOWN TO VERY LOW NEUTROPHIL 638 00:30:16,952 --> 00:30:22,258 COUNTS YOU GET INTO ISSUES WITH 639 00:30:22,258 --> 00:30:24,226 FEVER, NEUTROPENIA, AND DEATH. 640 00:30:24,226 --> 00:30:27,163 SO IN ORDER TO DO THAT, YOU NEED 641 00:30:27,163 --> 00:30:28,664 TO LIMIT CYCLE TIMES. 642 00:30:28,664 --> 00:30:30,533 YOU NEED TO HAVE BREAKS. 643 00:30:30,533 --> 00:30:37,239 AND YOU DON'T GIVE THE DRUGS 644 00:30:37,239 --> 00:30:38,874 CHRONICALLY. 645 00:30:38,874 --> 00:30:40,609 SO, WITH THESE PRINCIPLES, WE 646 00:30:40,609 --> 00:30:43,245 LOOKED TO SEE WHAT DRUGS ARE 647 00:30:43,245 --> 00:30:45,848 THERE OUT THERE THAT WOULD HIT 648 00:30:45,848 --> 00:30:51,020 DIFFERENT POINTS OF THE BCR 649 00:30:51,020 --> 00:30:51,921 RECEPTOR CASCADE. 650 00:30:51,921 --> 00:30:55,391 WE SPENT A LOT OF TIME TALKING 651 00:30:55,391 --> 00:30:56,392 ABOUT IBRUTINIB. 652 00:30:56,392 --> 00:31:01,430 WELL, IT ACTUALLY TURNS OUT 653 00:31:01,430 --> 00:31:08,871 PREDNISONE INHIBITS BCR 654 00:31:08,871 --> 00:31:11,407 SIGNALING UPSTREAM OF BRUIN 655 00:31:11,407 --> 00:31:13,909 TYROSINE KINASE, EFFECTS ON 656 00:31:13,909 --> 00:31:24,453 DECREASING BCR AND SAR KINASE, A 657 00:31:27,022 --> 00:31:27,189 FREEBIE. 658 00:31:27,189 --> 00:31:31,427 IF YOU GIVE IN LIMITED CYCLES 659 00:31:31,427 --> 00:31:32,628 THEY ARE WELL TOLERATED AND 660 00:31:32,628 --> 00:31:34,230 DON'T HAVE BAD SIDE EFFECTS. 661 00:31:34,230 --> 00:31:36,599 WHAT CAME OUT OF THE WORK WE 662 00:31:36,599 --> 00:31:38,367 WERE DOING HERE WAS THE FIRST 663 00:31:38,367 --> 00:31:41,003 EVIDENCE THAT IN FACT STEROIDS 664 00:31:41,003 --> 00:31:47,977 WAS A POTENT WAY TO INHIBIT BCR 665 00:31:47,977 --> 00:31:48,277 SIGNALING. 666 00:31:48,277 --> 00:31:49,678 SO, THAT ACTUALLY CAME OUT OF 667 00:31:49,678 --> 00:31:52,081 THIS WORK. 668 00:31:52,081 --> 00:31:57,353 AND THEN FINALLY WORK THAT LOU 669 00:31:57,353 --> 00:32:05,127 DID WAS LOOK AT LENALIDOMIDE, 670 00:32:05,127 --> 00:32:10,032 AND THIS INHIBITS DOWNSTREAM OF 671 00:32:10,032 --> 00:32:13,302 BRUTIN TYROSINE KINASE BY 672 00:32:13,302 --> 00:32:17,906 INHIBITING IRF 4 AND SPE-B, AS A 673 00:32:17,906 --> 00:32:23,712 RESULT NF-kappaB AND BY 674 00:32:23,712 --> 00:32:27,750 TURNING THOSE OFF BECAUSE THEY 675 00:32:27,750 --> 00:32:29,184 TURN OFF INTERFERON BETA, IT 676 00:32:29,184 --> 00:32:31,687 GOES UP, TOXIC TO LARGE CELLS. 677 00:32:31,687 --> 00:32:34,323 SO WE'RE NOW HITTING THE BCR 678 00:32:34,323 --> 00:32:36,525 SIGNALING AT THREE DIFFERENT 679 00:32:36,525 --> 00:32:37,826 POINTS. 680 00:32:37,826 --> 00:32:42,865 WELL, WE ALSO WANTED TO INHIBIT 681 00:32:42,865 --> 00:32:49,772 BCL-2 AS WELL, BCL-2 IS HIGHLY 682 00:32:49,772 --> 00:32:52,608 EXPRESSED WITHIN ABC TUMORS, AND 683 00:32:52,608 --> 00:32:55,544 SO WE ASSUMED IT PLAYED A 684 00:32:55,544 --> 00:33:01,350 CRITICAL ROLE BASICALLY BLOCKING 685 00:33:01,350 --> 00:33:06,055 APOPTOSIS, WE HAD THE DRUG 686 00:33:06,055 --> 00:33:08,257 VENETOCLAX AND USED ANTI-CD20 687 00:33:08,257 --> 00:33:11,327 ANTIBODIES, THIS IS ONE OF THE 688 00:33:11,327 --> 00:33:12,828 NEWER ONES, AND THESE DRUGS HAVE 689 00:33:12,828 --> 00:33:18,434 A NUMBER OF IMMUNE EFFECTS, AND 690 00:33:18,434 --> 00:33:22,805 KILL TUMOR CELLS ADCC AND 691 00:33:22,805 --> 00:33:25,641 COMPLEMENT MEDIATED 692 00:33:25,641 --> 00:33:27,309 CYTOTOXICITY. 693 00:33:27,309 --> 00:33:33,882 SO THIS WAS THE DRUGS IN OUR 694 00:33:33,882 --> 00:33:39,121 ARMAMENTARIUM THAT WE HAD TO 695 00:33:39,121 --> 00:33:39,388 PLAY WITH. 696 00:33:39,388 --> 00:33:42,624 AND SO, AS I SAID, YOU WANT 697 00:33:42,624 --> 00:33:47,763 THESE DRUGS TO SHOW SYNERGY, SO 698 00:33:47,763 --> 00:33:54,536 IN FACT IN THE LAB USING ABC 699 00:33:54,536 --> 00:34:00,442 LINES WE CAN SEE VENETOCLAX AND 700 00:34:00,442 --> 00:34:01,310 IBRUTINIB SHOW TREMENDOUS 701 00:34:01,310 --> 00:34:04,613 SYNERGY HERE. 702 00:34:04,613 --> 00:34:08,751 THIS IS A NUMBER OF LIVE CELLS, 703 00:34:08,751 --> 00:34:11,754 AND THE VENETOCLAX DOSE, AND YOU 704 00:34:11,754 --> 00:34:14,256 CAN SEE THE CURVE SHIFTING TO 705 00:34:14,256 --> 00:34:15,557 THE LEFT. 706 00:34:15,557 --> 00:34:21,029 SIMILARLY, STEROIDS IN THIS CASE 707 00:34:21,029 --> 00:34:23,132 WE USED DEXAMETHASONE, AND 708 00:34:23,132 --> 00:34:30,272 IBRUTINIB, ALSO SHOWED SYNERGY 709 00:34:30,272 --> 00:34:36,011 AS DID COMBINATIONS OF IBRUTINIB 710 00:34:36,011 --> 00:34:36,278 AND LEN. 711 00:34:36,278 --> 00:34:37,613 WHEN YOU LOOK AT THE SAME TIME 712 00:34:37,613 --> 00:34:40,783 YOU CAN SEE EACH OF THESE DRUGS 713 00:34:40,783 --> 00:34:42,618 ARE AS SINGLES, AND WHEN WE 714 00:34:42,618 --> 00:34:47,556 COMBINED ALL OF THEM YOU CAN SEE 715 00:34:47,556 --> 00:34:50,392 THIS CASPASE ASSAY WOULD GET 716 00:34:50,392 --> 00:34:56,865 VERY LARGE CELL KILL. 717 00:34:56,865 --> 00:34:58,700 SO, THIS REALLY WAS THE 718 00:34:58,700 --> 00:35:00,469 LABORATORY EVIDENCE BASED ON THE 719 00:35:00,469 --> 00:35:02,971 CLINICAL WORK WE HAD DONE THAT 720 00:35:02,971 --> 00:35:06,575 COMBINING THESE DRUGS, IF WE 721 00:35:06,575 --> 00:35:11,313 COULD, WOULD POSSIBLY CURE 722 00:35:11,313 --> 00:35:14,149 RELAPSE REFRACTORY LARGE CELL. 723 00:35:14,149 --> 00:35:15,584 AND SO BASED ON THOSE PRINCIPLES 724 00:35:15,584 --> 00:35:17,753 THAT I WENT OVER WITH YOU, THIS 725 00:35:17,753 --> 00:35:23,358 IS THE WAY WE DECIDED TO 726 00:35:23,358 --> 00:35:24,159 SCHEDULE. 