1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:46,560 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:46,560 --> 00:00:49,360 WE'RE HONORED TO HEAR FROM TWO 12 00:00:49,360 --> 00:00:51,360 COLLEAGUES, DR. STEVEN 13 00:00:51,360 --> 00:00:53,360 ROSENBERG, CHIEF NATIONAL CANCER 14 00:00:53,360 --> 00:00:55,320 INSTITUTE AND DR. ANNA LAU, NIH 15 00:00:55,320 --> 00:00:56,120 CLINICAL CENTER DEPARTMENT 16 00:00:56,120 --> 00:00:57,960 LABORATORY OF MEDICINE. OUR 17 00:00:57,960 --> 00:01:00,960 FIRST SPEAKER IS DR. ROSENBERG. 18 00:01:00,960 --> 00:01:02,240 NATIONAL CANCER INSTITUTE AND 19 00:01:02,240 --> 00:01:04,680 PROFESSOR AT THE UNIFORM SURGERY 20 00:01:04,680 --> 00:01:05,920 HEALTH SCIENCES GEORGE 21 00:01:05,920 --> 00:01:06,960 WASHINGTON UNIVERSITY SCHOOL OF 22 00:01:06,960 --> 00:01:10,520 HEALTH AND MEDICAL SCIENCES AND 23 00:01:10,520 --> 00:01:11,280 DEPARTMENT OF LABORATORY 24 00:01:11,280 --> 00:01:13,480 MEDICINE AT THE KAROLINSKA 25 00:01:13,480 --> 00:01:15,720 INSTITUTE STOCKHOLM, SWEDEN. DR. 26 00:01:15,720 --> 00:01:17,920 ROSENBERG EARN HIS M.D. AT JOHNS 27 00:01:17,920 --> 00:01:19,520 HOPKINS UNIVERSITY AT BALTIMORE 28 00:01:19,520 --> 00:01:21,080 AND Ph.D. IN BUY PHYSICS AT 29 00:01:21,080 --> 00:01:22,400 HARVARD UNIVERSITY. AFTER 30 00:01:22,400 --> 00:01:24,600 CLEATING RESIDENCY TRAINING IN 31 00:01:24,600 --> 00:01:26,520 SURGERY 1974 AT THE PETER 32 00:01:26,520 --> 00:01:29,080 BRIGHAM HOSPITAL IN BOSTON DR. 33 00:01:29,080 --> 00:01:30,120 ROSENBERG BECAME THE CHIEF 34 00:01:30,120 --> 00:01:31,680 SURGERY BRANCH AT THE NATIONAL 35 00:01:31,680 --> 00:01:33,720 CANCER INSTITUTE, A POSITION 36 00:01:33,720 --> 00:01:35,640 HELD SINCE PRESENT TIME. AS 37 00:01:35,640 --> 00:01:36,920 CHIEF OF THE SURGERY BRANCH DR. 38 00:01:36,920 --> 00:01:39,880 ROSENBERG OVERSEES THE BRANCHES 39 00:01:39,880 --> 00:01:42,200 EXTENSIVE CLINICAL PROGRAM AIMED 40 00:01:42,200 --> 00:01:43,560 TRANSLATING ADVANCES INTO 41 00:01:43,560 --> 00:01:44,920 EFFECTIVE IMMUNOTHERAPIES FOR 42 00:01:44,920 --> 00:01:48,440 PATIENTS WITH CANCER. DR. 43 00:01:48,440 --> 00:01:49,520 ROSENBERG PIONEERED THE FIRST 44 00:01:49,520 --> 00:01:50,360 IMMUNOTHERAPIES FOR PATIENTS 45 00:01:50,360 --> 00:01:52,040 WITH ADVANCE CANCER, HIS STUDIES 46 00:01:52,040 --> 00:01:54,440 OF THE ADOPTIVE TRANSFER OF 47 00:01:54,440 --> 00:01:57,200 GENETICALLY MODIFIED LYMPHOCYTES 48 00:01:57,200 --> 00:01:58,040 DEMONSTRATE PROGRESSION OF 49 00:01:58,040 --> 00:02:00,240 METASTATIC