1 00:00:04,839 --> 00:00:05,940 GOOD MORNING. 2 00:00:05,940 --> 00:00:12,580 YOU'LL VERY HAPPY TO INTRODUCE 3 00:00:12,580 --> 00:00:13,247 DR. ALTAN-BONNET. 4 00:00:13,247 --> 00:00:16,550 HEAD OF THE IMMUNODYNAMIC GROUP 5 00:00:16,550 --> 00:00:21,555 IN THE LABORATORY OF CANCER AND 6 00:00:21,555 --> 00:00:29,230 IMMUNOLOGY HERE IN BUILDING 37. 7 00:00:29,230 --> 00:00:31,198 GREGOIRE TRAINED AS A PHYSICIST 8 00:00:31,198 --> 00:00:32,700 IN PARIS AND Ph.D. IN 9 00:00:32,700 --> 00:00:38,606 STATISTICAL DYNAMICS AND HIS 10 00:00:38,606 --> 00:00:45,446 FILED OF EXPERTISE IS IMMUNE OLY 11 00:00:45,446 --> 00:00:46,914 FIRST AT SLOAN KETTERING AND IN 12 00:00:46,914 --> 00:00:54,055 THE LAST SEVERAL YEARS NOW AT 13 00:00:54,055 --> 00:00:54,655 NCI. 14 00:00:54,655 --> 00:00:58,092 AND WHAT DISTINGUISHES THE WORK 15 00:00:58,092 --> 00:00:59,593 AND YOU'LL UNDERSTAND THE SYSTEM 16 00:00:59,593 --> 00:01:02,396 IMMUNOLOGIES WE NEED GOOD DATA 17 00:01:02,396 --> 00:01:06,467 FOR WHAT HE'S DOING AND HE'S NOT 18 00:01:06,467 --> 00:01:07,501 TRUSTING ANYBODY'S DATA. 19 00:01:07,501 --> 00:01:10,504 HE WANTS TO HAVE THIS OWN DATA 20 00:01:10,504 --> 00:01:15,910 THAT'S LONGITUDINAL AND 21 00:01:15,910 --> 00:01:26,053 CONNECTED AND THEN TRUST I'LL 22 00:01:26,053 --> 00:01:31,559 INTRODUCE HIM. 23 00:01:31,559 --> 00:01:34,528 >> WE DO CLINICAL TRIAL WITH 24 00:01:34,528 --> 00:01:37,932 PEOPLE ON A STORY DAY. 25 00:01:37,932 --> 00:01:48,442 THERE'LL BE A QUIZ AT THE END. 26 00:02:01,188 --> 00:02:05,326 AND THERE'S COMPLEXITY OF THE 27 00:02:05,326 --> 00:02:08,095 LYMPH NODES AND WE TRIED TO 28 00:02:08,095 --> 00:02:11,332 BUILD A MODEL TO LEARN THE 29 00:02:11,332 --> 00:02:14,035 BREAKING POINT AND HOPEFULLY BE 30 00:02:14,035 --> 00:02:14,769 ABLE TO DESIGN. 31 00:02:14,769 --> 00:02:21,175 TO DO THAT WE HAVE TWO 32 00:02:21,175 --> 00:02:21,475 APPROACHES. 33 00:02:21,475 --> 00:02:24,278 YOU GET RID OF TISSUES AND TRY 34 00:02:24,278 --> 00:02:30,051 TO PROFILE THEM IN A HIGH 35 00:02:30,051 --> 00:02:35,689 DIMENSIONAL SPACE AND WHAT'S NEW 36 00:02:35,689 --> 00:02:39,226 IN THE FIELD YOU CAN GET A LOT 37 00:02:39,226 --> 00:02:42,329 OF CELLS IN A FAIRLY HIGH 38 00:02:42,329 --> 00:02:42,897 DIMENSIONAL SPACE AND DO 39 00:02:42,897 --> 00:02:44,298 CLASSICALLY WHAT WE'VE BEEN 40 00:02:44,298 --> 00:02:46,801 DOING IS DEFINING NEW BIOMARKERS 41 00:02:46,801 --> 00:02:56,911 AND IDENTIFY NEW SIGNATURES OF 42 00:02:56,911 --> 00:02:57,945 THE IMMUNE RESPONSE. 43 00:02:57,945 --> 00:02:59,513 WE START FROM INTERACTIONS OF 44 00:02:59,513 --> 00:03:00,815 INDIVIDUAL CELLS AND HOW THEY 45 00:03:00,815 --> 00:03:05,886 ARE GET ACTIVATED AND BUILD THE 46 00:03:05,886 --> 00:03:11,125 COMPLEXITY FROM THE GROUND UP 47 00:03:11,125 --> 00:03:15,129 LOOKING AT TUMORS AND LOOK AT 48 00:03:15,129 --> 00:03:16,931 THE SYSTEM AND THE SPACE WE'RE 49 00:03:16,931 --> 00:03:18,866 IN IS SOMETHING IN BETWEEN WHERE 50 00:03:18,866 --> 00:03:20,901 WE'LL TWRI TO LEARN WHAT WE'RE 51 00:03:20,901 --> 00:03:26,040 LOOKING AT IN TERMS OF TARGET 52 00:03:26,040 --> 00:03:30,845 AND MARKERS TO MODEL AND USE 53 00:03:30,845 --> 00:03:33,347 ROBOTICS TO CHARACTERIZE IN A 54 00:03:33,347 --> 00:03:38,052 COMPLEX WAY AND BUILD A MODEL 55 00:03:38,052 --> 00:03:39,787 AND ASK QUESTIONS AND IT'S ALL 56 00:03:39,787 --> 00:03:42,056 BASED ON THAT. 57 00:03:42,056 --> 00:03:47,628 THIS IS FROM THE INTERNET AND 58 00:03:47,628 --> 00:03:52,266 THE KIND OF METHOD WE'RE HAS 59 00:03:52,266 --> 00:03:54,034 REALLY BEEN DEVELOPED TODAY AND 60 00:03:54,034 --> 00:03:57,605 WHAT I'LL SHOW YOU TODAY. 61 00:03:57,605 --> 00:04:03,577 FIRST I'LL TALK TO ABOUT THE 62 00:04:03,577 --> 00:04:05,880 APPROACH AND HOW TO CHARACTERIZE 63 00:04:05,880 --> 00:04:11,152 THE RESPONSE HAPPENING AND WHEN 64 00:04:11,152 --> 00:04:13,154 WE START TO PUT NUMBERS WE CAN 65 00:04:13,154 --> 00:04:19,059 LEARN NEW ASPECTS OF CANCER 66 00:04:19,059 --> 00:04:20,761 IMMUNOTHERAPIES AND TRY TO BUILD 67 00:04:20,761 --> 00:04:27,601 MODELS AND REDESIGNING BETTER 68 00:04:27,601 --> 00:04:33,574 CAR T CELLS AND NCI IS ONE OF 69 00:04:33,574 --> 00:04:44,051 THE LANDMARK INSTITUTES AND 70 00:04:50,124 --> 00:04:54,028 COLLECT LEUKOCYTES FROM 71 00:04:54,028 --> 00:04:57,598 METASTASIS AND YOU HOPE THERE'S 72 00:04:57,598 --> 00:04:58,499 ENOUGH SPECIFICITY IN THE CELLS 73 00:04:58,499 --> 00:05:01,735 THAT CAN GROW TO TUMORS. 74 00:05:01,735 --> 00:05:03,804 THERE'S MANY EXAMPLES FROM LABS 75 00:05:03,804 --> 00:05:11,712 THAT SHOW IT CAN BE SUCCESSFUL. 76 00:05:11,712 --> 00:05:15,249 AND WE WOULD LIKE TO BE ABLE TO 77 00:05:15,249 --> 00:05:16,550 UNDERSTAND HOW WE GO FROM THE 78 00:05:16,550 --> 00:05:21,055 BAG OF CELLS AND CONNECT THE 79 00:05:21,055 --> 00:05:22,690 DOTS TO DESIGN AND DESIGN BETTER 80 00:05:22,690 --> 00:05:24,792 THE NEW THERAPY. 81 00:05:24,792 --> 00:05:26,393 AGAIN, ON ALL KALE WE'LL KNOW 82 00:05:26,393 --> 00:05:30,097 MORE OF THE BASIC APPROACH. 83 00:05:30,097 --> 00:05:38,105 WHEN WE STARTED TO DO HIGH 84 00:05:38,105 --> 00:05:40,841 DIMENSIONAL CYTOMETRY AND AU LEB 85 00:05:40,841 --> 00:05:44,678 SAID LET'S TRY TO CHARACTERIZE 86 00:05:44,678 --> 00:05:50,551 THE BAGS AND SEE HOW MUCH 87 00:05:50,551 --> 00:05:53,020 DIVERSITY THERE IS AND LEARN 88 00:05:53,020 --> 00:05:56,090 WHAT MATTERS. 89 00:05:56,090 --> 00:05:58,425 WE DEVELOPED THIS PANEL WITH 90 00:05:58,425 --> 00:06:01,562 MARKERS AND WHEN YOU 91 00:06:01,562 --> 00:06:03,030 CHARACTERIZE THE CELLS THEY'RE 92 00:06:03,030 --> 00:06:04,798 SIMPLE WHERE THEY'VE BEEN 93 00:06:04,798 --> 00:06:06,834 EXPANDED AND AFTER ONE OR TWO 94 00:06:06,834 --> 00:06:07,668 WEEKS OF EXPANSION YOU GET A LOT 95 00:06:07,668 --> 00:06:10,037 OF DIVERSITY IN TERMS OF THE 96 00:06:10,037 --> 00:06:15,609 TYPE OF T CELL AND IT'S NOT JUST 97 00:06:15,609 --> 00:06:20,781 T CELL IT'S NOT REALLY A PURE 98 00:06:20,781 --> 00:06:25,052 PRODUCT BUT IT'S VERY USEFUL IN 99 00:06:25,052 --> 00:06:26,787 TERMS OF TELLING US THE 100 00:06:26,787 --> 00:06:29,923 DIVERSITY AND WE CAN START TO 101 00:06:29,923 --> 00:06:34,795 PARS THE SPACE AN LEARN NEW 102 00:06:34,795 --> 00:06:38,098 BIOMARKERS AND WHICH PATIENT CAN 103 00:06:38,098 --> 00:06:38,332 BENEFIT. 104 00:06:38,332 --> 00:06:41,068 THE IDEA WHERE WE HELPED IN 105 00:06:41,068 --> 00:06:42,236 MAKING THE MEASUREMENTS AND 106 00:06:42,236 --> 00:06:44,305 QUICKLY WE DEVELOPED A PIPELINE 107 00:06:44,305 --> 00:06:45,673 TO DO MORE MACHINE LEARNING 108 00:06:45,673 --> 00:06:56,150 APPROACH AND THIS WAS VERY 109 00:06:56,583 --> 00:06:56,817 SUCCESSFUL. 110 00:06:56,817 --> 00:06:57,918 THEY WENT BACK TO THE BENCH AND 111 00:06:57,918 --> 00:07:03,657 CAME UP WITH A SIMPLE SIGNATURE 112 00:07:03,657 --> 00:07:05,259 AND FORMALIZE IT WITH MACHINE 113 00:07:05,259 --> 00:07:06,427 LEARNING AND TO TELL YOU AT SOME 114 00:07:06,427 --> 00:07:08,762 LEVEL WHEN YOU LOOK AT THE 115 00:07:08,762 --> 00:07:12,933 DIVERSITY OF WHAT IS PREPARED IN 116 00:07:12,933 --> 00:07:18,906 THE CLINIC YOU CAN IDENTIFY A 117 00:07:18,906 --> 00:07:29,450 SUB POPULATION OF CD CELLS AND 118 00:07:30,150 --> 00:07:32,653 VICE VERSA SOME DON'T DO WELL IF 119 00:07:32,653 --> 00:07:43,063 THEY'RE LOW RESPONDERS. 120 00:07:48,936 --> 00:07:53,774 WITH HAD' MOUSE MODEL TO PREPARE 121 00:07:53,774 --> 00:07:59,480 THE WAY YOU PREPARE THEM FOR 122 00:07:59,480 --> 00:08:05,319 HUMAN PATIENTS AND IT'S A SIMPLE 123 00:08:05,319 --> 00:08:15,696 SIGNATURE AND COMPARE IT AND 124 00:08:15,696 --> 00:08:17,097 THERE'S IMMUNOFUNCTION FOR TIME 125 00:08:17,097 --> 00:08:19,400 AND INDEED IN THE MOUSE MODELS 126 00:08:19,400 --> 00:08:21,034 THE SAME WAY WE EXPECT WE SEE 127 00:08:21,034 --> 00:08:23,036 THAT IN THE HUMAN PATIENTS. 128 00:08:23,036 --> 00:08:25,773 THESE ARE THE T CELL YOU WANT TO 129 00:08:25,773 --> 00:08:33,714 PREPARE FOR TUMORS. 130 00:08:33,714 --> 00:08:37,785 THIS IS QUICK SNIP TO SHOW WE 131 00:08:37,785 --> 00:08:40,821 CAN DO HIGH DIMENSIONAL PROFILES 132 00:08:40,821 --> 00:08:46,260 TO LOOK AT WHAT MATTERS. 133 00:08:46,260 --> 00:08:54,067 IN THIS CASE IT PUSHED US TO 134 00:08:54,067 --> 00:08:55,469 QUANTIFY THINGS EFFICIENTLY. 135 00:08:55,469 --> 00:08:57,104 THE SECOND PART IS THE FREQUENCY 136 00:08:57,104 --> 00:08:59,039 OF THE CELLS IN THE BAGS ARE 137 00:08:59,039 --> 00:09:03,977 VERY LOW WITHIN LIKE .1 TO 1%. 138 00:09:03,977 --> 00:09:05,379 IT'S NOT JUST A BIOMARKER THESE 139 00:09:05,379 --> 00:09:07,648 ARE THE ONLY T CELLS WHICH 140 00:09:07,648 --> 00:09:09,149 MATTER TO GO AFTER THE TUMOR. 141 00:09:09,149 --> 00:09:13,854 THE QUESTION WE HAD IN THE LAB 142 00:09:13,854 --> 00:09:18,058 IS HOW MANY T CELLS DO WE NEED 143 00:09:18,058 --> 00:09:21,195 AND WE SHOWED A PROJECT FROM THE 144 00:09:21,195 --> 00:09:23,363 LAB TO TAKE THE INSIGHT AND TRY 145 00:09:23,363 --> 00:09:25,165 TO DEVELOP A SIMPLE ASSAY AND 146 00:09:25,165 --> 00:09:26,800 TRY TO UNDERSTAND THE MATH OF 147 00:09:26,800 --> 00:09:28,602 THE WAY T CELLS CAN GO AFTER 148 00:09:28,602 --> 00:09:28,936 TUMORS. 149 00:09:28,936 --> 00:09:34,775 AND GOING BACK TO A CLASSICAL 150 00:09:34,775 --> 00:09:39,713 MODEL AND THE TUMOR LINE 151 00:09:39,713 --> 00:09:41,048 EXPRESSING THIS AND WE CAN DO IT 152 00:09:41,048 --> 00:09:43,317 IN A FLEX MANNER. 153 00:09:43,317 --> 00:09:46,253 WE HAVE A ROBOTICS APPROACH 154 00:09:46,253 --> 00:09:49,790 WHERE IT REPLICATES AND TEST 155 00:09:49,790 --> 00:09:52,659 MANY TYPES OF CONFIGURATIONS AND 156 00:09:52,659 --> 00:09:56,263 CAN RECHARACTERIZE THESE IN A 157 00:09:56,263 --> 00:09:58,065 VERY NICE WAY AND FIRST QUESTION 158 00:09:58,065 --> 00:10:00,067 IN THE LAB IN A WAY WAS TO CHECK 159 00:10:00,067 --> 00:10:07,241 WE'RE TRYING TO COUNT THE CELLS 160 00:10:07,241 --> 00:10:09,510 IN THE LAB AND THERE'S A SIMPLE 161 00:10:09,510 --> 00:10:09,810 EXPERIMENT. 