727 00:35:24,159 --> 00:35:27,629 FIRST, WE ONLY GAVE THE DRUGS 728 00:35:27,629 --> 00:35:28,297 FOR SIX CYCLES. 729 00:35:28,297 --> 00:35:31,900 SO YOU WOULD GIVE THEM IN 730 00:35:31,900 --> 00:35:33,535 PACKETS OF THREE WEEKS, AND YOU 731 00:35:33,535 --> 00:35:35,070 WOULD HAVE TWO WEEKS ON 732 00:35:35,070 --> 00:35:38,440 ESSENTIALLY AND ONE WEEK OFF. 733 00:35:38,440 --> 00:35:39,875 AND YOU CAN SEE HERE, I DON'T 734 00:35:39,875 --> 00:35:42,077 NEED TO GO OVER THE ACTUAL 735 00:35:42,077 --> 00:35:44,580 SCHEDULING, BUT YOU CAN SEE THAT 736 00:35:44,580 --> 00:35:47,449 THESE DRUGS ARE MOSTLY GIVEN FOR 737 00:35:47,449 --> 00:35:48,851 THE FIRST TWO WEEKS, THEN YOU'VE 738 00:35:48,851 --> 00:35:51,820 GOT A BREAK, AND WE DO THIS FOR 739 00:35:51,820 --> 00:35:53,655 SIX CYCLES AND STOP. 740 00:35:53,655 --> 00:35:56,291 AGAIN, QUITE DIFFERENT FROM THE 741 00:35:56,291 --> 00:35:59,795 WAY SINGLE AGENTS OR DOUBLETS 742 00:35:59,795 --> 00:36:03,165 ARE GIVEN IN LARGE CELL BECAUSE 743 00:36:03,165 --> 00:36:05,701 THEY ARE NOT CURATIVE, THEY 744 00:36:05,701 --> 00:36:08,003 DON'T STOP THEM UNTIL THE TUMORS 745 00:36:08,003 --> 00:36:08,337 GROW. 746 00:36:08,337 --> 00:36:10,205 WITH LARGE CELLS TUMORS GROW 747 00:36:10,205 --> 00:36:11,373 RELATIVELY SOON, SO, YES, 748 00:36:11,373 --> 00:36:12,708 SOMETIMES THEY CAN WORK VERY, 749 00:36:12,708 --> 00:36:16,078 VERY WELL, BUT ONLY IN A VERY 750 00:36:16,078 --> 00:36:18,714 SMALL NUMBER, AND ALMOST NEVER 751 00:36:18,714 --> 00:36:19,047 CURE. 752 00:36:19,047 --> 00:36:22,451 SO, THIS IS WHERE WE STARTED, 753 00:36:22,451 --> 00:36:27,356 AND THIS IS THE VIPOR THERAPY 754 00:36:27,356 --> 00:36:32,728 THAT I'M GOING TO SHOW YOU. 755 00:36:32,728 --> 00:36:36,532 SO WE DID A STUDY, THIS WAS ALL 756 00:36:36,532 --> 00:36:40,035 RELAPSE CASES, TOTAL OF 50 757 00:36:40,035 --> 00:36:40,235 CASES. 758 00:36:40,235 --> 00:36:44,106 MEDIAN AGE WAS 61, WITH A RANGE 759 00:36:44,106 --> 00:36:46,275 OF 29 TO 77. 760 00:36:46,275 --> 00:36:49,778 LARGE CELLS DO OCCUR MOSTLY IN 761 00:36:49,778 --> 00:36:51,413 MEN, IN THIS CASE 66%. 762 00:36:51,413 --> 00:36:54,383 AND THIS IS JUST GIVING YOU A 763 00:36:54,383 --> 00:37:01,924 BREAKDOWN AGAIN BY THE 764 00:37:01,924 --> 00:37:07,062 HISTOLOGY, BY THIS NOMENCLATURE 765 00:37:07,062 --> 00:37:09,364 FOR THE NON-GCB, 36%, FOR GCB IT 766 00:37:09,364 --> 00:37:10,666 WAS 24%. 767 00:37:10,666 --> 00:37:12,301 AND SOMETHING I'LL BE DISCUSSING 768 00:37:12,301 --> 00:37:16,471 IN A BIT IS SOMETHING CALLED 769 00:37:16,471 --> 00:37:17,573 HIGH GRADE B-CELL LYMPHOMA 770 00:37:17,573 --> 00:37:19,575 DOUBLE HIT. 771 00:37:19,575 --> 00:37:23,412 THESE ARE MOSTLY GCB TUMORS, BUT 772 00:37:23,412 --> 00:37:25,681 THEY HAVE TRANSLOCATIONS ABOVE 773 00:37:25,681 --> 00:37:27,549 MYC AND BCL-2. 774 00:37:27,549 --> 00:37:31,687 AND AMONG THE GCB TUMORS THEY DO 775 00:37:31,687 --> 00:37:33,555 VERY, VERY POORLY. 776 00:37:33,555 --> 00:37:34,556 CONVENTIONAL CHEMOTHERAPY DOES 777 00:37:34,556 --> 00:37:38,627 NOT WORK WELL. 778 00:37:38,627 --> 00:37:41,797 IT EPOCH SCATTER MOST EFFECTIVE 779 00:37:41,797 --> 00:37:44,299 THERAPY BUT ONLY THERE CURING 780 00:37:44,299 --> 00:37:45,434 65% OF CASES. 781 00:37:45,434 --> 00:37:55,944 THIS GROUP AGAIN THESE ARE ALL 782 00:37:57,279 --> 00:38:01,717 RELAPSE CASES, 68% HIGH RISK, 783 00:38:01,717 --> 00:38:03,585 THREE PRIOR THERAPIES, 40% 784 00:38:03,585 --> 00:38:05,754 THROUGH CAR T CELL. 785 00:38:05,754 --> 00:38:08,824 WHEN YOU GIVE CAR T CELL, AND 786 00:38:08,824 --> 00:38:11,460 YOU'RE NOT CURED, AGAIN 70% ARE 787 00:38:11,460 --> 00:38:20,435 NOT CURED, AS PART OF THE CAR-T 788 00:38:20,435 --> 00:38:29,177 CELLS YOU GIVE FLEWDEROBINE AND 789 00:38:29,177 --> 00:38:30,779 CYCLOPHOSPHORIDE TO MAKE ROOM, 790 00:38:30,779 --> 00:38:31,580 THAT'S CRITICAL. 791 00:38:31,580 --> 00:38:36,585 WHEN YOU WIPE OUT NORMAL T CELL 792 00:38:36,585 --> 00:38:41,423 REPERTOIRE, YOU CAUSE SEVERE 793 00:38:41,423 --> 00:38:43,058 LONG-TERM TOXICITY TO IMMUNE 794 00:38:43,058 --> 00:38:44,159 FUNCTION, BONE MARROW FUNCTION, 795 00:38:44,159 --> 00:38:46,795 AND IT'S VERY DIFFICULT TO GIVE 796 00:38:46,795 --> 00:38:48,730 THERAPY AFTER CAR-T CELLS AND IN 797 00:38:48,730 --> 00:38:52,401 FACT IN A NUMBER OF STUDIES THE 798 00:38:52,401 --> 00:38:56,938 CURE RATE AFTER CAR T CELL IS 799 00:38:56,938 --> 00:38:59,141 LIKE 5%, MOST PEOPLE DIE WITHIN 800 00:38:59,141 --> 00:38:59,574 SIX MONTHS. 801 00:38:59,574 --> 00:39:01,777 WE FOUND OUT IT'S A REAL 802 00:39:01,777 --> 00:39:02,978 CHALLENGE TO TAKE THESE CAR T 803 00:39:02,978 --> 00:39:05,247 CELL FAILURES BUT EVERYONE IS 804 00:39:05,247 --> 00:39:07,582 GETTING CAR-T CELLS, AND SO THEY 805 00:39:07,582 --> 00:39:12,287 SHOULD, BECAUSE COMPARED TO 806 00:39:12,287 --> 00:39:14,923 STANDARD THERAPY IT IS A BETTER 807 00:39:14,923 --> 00:39:15,357 OPTION. 808 00:39:15,357 --> 00:39:20,362 BUT, AGAIN, YOU'RE LEFT WITH 809 00:39:20,362 --> 00:39:21,663 SOME VERY SEVERE ISSUES. 