CANCER IN PATIENT 50 00:02:00,240 --> 00:02:02,600 WITH MELLOWNA SARCOMAS AND 51 00:02:02,600 --> 00:02:03,560 LYMPHOMAS. HE PIONEERED THE 52 00:02:03,560 --> 00:02:06,520 DEVELOPMENT OF GEN GENE THERAPY AND 53 00:02:06,520 --> 00:02:07,640 FIRST TO SUCCESSFULLY 54 00:02:07,640 --> 00:02:09,520 INTERCHANGE TO HUMANS AS WELL AS 55 00:02:09,520 --> 00:02:10,920 FIRST INVESTIGATOR DEMONSTRATE 56 00:02:10,920 --> 00:02:12,640 EFFECTIVENESS OFFER GENETICALLY 57 00:02:12,640 --> 00:02:15,720 ENGINEERED CAR T-CELLS TO 58 00:02:15,720 --> 00:02:18,720 MEDIATE REREGRESSION OF B CELLS 59 00:02:18,720 --> 00:02:20,440 IN MALIGNANCIES. HIS RESEARCH 60 00:02:20,440 --> 00:02:22,320 AIMS TO FIND HOST IMMUNE 61 00:02:22,320 --> 00:02:23,320 RESPONSE TOP PATIENTS WITH 62 00:02:23,320 --> 00:02:24,720 CANCER. THESE EMPHASIZE ABILITY 63 00:02:24,720 --> 00:02:26,080 OF LYMPHOCYTES TO RECOGNIZE 64 00:02:26,080 --> 00:02:28,920 UNIQUE CANCER ANTIGENS AND THE 65 00:02:28,920 --> 00:02:30,160 IDENTIFICATION OF ANTITUMOR 66 00:02:30,160 --> 00:02:32,240 T-CELL RECEPTORS EXPLOITED TO 67 00:02:32,240 --> 00:02:33,920 DEVELOP NEW CELL TRANSFER 68 00:02:33,920 --> 00:02:34,800 IMMUNOTHERAPIES FOR TREATMENT OF 69 00:02:34,800 --> 00:02:39,280 CANCER PATIENTS. FOR THESE 70 00:02:39,280 --> 00:02:39,920 CONTRIBUTIONS DR. ROSENBERG HAS 71 00:02:39,920 --> 00:02:40,800 RECEIVED HIGHEST AWARDS IN 72 00:02:40,800 --> 00:02:43,680 MEDICAL SCIENCE. TO INCLUDE 73 00:02:43,680 --> 00:02:45,640 KAGEL MEDICAL SCIENCE PRIZE, 74 00:02:45,640 --> 00:02:47,320 AMERICAN CANCER SOCIETY OF 75 00:02:47,320 --> 00:02:49,200 MEDICAL HONORS, THE NOVARTIS 76 00:02:49,200 --> 00:02:51,720 PRIZE FOR CLINICAL IMMUNOLOGY, 77 00:02:51,720 --> 00:02:53,000 AMERICAN ASSOCIATION OF 78 00:02:53,000 --> 00:02:55,320 IMMUNOLOGY STEINMAN AWARD FOR 79 00:02:55,320 --> 00:02:57,120 HUMAN IMMUNOLOGY RESEARCH, 80 00:02:57,120 --> 00:02:58,080 GEORGE PRIZE FOR PROGRESS IN 81 00:02:58,080 --> 00:03:01,480 CANCER RESEARCH. THE LLOYD J. 82 00:03:01,480 --> 00:03:06,000 OLD AWARD IN CANCER IMMUNOLOGY 83 00:03:06,000 --> 00:03:07,920 AND AMERICAN PHILADELPHIA 84 00:03:07,920 --> 00:03:10,960 ACADEMY OF SURGERY. IN 2020, THE 85 00:03:10,960 --> 00:03:12,520 SOCIETY FOR IMMUNOTHERAPY OF 86 00:03:12,520 --> 00:03:14,280 CANCER ESTABLISHED A STEVEN A 87 00:03:14,280 --> 00:03:17,000 ROSENBERG SCHOLARS PRIZE IN 88 00:03:17,000 --> 00:03:18,200 CANCER IMMUNOTHERAPY. DR. 89 00:03:18,200 --> 00:03:18,880 ROSENBERG IS MEMBER OF THE 90 00:03:18,880 --> 00:03:20,520 