162 00:10:09,810 --> 00:10:15,816 WE TOOK CELLS FROM 100,000 T 163 00:10:15,816 --> 00:10:22,656 CELLS TO ONE T CELL AND YOU SEE 164 00:10:22,656 --> 00:10:28,328 THE CRUX FOR UNDERSTANDING THE 165 00:10:28,328 --> 00:10:33,600 WAY IT BEHAVES AND SEE IT 166 00:10:33,600 --> 00:10:38,772 CORRELATES VERY NICELY BUT 167 00:10:38,772 --> 00:10:44,444 MEASURE THE NOISE AND 168 00:10:44,444 --> 00:10:48,849 COEFFICIENT OF EVALUATION AND IF 169 00:10:48,849 --> 00:10:50,551 THE SIMPLE ASSAY WHERE WE 170 00:10:50,551 --> 00:10:54,388 CALIBRATE INSTRUMENTS AND SHOW 171 00:10:54,388 --> 00:10:58,625 IT'S ESSENTIALLY AND WHEN YOU 172 00:10:58,625 --> 00:11:00,861 COUNT CELLS IF YOU'RE MEASURING 173 00:11:00,861 --> 00:11:09,670 THE CELLS YOU'LL BE 10 OR PLUS 174 00:11:09,670 --> 00:11:14,808 MINUS 3 AND 100 THIS IS DOWN TO 175 00:11:14,808 --> 00:11:20,914 A LOW LEVEL OF NOISE AND THEY'RE 176 00:11:20,914 --> 00:11:22,082 QUANTITATIVE. 177 00:11:22,082 --> 00:11:24,518 AND WE MIXED THE TUMORS WITH THE 178 00:11:24,518 --> 00:11:26,820 T CELLS AND SEE A NICE DOSE 179 00:11:26,820 --> 00:11:27,354 RESPONSE. 180 00:11:27,354 --> 00:11:34,394 EACH DOT IS A DIFFERENT ONE AND 181 00:11:34,394 --> 00:11:37,965 EACH SHOW YOU WHEN YOU HAVE A 182 00:11:37,965 --> 00:11:42,336 LOT OF T CELLS YOU GET NICE 183 00:11:42,336 --> 00:11:45,439 KILLING. 184 00:11:45,439 --> 00:11:47,474 IF WE TAKE 3200 BLAST CELLS AN 185 00:11:47,474 --> 00:11:48,508 MIX THEM WITH TUMORS SOMETIMES 186 00:11:48,508 --> 00:11:54,047 YOU'LL KILL ALL THE TUMORS 187 00:11:54,047 --> 00:12:04,558 INSIDE THE DISH WE'LL EMULATE 188 00:12:12,032 --> 00:12:14,368 WHAT'S SEEN IN THE SYSTEM AND 189 00:12:14,368 --> 00:12:17,771 PREFER THE VIABILITY WE CAN GET 190 00:12:17,771 --> 00:12:19,106 WHEN WE EVALUATE AGAINST TUMORS. 191 00:12:19,106 --> 00:12:21,642 YOU CAN SEE ONE THE T CELL BLAST 192 00:12:21,642 --> 00:12:27,914 AND QUANTIFY IT NICELY. 193 00:12:27,914 --> 00:12:33,720 WE GET THIS HONEYCOMB IS THE 194 00:12:33,720 --> 00:12:43,397 NUMBER OF WELLS WE MEASURED. 195 00:12:43,397 --> 00:12:49,436 BE TUMORS SURVIVING AND OTHER 196 00:12:49,436 --> 00:12:57,744 WELLS HAVE AND THINGS GET NOISY 197 00:12:57,744 --> 00:13:04,484 AND FROM ONE WELL TO ANOTHER YOU 198 00:13:04,484 --> 00:13:08,021 CAN GO TO 100% OF TUMORS 199 00:13:08,021 --> 00:13:09,756 ATTACKED AND KILLED IN THE 200 00:13:09,756 --> 00:13:10,023 RESPONSE. 201 00:13:10,023 --> 00:13:11,091 THIS COULD BE DUE TO THE 202 00:13:11,091 --> 00:13:21,501 VIABILITY OF THE TUMORS. 203 00:13:25,105 --> 00:13:28,742 AND USE DRUGS CAN HAVE NO NOISE 204 00:13:28,742 --> 00:13:31,011 AND HAVE 60% WILLING AND FROM 205 00:13:31,011 --> 00:13:32,245 WELL TO WELL IS FAIRLY 206 00:13:32,245 --> 00:13:32,546 CONSISTENT. 207 00:13:32,546 --> 00:13:34,581 IF YOU'RE KILLING THEM WITH THE 208 00:13:34,581 --> 00:13:39,786 DRUG YOU HAVE A CONSISTENT 209 00:13:39,786 --> 00:13:41,388 TREATMENT. 210 00:13:41,388 --> 00:13:51,932 AND I COMBELT -- GET TO A NOISY 211 00:13:52,265 --> 00:13:57,738 SITUATION AND AS PUREE SAMPLE WE 212 00:13:57,738 --> 00:14:08,281 CAN GET WE TRACED IT BACK WITH 213 00:14:17,958 --> 00:14:22,963 REGULATION UP TO 48 HOURS AND 214 00:14:22,963 --> 00:14:30,637 GET THE MONEY COMB AND SOMETIMES 215 00:14:30,637 --> 00:14:32,038 WE CAN GET THE DOSE RESPONSE AND 216 00:14:32,038 --> 00:14:35,342 YOU END UP WITH SOMETHING WHICH 217 00:14:35,342 --> 00:14:37,744 LOOKS LIKE MEASURING THE 218 00:14:37,744 --> 00:14:38,512 COEFFICIENT VARIATION FROM WELL 219 00:14:38,512 --> 00:14:40,547 TO WELL. 220 00:14:40,547 --> 00:14:42,315 WE REPEAT TO UNDERSTAND 221 00:14:42,315 --> 00:14:44,317 INTERACTIONS AND LOOK AT THE T 222 00:14:44,317 --> 00:14:46,987 CELL ACTIVATING IN THE CELLS AND 223 00:14:46,987 --> 00:14:49,122 MEASURE STANDARD DEVIATION BY 224 00:14:49,122 --> 00:14:54,661 THE MEAN CELL ACTIVATED AND GET 225 00:14:54,661 --> 00:14:55,462 THE LIGHT BLUE CURVE. 226 00:14:55,462 --> 00:14:57,430 THE MEASUREMENT LOOKS LIKE THAT. 227 00:14:57,430 --> 00:15:05,238 IT'S ESSENTIALLY THE SAME ONE 228 00:15:05,238 --> 00:15:11,411 BUT SLIGHTLY SHIFT ED AT SOME 229 00:15:11,411 --> 00:15:14,014 LEVEL THERE'S A NUMBER OF CELLS 230 00:15:14,014 --> 00:15:18,051 BEING ACTIVATED AND IT SEEMS TO 231 00:15:18,051 --> 00:15:19,119 BE SHIFTED. 232 00:15:19,119 --> 00:15:21,388 AND THE MODEL STATES AS THE CORE 233 00:15:21,388 --> 00:15:25,425 OF INTERACTIONS YOU'RE DEALING 234 00:15:25,425 --> 00:15:27,394 WITH A SMALL NUMBER OF CELLS AND 235 00:15:27,394 --> 00:15:29,429 BECAUSE IT WILL BE NOISY AND YET 236 00:15:29,429 --> 00:15:31,898 THE NUMBER OF CELL ACTIVATED 237 00:15:31,898 --> 00:15:33,733 SEEMS TO BE HIGH BECAUSE THERE'S 238 00:15:33,733 --> 00:15:34,968 SOME PROPAGATION WHICH EXPANDED 239 00:15:34,968 --> 00:15:38,305 THE NOISE AND YOU END UP WITH 240 00:15:38,305 --> 00:15:41,074 THIS. 241 00:15:41,074 --> 00:15:43,944 SO A LITTLE BIT OF MATH AND 242 00:15:43,944 --> 00:15:48,615 BASICALLY WHEN LIEU YOU LOOK AT 243 00:15:48,615 --> 00:15:53,353 THE DATA WE THINK WE'LL SEE THE 244 00:15:53,353 --> 00:15:54,654 HALLMARK AND THE CORE OF 245 00:15:54,654 --> 00:15:56,957 WHATEVER PROCESS YOU'RE LOOKING 246 00:15:56,957 --> 00:15:59,793 AT IT'S LIKELY A SMALL NUMBER OF 247 00:15:59,793 --> 00:16:02,462 CELLS WHICH DECIDE EVERYTHING. 248 00:16:02,462 --> 00:16:03,797 SO THE MODEL WE SPEND TIME 249 00:16:03,797 --> 00:16:07,534 LOOKING AT THE MECHANISM AND 250 00:16:07,534 --> 00:16:10,770 SHOW WHAT YOU END UP WITH THE 251 00:16:10,770 --> 00:16:14,074 CELLS THERE SEEMS TO BE SPECIAL 252 00:16:14,074 --> 00:16:14,341 ONES. 253 00:16:14,341 --> 00:16:21,348 WE CALL THEM SPARKING CELLS AND 254 00:16:21,348 --> 00:16:26,086 WHEN THEY ARE GET ACTIVATED THE 255 00:16:26,086 --> 00:16:29,322 TUMORS WILL LIFT UP THE 256 00:16:29,322 --> 00:16:31,892 BYSTANDERS AND LOWER THE 257 00:16:31,892 --> 00:16:33,226 ACTIVATION AND GIVE MASSIVE 258 00:16:33,226 --> 00:16:35,028 IMMUNE INTERACTION. 259 00:16:35,028 --> 00:16:39,499 THE KEY IDEA IS THERE WILL BE A 260 00:16:39,499 --> 00:16:40,901 SUBCLUSTER OF CELLS AND CONTROL 261 00:16:40,901 --> 00:16:43,603 THE WAY THE INTERACTION CAN GET 262 00:16:43,603 --> 00:16:43,870 TRIGGERED. 263 00:16:43,870 --> 00:16:45,805 AND AGAIN THE IDEA IS BECAUSE 264 00:16:45,805 --> 00:16:51,811 IT'S A LOW NUMBER YOU'LL GET 265 00:16:51,811 --> 00:16:55,382 SIGNATURES AND GET THE DEF 266 00:16:55,382 --> 00:16:58,618 INANTS AND WE MEASURED ALL THE 267 00:16:58,618 --> 00:17:00,387 PARAMETERS AND THE BLACK LINE 268 00:17:00,387 --> 00:17:02,055 WHERE YOU MEASURE AS A FUNCTION 269 00:17:02,055 --> 00:17:04,491 OF THE MEAN NUMBER OF ACTIVATED 270 00:17:04,491 --> 00:17:06,059 CELLS CAN BE FITTED WITH FEW 271 00:17:06,059 --> 00:17:07,494 PARAMETERS AND CAN EXPLAIN 272 00:17:07,494 --> 00:17:12,999 EVERYTHING WITH THE SIMPLE 273 00:17:12,999 --> 00:17:13,199 MODEL. 274 00:17:13,199 --> 00:17:15,335 AND THEY RESPOND AND THEY CAN 275 00:17:15,335 --> 00:17:18,038 ENTRAIN ALL THE T CELLS AND YOU 276 00:17:18,038 --> 00:17:19,973 END UP WITH THE NOISY 277 00:17:19,973 --> 00:17:25,812 INTERACTIONS AN CAN ALONG AT THE 278 00:17:25,812 --> 00:17:29,683 TUMOR WITH UP REGULATE THE 279 00:17:29,683 --> 00:17:31,217 SIGNAL TO BE NOISY BUT WE CAN 280 00:17:31,217 --> 00:17:32,419 ACCOUNT FOR ALL THESE THINGS AND 281 00:17:32,419 --> 00:17:36,856 AGAIN AT THE END VERY SIMPLE 282 00:17:36,856 --> 00:17:39,159 MODEL THE SUB CLUSTER OF T CELLS 283 00:17:39,159 --> 00:17:42,062 SPOT DIRECTIONS AND MAKE ENOUGH 284 00:17:42,062 --> 00:17:44,764 CYTOKINE AND BE ABLE TO REALLY 285 00:17:44,764 --> 00:17:46,099 CREATE THIS MASSIVE KILLING OF 286 00:17:46,099 --> 00:17:50,103 TUMORS WHERE EVERYBODY GETS 287 00:17:50,103 --> 00:17:55,342 KILLED AT THE END. 288 00:17:55,342 --> 00:17:56,643 IN THIS EXPERIMENT WE TITRATED 289 00:17:56,643 --> 00:17:57,844 THE NUMBER OF T CELLS AND EACH 290 00:17:57,844 --> 00:18:02,048 DOT IS A WELL. 291 00:18:02,048 --> 00:18:04,651 WE'RE DEALING WITH MASSIVE 292 00:18:04,651 --> 00:18:08,421 AMOUNT OF INTERACTIONS AN 293 00:18:08,421 --> 00:18:09,889 LOOKING AT A FRACTION OF THE 294 00:18:09,889 --> 00:18:12,792 WELL ACTIVATED TO SEE THE T 295 00:18:12,792 --> 00:18:15,161 CELLS WERE ACTIVATED WITH THE 296 00:18:15,161 --> 00:18:16,062 SIGNATURE OF INFLAMMATION 297 00:18:16,062 --> 00:18:16,329 HAPPENING. 298 00:18:16,329 --> 00:18:18,365 IF YOU HAVE NO T CELLS IN THE 299 00:18:18,365 --> 00:18:21,234 LEFT YOU HAVE ZERO WELLS BEING 300 00:18:21,234 --> 00:18:21,501 ACTIVATED. 301 00:18:21,501 --> 00:18:23,536 IF YOU HAVE A LOT OF T CELLS 302 00:18:23,536 --> 00:18:26,439 100% WILL BE ACTIVATED WITH 303 00:18:26,439 --> 00:18:29,642 NOISE IN THE ACTIVATION AND 100% 304 00:18:29,642 --> 00:18:30,577 PASSING THE THRESHOLD. 305 00:18:30,577 --> 00:18:33,380 IF WE MEASURE THE FRACTION OF 306 00:18:33,380 --> 00:18:35,315 WELLS WHICH HAVE BEEN SPARK AS A 307 00:18:35,315 --> 00:18:38,451 FUNCTION OF INPUT T CELLS WE GET 308 00:18:38,451 --> 00:18:41,087 THE DATA IN THE BLACK MARK AND 309 00:18:41,087 --> 00:18:43,156 IF IT'S A PROCESS WHERE WE HAVE 310 00:18:43,156 --> 00:18:44,991 THE CURVE IN BLACK WHERE THE 311 00:18:44,991 --> 00:18:47,894 FRACTION OF WELLS BEING 312 00:18:47,894 --> 00:18:52,499 ACTIVATED WILL BE ONE OF THE 313 00:18:52,499 --> 00:18:56,369 SQUARE ROOT OF N BUT WE ARE 314 00:18:56,369 --> 00:18:59,272 SHIFTED BECAUSE IT LOOKS LIKE 315 00:18:59,272 --> 00:19:01,641 THE REACTIONS AND ONLY ONE OF 316 00:19:01,641 --> 00:19:03,510 2500 WILL BE ABLE TO SPOT AND 317 00:19:03,510 --> 00:19:07,914 FROM THIS ANALYSIS WE'LL BE ABLE 318 00:19:07,914 --> 00:19:12,819 TO REALLY ESTIMATE THE FREQUENCY 319 00:19:12,819 --> 00:19:14,054 OF THE T CELL. 320 00:19:14,054 --> 00:19:18,525 IT'S IN THE A SIMPLE DOSE 321 00:19:18,525 --> 00:19:19,559 RESPONSE BECAUSE EACH CORRESPOND 322 00:19:19,559 --> 00:19:25,265 TO THE WELL AND LOOK AT THE 323 00:19:25,265 --> 00:19:27,167 MICRO DOMAIN AND YOU'LL GET 324 00:19:27,167 --> 00:19:29,069 INTERACTIONS OR NONE AT ALL AND 325 00:19:29,069 --> 00:19:32,639 FROM THIS ANALYSIS WE KNOW WE'RE 326 00:19:32,639 --> 00:19:35,975 LOOKING FOR 0.04% OF THE CELL I 327 00:19:35,975 --> 00:19:36,876 WANT TO ACTIVATE. 328 00:19:36,876 --> 00:19:40,146 SO THIS IS JUST THE BEGINNING OF 329 00:19:40,146 --> 00:19:41,815 THE START.WE KNOW HOW TO LOOK AT 330 00:19:41,815 --> 00:19:43,016 THE DATA. 331 00:19:43,016 --> 00:19:45,852 IF YOU LOOK AT THE POPULATION OF 332 00:19:45,852 --> 00:19:50,056 T CELLS YOU CAN DO SINGLE CELL 333 00:19:50,056 --> 00:19:52,559 RNA SEQ AND FLOW CYTOMETRY AND 334 00:19:52,559 --> 00:19:56,563 SEE DIVERSITY. 335 00:19:56,563 --> 00:19:58,631 WHAT DIVERSITY MEANS CAN BE LARD 336 00:19:58,631 --> 00:19:59,365 TO ANALYZE. 