810 00:39:21,663 --> 00:39:25,367 NOW, ONE THING THAT WAS VERY 811 00:39:25,367 --> 00:39:28,203 GRATIFYING, WE'RE COMBINING ALL 812 00:39:28,203 --> 00:39:29,971 THESE DRUGS, YOU WORRY ABOUT 813 00:39:29,971 --> 00:39:31,707 SIDE EFFECTS, BUT BECAUSE OF THE 814 00:39:31,707 --> 00:39:33,241 WAY WE SCHEDULED IT, BECAUSE OF 815 00:39:33,241 --> 00:39:36,311 THE TYPES OF DRUGS WE ACTUALLY 816 00:39:36,311 --> 00:39:40,482 CHOSE, IT TURNED OUT THAT THE 817 00:39:40,482 --> 00:39:42,684 THERAPY WAS EXTREMELY WELL 818 00:39:42,684 --> 00:39:42,951 TOLERATED. 819 00:39:42,951 --> 00:39:45,554 GENERALLY SPEAKING WHEN YOU 820 00:39:45,554 --> 00:39:47,489 TREAT RELAPSE REFRACTORY 821 00:39:47,489 --> 00:39:48,824 PATIENTS THEY ALREADY HAVE 822 00:39:48,824 --> 00:39:54,596 PRETTY BEAT UP MARROW FUNCTION, 823 00:39:54,596 --> 00:39:57,232 AND SO HEME TOXICITY IS 824 00:39:57,232 --> 00:39:59,201 RELATIVELY HIGH. 825 00:39:59,201 --> 00:40:00,435 WE FOUND GRADE 4, MUCH LESS 826 00:40:00,435 --> 00:40:02,938 CONCERNED ABOUT GRADE 3, WAS 827 00:40:02,938 --> 00:40:08,276 ONLY SEEN IN 8% OF CYCLES FOR 828 00:40:08,276 --> 00:40:11,379 PLATELETS, AND NEUTROPENIA ONLY 829 00:40:11,379 --> 00:40:14,116 SEEN IN 10% OF CYCLES, AND WHAT 830 00:40:14,116 --> 00:40:18,353 WAS MOST GRATIFYING IS THAT 831 00:40:18,353 --> 00:40:19,688 FEVER AND NEUTROPENIA, WHICH 832 00:40:19,688 --> 00:40:22,390 MEANS YOU HAVE A WHITE COUNT 833 00:40:22,390 --> 00:40:25,494 BELOW 500, YOU'RE AT RISK OF 834 00:40:25,494 --> 00:40:28,463 GETTING A BACTERIAL INFECTION, 835 00:40:28,463 --> 00:40:31,733 USUALLY DUE TO SEEDING FROM THE 836 00:40:31,733 --> 00:40:34,569 GUT, WITH STANDARD CHEMOTHERAPY 837 00:40:34,569 --> 00:40:37,539 UP FRONT IT'S AROUND 15% OF 838 00:40:37,539 --> 00:40:39,508 PEOPLE GET FEVER AND 839 00:40:39,508 --> 00:40:39,941 NEUTROPENIA. 840 00:40:39,941 --> 00:40:42,344 IN THE SALVAGE SETTING IT CAN 841 00:40:42,344 --> 00:40:43,545 APPROACH 40%. 842 00:40:43,545 --> 00:40:47,349 AND IN THIS STUDY WE SAW 1%. 843 00:40:47,349 --> 00:40:52,187 SO, IT WAS NOT CAUSING BONE 844 00:40:52,187 --> 00:40:55,457 MARROW DYSFUNCTION THE WAY 845 00:40:55,457 --> 00:40:56,024 STANDARD CHEMOTHERAPY DOES. 846 00:40:56,024 --> 00:41:01,429 AND SO THIS IS ACTUALLY SHOWING 847 00:41:01,429 --> 00:41:03,498 THE WATERFALL PLOT OF THE LARGE 848 00:41:03,498 --> 00:41:05,667 CELLS THAT WE TREATED. 849 00:41:05,667 --> 00:41:08,737 I JUST WANT TO POINT OUT THIS IS 850 00:41:08,737 --> 00:41:10,572 THE 50% MARK HERE. 851 00:41:10,572 --> 00:41:12,541 AND THIS IS GERMINAL CENTER, 852 00:41:12,541 --> 00:41:15,076 NON-GERMINAL CENTER, THIS IS THE 853 00:41:15,076 --> 00:41:18,313 GERMINAL CENTER WITH THE MYC 854 00:41:18,313 --> 00:41:20,315 TRANSLOCATION, WHICH IS THE 855 00:41:20,315 --> 00:41:22,083 SO-CALLED DOUBLE HIT. 856 00:41:22,083 --> 00:41:23,418 I THINK I'M MISSING SOME THINGS 857 00:41:23,418 --> 00:41:26,121 HERE, BUT THAT'S OKAY. 858 00:41:26,121 --> 00:41:29,491 LET ME NOW ZONE ON THE ACTUAL 859 00:41:29,491 --> 00:41:30,192 RESPONSE RATES WITHIN THIS 860 00:41:30,192 --> 00:41:30,926 CLINICAL TRIAL. 861 00:41:30,926 --> 00:41:34,095 IF WE LOOK AT ALL COMERS, AND 862 00:41:34,095 --> 00:41:38,700 AGAIN WE WERE FOCUSING ON BCR 863 00:41:38,700 --> 00:41:41,436 RECEPTOR SIGNALING HERE, SO OUR 864 00:41:41,436 --> 00:41:43,505 HYPOTHESIS WAS AS WE SHOWED WITH 865 00:41:43,505 --> 00:41:45,574 IBRUTINIB IN THE VERY FIRST 866 00:41:45,574 --> 00:41:49,211 TRIAL, THAT IS UNLIKELY THAT 867 00:41:49,211 --> 00:41:50,679 VIPOR WAS GOING TO CURE GERMINAL 868 00:41:50,679 --> 00:41:51,446 CENTER TUMORS. 869 00:41:51,446 --> 00:41:56,651 IF WE LOOK AT ALL COMERS, 870 00:41:56,651 --> 00:41:57,719 GERMINAL CENTER, NON-GERMINAL 871 00:41:57,719 --> 00:42:00,255 CENTER AND DOUBLE HIT MOST WHICH 872 00:42:00,255 --> 00:42:03,658 WERE GERMINAL CENTER, WE SAW A 873 00:42:03,658 --> 00:42:07,696 COMPLETE REMISSION RATE OF 38%. 874 00:42:07,696 --> 00:42:09,998 IF WE FOCUS DOWN ON NON-GERMINAL 875 00:42:09,998 --> 00:42:12,167 CENTER TYPE, THE GROUP THAT IS 876 00:42:12,167 --> 00:42:16,004 ENRICHED FOR THESE TUMORS THAT 877 00:42:16,004 --> 00:42:18,640 HAVE B CELL RECEPTOR SIGNALING, 878 00:42:18,640 --> 00:42:25,013 WE NOW SEE THAT THERE'S A 62% 879 00:42:25,013 --> 00:42:26,081 COMPLETE REMISSION RATE. 880 00:42:26,081 --> 00:42:28,383 THIS WAS A VERY GRATIFYING 881 00:42:28,383 --> 00:42:31,786 FINDING, NUMBER ONE, THAT IT WAS 882 00:42:31,786 --> 00:42:34,189 SO MUCH HIGHER THAN WE THOUGHT 883 00:42:34,189 --> 00:42:35,724 WE WOULD SEE. 884 00:42:35,724 --> 00:42:37,993 BUT WHAT WAS NOT EXPECTED AND 885 00:42:37,993 --> 00:42:40,829 I'M GOING TO SHOW WHY WE THINK 886 00:42:40,829 --> 00:42:43,698 IT'S THE CASE, AND THIS IS WHY 887 00:42:43,698 --> 00:42:45,533 WHEN YOU DO A CLINICAL TRIAL 888 00:42:45,533 --> 00:42:48,069 UNLESS YOU KNOW FOR SURE YOU 889 00:42:48,069 --> 00:42:49,504 INCLUDE ALL COMERS BECAUSE 890 00:42:49,504 --> 00:42:51,573 UNEXPECTED THINGS CAN SHOW UP. 891 00:42:51,573 --> 00:42:53,875 WE FOUND AMONG THESE DOUBLE HIT 892 00:42:53,875 --> 00:42:55,610 CASES, GERMINAL CENTER TYPES, 893 00:42:55,610 --> 00:42:59,881 THAT HAVE A TRANSLOCATION OF 894 00:42:59,881 --> 00:43:02,317 BOTH BCL-2 AND MYC, THIS 895 00:43:02,317 --> 00:43:04,386 COMPLETE REMISSION RATE WAS 53%. 