INSTITUTE OF MEDICINE OF THE 91 00:03:20,520 --> 00:03:23,120 NATIONAL ACADEMY OF SCIENCES. HE 92 00:03:23,120 --> 00:03:26,040 PUBLISHED OVER 1100 PAPERS IN 93 00:03:26,040 --> 00:03:27,640 PEER REVIEWED LITERATURE AND H 94 00:03:27,640 --> 00:03:29,320 INDEX OF 206 MAKES HIM ONE OF 95 00:03:29,320 --> 00:03:31,240 THE HIGHEST CITED CLINICIAN 96 00:03:31,240 --> 00:03:33,120 SCIENTISTS IN THE WORLD. OUR 97 00:03:33,120 --> 00:03:36,200 SECOND SPEAKER, DR. ANNA LAU. 98 00:03:36,200 --> 00:03:37,120 CHIEF OVERSTEER RILLETTESSING 99 00:03:37,120 --> 00:03:38,040 SERVICE DEPARTMENT OF LABORATORY 100 00:03:38,040 --> 00:03:40,960 MED SEN. DR. LAU EARNED HER 101 00:03:40,960 --> 00:03:42,720 Ph.D. FROM UNIVERSITY OF 102 00:03:42,720 --> 00:03:43,680 SIDNEY, AUSTRALIA, WHERE HER 103 00:03:43,680 --> 00:03:46,120 RESEARCH FOCUSED ON DEVELOPMENT 104 00:03:46,120 --> 00:03:47,680 OF NOVEL DIAGNOSTIC PLATFORMS 105 00:03:47,680 --> 00:03:50,280 FOR INNOVATIVE PUBLIC DISEASES. 106 00:03:50,280 --> 00:03:51,520 IN 2011 SHE JOINED THE NIH TO 107 00:03:51,520 --> 00:03:52,840 COMPLETE A FELLOWSHIP AND 108 00:03:52,840 --> 00:03:54,800 CLINICAL MICROBIOLOGY, IN THE 109 00:03:54,800 --> 00:03:55,600 DEPARTMENT OF LABORATORY 110 00:03:55,600 --> 00:03:58,480 MEDICINE. UPON HER FELLOWSHIP 111 00:03:58,480 --> 00:04:00,920 SHE JOINED A CLINICAL 112 00:04:00,920 --> 00:04:02,600 MICROBIOLOGY SERVICE AS A STAFF 113 00:04:02,600 --> 00:04:04,560 SCIENTIST, SHE CO-DIRECTED THE 114 00:04:04,560 --> 00:04:06,720 BACTERIOLOGY SPECIMEN PROCESSING 115 00:04:06,720 --> 00:04:09,280 PARACYTOLOGY AND MO LEK LEER 116 00:04:09,280 --> 00:04:10,920 EPIDEMIOLOGY SECTION. IN 2018 117 00:04:10,920 --> 00:04:13,120 DR. LAU PROMOTED TO CHIEF OF THE 118 00:04:13,120 --> 00:04:16,000 NEWLY CREATED STERILE TESTING 119 00:04:16,000 --> 00:04:19,800 SERVICE TO SUPPORT THE NIH WIDE 120 00:04:19,800 --> 00:04:21,720 CGMP PROCESSING AND 121 00:04:21,720 --> 00:04:25,320 MANUFACTURING CELLULAR THERAPY 122 00:04:25,320 --> 00:04:26,920 AND NIH CLINICAL PROTOCOLS. DR. 123 00:04:26,920 --> 00:04:30,880 LAU TRANSDIVISIONAL RESEARCH -- 124 00:04:30,880 --> 00:04:32,040 TRANSLATIONAL RESEARCH USES 125 00:04:32,040 --> 00:04:34,280 MOLECULAR BASED TECHNIQUES AND 126 00:04:34,280 --> 00:04:35,600 MASS SPECTROMETRY. CURRENT 127 00:04:35,600 --> 00:04:39,040 RESEARCH INVOLVES ADVANCING 128 00:04:39,040 --> 00:04:41,320 TESTING PLATFORMS AND FDA 129 00:04:41,320 --> 00:04:42,040 REQUIREMENTS FOR CLINICAL 130 00:04:42,040 --> 00:04:45,000 QUALITY