337 00:19:59,365 --> 00:20:01,768 HERE WE HAVE A CHANCE TO SET UP 338 00:20:01,768 --> 00:20:04,237 THE NUMBERS AND WE'RE LOOKING AT 339 00:20:04,237 --> 00:20:05,572 SOMETHING WHICH IS INFREQUENT 340 00:20:05,572 --> 00:20:08,308 AND USE THAT TO IDENTIFY WHAT 341 00:20:08,308 --> 00:20:09,843 CLUSTER OF T CELLS SEEM TO 342 00:20:09,843 --> 00:20:10,910 MATTER. 343 00:20:10,910 --> 00:20:12,879 THIS IS A PIPELINE DEVELOPED AND 344 00:20:12,879 --> 00:20:21,454 LOOK AT IDENTIFICATION OF CELL 345 00:20:21,454 --> 00:20:22,922 SUBSETS AND BE ABLE TO GO IN OUR 346 00:20:22,922 --> 00:20:25,425 DATA AND TRY TO IDENTIFY THE T 347 00:20:25,425 --> 00:20:28,128 CELL WHICH REALLY MATTER TRYING 348 00:20:28,128 --> 00:20:29,829 TO SPARK THE IMMUNE INTERACTS 349 00:20:29,829 --> 00:20:31,498 AGAINST THE TUMOR. 350 00:20:31,498 --> 00:20:35,268 THE PIPELINE GOES LIKE THAT AND 351 00:20:35,268 --> 00:20:36,469 HAVE EX VIVO REACTIONS AND GIVE 352 00:20:36,469 --> 00:20:39,839 ME A TUMOR AND POPULATION OF T 353 00:20:39,839 --> 00:20:42,475 CELL IF WE HAVE ENOUGH WE CAN 354 00:20:42,475 --> 00:20:47,614 REPLICATE BLOCKING DIFFERENT 355 00:20:47,614 --> 00:20:54,621 PATHWAYS AND MEASURE THE 356 00:20:54,621 --> 00:20:56,556 FRACTION OF TIME IT GOES RIGHT 357 00:20:56,556 --> 00:21:00,126 OR DOESN'T AND START TO BUILD A 358 00:21:00,126 --> 00:21:02,695 BIG MATRIX AND CHANGING THE 359 00:21:02,695 --> 00:21:08,334 NUMBER OF T CELLS AND YOU'LL 360 00:21:08,334 --> 00:21:09,435 REALLY NAVIGATE ALL THE 361 00:21:09,435 --> 00:21:14,641 POSSIBILITIES HOW THE T CELLS GO 362 00:21:14,641 --> 00:21:15,842 AFTER TUMORS. 363 00:21:15,842 --> 00:21:21,714 AND THE DIFFERENT TIME POINTS 364 00:21:21,714 --> 00:21:25,218 AND THE 12 HOURS AND THE CD T 365 00:21:25,218 --> 00:21:26,553 CELLS OR THE DIVERSITY SOME 366 00:21:26,553 --> 00:21:33,326 CELLS ACTIVATED AND SOME NOT. 367 00:21:33,326 --> 00:21:37,931 . 368 00:21:37,931 --> 00:21:40,033 AND WE KNOW FROM THE DATA WHAT 369 00:21:40,033 --> 00:21:41,834 FREQUENCY OF T CELLS WE'RE 370 00:21:41,834 --> 00:21:43,369 EXPECTING DEPENDING ON THE 371 00:21:43,369 --> 00:21:43,636 CONDITION. 372 00:21:43,636 --> 00:21:47,674 IF WE HAVE A LOT OF T CELLS WE 373 00:21:47,674 --> 00:21:53,213 KNOW THE NUMBER WHAT WE SHOULD 374 00:21:53,213 --> 00:21:57,550 GET AND NOW WE HAVE THE T CELL 375 00:21:57,550 --> 00:21:59,252 DIFFERENTIATION AND MATCH THE 376 00:21:59,252 --> 00:22:01,521 MEASUREMENT IN TERMS OF T CELL 377 00:22:01,521 --> 00:22:03,022 DIFFERENTIATION WITH WHAT WE 378 00:22:03,022 --> 00:22:04,557 PREDICT ARE THE INTERACTIONS. 379 00:22:04,557 --> 00:22:07,360 THIS IS A GAME OF MATCHING 380 00:22:07,360 --> 00:22:09,829 PATTERN BECAUSE YOU'RE IN SUCH A 381 00:22:09,829 --> 00:22:11,297 HIGH DIMENSIONAL SPACE YOU'LL 382 00:22:11,297 --> 00:22:16,502 HAVE ONE PROCESS AND BE ABLE TO 383 00:22:16,502 --> 00:22:21,841 LINE UP THE DATA FROM WHAT WE 384 00:22:21,841 --> 00:22:26,045 PREDICTED IN THE LONG TIME 385 00:22:26,045 --> 00:22:26,279 SCALES. 386 00:22:26,279 --> 00:22:27,981 IF YOU LOOK AT THE SMALL CLUSTER 387 00:22:27,981 --> 00:22:31,985 IT LOOKS LIKE WHEN YOU MEASURE 388 00:22:31,985 --> 00:22:33,586 THE FREQUENT FOR A NUMBER OF T 389 00:22:33,586 --> 00:22:37,590 CELLS AND ANTIGENS IT MATCHES 390 00:22:37,590 --> 00:22:46,499 THE PREDICTIONS WHEN WE LOOK AT 391 00:22:46,499 --> 00:22:49,168 THE PROCESS AND USE A MACHINE 392 00:22:49,168 --> 00:22:50,003 LEARNING APPROACH AND IDENTIFY 393 00:22:50,003 --> 00:22:51,537 THE BAGS OF T CELLS AND WHERE 394 00:22:51,537 --> 00:22:58,444 THE CELLS ARE COMING FROM AND WE 395 00:22:58,444 --> 00:23:01,881 END UP WITH SOMETHING SIMPLE ALL 396 00:23:01,881 --> 00:23:07,887 THE RAUR CELL -- RARE CELLS 397 00:23:07,887 --> 00:23:09,555 MAKES A STOCHASTIC SIGNATURE AND 398 00:23:09,555 --> 00:23:12,125 TRAINS THE OTHER CELL 399 00:23:12,125 --> 00:23:13,660 INTERACTIONS. 400 00:23:13,660 --> 00:23:21,768 IT TURNS UP IN SIDE THE NAIVE 401 00:23:21,768 --> 00:23:28,207 CAR T CELLS ARE HAVE THE 402 00:23:28,207 --> 00:23:33,846 PHENOTYPE AND 1% TO 2% IS A 403 00:23:33,846 --> 00:23:41,487 FAIRLY RARE POPULATION. 404 00:23:41,487 --> 00:23:45,325 AN YOU CAN GO BACK AND SOLVE THE 405 00:23:45,325 --> 00:23:50,963 SELVES AND TEST THEIR POTENTIAL 406 00:23:50,963 --> 00:23:54,067 AND WE'RE MEASURING TUMOR 407 00:23:54,067 --> 00:23:57,203 KILLING AS A MEASURE OF T CELLS 408 00:23:57,203 --> 00:24:02,642 AND SORTED FOR THE SIGNATURE OR 409 00:24:02,642 --> 00:24:04,344 SORTED FROM THE CD 5 HIGH AND 410 00:24:04,344 --> 00:24:07,747 YOU SEE THE POTENCY CHANGES BY A 411 00:24:07,747 --> 00:24:08,881 FACTOR OF ALMOST 1,000. 412 00:24:08,881 --> 00:24:09,816 THIS IS VERY STRIKING. 413 00:24:09,816 --> 00:24:20,360 WE STARTED WITH A POPULATION OF 414 00:24:22,562 --> 00:24:26,966 T CELLS AND YET A RAURL 415 00:24:26,966 --> 00:24:29,635 POPULATION AND YOU CAN BOOST THE 416 00:24:29,635 --> 00:24:32,438 PROBABILITY OF ACTIVATION AND 417 00:24:32,438 --> 00:24:35,508 THE FRENZY OF TUMORS BY SORTING 418 00:24:35,508 --> 00:24:36,109 THEM OUT AND INCREASING THEIR 419 00:24:36,109 --> 00:24:39,212 FREQUENCY. 420 00:24:39,212 --> 00:24:41,314 WE STARTED FROM A BASIC APPROACH 421 00:24:41,314 --> 00:24:47,120 OF MEASURING THE NOISE AND 422 00:24:47,120 --> 00:24:51,891 SEEING IT CAN BE NOISY AND 423 00:24:51,891 --> 00:24:59,632 QUANTIFY THE DIVERSITY IN SINGLE 424 00:24:59,632 --> 00:25:00,933 CELL AND PUSH THOSE TO GET 425 00:25:00,933 --> 00:25:01,200 ACTIVATED. 426 00:25:01,200 --> 00:25:03,269 THIS WAS ALL DONE IN THE CONTEXT 427 00:25:03,269 --> 00:25:09,008 OF THE T CELLS BECAUSE WE CAN 428 00:25:09,008 --> 00:25:15,047 SORT THEM OUT AND DO SINGLE CELL 429 00:25:15,047 --> 00:25:17,650 SEQ AND SIGNATURE WE EXPECT TO 430 00:25:17,650 --> 00:25:20,753 CONTAIN MOST THE CAR T CELLS AND 431 00:25:20,753 --> 00:25:26,058 WHEN YOU DO THE TAC SEQ THERE'S 432 00:25:26,058 --> 00:25:34,300 A CLUSTER WHICH HAS IT MAKING 433 00:25:34,300 --> 00:25:37,069 SENSE AND AGAIN CELLS ARE IN A 434 00:25:37,069 --> 00:25:38,304 QUIESCENT STATE AND THERE'S A 435 00:25:38,304 --> 00:25:41,441 SUBSET OF CELLS MAYBE LESS THAN 436 00:25:41,441 --> 00:25:44,677 1% WHICH SEEMS TO HAVE CHROMATIN 437 00:25:44,677 --> 00:25:46,345 IN THE LOCUS IT WILL BE EASY FOR 438 00:25:46,345 --> 00:25:49,816 THEM TO GET GOING AND MAKE THE 439 00:25:49,816 --> 00:25:51,551 CYTOKINE AND TRAIN EVERYBODY 440 00:25:51,551 --> 00:25:52,952 ELSE. 441 00:25:52,952 --> 00:25:55,955 INDEED WHEN WE TEST THAT 442 00:25:55,955 --> 00:26:00,059 PHYSIOLOGICALLY AND COMPARE THE 443 00:26:00,059 --> 00:26:09,335 QUICK ACTIVATION AND ACTIVATION 444 00:26:09,335 --> 00:26:14,073 THIS POPULATION WE'RE ABLE TO 445 00:26:14,073 --> 00:26:18,044 TEST IT WHERE TO THE OTHER CELLS 446 00:26:18,044 --> 00:26:21,113 THE CELLS WILL TAKE 24, 48 HOURS 447 00:26:21,113 --> 00:26:25,585 TO GET GOING. 448 00:26:25,585 --> 00:26:27,920 WE LOOKED AT THE DIVERSITY OF 449 00:26:27,920 --> 00:26:31,057 THE T CELLS AND EXPLAIN THE 450 00:26:31,057 --> 00:26:32,792 IMMUNOACTION OF THE TUMORS AND 451 00:26:32,792 --> 00:26:35,995 THEN IDENTIFY THE SUB POPULATION 452 00:26:35,995 --> 00:26:42,702 WITH BASAL MARKERS AN CHROMATIN 453 00:26:42,702 --> 00:26:45,872 STATE AND GET GOING. 454 00:26:45,872 --> 00:26:47,974 THIS WAS DONE IN A MOUSE MODEL. 455 00:26:47,974 --> 00:26:51,978 YOU CAN CHARACTERIZE THESE 456 00:26:51,978 --> 00:26:54,046 THINGS. 457 00:26:54,046 --> 00:27:02,054 WE LOOKED AT THE KIND OF 458 00:27:02,054 --> 00:27:05,191 PREPARED TRANSGENICS WHICH 459 00:27:05,191 --> 00:27:07,326 EXPRESSED THE TCR AGAINST THE 460 00:27:07,326 --> 00:27:09,929 ANTIGENS AND DID THE SAME 461 00:27:09,929 --> 00:27:14,100 INTERACTS AND MULTIPLIED THE 462 00:27:14,100 --> 00:27:15,668 ASSAY AND TESTED THE TYPE OF 463 00:27:15,668 --> 00:27:18,938 TUMORS AND TRIED TO BUILD A MAP 464 00:27:18,938 --> 00:27:19,639 OF THE RESPONSE. 465 00:27:19,639 --> 00:27:23,676 FIRST, WHAT WE OBSERVED IS 466 00:27:23,676 --> 00:27:26,078 THOUGH THEY'RE PREPARED IN A 467 00:27:26,078 --> 00:27:31,817 FAIRLY HOME -- HOMOGENEOUS CELLS 468 00:27:31,817 --> 00:27:33,386 THEY'LL GIVE DIVERSITY IN THE 469 00:27:33,386 --> 00:27:38,057 WAY THEY CAN KILL AN GET 470 00:27:38,057 --> 00:27:40,660 ACTIVITY AGAINST TUMORS. 471 00:27:40,660 --> 00:27:44,096 THIS IS WHAT WE SIMULATE IN THE 472 00:27:44,096 --> 00:27:44,764 CENTERS. 473 00:27:44,764 --> 00:27:50,303 THEY COULD BE DIVERSE WHEN YOU 474 00:27:50,303 --> 00:27:56,342 GO DOWN THE DOSE RESPONSE AND 475 00:27:56,342 --> 00:27:59,812 APPLY AND CAN IDENTIFY A 476 00:27:59,812 --> 00:28:03,950 SUBCLUSTER OF THE MATCHING 477 00:28:03,950 --> 00:28:08,721 PREDICTION IN TERMS OF 478 00:28:08,721 --> 00:28:12,425 STOCHASTICALLY AND HAVE CD 45 479 00:28:12,425 --> 00:28:17,063 PLUS AND WE CAN DO THIS MORE 480 00:28:17,063 --> 00:28:21,934 SYSTEM 481 00:28:21,934 --> 00:28:24,070 SYSTEM 482 00:28:24,070 --> 00:28:26,072 SYSTEMATICCALLY AND TRIGGER THE 483 00:28:26,072 --> 00:28:29,408 REACTION INSIDE THE SAMPLE SO 484 00:28:29,408 --> 00:28:37,750 COMPLEX TYPE AND IT'S VERY 485 00:28:37,750 --> 00:28:38,884 DIFFERENT WITH THE CD 2 HIGH AND 486 00:28:38,884 --> 00:28:44,924 WE CAN SORT THE CELLS AND CHECK 487 00:28:44,924 --> 00:28:47,660 AND WHEN WE ACTIVATE THEM THE 488 00:28:47,660 --> 00:28:50,262 CELLS WILL MAKE THE GAMMA 489 00:28:50,262 --> 00:28:51,764 QUICKLY AND IF YOU LOOK AT THE 490 00:28:51,764 --> 00:28:55,501 OTHER CELLS THEY'LL BE DELAYED 491 00:28:55,501 --> 00:29:06,045 AND LESS POTENT IN MAKING GAMMA. 492 00:29:06,045 --> 00:29:13,786 THERE'S WHEN WE LOC AT THIS IT 493 00:29:13,786 --> 00:29:16,789 VARIES A LOT AND EXPRESSING AND 494 00:29:16,789 --> 00:29:20,292 BY THE TIME WE TEST THEM IN THE 495 00:29:20,292 --> 00:29:23,462 ASSAY SOME CELLS MAY BE AROUND 496 00:29:23,462 --> 00:29:23,629 50%. 497 00:29:23,629 --> 00:29:27,566 SOME ARE AROUND 30%. 