896 00:43:04,386 --> 00:43:09,357 SALVAGE THERAPY OF THESE DOUBLE 897 00:43:09,357 --> 00:43:10,525 HITS IS RARELY EFFECTIVE. 898 00:43:10,525 --> 00:43:13,361 AND SO MOST OF THESE CASES USING 899 00:43:13,361 --> 00:43:15,130 STANDARD CHEMOTHERAPY DO VERY 900 00:43:15,130 --> 00:43:19,267 POORLY, AND AS IT TURNS OUT 901 00:43:19,267 --> 00:43:20,535 CAR-T CELLS IN SOME CLINICAL 902 00:43:20,535 --> 00:43:24,539 TRIALS DON'T SEEM TO DO WELL 903 00:43:24,539 --> 00:43:26,074 WITH THIS GROUP EITHER. 904 00:43:26,074 --> 00:43:28,076 AND THEN THESE OTHER TWO I'M NOT 905 00:43:28,076 --> 00:43:31,646 GOING TO REALLY FOCUS ON. 906 00:43:31,646 --> 00:43:35,917 OH, SO FINALLY, WHAT DID WE SEE 907 00:43:35,917 --> 00:43:37,452 WITHIN GERMINAL CENTER? 908 00:43:37,452 --> 00:43:39,321 THIS IS GERMINAL CENTER 909 00:43:39,321 --> 00:43:41,256 EXCLUDING THESE DOUBLE HIT, 910 00:43:41,256 --> 00:43:42,691 EXCLUDING GERMINAL CENTER TYPES 911 00:43:42,691 --> 00:43:46,294 THAT HAVE THE TRANSLOCATION OF 912 00:43:46,294 --> 00:43:49,297 MYC AND BCL-2. 913 00:43:49,297 --> 00:43:50,799 RESPONSE RATE 33%. 914 00:43:50,799 --> 00:43:52,667 C.R. RATE ZERO, MEANING IT IS 915 00:43:52,667 --> 00:43:56,271 UNLIKELY WE WERE CURING A SINGLE 916 00:43:56,271 --> 00:43:56,604 ONE. 917 00:43:56,604 --> 00:43:59,174 AND THIS IS JUST KIND OF SHOWING 918 00:43:59,174 --> 00:44:01,776 YOU WHAT HAPPENS WHEN YOU HAVE A 919 00:44:01,776 --> 00:44:05,613 VERY EFFECTIVE THERAPY. 920 00:44:05,613 --> 00:44:08,683 THIS IS A MIDDLE AGE MAN, 921 00:44:08,683 --> 00:44:10,118 NON-GERMINAL CENTER LARGE CELL, 922 00:44:10,118 --> 00:44:13,922 HAD FAILED SIX PRIOR THERAPIES, 923 00:44:13,922 --> 00:44:19,728 HAD CHEMOTHERAPY, CAR T CELLS, 924 00:44:19,728 --> 00:44:21,363 BI-SPECIFICS, CAME IN MASS 925 00:44:21,363 --> 00:44:22,464 DISEASE EVERYWHERE, BONES 926 00:44:22,464 --> 00:44:25,633 EVERYWHERE, WITHIN ONE CYCLE YOU 927 00:44:25,633 --> 00:44:29,004 CAN SEE TREMENDOUS SHRINKAGE, 928 00:44:29,004 --> 00:44:30,138 WITHIN TWO CYCLES IT WAS ALMOST 929 00:44:30,138 --> 00:44:31,006 ALL GONE. 930 00:44:31,006 --> 00:44:34,542 SO WHEN THESE DRUGS WORK, THEY 931 00:44:34,542 --> 00:44:39,014 WORK VERY, VERY QUICKLY. 932 00:44:39,014 --> 00:44:39,981 SO, ARE THESE DURABLE? 933 00:44:39,981 --> 00:44:43,051 AND WHAT I CAN TELL YOU WITH 934 00:44:43,051 --> 00:44:46,021 LARGE CELL IS THAT IF YOU DON'T 935 00:44:46,021 --> 00:44:49,624 RECUR BY 18 MONTHS, THE CHANCES 936 00:44:49,624 --> 00:44:52,460 THAT YOU'RE CURED IS 90%-PLUS. 937 00:44:52,460 --> 00:44:54,896 AND SO I'M JUST SHOWING YOU THIS 938 00:44:54,896 --> 00:44:58,500 IS FOR ALL COMERS. 939 00:44:58,500 --> 00:44:59,467 GCB, NON-GCB, DOUBLE HIT, BLAH, 940 00:44:59,467 --> 00:45:01,870 BLAH, BLAH. 941 00:45:01,870 --> 00:45:05,006 OVERALL WE'RE SITTING HERE AT 942 00:45:05,006 --> 00:45:06,708 34%, AT 24 MONTHS. 943 00:45:06,708 --> 00:45:09,110 THIS ONE TICK HERE IS 944 00:45:09,110 --> 00:45:11,846 UNFORTUNATELY A POOR SOUL THAT 945 00:45:11,846 --> 00:45:14,482 WAS IN REMISSION AND DIED FROM 946 00:45:14,482 --> 00:45:14,916 COVID. 947 00:45:14,916 --> 00:45:18,653 SO WE'VE NOT SEEN A SINGLE 948 00:45:18,653 --> 00:45:19,721 RECURRENCE AFTER 18 MONTHS. 949 00:45:19,721 --> 00:45:24,325 BUT IF WE LOOK AT USING VIPOR 950 00:45:24,325 --> 00:45:25,660 EARLIER ON, SHOWN WITH CAR T 951 00:45:25,660 --> 00:45:29,664 CELL AS WELL, THIS IS LOOKING AT 952 00:45:29,664 --> 00:45:31,099 VIPOR AFTER PEOPLE WHO HAD ONE 953 00:45:31,099 --> 00:45:33,301 PRIOR THERAPY, CAN YOU SEE THE 954 00:45:33,301 --> 00:45:36,704 DURABLE C.R. RATE, ALL COMERS 955 00:45:36,704 --> 00:45:37,572 INCLUDING GERMINAL CENTER, WAS 956 00:45:37,572 --> 00:45:37,906 60%. 957 00:45:37,906 --> 00:45:40,075 SO WHEN YOU MOVE THESE THERAPIES 958 00:45:40,075 --> 00:45:43,478 EARLIER ON, THEY TEND TO HAVE 959 00:45:43,478 --> 00:45:47,315 BETTER OUTCOMES AND THAT'S TRUE 960 00:45:47,315 --> 00:45:50,251 WITH CAR-T CELLS AND LOOKS TO BE 961 00:45:50,251 --> 00:45:51,453 TRUE WITH VIPOR. 962 00:45:51,453 --> 00:45:57,492 WHEN YOU GO INTO A C.R. 78% OF 963 00:45:57,492 --> 00:45:59,461 PATIENTS STAYED THERE. 964 00:45:59,461 --> 00:46:01,429 SO DURABLE, CURATIVE, IN 78% IN 965 00:46:01,429 --> 00:46:04,599 THIS PARTICULAR GROUP OF 966 00:46:04,599 --> 00:46:06,601 PATIENTS THAT WENT INTO C.R. 967 00:46:06,601 --> 00:46:13,274 AND SO WHEN WE LOOK AT THE 968 00:46:13,274 --> 00:46:21,916 CURVES BASED ON GCB, NON-GCB AND 969 00:46:21,916 --> 00:46:30,658 DOUBLE HIT, GCB, THE NON-GCB, 970 00:46:30,658 --> 00:46:34,062 THE DOUBLE HITS, AND THE T CELL 971 00:46:34,062 --> 00:46:40,735 RICH, WHICH MARK OUT AS NON-GCB, 972 00:46:40,735 --> 00:46:41,870 HAVE LONG-TERM PFSs AND 973 00:46:41,870 --> 00:46:45,440 PROBABLY CURES IN 38 TO 47% 974 00:46:45,440 --> 00:46:46,407 RANGE. 975 00:46:46,407 --> 00:46:50,345 LOOK AT GERMINAL CENTER, WHICH 976 00:46:50,345 --> 00:46:53,414 IS THE NON-DOUBLE HIT, IT IS NOT 977 00:46:53,414 --> 00:46:54,549 CURATIVE. 