AND PATIENT SAFETY. HER 131 00:04:45,000 --> 00:04:47,640 WORK REFLECTED NEARLY 50 132 00:04:47,640 --> 00:04:49,720 PUBLICATION BOOK CHAPTER AND 133 00:04:49,720 --> 00:04:51,760 RECOGNIZED NUMEROUS AWARDS 134 00:04:51,760 --> 00:04:52,600 INCLUDING 8 NIH CLINICAL 135 00:04:52,600 --> 00:04:54,280 CERTAINTY CEO AND DIRECTORS 136 00:04:54,280 --> 00:04:56,600 AWARDS AND RECOGNIZE BY FORBES 137 00:04:56,600 --> 00:04:58,680 FOR THE 30 UNDER 30 AWARD FOR 138 00:04:58,680 --> 00:05:02,240 HEALTHCARE SCIENCE. DR. LAU 139 00:05:02,240 --> 00:05:04,520 SERVES AS ON THE EDITORIAL BOARD 140 00:05:04,520 --> 00:05:06,000 TORR JOURNAL CLINICAL 141 00:05:06,000 --> 00:05:07,080 MICROBIOLOGY AS MEMBER OF THE 142 00:05:07,080 --> 00:05:08,360 AMERICAN SOCIETY FOR 143 00:05:08,360 --> 00:05:09,320 MICROBIOLOGY, THE PARENTAL DRUG 144 00:05:09,320 --> 00:05:12,960 ASSOCIATION AND THE U.S. 145 00:05:12,960 --> 00:05:14,240 PHARMACO PEEDIA. SHE CHAIRS THE 146 00:05:14,240 --> 00:05:16,640 NIH ENVIRONMENTAL MONITORING 147 00:05:16,640 --> 00:05:18,240 ADVISORY COMMITTEE FOR CGMP AND 148 00:05:18,240 --> 00:05:19,840 DR. LAU ALSO BOARD CERTIFIED TO 149 00:05:19,840 --> 00:05:22,480 THE AMERICAN BOARD OF MEDICAL 150 00:05:22,480 --> 00:05:25,080 MICROBIOLOGY. PLEASE WELCOME OUR 151 00:05:25,080 --> 00:05:26,320 FIRST SPEAKER, DR. ROSENBERG, 152 00:05:26,320 --> 00:05:27,840 WHOSE TALK IS ENTITLED 153 00:05:27,840 --> 00:05:29,880 LYMPHOCYTES AS A LIVING DRUG FOR 154 00:05:29,880 --> 00:05:32,080 TREATMENT OF CANCER. 155 00:05:32,080 --> 00:05:35,880 >> GOOD MORNING, I'M GOING TO BE 156 00:05:35,880 --> 00:05:38,840 DISCUSSING THE SUBJECT OF USING 157 00:05:38,840 --> 00:05:41,160 LYMPHOCYTES AS A LIVING DRUG FOR 158 00:05:41,160 --> 00:05:43,160 THE TREATMENT OF CANCER. NOT 159 00:05:43,160 --> 00:05:46,040 USING CHEMOTHERAPY AGENTS BUT 160 00:05:46,040 --> 00:05:48,040 RATHER THAN THAT USING A 161 00:05:48,040 --> 00:05:50,480 PATIENT'S OWN NORMAL IMMUNE 162 00:05:50,480 --> 00:05:52,280 CELLS, FOR THERAPY AND OUR 163 00:05:52,280 --> 00:05:55,320 ATTEMPTS TO DEVELOP THESE 164 00:05:55,320 --> 00:05:59,480 APPROACHES TO CANCER TREATMENT. 165 00:05:59,480 --> 00:06:00,680 I HAVE NO PERSONAL DISCLOSURES 166 00:06:00,680 --> 00:06:03,520 OF COURSE. THOUGH THE NCI AND 167 00:06:03,520 --> 00:06:04,680 SURGERY BRANCH COOPERATIVE 168 00:06:04,680 --> 00:06:05,960 RESEARCH AND DEVELOPMENT 169 00:06:05,960 --> 00:06:10,280 AGREEMENTS CREDAS WITH 170 00:06:10,280 --> 00:06:17,480 BIOTHERAPEUTICS AND ONCOLOGY. 