498 00:29:27,566 --> 00:29:30,870 THERE'S DIFFERENT WAYS THE 499 00:29:30,870 --> 00:29:33,205 DONORS WILL GENERATE AND MAKING 500 00:29:33,205 --> 00:29:34,807 A DIFFERENT GAMMA AFTER ONE 501 00:29:34,807 --> 00:29:35,007 HOUR. 502 00:29:35,007 --> 00:29:37,443 SO IN A SENSE WHAT IT'S SAYING 503 00:29:37,443 --> 00:29:41,280 THE WAY THE CELLS ARE BEING 504 00:29:41,280 --> 00:29:42,948 PREPARED PUTS THEM IN MANY 505 00:29:42,948 --> 00:29:49,288 STATES AND BEING ABLE TO PARSE 506 00:29:49,288 --> 00:29:50,489 WILL BE A CHALLENGE AND WE CARE 507 00:29:50,489 --> 00:29:52,191 ABOUT THE GAMMA AND DRIVE THE 508 00:29:52,191 --> 00:29:54,260 OTHER CELLS DEPENDING ON WHAT WE 509 00:29:54,260 --> 00:29:56,529 CARE ABOUT, T CELL RESISTANCE 510 00:29:56,529 --> 00:29:58,497 AND GOING TO DIFFERENT TISSUE 511 00:29:58,497 --> 00:30:02,902 AND SO ON AND SO FORM AND 512 00:30:02,902 --> 00:30:04,537 THERE'S A LOT OF DIVERSITY AND 513 00:30:04,537 --> 00:30:07,807 WILL ALLOW US TO REQUANTIFY THE 514 00:30:07,807 --> 00:30:09,942 VIABILITY. 515 00:30:09,942 --> 00:30:11,877 THE LAST THING IS TO IMPRESS HE 516 00:30:11,877 --> 00:30:13,145 HAD TOWARDS HOPEFULLY WHAT WE 517 00:30:13,145 --> 00:30:18,584 WENT BACK TO SOME CLINICAL DATA 518 00:30:18,584 --> 00:30:24,590 AND LOOKED AT THE SIGNATURE AND 519 00:30:24,590 --> 00:30:29,695 SEE IF IT COALESCES WITH READOUT 520 00:30:29,695 --> 00:30:33,399 AND IF YOU LOOK AT THE 521 00:30:33,399 --> 00:30:35,301 CHECKPOINT INHIBITORS AND PASS 522 00:30:35,301 --> 00:30:39,438 THEM FOR IMAGING LOW TUMORS 523 00:30:39,438 --> 00:30:42,742 COMPARED TO THE IMAGE AND 524 00:30:42,742 --> 00:30:45,811 SEPARATE THE PATIENT FOR LOW 525 00:30:45,811 --> 00:30:49,048 SIGNATURE VERSUS HIGH SIGNATURE 526 00:30:49,048 --> 00:30:50,316 AND INDEED THE PATIENTS WITH LOW 527 00:30:50,316 --> 00:30:56,589 LEVEL OF IMAGING AND HIGH 528 00:30:56,589 --> 00:30:57,590 SIGNATURE OF THE CD 39 HIGH 529 00:30:57,590 --> 00:31:01,193 THESE ARE THE PATIENT WHICH CAN 530 00:31:01,193 --> 00:31:04,697 DO WELL AND SAME COHORT THE 531 00:31:04,697 --> 00:31:11,003 PATIENT DON'T HAVE MANY AND NOT 532 00:31:11,003 --> 00:31:13,072 PRESENTING A LOT OF THE CAR T 533 00:31:13,072 --> 00:31:13,439 CELLS. 534 00:31:13,439 --> 00:31:15,941 WHAT IT SAYS IN THE CARTOON IS 535 00:31:15,941 --> 00:31:17,676 ALL THE PATIENTS WHICH ARE HIGH 536 00:31:17,676 --> 00:31:20,379 LEVEL IMAGERY YOU DO WELL WHEN 537 00:31:20,379 --> 00:31:26,352 YOU DO THE THERAPY BUT THE 538 00:31:26,352 --> 00:31:30,055 PATIENTS WHICH HAS AN IMAGE VERY 539 00:31:30,055 --> 00:31:32,758 LOW AND HAVE A CELL EXPRESSING A 540 00:31:32,758 --> 00:31:34,894 LOT OF THE SIGNATURE SEEMS TO BE 541 00:31:34,894 --> 00:31:36,695 RESCUED AND BENEFIT. 542 00:31:36,695 --> 00:31:39,431 SO THIS IS LIKE 50% OF THE 543 00:31:39,431 --> 00:31:41,600 PATIENTS AND GET INTO A REGIME 544 00:31:41,600 --> 00:31:44,837 TO EXPLAIN WHY WE DO SO WELL IN 545 00:31:44,837 --> 00:31:47,907 TERMS OF THE COMBINED 546 00:31:47,907 --> 00:31:48,374 IMMUNOTHERAPY. 547 00:31:48,374 --> 00:31:54,046 THE CONCLUSION IS THERE'S REALLY 548 00:31:54,046 --> 00:31:55,347 WE CALL INTRINSIC VARIABILITY IN 549 00:31:55,347 --> 00:32:00,452 THE WAY THEY CAN TAKE PLACE. 550 00:32:00,452 --> 00:32:02,054 AND WITH HELP WITH THE MACHINE 551 00:32:02,054 --> 00:32:05,791 LEARNING AND PROCESSING OF THE 552 00:32:05,791 --> 00:32:07,626 SINGLE CELL AND A SIMPLE MODEL 553 00:32:07,626 --> 00:32:11,363 DEALING WITH A SMALL FRACTION OF 554 00:32:11,363 --> 00:32:12,498 T CELLS AND EXPRESS GAMMA 555 00:32:12,498 --> 00:32:12,731 QUICKLY. 556 00:32:12,731 --> 00:32:14,633 THIS IS CRITICAL BECAUSE WE ARE 557 00:32:14,633 --> 00:32:15,901 DEALING WITH TUMORS WHICH 558 00:32:15,901 --> 00:32:17,436 EXPRESS LOW LEVEL OF IMAGING. 559 00:32:17,436 --> 00:32:18,637 IF THE CELLS ARE PRESENT, THEY 560 00:32:18,637 --> 00:32:20,873 GET ACTIVITY QUICKLY AND MAKING 561 00:32:20,873 --> 00:32:24,710 A DIFFERENT GAMMA AND UPREGULATE 562 00:32:24,710 --> 00:32:30,749 AND WHY EN TRAIN THE BYSTANDERS 563 00:32:30,749 --> 00:32:32,051 AND THESE ARE RARE AND DEALING 564 00:32:32,051 --> 00:32:34,587 WITH A SMALL NUMBER OF CELLS 565 00:32:34,587 --> 00:32:36,789 FROM ONE TO 10 CELLS AN GET INTO 566 00:32:36,789 --> 00:32:40,626 A REGIME WHERE SUDDENLY IT 567 00:32:40,626 --> 00:32:41,861 BECOMES RARE AND NOISY. 568 00:32:41,861 --> 00:32:44,964 YOU HAVE A PIPELINE YOU CAN 569 00:32:44,964 --> 00:32:55,507 APPLY TO LOOK AT THE STOCHASTIC 570 00:32:55,975 --> 00:33:01,914 ITY AND -- AND THIS IS THE 571 00:33:01,914 --> 00:33:03,983 PIPELINE YOU WANT TO USE TO 572 00:33:03,983 --> 00:33:05,784 MRACH THE NUMBER OF CELLS IN 573 00:33:05,784 --> 00:33:07,119 YOUR REACTION WITH THE DIVERSITY 574 00:33:07,119 --> 00:33:09,588 OF THE IMMUNE FUNCTION AND 575 00:33:09,588 --> 00:33:14,360 IDENTIFY THE CAR T CELLS AND CD 576 00:33:14,360 --> 00:33:19,365 5 LOW IN HUMAN T CELLS AND MAKE 577 00:33:19,365 --> 00:33:20,299 THE DPA MA QUICKLY AND THE CELLS 578 00:33:20,299 --> 00:33:21,901 YOU CARE ABOUT IF YOU WANT TO GO 579 00:33:21,901 --> 00:33:24,470 AFTER TUMORS AND WE HOPE TO 580 00:33:24,470 --> 00:33:28,040 REALLY GET PROTOCOLS TO BOOST 581 00:33:28,040 --> 00:33:31,777 THE COMPARTMENT AND INCREASE THE 582 00:33:31,777 --> 00:33:32,011 SUCCESS. 583 00:33:32,011 --> 00:33:35,447 AND THIS IS UNDER REVIEW BUT YOU 584 00:33:35,447 --> 00:33:37,616 CAN DOWNLOAD IT IF YOU WANT TO 585 00:33:37,616 --> 00:33:38,684 SEE MORE DETAILS AND WANT TO 586 00:33:38,684 --> 00:33:40,486 DISCUSS MORE OF THIS. 587 00:33:40,486 --> 00:33:42,054 NOW LET'S MAKE A TRANSITION. 588 00:33:42,054 --> 00:33:46,058 I'LL DO MORE MATH. 589 00:33:46,058 --> 00:33:50,696 YOU COULD BE SHOCKED AND WE THIS 590 00:33:50,696 --> 00:33:53,632 GIVES YOU THE INTERACTIONS. 591 00:33:53,632 --> 00:33:58,037 IS IT POSSIBLE FOR A SINGLE 592 00:33:58,037 --> 00:34:00,272 LYMPHOCYTE TO DECIDE THE FATE OF 593 00:34:00,272 --> 00:34:01,040 THE REACTION? 594 00:34:01,040 --> 00:34:01,941 ARE WE FOOLING OURSELVES? 595 00:34:01,941 --> 00:34:06,145 IF YOU LOOK AT THE MATH IT'S NOT 596 00:34:06,145 --> 00:34:06,512 CRAZY. 597 00:34:06,512 --> 00:34:09,214 THE SINGLE T CELL CAN SECRETE AT 598 00:34:09,214 --> 00:34:11,317 THE RATE OF 1,000 MOLECULES PER 599 00:34:11,317 --> 00:34:11,550 SECOND. 600 00:34:11,550 --> 00:34:14,987 SO BECAUSE YOU'RE ALL VERY GOOD 601 00:34:14,987 --> 00:34:16,155 AT MATH AND IT'S EARLY IN THE 602 00:34:16,155 --> 00:34:21,226 WEEK YOU CAN GO FROM ONE TL SO 603 00:34:21,226 --> 00:34:24,630 ONE LYMPH NODE OR THE CRITICAL 604 00:34:24,630 --> 00:34:27,599 LEVEL IS A SMALL LYMPH NODE DO 605 00:34:27,599 --> 00:34:29,768 YOU THINK IT TAKES ONE HOUR, ONE 606 00:34:29,768 --> 00:34:32,538 DAY OR 100 DAYS TO GET TO SINGLE 607 00:34:32,538 --> 00:34:33,272 CELL? 608 00:34:33,272 --> 00:34:34,907 IT TAKES 17 HOURS. 609 00:34:34,907 --> 00:34:37,977 WE CAN DO THE MATH AND SEE THE 610 00:34:37,977 --> 00:34:40,879 SINGLE T CELLS AND SECRETING AT 611 00:34:40,879 --> 00:34:43,816 1,000 PER SECOND WITHIN 17 HOURS 612 00:34:43,816 --> 00:34:46,719 WILL MAKE ENOUGH CYTOKINE AND 613 00:34:46,719 --> 00:34:52,024 FLOOD IT WITH THE GAMMA FOR 614 00:34:52,024 --> 00:34:53,525 EVERYBODY TO RESPOND. 615 00:34:53,525 --> 00:34:58,931 SINGLE CELL IS ENOUGH TO GET 616 00:34:58,931 --> 00:35:02,768 THERE AND ON TOP OF THAT IF YOU 617 00:35:02,768 --> 00:35:03,802 LOOK AT THE SINGLE T CELL WHICH 618 00:35:03,802 --> 00:35:09,375 STARTS TO PROLIFERATE IT'S ONE 619 00:35:09,375 --> 00:35:10,442 EVERY SIX HOURS. 620 00:35:10,442 --> 00:35:12,578 AND IT TAKES ONE HOUR, ONE DAY, 621 00:35:12,578 --> 00:35:13,212 100 DAYS. 622 00:35:13,212 --> 00:35:16,749 IT'S VERY FAST. 623 00:35:16,749 --> 00:35:23,789 WITHIN FOUR DAYS YOU GET 50% TO 624 00:35:23,789 --> 00:35:29,461 10% OF THE LYMPH NODE IS MADE OF 625 00:35:29,461 --> 00:35:38,103 THIS AND IF THEY ARE MAKE THE 626 00:35:38,103 --> 00:35:46,045 RIGHT CYTOKINE HU THE SYSTEM 627 00:35:46,045 --> 00:35:48,280 BEHAVES AND I HOPE I'VE GIVEN 628 00:35:48,280 --> 00:35:51,950 YOU ENOUGH MATH TO GET GOING AND 629 00:35:51,950 --> 00:35:53,185 LOVE DOING THE CALCULATION TO 630 00:35:53,185 --> 00:35:55,554 SEE WHERE WE ARE IN TERMS OF 631 00:35:55,554 --> 00:36:02,061 TRIGGERING AN IMMUNE RESPONSE. 632 00:36:02,061 --> 00:36:12,237 [OFF-MIC] 633 00:36:19,812 --> 00:36:24,416 >> THEY'RE ASKING ABOUT WHAT 634 00:36:24,416 --> 00:36:28,020 WOULD HAPPEN IF WE DELIVER 635 00:36:28,020 --> 00:36:28,720 DIFFERENT GAMMA. 636 00:36:28,720 --> 00:36:32,224 YOU GET PD 1 VERY QUICKLY AS 637 00:36:32,224 --> 00:36:32,424 WELL. 638 00:36:32,424 --> 00:36:35,561 THE TIME GOING FROM LOCAL 639 00:36:35,561 --> 00:36:37,496 DELIVERY TO THE INTERFERON GAMMA 640 00:36:37,496 --> 00:36:41,600 AND SECRETION OF THE CYTOKINES 641 00:36:41,600 --> 00:36:42,601 THEY'RE NOT ADDRESSED YET BUT 642 00:36:42,601 --> 00:36:48,707 KNOW SYSTEMIC DELIVERY HAS BEEN 643 00:36:48,707 --> 00:36:51,643 A BIT OF A FAILURE IN TERMS 644 00:36:51,643 --> 00:36:53,946 OF -- WE'RE IN THE IDEA THAT. 645 00:36:53,946 --> 00:37:00,819 SO DIFFERENT GAMMA TO BE ABLE 646 00:37:00,819 --> 00:37:03,388 AND WE HAVE NOT EXPLORED IT BUT 647 00:37:03,388 --> 00:37:05,691 CAN ADD THAT TO THE MODEL. 648 00:37:05,691 --> 00:37:07,359 VERY GOOD IDEA. 649 00:37:07,359 --> 00:37:11,497 WE'LL SWITCH TO THE LAST PART 650 00:37:11,497 --> 00:37:15,167 AND HOW TO PROFILE THE T CELLS 651 00:37:15,167 --> 00:37:17,669 AND IN A REGIME TO UNDERSTAND 652 00:37:17,669 --> 00:37:19,404 IT'S EASY TO SEE THE DIVERSE 653 00:37:19,404 --> 00:37:21,740 TYPE OF T CELLS AND WHERE THATRY 654 00:37:21,740 --> 00:37:28,013 COMING FROM AND BUILD A MODEL 655 00:37:28,013 --> 00:37:33,752 WHERE YOU'LL BE ABLE TO EXPLAIN 656 00:37:33,752 --> 00:37:35,687 AND MARK WHERE THE T CELLS ARE 657 00:37:35,687 --> 00:37:36,054 ACTIVATED. 658 00:37:36,054 --> 00:37:37,556 WE'RE DOING THAT IN CONTEXT OF T 659 00:37:37,556 --> 00:37:41,760 CELLS AND IN THE CONTEXT OF CAR 660 00:37:41,760 --> 00:37:42,594 T CELLS AND THEN I'LL SHOW YOU 661 00:37:42,594 --> 00:37:44,730 WHAT WE DO IN THE CONTEXT. 662 00:37:44,730 --> 00:37:48,033 SO THIS COMES FROM AN OLD IDEA 663 00:37:48,033 --> 00:37:51,203 WHICH IS IN THE FIELD IS AN OLD 664 00:37:51,203 --> 00:37:53,705 PAPER FROM MY POSTDOC ADVISER 665 00:37:53,705 --> 00:37:55,307 AND WE WERE TESTING THE 666 00:37:55,307 --> 00:37:55,941 ACTIVATION OF T CELLS AGAINST 667 00:37:55,941 --> 00:37:57,910 DIFFERENT PEPTIDES AND THE 668 00:37:57,910 --> 00:37:59,144 SIMPLE DOSE RESPONSE AND THE 669 00:37:59,144 --> 00:38:01,914 POINT OF THE PAPER WAS TO SHOW 670 00:38:01,914 --> 00:38:03,382 THE DIFFERENT READOUT SEEM TO 671 00:38:03,382 --> 00:38:05,484 RESPOND TO DIFFERENT DOSES OF 672 00:38:05,484 --> 00:38:05,751 ANTIGENS. 