978 00:46:54,549 --> 00:46:58,119 AND ACTUALLY TURNS OUT THAT THIS 979 00:46:58,119 --> 00:46:59,988 THERAPY IS HIGHLY TARGETED, IT'S 980 00:46:59,988 --> 00:47:01,723 MUCH MORE EFFECTIVE IN 981 00:47:01,723 --> 00:47:02,924 NON-GERMINAL CENTER TYPE 982 00:47:02,924 --> 00:47:05,560 COMPARED TO GERMINAL CENTER 983 00:47:05,560 --> 00:47:08,296 TYPE, AND IN DOUBLE HIT GERMINAL 984 00:47:08,296 --> 00:47:10,431 CENTER TYPE VERSUS GERMINAL 985 00:47:10,431 --> 00:47:11,232 CENTER TYPE. 986 00:47:11,232 --> 00:47:15,403 AND IF WE LOOKED AT ITS USE IN 987 00:47:15,403 --> 00:47:20,008 CAR T CELLS, AGAIN THIS IS A 988 00:47:20,008 --> 00:47:26,881 DEATH DUE TO COVID, 30% OF ALL 989 00:47:26,881 --> 00:47:29,651 COMERS WITH POST CAR T FAILURE 990 00:47:29,651 --> 00:47:33,788 HAVE REMAINED IN C.R., AGAIN 991 00:47:33,788 --> 00:47:35,190 SMALL NUMBERS, BUT THE DATA 992 00:47:35,190 --> 00:47:40,895 SEEMS TO BE HOLDING UP. 993 00:47:40,895 --> 00:47:45,400 AND SO FINALLY WE ALSO DID CTDNA 994 00:47:45,400 --> 00:47:51,272 AS WELL, TO MAKE SURE THAT THERE 995 00:47:51,272 --> 00:47:52,507 WEREN'T SMALL NUMBERS OF CLONES, 996 00:47:52,507 --> 00:47:57,845 AND SO WHAT WE SHOW HERE IS THIS 997 00:47:57,845 --> 00:48:00,148 IS ACTUALLY SHOWING 998 00:48:00,148 --> 00:48:02,317 QUANTITATIVELY THE ctDNA 999 00:48:02,317 --> 00:48:04,519 AMOUNT AS BASELINE STATUS POST 1000 00:48:04,519 --> 00:48:06,154 CYCLE 1, 2, AND OF TREATMENT, 1001 00:48:06,154 --> 00:48:10,124 THIS IS LOOKING AT ALL COMERS, 1002 00:48:10,124 --> 00:48:12,961 I'M GOING TO BE REMINDING YOU 1003 00:48:12,961 --> 00:48:18,633 THAT WE HAD ABOUT 38% COMPLETE 1004 00:48:18,633 --> 00:48:23,805 REMISSION RATE, BY PET, AND YOU 1005 00:48:23,805 --> 00:48:26,074 CAN SEE LOOKING AT MRD NEGATIVE 1006 00:48:26,074 --> 00:48:27,075 IT'S AT 38%. 1007 00:48:27,075 --> 00:48:29,377 BUT I THINK TELLS YOU A LITTLE 1008 00:48:29,377 --> 00:48:32,981 BIT MORE HERE IS IF WE SIMPLY 1009 00:48:32,981 --> 00:48:37,018 LOOK AT PATIENTS THAT WENT INTO 1010 00:48:37,018 --> 00:48:40,521 C.R., WHAT I WANT TO POINT OUT 1011 00:48:40,521 --> 00:48:45,994 IS THAT BY CYCLE 1, 73% OF THE 1012 00:48:45,994 --> 00:48:47,428 PATIENTS THAT ACHIEVED CLINICAL 1013 00:48:47,428 --> 00:48:49,697 C.R. WERE MRD NEGATIVE BY CYCLE 1014 00:48:49,697 --> 00:48:51,232 1. 1015 00:48:51,232 --> 00:48:53,201 THIS IS EVIDENCE OF HIGHLY 1016 00:48:53,201 --> 00:48:55,169 EFFECTIVE AND HIGHLY SENSITIVE 1017 00:48:55,169 --> 00:48:57,138 TUMORS TO THIS PARTICULAR 1018 00:48:57,138 --> 00:48:58,306 THERAPY, IT INCREASED SOMEWHAT 1019 00:48:58,306 --> 00:49:03,711 BY CYCLE 2, AND BY THE END OF 1020 00:49:03,711 --> 00:49:09,550 TREATMENT 93% OF THE C.R.s 1021 00:49:09,550 --> 00:49:11,519 ARE ctDNA NEGATIVE AND STAYED 1022 00:49:11,519 --> 00:49:14,522 THAT WAY AMONG THOSE THAT HAVE 1023 00:49:14,522 --> 00:49:17,992 NOT RECURRED AFTER 18 MONTHS. 1024 00:49:17,992 --> 00:49:22,063 AND SO I'M JUST GOING TO SHOW 1025 00:49:22,063 --> 00:49:22,930 YOU SOME KAPLAN-MEIER CURVES. 1026 00:49:22,930 --> 00:49:25,733 THIS IS FOR ALL CASES. 1027 00:49:25,733 --> 00:49:27,502 AMONG THOSE PATIENTS THAT BECAME 1028 00:49:27,502 --> 00:49:30,104 MRD NEGATIVE BY CYCLE 2 YOU CAN 1029 00:49:30,104 --> 00:49:32,407 SEE 70% OF THOSE HAVE DURABLE 1030 00:49:32,407 --> 00:49:37,578 C.R.s, AND THAT THIS IS JUST 1031 00:49:37,578 --> 00:49:40,848 SHOWING END OF THERAPY. 1032 00:49:40,848 --> 00:49:48,289 SO, MY FINAL THING IS GOING TO 1033 00:49:48,289 --> 00:49:50,358 BE WHY IS VIPOR EFFECTIVE IN 1034 00:49:50,358 --> 00:49:51,326 THESE DOUBLE HITS? 1035 00:49:51,326 --> 00:49:55,830 I WANT TO FOCUS ON HERE AS PART 1036 00:49:55,830 --> 00:50:02,603 OF THIS GENOMICS THAT LOU DID 1037 00:50:02,603 --> 00:50:04,572 THERE'S A GROUP CALLED EZB, 1038 00:50:04,572 --> 00:50:05,873 MUTATIONS WITHIN THOSE PATHWAYS, 1039 00:50:05,873 --> 00:50:10,244 YOU CAN GIVED THEM INTO MYC 1040 00:50:10,244 --> 00:50:11,579 PLUS, TRANSLOCATED VERSUS MYC 1041 00:50:11,579 --> 00:50:12,180 NEGATIVE. 1042 00:50:12,180 --> 00:50:14,549 AND IF YOU GO TO THE OLD 1043 00:50:14,549 --> 00:50:16,617 LITERATURE, YOU'LL SEE THAT MYC 1044 00:50:16,617 --> 00:50:18,152 IS A DOUBLE-EDGED SWORD. 1045 00:50:18,152 --> 00:50:23,524 ON ONE HAND IT PROMOTES SURVIVAL 1046 00:50:23,524 --> 00:50:24,158 AND PROMOTES PROLIFERATION, BUT 1047 00:50:24,158 --> 00:50:26,794 ON THE OTHER HAND IT ACTUALLY 1048 00:50:26,794 --> 00:50:28,896 SETS THE TUMORS UP FOR 1049 00:50:28,896 --> 00:50:31,733 APOPTOSIS, AND IN FACT WHEN YOU 1050 00:50:31,733 --> 00:50:33,568 LOOK AT BURKETT LYMPHOMA, 1051 00:50:33,568 --> 00:50:37,438 CHARACTERIZED BY HAVING A MYC 1052 00:50:37,438 --> 00:50:43,044 TRANSLOCATION, HIGH RATE OF 1053 00:50:43,044 --> 00:50:44,779 SPONTANEOUS RATE OF APOPTOSIS. 1054 00:50:44,779 --> 00:50:48,483 MAYBE WHAT'S GOING ON BCL-2, 1055 00:50:48,483 --> 00:50:50,885 TRANSLOCATED IN THESE TUMORS, 1056 00:50:50,885 --> 00:50:53,755 ARE CRITICAL TO BLOCK THAT 1057 00:50:53,755 --> 00:50:55,156 APOPTOTIC SIGNAL AND THEREFORE 1058 00:50:55,156 --> 00:51:01,729 ALLOWING THESE DOUBLE HIT TUMORS 1059 00:51:01,729 --> 00:51:04,699 TO ACTUALLY PROLIFERATE AND 1060 00:51:04,699 --> 00:51:04,932 SURVIVE. 