171 00:06:17,480 --> 00:06:20,560 USING CELLS AS A CELL TRANSFER 172 00:06:20,560 --> 00:06:23,880 THERAPY, FOR PATIENTS WE CAN SEE 173 00:06:23,880 --> 00:06:27,400 A LARGE NUMBER OF POTENTIAL 174 00:06:27,400 --> 00:06:29,520 ADVANTAGES, WE CAN IDENTIFY AND 175 00:06:29,520 --> 00:06:31,680 GROW A LARGE NUMBERS OF HIGHLY 176 00:06:31,680 --> 00:06:33,280 SELECTIVE CELLS WITH HIGH 177 00:06:33,280 --> 00:06:36,080 AVIDITY FOR RECOGNIZING TUMOR. 178 00:06:36,080 --> 00:06:37,680 BECAUSE WE HAVE THESE CELLS IN 179 00:06:37,680 --> 00:06:40,680 TEST TUBE WE CAN POTENTIALLY 180 00:06:40,680 --> 00:06:41,840 IDENTIFY EXACT CELL 181 00:06:41,840 --> 00:06:42,720 SUBPOPULATIONS AND EFFECTIVE 182 00:06:42,720 --> 00:06:44,400 FUNCTIONS REQUIRED FOR CANCER 183 00:06:44,400 --> 00:06:46,720 REGRESSION IN VIVO, AND FINALLY 184 00:06:46,720 --> 00:06:49,000 WE CAN MANIPULATE THOSE PRIOR TO 185 00:06:49,000 --> 00:06:51,600 CELL TRANSFER, TO PROVIDE AN 186 00:06:51,600 --> 00:06:53,560 ALTERED MICROENVIRONMENT FOR THE 187 00:06:53,560 --> 00:06:56,240 TRANSFERRED CELLS, THIS TURNED 188 00:06:56,240 --> 00:06:59,200 OUT TO BE QUITE IMPORTANT CHANGE 189 00:06:59,200 --> 00:07:01,080 AND ONE THAT'S ONLY AVAILABLE 190 00:07:01,080 --> 00:07:02,560 CELL TRANSFER THERAPY BECAUSE 191 00:07:02,560 --> 00:07:04,480 THE IMMUNE CELLS HAVE BEEN 192 00:07:04,480 --> 00:07:05,840 REMOVED FROM THE BODY AND WILL 193 00:07:05,840 --> 00:07:09,760 NOT BE DAMAGED BY OTHER 194 00:07:09,760 --> 00:07:13,400 MANIPULATIONS OF THE HOST. NOW, 195 00:07:13,400 --> 00:07:15,800 THERE ARE TWO KINDS OF RECEPTORS 196 00:07:15,800 --> 00:07:19,280 THAT A LYMPHOCYTE CAN USE TO 197 00:07:19,280 --> 00:07:21,000 RECOGNIZE ANY ANTIGEN INCLUDE 198 00:07:21,000 --> 00:07:24,080 TAUGHT MORE ANTIGENS, 199 00:07:24,080 --> 00:07:25,520 CONVENTIONAL T-CELL RECEPTORS 200 00:07:25,520 --> 00:07:28,920 ARE USED BY NATURALLY OCCURRING 201 00:07:28,920 --> 00:07:29,960 IMMUNE LYMPHOCYTES THAT USE THE 202 00:07:29,960 --> 00:07:32,680 ALPHA BETA CHAIN OF T-CELL 203 00:07:32,680 --> 00:07:34,480 RECEPTOR TO RECOGNIZE A SMALL 204 00:07:34,480 --> 00:07:36,880 PEPTIDE FROM AN INTRACELLULAR 205 00:07:36,880 --> 00:07:39,080 PROTEIN, PRESENTED ON SURFACE 206 00:07:39,080 --> 00:07:42,440 MHC POLL MOLECULE. A LABORATORY 207 00:07:42,440 --> 00:07:46,040 CREATION HOWEVER IS GIVEN RISE 208 00:07:46,040 --> 00:07:47,320 TO A DIFFERENT RECEPTOR CALLED 209 00:07:47,320 --> 00:07:49,000 THE CHIMERIC ANTIGEN RECEPTOR OR 210 00:07:49,000 --> 00:07:51,560 