673 00:38:05,751 --> 00:38:07,686 SO IF YOU CARE ABOUT MAKING 674 00:38:07,686 --> 00:38:10,923 GAMMA YOU NEED A LOW DOSE OF 675 00:38:10,923 --> 00:38:14,059 PEPTIDES AND SHOULD CARE OF 676 00:38:14,059 --> 00:38:14,826 MAKING IL3. 677 00:38:14,826 --> 00:38:15,928 AND WHEN WE LOOK AT THE 678 00:38:15,928 --> 00:38:19,765 DIVERSITY OF THE RESPONSE OF THE 679 00:38:19,765 --> 00:38:22,601 IMMUNE SYSTEM IT MIGHT INFER 680 00:38:22,601 --> 00:38:24,603 SOMETHING ABOUT THE QUANTITY OF 681 00:38:24,603 --> 00:38:25,871 ANTIGEN IN THE SYSTEM. 682 00:38:25,871 --> 00:38:27,906 THIS GOES BACK TO WORK WE'VE 683 00:38:27,906 --> 00:38:29,408 BEEN DOING SINCE MY POSTDOC HERE 684 00:38:29,408 --> 00:38:30,776 AT NIH AND OVER THE YEARS WE 685 00:38:30,776 --> 00:38:33,946 HAVE A MODEL SO GOOD IT HAS BEEN 686 00:38:33,946 --> 00:38:36,949 STANDING FOR 20 YEARS TO REVISE 687 00:38:36,949 --> 00:38:38,617 IT WHEN WORK ON CAR T CELL 688 00:38:38,617 --> 00:38:38,984 CELLS. 689 00:38:38,984 --> 00:38:43,255 WE'RE SEEING WHEN WE LOOK AT THE 690 00:38:43,255 --> 00:38:45,824 LIGAND INTERACTING WITH PCR WITH 691 00:38:45,824 --> 00:38:48,393 THE RECEPTORS, YOU GO FROM THE 692 00:38:48,393 --> 00:38:51,230 CHAIN OF SIGNALLING WHERE YOU'LL 693 00:38:51,230 --> 00:38:55,667 PHOSPHORYLATE ONCE, TWICE, 10 694 00:38:55,667 --> 00:38:56,668 TIMES AND THE DIFFERENT STAGES 695 00:38:56,668 --> 00:38:57,536 MIGHT CONNECT TO DIFFERENT 696 00:38:57,536 --> 00:38:58,003 READOUT. 697 00:38:58,003 --> 00:39:03,075 SO THE IDEA IS AGAIN THE TCR IS 698 00:39:03,075 --> 00:39:09,781 COMPLEX BECAUSE TEA VERY GOOD AT 699 00:39:09,781 --> 00:39:13,051 DISTINGUISH DIFFERENT PEPTIDES 700 00:39:13,051 --> 00:39:17,389 AND MAKE THE GAMMA AND SO ON AND 701 00:39:17,389 --> 00:39:18,357 SO FORTH. 702 00:39:18,357 --> 00:39:21,059 COMING TO NIH WE WANTED TO STUDY 703 00:39:21,059 --> 00:39:24,196 THIS IN MORE DETAILS AND TO 704 00:39:24,196 --> 00:39:26,031 BUILD A MODEL OF THE WAY T CELLS 705 00:39:26,031 --> 00:39:29,234 ARE ABLE TO INTERACT WITH 706 00:39:29,234 --> 00:39:31,270 IMAGING AND GO TO THE COMPLEX 707 00:39:31,270 --> 00:39:31,470 SPACE. 708 00:39:31,470 --> 00:39:33,872 NOW, TO DO THAT WE BUILT A 709 00:39:33,872 --> 00:39:34,139 PIPELINE. 710 00:39:34,139 --> 00:39:40,012 I'M VERY THANKFUL TO THE 711 00:39:40,012 --> 00:39:42,648 LEADERSHIP AND WAS ENCOURAGING 712 00:39:42,648 --> 00:39:44,149 TO BUILD THE ROBOT. 713 00:39:44,149 --> 00:39:47,819 WE'RE DOING ESSENTIALLY WHAT YOU 714 00:39:47,819 --> 00:39:53,258 WOULD DO EXCEPT BUILT IN SUCH A 715 00:39:53,258 --> 00:39:55,093 WAY TO BUILD ACCESSORY QUICKLY 716 00:39:55,093 --> 00:39:57,696 AND YOU GET T CELLS FROM 717 00:39:57,696 --> 00:40:00,132 PATIENTS AND FROM MOUSE MODEL 718 00:40:00,132 --> 00:40:04,670 AND TOMB TUMORS AND MIX THAT 719 00:40:04,670 --> 00:40:10,876 WITH PLAMACROPHAGES AND PUT THEN 720 00:40:10,876 --> 00:40:13,011 THE WELL AND IF IT WORKS WELL 721 00:40:13,011 --> 00:40:15,480 YOU CAN COLLECT ALL THE CELLS 722 00:40:15,480 --> 00:40:20,118 AND COLLECT THE COLLECT THE 723 00:40:20,118 --> 00:40:22,354 CELLS IN TERMS OF 724 00:40:22,354 --> 00:40:27,559 DIFFERENTIATION AND MARKERS AND 725 00:40:27,559 --> 00:40:29,661 YOU'LL SEE ON THE GRAPH WE HAVE 726 00:40:29,661 --> 00:40:32,030 THE B CELLS AND THE BYSTANDERS 727 00:40:32,030 --> 00:40:33,865 BEING ACTIVATED. 728 00:40:33,865 --> 00:40:36,468 THE T CELLS ON THE RIGHT AND YOU 729 00:40:36,468 --> 00:40:37,969 SEE THERE'S A LOT OF DIVERSITY 730 00:40:37,969 --> 00:40:41,106 IN TERMS OF CLUSTER OR CELLS 731 00:40:41,106 --> 00:40:42,007 BEING ACTIVATE AND COMPLEXITY IN 732 00:40:42,007 --> 00:40:43,709 THE SIMPLE MAP IN TERMS OF THE 733 00:40:43,709 --> 00:40:46,678 WAY THE CELL IS ACTIVATED. 734 00:40:46,678 --> 00:40:48,213 WHAT IT LOOKS LIKE IN THE LAB 735 00:40:48,213 --> 00:40:50,048 AND COME TO TOP BY AND PEOPLE 736 00:40:50,048 --> 00:40:55,354 HAVE BEEN USING THE PLATFORM TO 737 00:40:55,354 --> 00:40:56,321 DO THAT. 738 00:40:56,321 --> 00:40:58,056 SO I HOPE THE MOVIE WORKS. 739 00:40:58,056 --> 00:41:02,060 IT'S A SIMPLE PLATFORM WHICH 740 00:41:02,060 --> 00:41:04,796 ENABLES TO DO WHAT YOU'D DO AT 741 00:41:04,796 --> 00:41:06,732 THE BENCH AND THE INCUBATOR ON 742 00:41:06,732 --> 00:41:12,471 THE RIGHT AND WE MOVE THE COVER 743 00:41:12,471 --> 00:41:18,043 AND STOP IT'S ROBUST ENOUGH MANY 744 00:41:18,043 --> 00:41:19,277 PEOPLE CAN HAVE THE PLATFORM IN 745 00:41:19,277 --> 00:41:20,312 THE LAB. 746 00:41:20,312 --> 00:41:25,684 HERE ON THE RIGHT I'M SHOWING A 747 00:41:25,684 --> 00:41:29,421 PIPELINE INTERFACE AND ENCODE 748 00:41:29,421 --> 00:41:29,755 THE DATA. 749 00:41:29,755 --> 00:41:32,991 ONCE THE ROBOT IS DONE YOU'LL 750 00:41:32,991 --> 00:41:41,900 GET A BIG MATRIX OF CYTOKINES 751 00:41:41,900 --> 00:41:43,335 AND ENCODE THINGS QUICKLY. 752 00:41:43,335 --> 00:41:46,938 AND THANKS TO ALL THE TOOLS 753 00:41:46,938 --> 00:41:49,975 WE'RE ONE GIGANTIC TO ENCODE 754 00:41:49,975 --> 00:41:51,376 EVERY CYTOKINE AND MARKER 755 00:41:51,376 --> 00:41:58,950 MEASURED FOR THE LAST TWO YEARS. 756 00:41:58,950 --> 00:42:01,019 AND THIS IS BILLIONS AND 757 00:42:01,019 --> 00:42:02,788 BILLIONS OF CELLS WHERE FOR EACH 758 00:42:02,788 --> 00:42:03,789 CELL WE KNOW HOW LONG THEY'VE 759 00:42:03,789 --> 00:42:06,057 BEEN ACTIVATED AND THE TYPE OF 760 00:42:06,057 --> 00:42:07,726 ACTIVATION AND WHAT RESPONSE WE 761 00:42:07,726 --> 00:42:09,494 HAVE AND NOW WE'RE IN THE SYSTEM 762 00:42:09,494 --> 00:42:12,264 TO START TO DO A BIT OF MACHINE 763 00:42:12,264 --> 00:42:14,599 LEARNING TO REBUILD MODELS OF 764 00:42:14,599 --> 00:42:15,100 THESE THINGS. 765 00:42:15,100 --> 00:42:18,069 FIRST ORDER OF BUSINESS IS THE 766 00:42:18,069 --> 00:42:26,044 TRAINING SET WHERE WE TAKE T1 T 767 00:42:26,044 --> 00:42:28,847 CELLS AND MEASURE DIFFERENT TIME 768 00:42:28,847 --> 00:42:31,917 POINTS ON THE Y AXIS AND 769 00:42:31,917 --> 00:42:35,487 DIFFERENT CYTOKINES AND IF WE 770 00:42:35,487 --> 00:42:37,255 DON'T HAVE THE RIGHT MAP OR HOW 771 00:42:37,255 --> 00:42:41,293 TO LOOK AT THE DATA, IT'S KIND 772 00:42:41,293 --> 00:42:41,993 OF A MESS. 773 00:42:41,993 --> 00:42:46,298 AND THE IDEA IS THAT THE DATA WE 774 00:42:46,298 --> 00:42:48,767 ARE COLLECTING AND I THINK WE'RE 775 00:42:48,767 --> 00:42:51,169 IN THE STATE OF LOOKING AT T 776 00:42:51,169 --> 00:42:56,608 CELLS THE WAY ASTROLOGISTS AND 777 00:42:56,608 --> 00:43:02,481 GREEK ASTRONOMERS LOOK AT THIS 778 00:43:02,481 --> 00:43:06,551 AND IF YOU BELIEF THE EARTH IS 779 00:43:06,551 --> 00:43:07,686 THE CENTER OF THE UNIVERSE AND 780 00:43:07,686 --> 00:43:08,954 MAYBE THINGS WILL CHANGE WE HAVE 781 00:43:08,954 --> 00:43:14,426 A MODEL OF THE SOLAR SYSTEM AND 782 00:43:14,426 --> 00:43:17,028 IT'S BEAUTIFUL AND OF COURSE IF 783 00:43:17,028 --> 00:43:19,564 YOU START TO LOOK AT THE DATA 784 00:43:19,564 --> 00:43:21,766 AND PUT THE VARIABLES AND LOOK 785 00:43:21,766 --> 00:43:25,103 AT THE DATA IN THE PROPER WAY 786 00:43:25,103 --> 00:43:30,008 THINGS LOOK WAY MORE 787 00:43:30,008 --> 00:43:34,012 ORGANIZED -- COMMENTS? 788 00:43:34,012 --> 00:43:34,179 >> 789 00:43:34,179 --> 00:43:34,646 [OFF-MIC] 790 00:43:34,646 --> 00:43:35,247 . 791 00:43:35,247 --> 00:43:37,182 >> WHAT YOU STAND FOR BUT 792 00:43:37,182 --> 00:43:38,049 SOMETIMES YOU WANT TO FLY, I 793 00:43:38,049 --> 00:43:42,821 KNOW. 794 00:43:42,821 --> 00:43:45,757 I AGREE. 795 00:43:45,757 --> 00:43:48,460 SO THE BEAUTY IS THESE DAYS IN 796 00:43:48,460 --> 00:43:50,028 MACHINE LEARNING THERE'S AN 797 00:43:50,028 --> 00:43:51,763 ALGORITHM THAT CAN TAKE A HUGE 798 00:43:51,763 --> 00:43:53,765 AMOUNT OF DATA AND LEARN THE 799 00:43:53,765 --> 00:43:54,232 MODELS AUTOMATICALLY. 800 00:43:54,232 --> 00:43:56,434 THE IDEA IS NOT LOOK FOR 801 00:43:56,434 --> 00:43:58,036 SOMETHING PRETTY BUT SOMETHING 802 00:43:58,036 --> 00:44:03,341 SIMPLE. 803 00:44:03,341 --> 00:44:10,048 SIMPLE MEANS YOU CAN GO TO A LOW 804 00:44:10,048 --> 00:44:13,451 DIMENSIONAL SPACE AND LOOKED AT 805 00:44:13,451 --> 00:44:16,121 THE SOLAR SYSTEM AND FED IT INTO 806 00:44:16,121 --> 00:44:18,790 THE NETWORK AND FOUND THE BEST 807 00:44:18,790 --> 00:44:22,727 WAY TO CAPTURE THE DYNAMICS WAS 808 00:44:22,727 --> 00:44:24,062 TO PUT THE SUN IN THE MIDDLE OF 809 00:44:24,062 --> 00:44:25,564 THE UNIVERSE. 810 00:44:25,564 --> 00:44:28,900 THIS IS A START IN TERMS OF THE 811 00:44:28,900 --> 00:44:34,039 PHYSICS AND WE'RE NOT LEARNING 812 00:44:34,039 --> 00:44:38,076 ANYTHING BUT PROOF OF PRINCIPLE 813 00:44:38,076 --> 00:44:40,245 TO SAY IF START TO TRY TO 814 00:44:40,245 --> 00:44:41,846 SQUEEZE THE DATA INTO LOW 815 00:44:41,846 --> 00:44:45,984 DIMENSIONAL SPACE YOU MAY BE 816 00:44:45,984 --> 00:44:48,119 ABLE TO LEARN NEW VARIABLES. 817 00:44:48,119 --> 00:44:50,822 WE DID EXACTLY THAT IN THE 818 00:44:50,822 --> 00:44:56,428 CONTEXT OF THE CYTOKINE DIYNAMIS 819 00:44:56,428 --> 00:44:59,864 AND THE DIMENSIONAL SPACE AND 820 00:44:59,864 --> 00:45:02,867 DEPENDING ON THE SYSTEM YOU MAY 821 00:45:02,867 --> 00:45:04,202 NOT NEED A LOT OF CYTOKINE AND 822 00:45:04,202 --> 00:45:06,705 DO PROCESSING OF THE DATA AND 823 00:45:06,705 --> 00:45:08,373 FEED IT INTO A SIMPLE NEURAL 824 00:45:08,373 --> 00:45:09,341 NET. 825 00:45:09,341 --> 00:45:12,077 THE IDEA IS THE DATA LOOK 826 00:45:12,077 --> 00:45:14,045 COMPLICATED AND MESSY. 827 00:45:14,045 --> 00:45:18,049 THE COLOR CODE CORRESPONDS TO 828 00:45:18,049 --> 00:45:21,486 DIFFERENT RESPONSE AND WE HAVE A 829 00:45:21,486 --> 00:45:22,587 LOT OF CONSIDERATION. 830 00:45:22,587 --> 00:45:25,190 ONCE YOU PUT THEM INSIDE THE 831 00:45:25,190 --> 00:45:31,029 NEURAL NET AND DESIGN IT AND 832 00:45:31,029 --> 00:45:34,933 DESIGN THE ARCHITECTURE AND 833 00:45:34,933 --> 00:45:37,802 THERE'S LOW DIMENSIONAL SPACE 834 00:45:37,802 --> 00:45:40,205 AND TAKING A COMPLEX OR HIGH 835 00:45:40,205 --> 00:45:45,343 DIMENSIONAL SPACE AND SQUEEZE 836 00:45:45,343 --> 00:45:46,411 THE INFORMATION AND DO THAT WITH 837 00:45:46,411 --> 00:45:48,947 THIS KIND OF STUFF AND THESE 838 00:45:48,947 --> 00:45:50,115 TOOLS ARE NOT GOOD ENOUGH 839 00:45:50,115 --> 00:45:53,418 BECAUSE WE'RE DOING DIMENSIONAL 840 00:45:53,418 --> 00:45:54,653 REDUCTION WITHOUT LINING IT UP 841 00:45:54,653 --> 00:45:55,520 WITH THE DATA. 842 00:45:55,520 --> 00:45:58,423 WE TAKE OUR VERY COMPLEX DATA 843 00:45:58,423 --> 00:46:00,992 SETS AND SQUEEZE IT INTO A LOW 844 00:46:00,992 --> 00:46:02,727 DIMENSIONAL SPACE WITH AN EYE TO 845 00:46:02,727 --> 00:46:05,163 A FUNCTION AND WITH THE TYPE OF 846 00:46:05,163 --> 00:46:07,565 ANTIGEN WE FEED INTO THE CENTER. 