1061 00:51:04,932 --> 00:51:08,469 SO, WE ASKED THE QUESTION, 1062 00:51:08,469 --> 00:51:10,838 WHETHER OR NOT AS A SINGLE AGENT 1063 00:51:10,838 --> 00:51:16,544 THIS WOULD BE MORE ACTIVE IN GCB 1064 00:51:16,544 --> 00:51:23,084 TUMORS THAT HAVE Bcl TWO AND 1065 00:51:23,084 --> 00:51:24,318 MYC TRANSLOCATION, WITH 1066 00:51:24,318 --> 00:51:27,054 VENETOCLAX, AS A SURROGATE FOR 1067 00:51:27,054 --> 00:51:30,525 WHETHER OR NOT INHIBITING BCL-2 1068 00:51:30,525 --> 00:51:32,193 WOULD CAUSE THOSE TUMORS TO 1069 00:51:32,193 --> 00:51:33,494 ACTUALLY DIE. 1070 00:51:33,494 --> 00:51:36,264 AND THIS IS WORK DONE BY JIM 1071 00:51:36,264 --> 00:51:37,965 PHALEN, AND I'M JUST GOING TO 1072 00:51:37,965 --> 00:51:42,136 SHOW YOU HERE THESE ARE MULTIPLE 1073 00:51:42,136 --> 00:51:49,243 DOUBLE HIT LINES. 1074 00:51:49,243 --> 00:51:50,244 VENETOCLAX KILLS THEM. 1075 00:51:50,244 --> 00:51:52,980 WE THINK THIS IS PROBABLY A 1076 00:51:52,980 --> 00:51:54,949 MAJOR REASON WHY VIPOR TURNED 1077 00:51:54,949 --> 00:51:56,784 OUT TO BE HIGHLY EFFECTIVE IN 1078 00:51:56,784 --> 00:52:03,257 DOUBLE HITS, NO IDEA GOING INTO 1079 00:52:03,257 --> 00:52:03,791 THIS. 1080 00:52:03,791 --> 00:52:05,259 FINALLY, LAST SLIDE, LOTS OF 1081 00:52:05,259 --> 00:52:07,094 DRUGS AND YOU ALL MIGHT SAY OH 1082 00:52:07,094 --> 00:52:11,165 MY GOD, YOU KNOW, THESE DRUGS, 1083 00:52:11,165 --> 00:52:14,035 THEY COST $120,000 FOR A YEAR'S 1084 00:52:14,035 --> 00:52:14,235 WORTH. 1085 00:52:14,235 --> 00:52:16,871 THIS MUST COST A FORTUNE. 1086 00:52:16,871 --> 00:52:19,507 AND THE ANSWER IS NOT REALLY. 1087 00:52:19,507 --> 00:52:23,978 I MEAN, IT'S STILL COSTLY BUT 1088 00:52:23,978 --> 00:52:24,879 COMPARED TO GIVING SINGLE 1089 00:52:24,879 --> 00:52:28,483 AGENTS, ON A CHRONIC BASIS, EVEN 1090 00:52:28,483 --> 00:52:32,854 CAR-T CELLS, IT'S ACTUALLY A 1091 00:52:32,854 --> 00:52:36,123 BARGAIN, SIX CYCLES OF THIS 1092 00:52:36,123 --> 00:52:40,828 COSTS $169,000, AND THESE ARE 1093 00:52:40,828 --> 00:52:48,402 USING THE VENETOCLAX AS A SINGLE 1094 00:52:48,402 --> 00:52:56,143 AGENT, IBRUTINIB, R SQUARED, 1095 00:52:56,143 --> 00:52:57,245 THIS IS BENOTUZOMBAB, GIVING 1096 00:52:57,245 --> 00:52:59,013 THEM THE OLD-FASHIONED WAY WHERE 1097 00:52:59,013 --> 00:53:02,450 YOU DON'T GET CURES IT COSTS -- 1098 00:53:02,450 --> 00:53:05,453 MANY OF THESE ARE YEARLY COSTS, 1099 00:53:05,453 --> 00:53:07,755 THESE DRUGS ARE GIVEN FOR 1100 00:53:07,755 --> 00:53:08,422 MULTIPLE YEARS. 1101 00:53:08,422 --> 00:53:12,026 SO I WANT TO HIGHLIGHT THAT THIS 1102 00:53:12,026 --> 00:53:17,632 CLINICAL TRIAL WAS DONE BY MY 1103 00:53:17,632 --> 00:53:20,568 COLLEAGUE CHRIS MELANI WHO DID A 1104 00:53:20,568 --> 00:53:21,802 FANTASTIC JOB AND CONTINUES TO 1105 00:53:21,802 --> 00:53:25,406 DO A WONDERFUL JOB WITH THIS 1106 00:53:25,406 --> 00:53:25,740 THERAPY. 1107 00:53:25,740 --> 00:53:28,676 I'VE NOT GONE INTO IT BUT WE'RE 1108 00:53:28,676 --> 00:53:31,078 DOING IT IN MANTLE CELL, ALSO A 1109 00:53:31,078 --> 00:53:33,180 TUMOR THAT'S HIGHLY DEPEND ON 1110 00:53:33,180 --> 00:53:36,450 BCR SIGNALING, AND THERE BELIEVE 1111 00:53:36,450 --> 00:53:42,056 IT OR NOT LOOKS TO BE MORE 1112 00:53:42,056 --> 00:53:44,992 EFFECTIVE IN LARGE CELL. 1113 00:53:44,992 --> 00:53:50,131 I ALSO WANT TO -- OKAY, GOOD. 1114 00:53:50,131 --> 00:53:53,834 AND ALSO WANT TO HIGHLIGHT MARK, 1115 00:53:53,834 --> 00:53:56,804 OUR CLINICAL DIRECTOR, AND PLAYS 1116 00:53:56,804 --> 00:53:59,974 A PIVOTAL ROLE IN HELPING WITH 1117 00:53:59,974 --> 00:54:05,880 THIS, AND OUR CLINICAL AND ONE 1118 00:54:05,880 --> 00:54:08,649 OF OUR CLINICIANS, RAUL, WHO 1119 00:54:08,649 --> 00:54:11,052 ALSO WORKS WITH MARK AND CHRIS 1120 00:54:11,052 --> 00:54:13,321 AND ME, AND THEN FINALLY ALL 1121 00:54:13,321 --> 00:54:14,889 THIS WORK COULD NOT HAVE BEEN 1122 00:54:14,889 --> 00:54:17,525 DONE WITHOUT A VERY CLOSE 1123 00:54:17,525 --> 00:54:19,060 COLLABORATION BETWEEN LOU AND 1124 00:54:19,060 --> 00:54:20,928 MYSELF, I DON'T KNOW WHY THIS 1125 00:54:20,928 --> 00:54:25,733 KEEPS ON DOING THIS. 1126 00:54:25,733 --> 00:54:30,304 AND SO LOU HAS PLAYED A CENTRAL 1127 00:54:30,304 --> 00:54:35,376 ROLE HERE, AND SO HAS JAMES 1128 00:54:35,376 --> 00:54:39,313 PHALEN AND GEORGE WRIGHT, AND 1129 00:54:39,313 --> 00:54:43,150 YANDAN AND DA WEI AND WORKING 1130 00:54:43,150 --> 00:54:44,885 WITH NCATS, CRAIG THOMAS, WHERE 1131 00:54:44,885 --> 00:54:46,320 MANY OF THESE SYNERGY ASSAYS 1132 00:54:46,320 --> 00:54:47,421 WERE BEING DONE. 1133 00:54:47,421 --> 00:54:48,089 THANK YOU VERY MUCH. 1134 00:54:48,089 --> 00:54:50,458 [APPLAUSE] 1135 00:54:50,458 --> 00:54:56,497 1136 00:54:56,497 --> 00:55:00,868 1137 00:55:00,868 --> 00:55:03,604 >> QUESTIONS FOR WYNDHAM? 1138 00:55:03,604 --> 00:55:09,644 1139 00:55:09,644 --> 00:55:11,278 1140 00:55:11,278 --> 00:55:13,147 >> THANK YOU VERY MUCH FOR YOUR 1141 00:55:13,147 --> 00:55:13,481 TALK. 1142 00:55:13,481 --> 00:55:16,317 VERY EXCITING. 1143 00:55:16,317 --> 00:55:19,253 MY QUESTION IS ABOUT THE -- ONE 1144 00:55:19,253 --> 00:55:21,122 OF THE INGREDIENTS IN VIPOR, ONE 1145 00:55:21,122 --> 00:55:23,090 OF THE DRUGS I BELIEVE YOU 1146 00:55:23,090 --> 00:55:26,427 MENTIONED A STEROID THAT HAD 1147 00:55:26,427 --> 00:55:27,128 MILDER TOXICITY. 