CAR RECEPTOR. THIS WAS DEVELOPED 211 00:07:51,560 --> 00:07:53,880 BY GESHAR AT THE WISEMAN 212 00:07:53,880 --> 00:07:56,080 INSTITUTE A DOZEN YEARS AGO. ONE 213 00:07:56,080 --> 00:07:57,560 CAN TAKE THE HEAVY AND LIGHT 214 00:07:57,560 --> 00:08:00,800 CHAINS OF ANTIBODY, MAKE A 215 00:08:00,800 --> 00:08:03,080 SINGLE CHAIN AND CONNECT THAT 216 00:08:03,080 --> 00:08:05,080 SINGLE CHAIN ANTIBODY TO 217 00:08:05,080 --> 00:08:06,280 INTRACELLULAR SIGNALING CHANGE 218 00:08:06,280 --> 00:08:10,160 THAT ENABLED LYMPHOCYTES TO 219 00:08:10,160 --> 00:08:14,560 RECOGNIZE ANTIGENS BASED ON ANT 220 00:08:14,560 --> 00:08:16,600 ANTIBODY RECOGNITION RATHER THAN 221 00:08:16,600 --> 00:08:18,480 CONVENTIONAL T-CELL RECEPTOR 222 00:08:18,480 --> 00:08:20,560 RECOGNITION. WE WILL SPEND A 223 00:08:20,560 --> 00:08:22,440 MOMENT TALKING APPLICATION OF 224 00:08:22,440 --> 00:08:23,280 CHIMERIC ANTIGEN RECEPTORS 225 00:08:23,280 --> 00:08:25,720 BECAUSE THIS REPRESENTS THE 226 00:08:25,720 --> 00:08:30,280 FIRST FDA APPROVED EXAMPLE OF 227 00:08:30,280 --> 00:08:33,560 CELL AND GENE THERAPY FOR THE 228 00:08:33,560 --> 00:08:38,920 TREATMENT OF CANCER PATIENTS. 229 00:08:38,920 --> 00:08:40,320 THIS DEVELOPMENT OF THIS 230 00:08:40,320 --> 00:08:43,080 CHIMERIC ANTIGEN APPROACH 231 00:08:43,080 --> 00:08:46,480 TARGETED CD 19 WHICH IS A CELL 232 00:08:46,480 --> 00:08:48,400 SURFACE MOLECULE ON B 233 00:08:48,400 --> 00:08:50,080 LYMPHOCYTES AND MANY P IF NOT 234 00:08:50,080 --> 00:08:53,560 MOST B CELL LYMPHOMAS AND 235 00:08:53,560 --> 00:08:56,480 LEUKEMIAS. JAMES COPE INMDORFER 236 00:08:56,480 --> 00:08:58,880 A FELLOW IN ONCOLOGY HEMATOLOGY 237 00:08:58,880 --> 00:09:02,160 PROGRAMS AT NIH CAME TO MY 238 00:09:02,160 --> 00:09:03,640 LABORATORY ABOUT 2008 TO EXPLORE 239 00:09:03,640 --> 00:09:05,400 WHETHER OR NOT WE CAN UTILIZE 240 00:09:05,400 --> 00:09:09,360 CAR C TELLS TARGETING CD 19. TO 241 00:09:09,360 --> 00:09:10,960 TREAT CANCER. IN THESE EARLY 242 00:09:10,960 --> 00:09:13,920 STUDIES T-CELLS TRANSDUCED WITH 243 00:09:13,920 --> 00:09:16,840 A ANTI-CD 19 CAR ELIMINATE 244 00:09:16,840 --> 00:09:19,160 LYMPHOMAS AND SYNGENEIC MOUSE 245 00:09:19,160 --> 00:09:23,280 MODEL, HE PUBLISHED THAT IN 246 00:09:23,280 --> 00:09:27,000 20106789 WE WENT ON TO UTILIZE 247 00:09:27,000 --> 00:09:29,360 SURGERY BRANCH RESOURCES TO 248 00:09:29,360 --> 00:09:31,080 TREAT THE FIRST PATIENT WITH 249 00:09:31,080 --> 00:09:32,280 ANTI-CD 19 CAR SHOWING TO 250 00:09:32,280 --> 00:09:35,880 