847 00:46:07,565 --> 00:46:11,770 IT GOES BACK AND FORM BY 848 00:46:11,770 --> 00:46:13,505 SQUEEZING THE DATA INTO LOW 849 00:46:13,505 --> 00:46:14,906 DIMENSIONAL SPACE AND MAKING 850 00:46:14,906 --> 00:46:19,744 SURE IT CAN WE PREDICT THE 851 00:46:19,744 --> 00:46:20,412 ANTIGENS. 852 00:46:20,412 --> 00:46:22,380 WE'RE REVERSE ENGINEERING AND 853 00:46:22,380 --> 00:46:29,454 TAKE THE PATTERN AND GO THE 854 00:46:29,454 --> 00:46:31,489 BINDING RECEPTOR AND GO TO SOME 855 00:46:31,489 --> 00:46:32,357 SIGNALLING AND TRANSCRIPTIONAL 856 00:46:32,357 --> 00:46:33,491 NETWORK AND THEN GIVE YOU A 857 00:46:33,491 --> 00:46:33,792 RESPONSE. 858 00:46:33,792 --> 00:46:37,629 WHAT YOU CAN DO IN THE LAB IS 859 00:46:37,629 --> 00:46:41,533 GENERATE ALL THE OUTPUT DATA AND 860 00:46:41,533 --> 00:46:43,068 CALCULATE WHAT THE T CELLS DO 861 00:46:43,068 --> 00:46:45,136 AND YOU END UP WITH THIS MODEL. 862 00:46:45,136 --> 00:46:47,272 IT'S A LOW DIMENSIONAL SPACE YOU 863 00:46:47,272 --> 00:46:51,476 CAN SHOW ON THE SCREEN. 864 00:46:51,476 --> 00:46:54,979 IT'S MADE OF ABSTRACT LATENT 865 00:46:54,979 --> 00:46:56,181 VARIABLES AND COMBINATION OF 866 00:46:56,181 --> 00:46:59,784 MANY THINGS AND HERE WHAT YOU 867 00:46:59,784 --> 00:47:01,720 SEE IS THAT FOR THE LE 868 00:47:01,720 --> 00:47:02,721 DIMENSIONAL SPACE YOU CORRESPOND 869 00:47:02,721 --> 00:47:05,857 TO THE TIME ASPECT OF T CELL 870 00:47:05,857 --> 00:47:08,860 ACTIVATION AND THE COLOR CODING 871 00:47:08,860 --> 00:47:10,528 CORRESPONDS TO DIFFERENT 872 00:47:10,528 --> 00:47:13,064 ANTIGENS AND THAT WAS NOT THE 873 00:47:13,064 --> 00:47:15,200 CASE IN THE OTHER DATA. 874 00:47:15,200 --> 00:47:20,338 WE CAN LOOK AT THE VECTORS AND 875 00:47:20,338 --> 00:47:21,840 YOU'LL SEE TE SPEED AND IF YOU 876 00:47:21,840 --> 00:47:25,443 GIVE ME SOME T CELLS AND ATCs 877 00:47:25,443 --> 00:47:27,212 AND TUMOR CELL AND MIX THEM IN 878 00:47:27,212 --> 00:47:32,417 THE ROBOT YOU'LL GET A COMPLEX 879 00:47:32,417 --> 00:47:34,052 CYTOKINE MARKERS AND PROJECT IT 880 00:47:34,052 --> 00:47:38,656 INTO A LOW DIMENSIONAL SPACE AND 881 00:47:38,656 --> 00:47:41,926 THIS RESPONSE TO THE QUALITY. 882 00:47:41,926 --> 00:47:46,030 WHAT I'M SHOWING THE OUTPUT OF 883 00:47:46,030 --> 00:47:48,099 THE ROBOT AND MACHINE LEARNING 884 00:47:48,099 --> 00:47:57,509 ON THE Y AXIS AND WE CAN WE CAN 885 00:47:57,509 --> 00:48:00,612 CHARACTERIZE THEM WITH A SIMPLE 886 00:48:00,612 --> 00:48:02,147 RESPONSE AND THEY'VE BEEN DONE 887 00:48:02,147 --> 00:48:06,451 WITH T CELLS AND QUANTITY OF 888 00:48:06,451 --> 00:48:09,387 ANTIGENS AND THE MODEL IS A HIGH 889 00:48:09,387 --> 00:48:11,589 DIMENSIONAL SPACE AND ALL THE 890 00:48:11,589 --> 00:48:13,358 COMPLEXITY LOOKING AT THE T CELL 891 00:48:13,358 --> 00:48:15,627 BEING ACTIVATED CAN BE SQUEEZED 892 00:48:15,627 --> 00:48:18,830 AND LINED UP AGAINST THE 893 00:48:18,830 --> 00:48:19,697 ANTIGENS. 894 00:48:19,697 --> 00:48:21,533 MAYBE THEY'RE NOT AS BEAUTIFUL 895 00:48:21,533 --> 00:48:25,036 AS YOU WERE THINK BUT USEFUL 896 00:48:25,036 --> 00:48:26,771 BECAUSE BY LOOKING AT THE T 897 00:48:26,771 --> 00:48:31,042 CELLS AND WE CAN TELL YOU IT'S A 898 00:48:31,042 --> 00:48:33,278 TUMOR INDEPENDENT OF THE CONTEXT 899 00:48:33,278 --> 00:48:34,112 OF THE TYPE OF TISSUE. 900 00:48:34,112 --> 00:48:39,050 THE CRAZY PART IS WE TRAIN THE 901 00:48:39,050 --> 00:48:41,286 MODEL WITH A MOUSE NAIVE CELLS 902 00:48:41,286 --> 00:48:43,822 WELL CHARACTERIZED AND APPLY IT 903 00:48:43,822 --> 00:48:46,024 TO THE CELLS THAT WE WERE 904 00:48:46,024 --> 00:48:52,163 DISCUSSING EARLIER AND YOU SEE 905 00:48:52,163 --> 00:48:53,531 THE DETAILS. 906 00:48:53,531 --> 00:48:56,134 THE SAME PARAMETER AND MODEL 907 00:48:56,134 --> 00:49:01,372 WHICH MIX ALL THE CYTOKINES AND 908 00:49:01,372 --> 00:49:04,209 SEEMS TO TRANSLATE WELL TO T 909 00:49:04,209 --> 00:49:09,480 CELL BLASTS LIKE WE DO AND IT'S 910 00:49:09,480 --> 00:49:11,115 DEALING WITH THIS SO ON AND SO 911 00:49:11,115 --> 00:49:11,482 FORTH. 912 00:49:11,482 --> 00:49:13,885 WE BUILT A MODEL OF THE WAY 913 00:49:13,885 --> 00:49:14,919 CELLS RECOGNIZE ANTIGEN AND CAN 914 00:49:14,919 --> 00:49:23,461 MOVE FORWARD. 915 00:49:23,461 --> 00:49:27,832 I'LL MOVE TO CAR T CELLS AND 916 00:49:27,832 --> 00:49:33,338 ONCE WE BUILD THE MODEL WE 917 00:49:33,338 --> 00:49:35,273 WANTED TO CHARACTERIZE THE CAR T 918 00:49:35,273 --> 00:49:37,275 CELLS AND WE HAVE AN ANTIBODY 919 00:49:37,275 --> 00:49:39,410 WHICH BINDS WELL TO THE TARGET 920 00:49:39,410 --> 00:49:42,046 AND THE DOMAIN OF THE TCR THAT'S 921 00:49:42,046 --> 00:49:42,780 VERY DIFFERENT. 922 00:49:42,780 --> 00:49:46,217 IT COULD BE A TOTALLY DIFFERENT 923 00:49:46,217 --> 00:49:49,254 MODEL AND LOOK VERY ABSTRACT. 924 00:49:49,254 --> 00:49:52,457 WE TRAIN OUR MODELS AND NORMAL T 925 00:49:52,457 --> 00:49:55,960 CELLS AND THE THEY PREPARE THE 926 00:49:55,960 --> 00:50:00,031 MOUSE CAR T CELLS AND CAN LINE 927 00:50:00,031 --> 00:50:02,667 THEM UP AND REALLY HAVE THE SAME 928 00:50:02,667 --> 00:50:06,037 KIND OF MATH OF A NORMAL T CELL 929 00:50:06,037 --> 00:50:09,474 EXCEPT WHEN WE COMPARE THE CAR T 930 00:50:09,474 --> 00:50:14,045 CELLS WE NOTICE IT COMPARES TO 931 00:50:14,045 --> 00:50:15,980 ONE OF THE WEAKEST ANTIGENS WE 932 00:50:15,980 --> 00:50:17,181 CAN EXPECT. 933 00:50:17,181 --> 00:50:18,316 IT'S VERY SURPRISING BECAUSE 934 00:50:18,316 --> 00:50:19,951 THEY ARE WERE DESIGN WITH 935 00:50:19,951 --> 00:50:20,685 ANTIBODIES SO YOU WOULD EXPECT 936 00:50:20,685 --> 00:50:23,588 THEM TO BIND WELL TO THE TARGETS 937 00:50:23,588 --> 00:50:27,258 AND BE GOOD AT BEING ACTIVATED 938 00:50:27,258 --> 00:50:30,828 AND BECAUSE IT'S SUB OPTIMAL YOU 939 00:50:30,828 --> 00:50:35,900 WIND UP WITH CAR T CELLS WHICH 940 00:50:35,900 --> 00:50:38,102 WINDS UP BEING THE WEAKEST 941 00:50:38,102 --> 00:50:43,708 ACTIVATION YOU CAN GET AND IF 942 00:50:43,708 --> 00:50:48,246 YOU GO TO MOUSE CAR T CELLS AND 943 00:50:48,246 --> 00:50:50,114 EXPOSE THEM TO A DIFFERENT 944 00:50:50,114 --> 00:50:51,849 PEPTIDE SUDDENLY YOU GET LESS OF 945 00:50:51,849 --> 00:50:52,417 A RESPONSE. 946 00:50:52,417 --> 00:50:55,320 AND THIS IS SOMETHING THAT WE 947 00:50:55,320 --> 00:50:58,957 CARE ABOUT IN MODELLING AND WE 948 00:50:58,957 --> 00:51:04,629 NOTICED THE LATENT SPACE AND IT 949 00:51:04,629 --> 00:51:07,999 GOES TO AN ANTAGONISM IN THE 950 00:51:07,999 --> 00:51:13,404 SYSTEM BY MEASURING THE VELOCITY 951 00:51:13,404 --> 00:51:22,080 OF THE CAR T CELLS AND SO WE RAN 952 00:51:22,080 --> 00:51:24,949 A DIFFERENT STORY AND 953 00:51:24,949 --> 00:51:26,351 COLLABORATION WHERE WE ARE 954 00:51:26,351 --> 00:51:27,785 LOOKING AT THE CROSS TALK 955 00:51:27,785 --> 00:51:29,554 BETWEEN THE TCR AND CAR AND YOU 956 00:51:29,554 --> 00:51:31,189 CAN SEE WE CAN DO NEED THINGS 957 00:51:31,189 --> 00:51:34,292 WITH THAT. 958 00:51:34,292 --> 00:51:37,628 WE PREPARED CAR T CELL AND THE 959 00:51:37,628 --> 00:51:44,736 TCR AND PREPARED TUMORS TO 960 00:51:44,736 --> 00:51:46,404 PREVENT THE IMAGING AND THE 961 00:51:46,404 --> 00:51:50,074 FIRST SURPRISE WHEN WE DO THAT 962 00:51:50,074 --> 00:51:54,078 IN THE MOUSE MODEL WHERE WE 963 00:51:54,078 --> 00:52:00,318 EXPOSED TRANSFER AND TREATED THE 964 00:52:00,318 --> 00:52:02,120 NICE WITH THE PROJECT IT CAN 965 00:52:02,120 --> 00:52:03,421 PROTECT THE MOUSE A LITTLE BIT. 966 00:52:03,421 --> 00:52:06,057 IF YOU HAVE A CAR T CELL WHICH 967 00:52:06,057 --> 00:52:07,792 EXPRESSES AND IS EXPOSED TO 968 00:52:07,792 --> 00:52:09,994 ANTIGEN YOU END UP WITH GOOD 969 00:52:09,994 --> 00:52:11,429 PROTECTION THEIR MOUSE BUT 970 00:52:11,429 --> 00:52:12,397 SURPRISINGLY WHEN YOU TALK THE 971 00:52:12,397 --> 00:52:17,635 CAR AND WEAK ANTIGENS YOU END UP 972 00:52:17,635 --> 00:52:19,070 WITH SOMETHING WHICH IS WORSE. 973 00:52:19,070 --> 00:52:21,572 WHEN YOU HAVE TWO SIGNALS COMING 974 00:52:21,572 --> 00:52:24,342 OUT OF THE T CELLS YOU MIX THE 975 00:52:24,342 --> 00:52:27,578 CAR SIGNAL AND TCR SIGNAL, IT 976 00:52:27,578 --> 00:52:28,846 COULD BE LESS. 977 00:52:28,846 --> 00:52:31,716 AND THAT'S A CAUTIONARY TALE 978 00:52:31,716 --> 00:52:33,885 BECAUSE DEPENDING ON THE TYPE OF 979 00:52:33,885 --> 00:52:36,154 SIGNAL YOUR CAR IS LOOKING AT 980 00:52:36,154 --> 00:52:40,792 YOU COULD BE IN A REGIME WHERE 981 00:52:40,792 --> 00:52:45,463 THE TUMORS ANTAGONIZE THE CAR 982 00:52:45,463 --> 00:52:47,465 RESPONSE AND END UP WITH WORSE 983 00:52:47,465 --> 00:52:50,001 TREATMENT THAN THE NORMAL CAR. 984 00:52:50,001 --> 00:52:51,102 WE LEARN FROM MACHINE LEARNING 985 00:52:51,102 --> 00:52:52,336 FROM THE LATENT SPACE AND 986 00:52:52,336 --> 00:52:57,442 THERE'S A PATHWAY THERE TO 987 00:52:57,442 --> 00:52:58,409 ANTAGONIZE AND BLOCK THE 988 00:52:58,409 --> 00:52:58,976 RESPONSE. 989 00:52:58,976 --> 00:53:01,579 THIS IS GOOD IN NORMAL T CELL 990 00:53:01,579 --> 00:53:03,681 AND USE THAT TO BLOCK THE 991 00:53:03,681 --> 00:53:06,084 ACTIVATION IN THE CONTEXT OF THE 992 00:53:06,084 --> 00:53:09,087 CAR YOU SHOULD END UP WITH THE 993 00:53:09,087 --> 00:53:10,488 TCR AND SHUT DOWN THE ACTIVATION 994 00:53:10,488 --> 00:53:12,557 OF THE CAR. 995 00:53:12,557 --> 00:53:16,327 IN A SENSE T CELLS ARE BAD AT 996 00:53:16,327 --> 00:53:20,164 MATH AND WOULD THINK YOU MIX CAR 997 00:53:20,164 --> 00:53:23,801 WITH SIGNALS YOU GET TWO AND WIN 998 00:53:23,801 --> 00:53:26,070 WEAK SIGNAL YOU GET A DIFFERENT 999 00:53:26,070 --> 00:53:29,040 SIGNAL AND THE MATH WILL BE VERY 1000 00:53:29,040 --> 00:53:29,340 COMPLICATED. 1001 00:53:29,340 --> 00:53:31,909 AND T CELLS ARE VERY BAD AT 1002 00:53:31,909 --> 00:53:32,877 MATH. 1003 00:53:32,877 --> 00:53:37,014 SO WE DID THIS IN A ROBOT AND 1004 00:53:37,014 --> 00:53:38,249 CHARACTERIZE THE CONDITION. 1005 00:53:38,249 --> 00:53:40,218 WE TESTED DIFFERENT 1006 00:53:40,218 --> 00:53:41,252 CONFIGURATION OF THE CAR AND 1007 00:53:41,252 --> 00:53:44,989 LEVEL OF ANTIGENS AND WE STARTED 1008 00:53:44,989 --> 00:53:47,191 TO BUILD A VERY COMPLEX VIEW OF 1009 00:53:47,191 --> 00:53:49,627 MANY DIFFERENT READOUTS AND SO 1010 00:53:49,627 --> 00:53:51,329 ON AND DEPENDING ON THE READ OUT 1011 00:53:51,329 --> 00:53:54,098 AND TYPE OF SETTINGS YOU'LL GET 1012 00:53:54,098 --> 00:53:56,100 A BOOST OF ACTIVATION WHEN YOU 1013 00:53:56,100 --> 00:53:59,003 HAVE A TCR SIGNAL OR GET 1014 00:53:59,003 --> 00:53:59,303 ANTAGONISM. 