1148 00:55:27,128 --> 00:55:28,562 DO YOU HAVE -- WERE THERE ANY 1149 00:55:28,562 --> 00:55:31,632 OTHER DRUGS THAT HAD KIND OF 1150 00:55:31,632 --> 00:55:33,501 MILDER TOXICITY AMONG THOSE THAT 1151 00:55:33,501 --> 00:55:33,768 YOU USED? 1152 00:55:33,768 --> 00:55:36,437 AND HAVE YOU THOUGHT IF THERE'S 1153 00:55:36,437 --> 00:55:39,940 MORE THAN ONE, USING THEM DURING 1154 00:55:39,940 --> 00:55:43,444 THAT INTERVAL WHEN CURRENTLY 1155 00:55:43,444 --> 00:55:44,512 NOT TREATING WITH ANYTHING, 1156 00:55:44,512 --> 00:55:45,446 DURING THE GAP? 1157 00:55:45,446 --> 00:55:45,746 >> RIGHT. 1158 00:55:45,746 --> 00:55:50,451 WE ARE LIMITED BY DRUGS THAT 1159 00:55:50,451 --> 00:55:52,653 ACTUALLY AFFECT PATHWAYS, AND 1160 00:55:52,653 --> 00:55:55,289 THERE IS ANOTHER DRUG CLASS 1161 00:55:55,289 --> 00:55:58,225 WHICH IS CALLED PI3 KINASE THAT 1162 00:55:58,225 --> 00:55:59,894 CAN ALSO AFFECT DIFFERENT 1163 00:55:59,894 --> 00:56:00,995 ASPECTS OF THAT PATHWAY. 1164 00:56:00,995 --> 00:56:02,463 UNFORTUNATELY, THAT TURNS OUT TO 1165 00:56:02,463 --> 00:56:05,232 BE AN EVEN MORE TOXIC DRUG. 1166 00:56:05,232 --> 00:56:08,402 SO, I THINK THAT WE TRY TO FIND 1167 00:56:08,402 --> 00:56:10,805 DRUGS THAT BOTH HIT THE PATHWAY 1168 00:56:10,805 --> 00:56:12,440 BUT WERE THE BEST TOLERATED. 1169 00:56:12,440 --> 00:56:14,742 AND SO YOU BRING UP A VERY GOOD 1170 00:56:14,742 --> 00:56:16,377 POINT BUT I THINK THAT'S WHAT WE 1171 00:56:16,377 --> 00:56:17,244 DID HERE. 1172 00:56:17,244 --> 00:56:19,780 WE WOULD LOVE TO USE PI3 KINASE 1173 00:56:19,780 --> 00:56:23,984 BUT THAT'S JUST A VERY SPICY 1174 00:56:23,984 --> 00:56:27,354 DRUG. 1175 00:56:27,354 --> 00:56:31,926 >> SO, THIS IS A QUESTION THAT 1176 00:56:31,926 --> 00:56:35,029 PERHAPS MORE PHILOSOPHICAL. 1177 00:56:35,029 --> 00:56:36,664 BUT THESE SPECTACULAR RESULTS 1178 00:56:36,664 --> 00:56:43,337 THAT YOU AND LOU AND THE TEAM 1179 00:56:43,337 --> 00:56:45,339 HAVE OBTAINED RESTS ON A LOT OF 1180 00:56:45,339 --> 00:56:47,708 FANTASTIC STUDIES OF B CELL 1181 00:56:47,708 --> 00:56:48,242 BIOLOGY. 1182 00:56:48,242 --> 00:56:50,211 AND DISSECTION OF THE PATHWAYS. 1183 00:56:50,211 --> 00:56:53,180 TO WHAT EXTEND DO YOU THINK THIS 1184 00:56:53,180 --> 00:56:55,149 APPROACH WOULD BE GENERALIZABLE 1185 00:56:55,149 --> 00:56:56,383 TO OTHER TUMORS? 1186 00:56:56,383 --> 00:56:58,652 IS IT THAT B CELLS, IMMUNE CELLS 1187 00:56:58,652 --> 00:56:59,854 ARE REALLY SPECIAL? 1188 00:56:59,854 --> 00:57:02,590 OR IS IT THAT WE UNDERSTAND 1189 00:57:02,590 --> 00:57:04,992 THEIR PATHWAYS MUCH BETTER AND 1190 00:57:04,992 --> 00:57:07,394 THAT IF WE HAD EQUIVALENT 1191 00:57:07,394 --> 00:57:08,295 UNDERSTANDING OF SIGNAL, DIVERSE 1192 00:57:08,295 --> 00:57:09,797 SIGNALING IN OTHER SORTS OF 1193 00:57:09,797 --> 00:57:11,766 TUMORS, THAT THE SAME SORTS OF 1194 00:57:11,766 --> 00:57:13,534 APPROACHES COULD BE APPLIED? 1195 00:57:13,534 --> 00:57:17,238 >> SO, I WOULD ANSWER THAT BY 1196 00:57:17,238 --> 00:57:21,208 SAYING THAT EVEN IN SOLID 1197 00:57:21,208 --> 00:57:22,843 TUMORS, IDENTIFYING WHERE THE 1198 00:57:22,843 --> 00:57:25,045 PATHWAYS ARE AND USING MULTIPLE 1199 00:57:25,045 --> 00:57:27,748 DRUGS IS GOING TO TRANSLATE INTO 1200 00:57:27,748 --> 00:57:29,383 A BETTER OUTCOME. 1201 00:57:29,383 --> 00:57:32,453 BUT WHERE WE'RE LUCKY WITH 1202 00:57:32,453 --> 00:57:34,855 LYMPHOID TUMORS, IS AS YOU KNOW, 1203 00:57:34,855 --> 00:57:37,925 BECAUSE OF THE WAY SELECTION 1204 00:57:37,925 --> 00:57:41,328 GOES ON, THEY ARE REALLY -- THEY 1205 00:57:41,328 --> 00:57:43,297 ARE RELATIVELY EASY TO PUT INTO 1206 00:57:43,297 --> 00:57:47,268 APOPTOSIS, BUT YOU JUST NEED THE 1207 00:57:47,268 --> 00:57:51,572 RIGHT -- NEED TO SHUT DOWN THE 1208 00:57:51,572 --> 00:57:53,174 RIGHT PATHWAYS. 1209 00:57:53,174 --> 00:57:54,875 I DON'T THINK THAT'S NEARLY AS 1210 00:57:54,875 --> 00:57:57,278 CLEAR WITH A LOT OF SOLID 1211 00:57:57,278 --> 00:57:57,511 TUMORS. 1212 00:57:57,511 --> 00:57:58,879 YES AND NO. 1213 00:57:58,879 --> 00:58:03,250 WE'RE LUCKY WE HAVE RELATIVELY 1214 00:58:03,250 --> 00:58:04,451 SENSITIVE TUMORS BUT IN ABSENCE 1215 00:58:04,451 --> 00:58:05,653 OF DRUGS LIKE WE'RE DOING YOU 1216 00:58:05,653 --> 00:58:08,289 CAN SEE MOST PEOPLE WHEN THEY 1217 00:58:08,289 --> 00:58:09,290 RECURRED DIED, SO I DON'T THINK 1218 00:58:09,290 --> 00:58:11,158 WE'RE GOING TO FIND THAT 1219 00:58:11,158 --> 00:58:12,927 NECESSARILY WITH SOLID TUMORS 1220 00:58:12,927 --> 00:58:17,097 BUT THE EXCITING THING IS 1221 00:58:17,097 --> 00:58:18,432 IMMUNOTHERAPY SEEMS TO BE, YOU 1222 00:58:18,432 --> 00:58:21,035 KNOW, EFFECTIVE IN BOTH. 1223 00:58:21,035 --> 00:58:25,973 SO MAYBE WE'LL FIND OUT OTHER 1224 00:58:25,973 --> 00:58:29,443 PATHWAYS IN SOLID TUMORS THAT 1225 00:58:29,443 --> 00:58:29,844 ENHANCE OUTCOME. 1226 00:58:29,844 --> 00:58:32,213 CERTAINLY THEY ARE NOW USING A 1227 00:58:32,213 --> 00:58:35,049 NUMBER OF THESE TARGET AGENTS IN 1228 00:58:35,049 --> 00:58:36,784 ADJUVANT SETTING IN SOLID 1229 00:58:36,784 --> 00:58:38,886 TUMORS, WHERE THE TUMOR LOADS 1230 00:58:38,886 --> 00:58:40,621 ARE RELATIVELY LOW AND FINDING 1231 00:58:40,621 --> 00:58:41,822 THEY ARE INCREASING CURE RATE. 1232 00:58:41,822 --> 00:58:43,824 WELL, THEY ARE DECREASING THE 1233 00:58:43,824 --> 00:58:45,659 CHANCE OF SOMEONE RECURRING. 