MEDIATE REGRESSION OF LYMPHOMA 251 00:09:35,880 --> 00:09:38,520 IN HUMANS, DONE IN 2009, 252 00:09:38,520 --> 00:09:40,080 PUBLISHED IN 2010 AND SINCE THEN 253 00:09:40,080 --> 00:09:41,240 THE FIRST TEN PATIENTS WE 254 00:09:41,240 --> 00:09:42,880 TREATED EXPERIENCED A COMPLETE 255 00:09:42,880 --> 00:09:45,600 REGRESSION FIVE OF WHOM ARE 256 00:09:45,600 --> 00:09:49,920 ONGOING TEN YEARS LATER. THIS 257 00:09:49,920 --> 00:09:51,280 PATIENT HAD LARGE AMOUNTS OF 258 00:09:51,280 --> 00:09:53,360 LYMPHOMA, NO RELATIONSHIP 259 00:09:53,360 --> 00:09:54,360 BETWEEN AMOUNT OF DISEASE AND 260 00:09:54,360 --> 00:09:57,960 ABILITY TO ACHIEVE A COMPLETE 261 00:09:57,960 --> 00:09:59,960 REGRESSION, THIS PATIENT 262 00:09:59,960 --> 00:10:01,200 RECEIVED FOUR DIFFERENT 263 00:10:01,200 --> 00:10:03,000 TREATMENTS AND OCCURRED AND HAS 264 00:10:03,000 --> 00:10:04,240 PROGRESSIVE DISEASE YOU CAN SEE 265 00:10:04,240 --> 00:10:05,720 LARGE LESIONS IN THE MEDIA STY 266 00:10:05,720 --> 00:10:08,360 NUMBER, LYMPH NODES IN BOTH 267 00:10:08,360 --> 00:10:10,000 AXILLA, HUGE SPLEENS, AND THE 268 00:10:10,000 --> 00:10:13,040 LARGE AMOUNTS OF TUMOR 269 00:10:13,040 --> 00:10:16,200 SURROUNDING THE AORTA AND THE 270 00:10:16,200 --> 00:10:17,480 VIENA CAVA, LARGE ILIAC LYMPH 271 00:10:17,480 --> 00:10:21,680 NODES ALL WHICH WENT ON TO 272 00:10:21,680 --> 00:10:24,360 DISAPPEAR AND REMAIN SO TEN 273 00:10:24,360 --> 00:10:25,520 YEARS LATER THIS PATIENT HAD A 274 00:10:25,520 --> 00:10:29,640 BONE MARROW FULL OF TUMOR THAT 275 00:10:29,640 --> 00:10:31,600 CLEARED AS WELL AND HAS GONE ON 276 00:10:31,600 --> 00:10:41,160 NOW TO LIVE NORMALLY. ONE OF MY 277 00:10:41,160 --> 00:10:42,720 FORMER FELLOWS WAS WARE OF THE 278 00:10:42,720 --> 00:10:44,480 RESULTS HE STARTED A BIOTECH 279 00:10:44,480 --> 00:10:50,880 COMPANY CALLED KITE PHARMA, IN 280 00:10:50,880 --> 00:10:51,840 2012, SURGERY BRANCH SIGNED A 281 00:10:51,840 --> 00:10:53,000 COOPERATIVE RESEARCH DEVELOPMENT 282 00:10:53,000 --> 00:10:54,480 AGREEMENT AND WE TRANSFERRED 283 00:10:54,480 --> 00:10:56,840 TECHNOLOGY FOR THIS CAR T-CELL 284 00:10:56,840 --> 00:11:00,920 TREATMENT TO PHARMA. IT 285 00:11:00,920 --> 00:11:02,080 PERFORMED A MULTI-INSTITUTIONAL 286 00:11:02,080 --> 00:11:05,560 STUDY TO EVALUATE ANTI-CD 19 CAR 287 00:11:05,560 --> 00:11:07,280 AND THE PATIENTS WITH DIFFUSE 288 00:11:07,280 --> 00:11:09,080 LARGE B CELL LYMPHOMA, THEY 289 00:11:09,080 --> 00:11:10,680 CORROBORATED THE RESULTS WE HAD 290 00:11:10,680 --> 