1015 00:53:59,303 --> 00:54:01,739 WE CAN DO A LOT OF MATH AND I'LL 1016 00:54:01,739 --> 00:54:03,040 SKIP THAT FOR THE SAKE OF TIME 1017 00:54:03,040 --> 00:54:05,176 AND THE MODEL WE HAD IN 2005 TO 1018 00:54:05,176 --> 00:54:06,244 BE UPDATED FINALLY. 1019 00:54:06,244 --> 00:54:08,045 WE HAVE A DIFFERENT PATHWAY AND 1020 00:54:08,045 --> 00:54:09,847 WE CAN FIT ALL THE DATA. 1021 00:54:09,847 --> 00:54:11,349 AND MOVE VERY QUICKLY BECAUSE WE 1022 00:54:11,349 --> 00:54:14,152 USE THAT TO BE ABLE TO MODULATE 1023 00:54:14,152 --> 00:54:17,388 CAR T CELLS. 1024 00:54:17,388 --> 00:54:20,558 NORMAL CAR T CELLS IS EXCELLENT 1025 00:54:20,558 --> 00:54:26,063 TO GO AFTER LIQUID LEUKEMIA AND 1026 00:54:26,063 --> 00:54:30,134 THE ATTEMPT TO KILL ALL THE 1027 00:54:30,134 --> 00:54:34,372 NORMAL B CELLS AND HAVE THE HER 1028 00:54:34,372 --> 00:54:38,075 T CAR T CELLS AND CAN BE VERY 1029 00:54:38,075 --> 00:54:40,578 GOOD AT KILLING AND THE LEVELS 1030 00:54:40,578 --> 00:54:42,880 YOU END UP WITH A LOT OF 1031 00:54:42,880 --> 00:54:43,147 TOXICITY. 1032 00:54:43,147 --> 00:54:45,850 SO THE IDEA WE HAVE IS NOW THAT 1033 00:54:45,850 --> 00:54:48,352 WE KNOW THE TCR CAN MODULATE CAR 1034 00:54:48,352 --> 00:54:49,987 ACTIVATION WE WANTED TO SEE IF 1035 00:54:49,987 --> 00:54:52,356 WE CAN USE THE MODEL TO DESIGN 1036 00:54:52,356 --> 00:54:57,595 THE SYSTEM TO PROTECT THE TISSUE 1037 00:54:57,595 --> 00:55:01,999 AND ATTACK THE TUMOR VERY WELL. 1038 00:55:01,999 --> 00:55:06,070 THIS IS A CONCEPT OF CAR T CELLS 1039 00:55:06,070 --> 00:55:13,077 ANDAA THE ABS SYSTEM AND WE 1040 00:55:13,077 --> 00:55:16,347 WANTED TO MAKE SOMETHING AND THE 1041 00:55:16,347 --> 00:55:18,082 IDEA THE CAR WHICH HAS BEEN 1042 00:55:18,082 --> 00:55:19,450 ENGINEERED IN A WAY IT CAN 1043 00:55:19,450 --> 00:55:21,686 RECOGNIZE THE TUMOR IN A 1044 00:55:21,686 --> 00:55:24,322 POSITIVE WAY AND BOOST THE 1045 00:55:24,322 --> 00:55:26,991 ACTIVATION OF THE CAR AND THE 1046 00:55:26,991 --> 00:55:32,797 TCR IS ONE MUTATION FROM 1047 00:55:32,797 --> 00:55:39,337 ANTIGENS FROM WHICH WILL BE AN 1048 00:55:39,337 --> 00:55:44,742 ANTAGONIST AND WE KNOW IT CAN BE 1049 00:55:44,742 --> 00:55:46,377 POSITIVE OR NEGATIVE AND IF WE 1050 00:55:46,377 --> 00:55:48,613 DESIGN IT PROPERLY WE SHOULD BE 1051 00:55:48,613 --> 00:55:52,416 ABLE TO SHUT DOWN CAR ACTIVATION 1052 00:55:52,416 --> 00:55:58,489 AND BOOST IT IN THE TOUMORS. 1053 00:55:58,489 --> 00:56:05,263 WE DESIGN THE TCR AND CAN DO 1054 00:56:05,263 --> 00:56:07,164 TESTING AND THE TIME OF TCR WILL 1055 00:56:07,164 --> 00:56:13,604 RECOGNIZE THE ANTIGENS VERY WELL 1056 00:56:13,604 --> 00:56:17,341 AND RECOGNIZE TE THE COUNTERPART 1057 00:56:17,341 --> 00:56:21,512 WHEN YOU EXPOSE THE T CELL YOU 1058 00:56:21,512 --> 00:56:23,948 GET A RESPONSE. 1059 00:56:23,948 --> 00:56:25,883 IT TELLS US THIS IS HEAVILY 1060 00:56:25,883 --> 00:56:28,352 NEGATIVE FEEDBACK AND YOU CAN 1061 00:56:28,352 --> 00:56:36,827 USE THAT TO BLOCK ACTIVATION I'M 1062 00:56:36,827 --> 00:56:39,997 RUSHING THROUGH THIS PART BUT 1063 00:56:39,997 --> 00:56:41,098 IT'S A COOL MODEL WE DEVELOPED 1064 00:56:41,098 --> 00:56:44,769 AND THE IDEA IS WE HAVE TWO 1065 00:56:44,769 --> 00:56:49,740 TISSUE WE'RE TRYING TO TEST. 1066 00:56:49,740 --> 00:56:54,545 A HEALTHY TISSUE AND TRANSFER 1067 00:56:54,545 --> 00:57:00,718 THE LONG CELL AND BE ABLE TO SEE 1068 00:57:00,718 --> 00:57:03,254 THE SYSTEM AND EXPRESS AND 1069 00:57:03,254 --> 00:57:04,322 MEASURE TUMOR GROWTH AND NOW 1070 00:57:04,322 --> 00:57:07,725 YOU'LL BE ABLE TO COMPARE THE 1071 00:57:07,725 --> 00:57:12,396 WAY THE CAR T CELLS COMPARE FROM 1072 00:57:12,396 --> 00:57:18,002 HEALTHY TISSUE TO TUMORS AND YOU 1073 00:57:18,002 --> 00:57:19,270 MEASURE AND SEE IF YOU CAN 1074 00:57:19,270 --> 00:57:21,172 PROTECT THE CELLS AT THE END. 1075 00:57:21,172 --> 00:57:24,875 AND THE KIND OF DATA WE HAVE IS 1076 00:57:24,875 --> 00:57:26,944 MEASURE ON THE Y AXIS A MEASURE 1077 00:57:26,944 --> 00:57:32,750 OF HOW WELL WE CAN PROTECT THE 1078 00:57:32,750 --> 00:57:39,690 LONG CELLS ON THE Y AXIS THE 1079 00:57:39,690 --> 00:57:41,459 BIGGER IT GETS THE SMALLER THE 1080 00:57:41,459 --> 00:57:42,993 KILLING AND YOU CAN KILL THE 1081 00:57:42,993 --> 00:57:46,063 TUMOR WELL BUT CAN KILL A LOT OF 1082 00:57:46,063 --> 00:57:49,300 CELL INSIDE THE LUNG AND IF YOU 1083 00:57:49,300 --> 00:57:51,369 TAKE A LOT OF ANTIGENS IT DIDN'T 1084 00:57:51,369 --> 00:57:54,739 KILL THE TUMOR VERY WELL AND 1085 00:57:54,739 --> 00:57:59,643 ONLY ABS CAR T CELLS CAN DO BOTH 1086 00:57:59,643 --> 00:58:02,079 HEAL THE TUMORS AND PROTECT THE 1087 00:58:02,079 --> 00:58:04,615 HEALTHY CELL INSIDE THE LUNG. 1088 00:58:04,615 --> 00:58:10,287 SO THIS IS A COOL SYSTEM AND 1089 00:58:10,287 --> 00:58:14,592 MOVE FORWARD TO REALLY FINE TUNE 1090 00:58:14,592 --> 00:58:16,060 THE WAY THAT YOU CAN GO AFTER 1091 00:58:16,060 --> 00:58:18,829 TUMORS AND PROTECT THE TISSUES. 1092 00:58:18,829 --> 00:58:26,070 THIS IS THE WORK OF MANY YEARS. 1093 00:58:26,070 --> 00:58:33,411 AND THAT'S THE WORK OF FRANCOISE 1094 00:58:33,411 --> 00:58:43,287 AND THOMAS TO MAKE THE CELLS AND 1095 00:58:43,287 --> 00:58:46,924 COLLABORATION BETWEEN LABS AND 1096 00:58:46,924 --> 00:58:48,592 MYSELF AND WITH CAN DRIVE THE 1097 00:58:48,592 --> 00:58:50,895 CAR BY ADJUSTING IT WITH THE 1098 00:58:50,895 --> 00:58:51,162 TCR. 1099 00:58:51,162 --> 00:58:53,431 THERE'S THE IDEA WE CAN LEARN 1100 00:58:53,431 --> 00:58:58,068 ABOUT THE WAY TCR INTERACT WITH 1101 00:58:58,068 --> 00:59:03,741 EACH OTHER AND USE THAT TO BLOCK 1102 00:59:03,741 --> 00:59:07,445 THE TISSUES AND FINE TUNE THE 1103 00:59:07,445 --> 00:59:13,984 CARS AND GET BETTER PROTECTION 1104 00:59:13,984 --> 00:59:15,786 TISSUES AND BETTER KILLING OF 1105 00:59:15,786 --> 00:59:16,420 TISSUES. 1106 00:59:16,420 --> 00:59:22,993 THIS IS THE ROBOT IS IN THE BACK 1107 00:59:22,993 --> 00:59:24,395 AND WE'RE PROUD OF THE ROBOT AND 1108 00:59:24,395 --> 00:59:25,830 ALL THE OTHER MEMBERS. 1109 00:59:25,830 --> 00:59:31,068 I DIDN'T HAVE TIME TO SPEAK 1110 00:59:31,068 --> 00:59:38,609 ABOUT EVERYTHING ELSE AND A LOT 1111 00:59:38,609 --> 00:59:43,547 OF A BIG PARTNER IN CRIME IS NOW 1112 00:59:43,547 --> 00:59:49,386 ME AND DOING ALL THE MEMBERS OF 1113 00:59:49,386 --> 00:59:53,858 THE LAB AND A LOT OF WORK IN 1114 00:59:53,858 --> 00:59:55,759 MACHINE MODELLING AND OTHERS ON 1115 00:59:55,759 --> 00:59:58,395 THE CAMPUS AND WE THANK THE 1116 00:59:58,395 --> 00:59:59,697 ROBOT AS WELL. 1117 00:59:59,697 --> 01:00:01,165 THEY GIVE US TROUBLE BUT HELP A 1118 01:00:01,165 --> 01:00:03,934 LOT AND THIS IS ALL THE LABS 1119 01:00:03,934 --> 01:00:09,039 USING THE ROBOT DOING 1120 01:00:09,039 --> 01:00:10,074 COLLABORATIONS WE'RE GOING VERY 1121 01:00:10,074 --> 01:00:14,111 FAR AND GETTING FUNDING FROM 1122 01:00:14,111 --> 01:00:20,117 DIFFERENT SOURCES AND IT'S BEEN 1123 01:00:20,117 --> 01:00:21,886 FANTASTIC AND THANKS FOL FOR 1124 01:00:21,886 --> 01:00:26,056 THOSE WHO SAVED ME FROM WRITING 1125 01:00:26,056 --> 01:00:28,692 GRANTS ALL MY LIFE AND THANK 1126 01:00:28,692 --> 01:00:38,769 YOU. 1127 01:00:45,142 --> 01:00:46,644 >> THAT WAS REALLY TERRIFIC. 1128 01:00:46,644 --> 01:00:48,779 THANKS, I WAS FASCINATING BY 1129 01:00:48,779 --> 01:00:51,382 YOUR ANALYSIS AND IDENTIFICATION 1130 01:00:51,382 --> 01:00:53,050 OF THE SPARK T CELLS. 1131 01:00:53,050 --> 01:00:56,720 AND I WAS JUST -- I HAVE TWO 1132 01:00:56,720 --> 01:00:56,987 QUESTIONS. 1133 01:00:56,987 --> 01:01:01,292 ONE IS HOW DOES FROM YOUR 1134 01:01:01,292 --> 01:01:02,893 INITIAL EVALUATION USING THE 1135 01:01:02,893 --> 01:01:06,063 MELANOMA CELLS, WE MAKE THE 1136 01:01:06,063 --> 01:01:08,265 ASSUMPTION THEY'RE CLONAL AND 1137 01:01:08,265 --> 01:01:10,067 THEY'RE NOT HETEROGENEOUS BUT WE 1138 01:01:10,067 --> 01:01:13,070 KNOW REALLY THEY ARE ARE 1139 01:01:13,070 --> 01:01:13,504 HETEROGENEOUS. 1140 01:01:13,504 --> 01:01:16,440 HOW DO THINK THAT AFFECTS -- 1141 01:01:16,440 --> 01:01:19,843 >> I CAN TELL YOU WE SPEND A LOT 1142 01:01:19,843 --> 01:01:21,378 OF TIME ON THE DISEASE ALL CAME 1143 01:01:21,378 --> 01:01:23,881 FROM THE TUMORS. 1144 01:01:23,881 --> 01:01:30,054 AND WE DID A MYRIAD OF 1145 01:01:30,054 --> 01:01:34,058 EXPERIMENTS AND LOOK BETWEEN THE 1146 01:01:34,058 --> 01:01:35,793 TWO REACTIONS. 1147 01:01:35,793 --> 01:01:38,195 WE FIND BASICALLY THE VIABILITY 1148 01:01:38,195 --> 01:01:39,597 DOESN'T COME FROM THE TUMORS. 1149 01:01:39,597 --> 01:01:42,533 THERE'S NO CLONES WHICH SEEMS TO 1150 01:01:42,533 --> 01:01:43,300 CONTROL THINGS. 1151 01:01:43,300 --> 01:01:45,636 IN ALL SYSTEMS WE REDUCE THE 1152 01:01:45,636 --> 01:01:47,304 DIVERSITY OF THE TUMORS AND 1153 01:01:47,304 --> 01:01:49,073 MOVING FORWARD WE HAVE PROJECTS 1154 01:01:49,073 --> 01:01:52,209 IN THE LAB WHERE WE LOOK AT 1155 01:01:52,209 --> 01:01:53,544 TUMORS AND YOU'RE RIGHT, IT 1156 01:01:53,544 --> 01:01:55,813 BUILDS COMPLEXITY ON TOP OF 1157 01:01:55,813 --> 01:01:56,146 THAT. 1158 01:01:56,146 --> 01:01:58,616 IF YOU HAVE GAMMA RECEPTOR MIXED 1159 01:01:58,616 --> 01:02:00,751 WITH DIFFERENT GAMMA RECEPTORS 1160 01:02:00,751 --> 01:02:03,287 THE WAY THE TWO CELLS ACTIVATE 1161 01:02:03,287 --> 01:02:04,989 THE IMMUNE INTERACTION IS 1162 01:02:04,989 --> 01:02:10,060 COMPLICATED AND YOU BUILD ON TOP 1163 01:02:10,060 --> 01:02:12,529 OF WHAT WE HAVE. 1164 01:02:12,529 --> 01:02:14,064 >> LOOKING AT THE SPARK CELLS 1165 01:02:14,064 --> 01:02:17,768 AND THE CHROMATIN IS OPEN ARE 1166 01:02:17,768 --> 01:02:20,537 THEY ARE IN THEIR NATURAL STATE 1167 01:02:20,537 --> 01:02:25,476 SECRETING INTERFERON GAMMA. 1168 01:02:25,476 --> 01:02:28,946 >> THEY ARE DON'T SECRETE BUT 1169 01:02:28,946 --> 01:02:31,382 YOU NEED THE SIGNAL. 1170 01:02:31,382 --> 01:02:33,283 >> EITHER THEY REACT WITH THE 1171 01:02:33,283 --> 01:02:33,517 LIGAND. 