1234 00:58:45,659 --> 00:58:47,394 SO, I THINK YOU'VE JUST GOT TO 1235 00:58:47,394 --> 00:58:49,029 MOVE EARLIER. 1236 00:58:49,029 --> 00:58:51,866 BUT THE ANSWER IS YES, YOU WOULD 1237 00:58:51,866 --> 00:58:53,067 IMPROVE IT, BUT I DON'T THINK 1238 00:58:53,067 --> 00:58:55,502 THEY ARE GOING TO BE QUITE AS 1239 00:58:55,502 --> 00:59:00,207 EFFECTIVE AS WE HAVE FOUND. 1240 00:59:00,207 --> 00:59:01,609 >> I'M GOING TO TAKE THE 1241 00:59:01,609 --> 00:59:05,112 PREROGATIVE TO ASK ONE QUESTION. 1242 00:59:05,112 --> 00:59:07,848 THE QUESTION, WYNDHAM AND I HAVE 1243 00:59:07,848 --> 00:59:10,084 THOUGHT ABOUT AND WONDERED WHERE 1244 00:59:10,084 --> 00:59:13,754 HIS CURRENT THINKING IS. 1245 00:59:13,754 --> 00:59:16,056 YOU'RE DEALING WITH A TUMOR THAT 1246 00:59:16,056 --> 00:59:21,362 CAN BE CURED IN THE UP-FRONT 1247 00:59:21,362 --> 00:59:22,696 PREVIOUSLY UNTREATED SETTING 1248 00:59:22,696 --> 00:59:24,164 WITH CHEMOTHERAPY. 1249 00:59:24,164 --> 00:59:27,701 YOU HAVE A NEW THERAPY THAT HAS 1250 00:59:27,701 --> 00:59:29,370 A HIGH CURE RATE, AS YOU JUST 1251 00:59:29,370 --> 00:59:30,871 GOT THROUGH SAYING, MAYBE EVEN 1252 00:59:30,871 --> 00:59:34,408 HIGHER IF YOU MOVE IT EARLY. 1253 00:59:34,408 --> 00:59:37,811 SO, IS THERE A PATH TO TAKE A 1254 00:59:37,811 --> 00:59:40,447 TUMOR FOR WHICH THERE'S A GOOD 1255 00:59:40,447 --> 00:59:44,151 THERAPY BUT NOT 100% THERAPY, 1256 00:59:44,151 --> 00:59:47,721 AND CHANGE IT UP AND USE -- 1257 00:59:47,721 --> 00:59:50,624 >> THE ANSWER IS YES. 1258 00:59:50,624 --> 00:59:52,459 WITH THE RIGHT INFORMED CONSENT. 1259 00:59:52,459 --> 00:59:54,662 SO, THE WAY WE WOULD, NUMBER 1260 00:59:54,662 --> 01:00:00,567 ONE, I THINK THAT FOR THE TUMORS 1261 01:00:00,567 --> 01:00:03,203 THAT THIS APPEARS TO BE VERY 1262 01:00:03,203 --> 01:00:08,242 EFFECTIVE FOR, I THINK YOU COULD 1263 01:00:08,242 --> 01:00:10,644 EASILY JUSTIFY GIVING VIPOR AS 1264 01:00:10,644 --> 01:00:12,546 THE PRIMARY THERAPY. 1265 01:00:12,546 --> 01:00:16,250 AND WHAT I'VE SHOWN YOU IS THAT 1266 01:00:16,250 --> 01:00:18,652 WHEN IT WORKS, THE TUMOR GOES 1267 01:00:18,652 --> 01:00:19,853 AWAY WITHIN ONE CYCLE. 1268 01:00:19,853 --> 01:00:22,790 AND WHAT I THINK YOU WOULD DO 1269 01:00:22,790 --> 01:00:27,728 HERE IS THAT YOU WOULD MONITOR 1270 01:00:27,728 --> 01:00:30,331 THE TUMOR, MONITOR THE ctDNA, 1271 01:00:30,331 --> 01:00:32,399 A GOOD QUANTITATIVE WAY TO TELL 1272 01:00:32,399 --> 01:00:34,401 YOU HOW MUCH TUMOR THERE IS 1273 01:00:34,401 --> 01:00:37,571 ACTUALLY THERE, AND IF THE TUMOR 1274 01:00:37,571 --> 01:00:41,875 GOES DOWN TO ZERO, I THINK YOU 1275 01:00:41,875 --> 01:00:43,510 COULD COMPLETE SIX CYCLES OF THE 1276 01:00:43,510 --> 01:00:45,713 VIPOR AND STOP AND WATCH THEM 1277 01:00:45,713 --> 01:00:48,649 VERY, VERY CLOSELY. 1278 01:00:48,649 --> 01:00:51,051 IF THE TUMOR DOESN'T GO AWAY OR 1279 01:00:51,051 --> 01:00:55,322 YOU HYPOTHESIZE IF IT'S NOT BY 1280 01:00:55,322 --> 01:00:57,958 ctDNA GONE WITHIN TWO CYCLES, 1281 01:00:57,958 --> 01:01:00,227 YOU WOULD THEN MOVE THEM TO 1282 01:01:00,227 --> 01:01:01,161 CONVENTIONAL CHEMOTHERAPY. 1283 01:01:01,161 --> 01:01:02,396 YOU COULD MOVE THIS UP FRONT BUT 1284 01:01:02,396 --> 01:01:06,567 AS I SAID YOU HAVE TO HAVE VERY 1285 01:01:06,567 --> 01:01:07,267 CAREFUL INFORMED CONSENT BECAUSE 1286 01:01:07,267 --> 01:01:09,236 YOU WOULD TELL THE PEOPLE YOU'RE 1287 01:01:09,236 --> 01:01:10,738 DOING SOMETHING VERY NOVEL, 1288 01:01:10,738 --> 01:01:12,606 SOMETHING THAT YOU KNOW WILL 1289 01:01:12,606 --> 01:01:15,709 CURE SOME OF THEM BECAUSE WE CAN 1290 01:01:15,709 --> 01:01:18,645 CURE THEM IN THE RELAPSED STATE, 1291 01:01:18,645 --> 01:01:20,214 AND THAT WE'RE GOING TO DO 1292 01:01:20,214 --> 01:01:23,117 EVERYTHING WE CAN BASED ON THIS 1293 01:01:23,117 --> 01:01:25,953 ALGORITHM TO MAKE SURE THAT THEY 1294 01:01:25,953 --> 01:01:28,255 ARE CURATIVE, IF THEY ARE 1295 01:01:28,255 --> 01:01:28,522 CURATIVE. 1296 01:01:28,522 --> 01:01:30,224 SO THAT IS IN FACT A CLINICAL 1297 01:01:30,224 --> 01:01:35,896 TRIAL THAT WE ARE ACTUALLY 1298 01:01:35,896 --> 01:01:36,363 PLANNING. 1299 01:01:36,363 --> 01:01:38,098 LET ME ALSO SAY WE'VE NOW GOTTEN 1300 01:01:38,098 --> 01:01:40,634 ALL THE COMPANIES TO AGREE TO 1301 01:01:40,634 --> 01:01:47,408 GIVE US THE DRUGS TO DO A LARGE 1302 01:01:47,408 --> 01:01:51,779 CONFIRMATORY OF VIPOR IN 1303 01:01:51,779 --> 01:01:52,880 RELAPSED REFRACTORY NON-GCB AND 1304 01:01:52,880 --> 01:01:55,582 DOUBLE HIT IN THE COOPERATIVE 1305 01:01:55,582 --> 01:01:56,050 GROUPS. 1306 01:01:56,050 --> 01:01:57,017 >> WELL, THANK YOU, BECAUSE THAT 1307 01:01:57,017 --> 01:01:59,319 MEANS THAT YOU'RE NOT GOING TO 1308 01:01:59,319 --> 01:02:02,856 RETIRE FOR AT LEAST 15 MORE 1309 01:02:02,856 --> 01:02:03,157 YEARS. 1310 01:02:03,157 --> 01:02:04,591 >> OH, NO WAY. 1311 01:02:04,591 --> 01:02:06,226 >> TWENTY, TWO KNOWS, BECAUSE 1312 01:02:06,226 --> 01:02:10,497 YOU WANT TO FINISH THE STORY, 1313 01:02:10,497 --> 01:02:10,998 RIGHT? 1314 01:02:10,998 --> 01:02:14,134 >> OH, YEAH. 1315 01:02:14,134 --> 01:02:15,469 >> SO LET'S THANK WYNDHAM. 1316 01:02:15,469 --> 01:02:25,469 >> THANK YOU.