1172 01:02:33,517 --> 01:02:40,290 >> THE CRAN -- TRANSCRIPTOMICS 1173 01:02:40,290 --> 01:02:43,360 AND WE THEY ARE LOOK SIMILAR AND 1174 01:02:43,360 --> 01:02:45,863 THEY'RE A LITTLE BIT MORE OF ANA 1175 01:02:45,863 --> 01:02:52,469 AND MOST LIKELY THE WAY WAY 1176 01:02:52,469 --> 01:02:53,671 THEY'RE EXPOSED TO INFLAMMATION 1177 01:02:53,671 --> 01:02:55,072 IN THE TISSUES PUTS THEM IN THE 1178 01:02:55,072 --> 01:02:56,640 STATE WHICH IS RARE. 1179 01:02:56,640 --> 01:02:59,943 BUT AGAIN AS FAR AS YOU CAN TELL 1180 01:02:59,943 --> 01:03:01,145 THAT'S WHY THEY'RE HARD TO 1181 01:03:01,145 --> 01:03:02,079 IDENTIFY. 1182 01:03:02,079 --> 01:03:06,784 WE COULD NOT IDENTIFY THEM ONLY 1183 01:03:06,784 --> 01:03:12,356 BY DOING ALL THE BIO 1184 01:03:12,356 --> 01:03:13,023 AVAILABILITY OF LONG-TERM SCALES 1185 01:03:13,023 --> 01:03:19,563 WE WERE ABLE TO SORT THEM OUT. 1186 01:03:19,563 --> 01:03:20,731 HOPEFULLY WE CAN CREATE THAT IN 1187 01:03:20,731 --> 01:03:26,570 THE DISH AND MAKE BIG BUCKETS OF 1188 01:03:26,570 --> 01:03:26,970 CELLS. 1189 01:03:26,970 --> 01:03:28,472 >> THAT'S THE NEXT QUESTION I 1190 01:03:28,472 --> 01:03:28,639 HAD. 1191 01:03:28,639 --> 01:03:34,078 WHAT WOULD YOU IMAGINE IF YOU 1192 01:03:34,078 --> 01:03:35,946 PUT THE PURIFIED SPARK CELLS 1193 01:03:35,946 --> 01:03:40,484 INTO A REACTION WITH NO SPARK 1194 01:03:40,484 --> 01:03:40,718 CELLS? 1195 01:03:40,718 --> 01:03:43,320 >> WE CAN BOOST FOR THE 1196 01:03:43,320 --> 01:03:44,088 PROBABILITY OF GOING THE RIGHT 1197 01:03:44,088 --> 01:03:44,254 WAY. 1198 01:03:44,254 --> 01:03:47,725 YOU DON'T WANT TO DO THAT ALL 1199 01:03:47,725 --> 01:03:49,560 THE TIME BECAUSE LIKELY IT SEEMS 1200 01:03:49,560 --> 01:03:50,994 THE PARTICULAR CONTEXT OF GOING 1201 01:03:50,994 --> 01:03:54,998 AFTER THE TUMOR IF WE CAN MAKE 1202 01:03:54,998 --> 01:03:57,401 THE CELLS ON DEMAND. 1203 01:03:57,401 --> 01:03:59,470 >> THAT WAS TERRIFIC. 1204 01:03:59,470 --> 01:04:03,507 MY QUESTION IS RELATED ABOUT THE 1205 01:04:03,507 --> 01:04:05,209 SPARK CELLS. 1206 01:04:05,209 --> 01:04:09,046 ARE THEY A COMPLETELY STABLE 1207 01:04:09,046 --> 01:04:16,386 POPULATION OR DO THEY 1208 01:04:16,386 --> 01:04:19,256 INTERCONVERT STOCHASTICALLY OR 1209 01:04:19,256 --> 01:04:19,723 OTHERWISE? 1210 01:04:19,723 --> 01:04:21,458 >> WHEN WE PUT THEM BACK IN THE 1211 01:04:21,458 --> 01:04:24,795 DISH I THINK IN ONE WEEK, FIVE 1212 01:04:24,795 --> 01:04:26,997 DAYS WE ARE STILL SPARK T CELLS. 1213 01:04:26,997 --> 01:04:30,000 WE WE NEED TO DO TRANSFERS AND 1214 01:04:30,000 --> 01:04:31,702 GO BACK AT DIFFERENT TIME POINT 1215 01:04:31,702 --> 01:04:35,672 TO SEE IF NORMAL SETTINGS WILL 1216 01:04:35,672 --> 01:04:42,146 CONVERT AND BECAUSE OF THE CR 1217 01:04:42,146 --> 01:04:44,181 CHROMATIN LEVEL THEY'RE STABLE. 1218 01:04:44,181 --> 01:04:46,850 >> THEY CONDITION CONVERT 1219 01:04:46,850 --> 01:04:47,184 QUICKLY. 1220 01:04:47,184 --> 01:04:56,727 COME BACK IN A FEW WEEKS. 1221 01:04:56,727 --> 01:05:01,999 >> I HAVE TWO QUESTION. 1222 01:05:01,999 --> 01:05:07,471 ONE IS ABOUT DO YOU KNOW WHETHER 1223 01:05:07,471 --> 01:05:12,242 THEY SHARE THE SAME T CELL WITH 1224 01:05:12,242 --> 01:05:14,645 THE OTHER HETEROGENEITY OF T 1225 01:05:14,645 --> 01:05:14,878 CELL. 1226 01:05:14,878 --> 01:05:20,951 >> THEY ALL EXPRESS AND ALL 1227 01:05:20,951 --> 01:05:24,054 NAIVE THAT'S HOW YOU CAN TEST 1228 01:05:24,054 --> 01:05:26,857 AND YET IT SEEMS TO BE A BIT 1229 01:05:26,857 --> 01:05:27,157 DIFFERENT. 1230 01:05:27,157 --> 01:05:29,660 WE HAVE NOT DONE ENOUGH WORK TO 1231 01:05:29,660 --> 01:05:30,961 SEE IF IT CORRELATES WITH 1232 01:05:30,961 --> 01:05:34,464 DIFFERENT TCR BUT WE'RE 1233 01:05:34,464 --> 01:05:34,865 INTERESTED. 1234 01:05:34,865 --> 01:05:38,101 >> THEY'RE NAIVE T CELL? 1235 01:05:38,101 --> 01:05:40,470 >> YEAH. 1236 01:05:40,470 --> 01:05:42,272 >> BUT YOU PROLIFERATE -- 1237 01:05:42,272 --> 01:05:45,075 >> SORRY, WHEN YOU SPEAK ABOUT 1238 01:05:45,075 --> 01:05:45,776 HUMAN ONES? 1239 01:05:45,776 --> 01:05:47,377 >> YEAH. 1240 01:05:47,377 --> 01:05:49,313 >> THE HUMAN ARE A DIFFERENT 1241 01:05:49,313 --> 01:05:50,414 STORY. 1242 01:05:50,414 --> 01:05:55,853 THE T CELL BLAST AND THE MAIN 1243 01:05:55,853 --> 01:06:05,329 POINT IS THE TELOMERES ARE DIN 1244 01:06:05,329 --> 01:06:07,030 DIFFERENT STATES AND THE WAY 1245 01:06:07,030 --> 01:06:14,438 THERE'S GET ACTIVATED 1% MAKING 1246 01:06:14,438 --> 01:06:16,740 IT WITHIN AN HOUR. 1247 01:06:16,740 --> 01:06:21,378 WE HAVE NOT DOWN ALL BUT MORE 1248 01:06:21,378 --> 01:06:22,512 SIMPLER AND A PHENOTYPE AND YOU 1249 01:06:22,512 --> 01:06:27,251 CAN END UP WITH A DIFFERENT 1250 01:06:27,251 --> 01:06:27,484 PLACE. 1251 01:06:27,484 --> 01:06:31,355 >> ANOTHER QUESTION IS YOU SAY 1252 01:06:31,355 --> 01:06:32,789 BASED ON YOUR MODEL YOU CAN 1253 01:06:32,789 --> 01:06:34,057 IDENTIFY THE SPARK CELL. 1254 01:06:34,057 --> 01:06:37,060 IN THIS MODEL YOU STILL HAVE 1255 01:06:37,060 --> 01:06:38,028 OTHER CELLS IN THERE. 1256 01:06:38,028 --> 01:06:42,065 IS THERE A WAY TO CALCULATE HOW 1257 01:06:42,065 --> 01:06:44,568 DOES THE OTHER CELL EFFECT THE 1258 01:06:44,568 --> 01:06:45,469 SPARK CELL RESPONSE? 1259 01:06:45,469 --> 01:06:49,239 >> GOOD QUESTION. 1260 01:06:49,239 --> 01:06:52,476 WE'RE WONDERING WHAT HAPPENS TO 1261 01:06:52,476 --> 01:06:55,946 THE BYSTANDERS ARE IMPORTANT. 1262 01:06:55,946 --> 01:06:58,048 THEY ARE JUMP IN AND GET 1263 01:06:58,048 --> 01:06:58,315 ACTIVATED. 1264 01:06:58,315 --> 01:07:01,385 WHEN YOU LOOK AT 48 HOURS THE 1265 01:07:01,385 --> 01:07:04,488 BULK OF THE T CELLS IN THE DISH 1266 01:07:04,488 --> 01:07:05,856 WILL BE ACTIVATED. 1267 01:07:05,856 --> 01:07:09,126 NOW, WHETHER THE BALANCE OR 1268 01:07:09,126 --> 01:07:13,330 RATIO OF SPARK TO NON-SPARK 1269 01:07:13,330 --> 01:07:17,000 CHANGES WE DON'T KNOW WE HAVE TO 1270 01:07:17,000 --> 01:07:17,200 CHECK. 1271 01:07:17,200 --> 01:07:18,635 >> THANK YOU. 1272 01:07:18,635 --> 01:07:20,203 >> THAT WAS GREAT. 1273 01:07:20,203 --> 01:07:22,940 SORRY, THE LIGHTS ARE EXTREMELY 1274 01:07:22,940 --> 01:07:23,173 BRIGHT. 1275 01:07:23,173 --> 01:07:28,478 GOING BACK TO MANUELS WORK ON 1276 01:07:28,478 --> 01:07:36,653 THE PROTO SPARK? 1277 01:07:36,653 --> 01:07:39,156 >> ONCE YOU GET ACTIVITY YOU'LL 1278 01:07:39,156 --> 01:07:40,490 BLAST THE CHROMATIN ANYWAY. 1279 01:07:40,490 --> 01:07:42,225 YOU'LL HAVE TO CHECK WHETHER YOU 1280 01:07:42,225 --> 01:07:45,662 GO BACK TO THE DATA -- I DOUBT 1281 01:07:45,662 --> 01:07:46,964 IT. 1282 01:07:46,964 --> 01:07:49,700 >> DOES IT REMAIN OPEN AND START 1283 01:07:49,700 --> 01:07:51,735 FROM AN OPEN CHROMATIN OR EVER 1284 01:07:51,735 --> 01:07:52,102 GO BACK? 1285 01:07:52,102 --> 01:07:54,237 >> WE CAN CHECK WITH MEMORY 1286 01:07:54,237 --> 01:07:55,205 CELLS. 1287 01:07:55,205 --> 01:07:58,075 WE HAVE NOT DONE IT, YEAH, 1288 01:07:58,075 --> 01:07:58,275 SORRY. 1289 01:07:58,275 --> 01:07:59,309 >> ANOTHER SPARK QUESTION. 1290 01:07:59,309 --> 01:08:02,446 IF YOU TAKE YOUR T CELL AND 1291 01:08:02,446 --> 01:08:04,881 CONTAINS A LOW PERCENTAGE OF 1292 01:08:04,881 --> 01:08:07,517 SPARK T CELLS AND TREAT THEM 1293 01:08:07,517 --> 01:08:13,223 GAMMA ACTIVATORSES AND TREX 1 1294 01:08:13,223 --> 01:08:15,192 CAN YOU GET A HIGHER PERCENTAGE? 1295 01:08:15,192 --> 01:08:17,494 >> WE'RE DOING THAT NOW. 1296 01:08:17,494 --> 01:08:21,365 BASED ON THE SIGNATURE AND THE 1297 01:08:21,365 --> 01:08:26,636 SEQ WAS DONE AND GIVE A LIST OF 1298 01:08:26,636 --> 01:08:30,040 FACTORS WHICH IMPLY RESPONSE 1299 01:08:30,040 --> 01:08:32,242 WE'RE THINKING RIGHT NOW. 1300 01:08:32,242 --> 01:08:34,077 >> WOULD BE NICE FOR HIGH 1301 01:08:34,077 --> 01:08:34,544 THROUGHPUT SCREENING. 1302 01:08:34,544 --> 01:08:40,450 >> SURE. 1303 01:08:40,450 --> 01:08:42,486 >> I WAS THINKING ABOUT THE 1304 01:08:42,486 --> 01:08:44,488 LATTER PART OF YOUR TALK ABOUT 1305 01:08:44,488 --> 01:08:48,492 THE ANTAGONISM OF CART. 1306 01:08:48,492 --> 01:08:51,194 WE KNOW CERTAIN CARS HAVE BASAL 1307 01:08:51,194 --> 01:08:53,497 SIGNALLING ON THEIR OWN. 1308 01:08:53,497 --> 01:08:56,666 DO YOU THINK THAT MAY ACTUALLY 1309 01:08:56,666 --> 01:08:58,201 BE INHIBITING THE ENGINE 1310 01:08:58,201 --> 01:08:58,702 SPECIFIC? 1311 01:08:58,702 --> 01:08:59,870 >> ABSOLUTELY. 1312 01:08:59,870 --> 01:09:04,374 WHEN YOU LOOK AT THE MODEL IT 1313 01:09:04,374 --> 01:09:05,575 CUTS BOTH WAYS. 1314 01:09:05,575 --> 01:09:06,910 YOU'RE IN DANGER BECAUSE YOU'RE 1315 01:09:06,910 --> 01:09:09,780 GOING TO ACTIVATE THE 1316 01:09:09,780 --> 01:09:12,816 PHOSPHATASES TO GO AFTER THE 1317 01:09:12,816 --> 01:09:12,983 TCR. 1318 01:09:12,983 --> 01:09:17,120 AND CONTROL WITH THE TCR SIGNAL 1319 01:09:17,120 --> 01:09:19,856 WITH THAT POSSIBILITY AND VICE 1320 01:09:19,856 --> 01:09:20,390 VERSA. 1321 01:09:20,390 --> 01:09:21,925 IF WE DON'T BE CAREFUL IT COULD 1322 01:09:21,925 --> 01:09:24,995 BE A BLOCK OF A TCR SIGNAL. 1323 01:09:24,995 --> 01:09:26,496 SO WE'VE NOT DONE ENOUGH AND 1324 01:09:26,496 --> 01:09:28,231 BASED ON THE MODEL WE CAN MAKE 1325 01:09:28,231 --> 01:09:31,001 PREDICTS AND WHOEVER WANTS TO 1326 01:09:31,001 --> 01:09:36,206 TEST IT, WELCOME TO IT. 1327 01:09:36,206 --> 01:09:39,443 >> THE INTERPLAY BETWEEN THE CAR 1328 01:09:39,443 --> 01:09:45,048 AND ENDOGENOUS TCR SIGNAL CAN 1329 01:09:45,048 --> 01:09:48,685 YOU OVERCOME THAT WITH 1330 01:09:48,685 --> 01:09:50,053 EXPRESSING THE CELLS. 1331 01:09:50,053 --> 01:09:52,289 >> THE SURPRISING PART IS THE 1332 01:09:52,289 --> 01:09:56,126 ANTAGONISM WORKS IN A LARGE 1333 01:09:56,126 --> 01:09:56,760 REGIME. 1334 01:09:56,760 --> 01:09:58,462 WE'RE IN OUR ORIGINAL MODEL IT 1335 01:09:58,462 --> 01:10:01,031 WAS WORKING ONLY FOR HIGH DOSE. 1336 01:10:01,031 --> 01:10:05,135 IT TURNS OUT THE WAY IT'S WIRED 1337 01:10:05,135 --> 01:10:08,038 EVEN LOW DOSE ANTAGONIST CAN BE 1338 01:10:08,038 --> 01:10:09,039 ENOUGH AND IF YOU OVERCOME THAT 1339 01:10:09,039 --> 01:10:11,141 THERE SEEMS TO BE A NEGATIVE 1340 01:10:11,141 --> 01:10:13,210 FEEDBACK AND SHOULD BE ABLE TO 1341 01:10:13,210 --> 01:10:15,112 BYPASS AND GET GOING. 1342 01:10:15,112 --> 01:10:18,048 WE'RE FOLLOWING UP ON THAT ONE 1343 01:10:18,048 --> 01:10:20,650 WILL THE T CELLS AND HOPEFULLY 1344 01:10:20,650 --> 01:10:22,018 THE CAR SOON. 1345 01:10:22,018 --> 01:10:22,552 THANK YOU SO MUCH. 1346 01:10:22,552 --> 01:10:22,886 THANK YOU ALL. 1347 01:10:22,886 --> 01:10:22,953