00:11:12,080 SEEN OBJECTIVE RESPONSES IN 291 00:11:12,080 --> 00:11:16,480 ALMOST THREE QUARTERS OF 292 00:11:16,480 --> 00:11:18,080 PATIENT, WITH COMPLETE RESPONSE 293 00:11:18,080 --> 00:11:20,400 AND OVER 40% REPRODUCE THOSE 294 00:11:20,400 --> 00:11:22,120 RESULTS IN MULTI-INSTITUTIONAL 295 00:11:22,120 --> 00:11:27,040 STUDY, AND IN 2017 THEY RECEIVED 296 00:11:27,040 --> 00:11:31,040 FDA APPROVE TO OFFER THIS 297 00:11:31,040 --> 00:11:34,560 TREATMENT AND SOLD TO GILIAD 298 00:11:34,560 --> 00:11:39,080 SCIENCES FOR $11.9 BILLION. THIS 299 00:11:39,080 --> 00:11:40,240 IS AVAILABLE THROUGHOUT THE 300 00:11:40,240 --> 00:11:40,840 UNITED STATES AND EUROPE AND 301 00:11:40,840 --> 00:11:43,040 ASIA AND REPRESENTS A PROUD 302 00:11:43,040 --> 00:11:46,880 EXAMPLE OF HOW NIH TECHNOLOGY IS 303 00:11:46,880 --> 00:11:51,920 TRANSFERRED TO WIDESPREAD USE. 304 00:11:51,920 --> 00:11:54,080 CAR T-CELLS ARE GENERALLY ARE 305 00:11:54,080 --> 00:11:56,320 NOT AVAILABLE FOR THE TREATMENT 306 00:11:56,320 --> 00:11:58,000 OF NOT ONLY LYMPHOMAS BUT NOW 307 00:11:58,000 --> 00:12:01,000 PATIENTS WITH MULTIPLE MYELOMA 308 00:12:01,000 --> 00:12:02,440 AS WELL, BUT THE CONVENTIONAL 309 00:12:02,440 --> 00:12:04,960 T-CELL RECEPTORS ON LYMPHOCYTES 310 00:12:04,960 --> 00:12:08,520 THAT WOULD BE MOST APPLICABLE TO 311 00:12:08,520 --> 00:12:10,280 TREATMENT OF SOLID CANCER. IF 312 00:12:10,280 --> 00:12:13,760 WE LOOK AT CANCER DEATH IN 2021 313 00:12:13,760 --> 00:12:17,280 USING AMERICAN CANCER SOCIETY 314 00:12:17,280 --> 00:12:19,240 STATISTICS TOTAL OF OF 608,000 315 00:12:19,240 --> 00:12:21,080 AMERICANS WHO DIED OF CANCER, 316 00:12:21,080 --> 00:12:24,240 550,000 OR ABOUT 90% DIED OF THE 317 00:12:24,240 --> 00:12:29,760 SOLID EPITHELIAL CANCER. SO THE 318 00:12:29,760 --> 00:12:32,440 MAYOR CHALLENGE THAT CONFRONTS 319 00:12:32,440 --> 00:12:33,440 CANCER IMMUNOTHERAPY IS THE 320 00:12:33,440 --> 00:12:34,520 DEVELOPMENT OF EFFECTIVE 321 00:12:34,520 --> 00:12:35,520 IMMUNOTHERAPIES FOR PATIENTS 322 00:12:35,520 --> 00:12:37,560 WITH METASTATIC EPITHELIAL SOLID 323 00:12:37,560 --> 00:12:40,880 CANCER. THAT CANNOT BE CURED BY 324 00:12:40,880 --> 00:12:42,200 ANY AVAILABLE TREATMENT AND 325 00:12:42,200 --> 00:12:44,640 RESULT IN 90% OF CANCER DEATH IN 326 00:12:44,640 --> 00:12:46,080 THIS COUNTRY AND AROUND THE 327 00:12:46,080 --> 00:12:49,920 WORLD. TWO BASIC QUESTIONS I 328 00:12:49,920 --> 00:12:52,880 WOULD LIKE TO ADDRESS FROM OUR 329 00:12:52,880 --> 00:12:55,080 BOTH SCIENTIFIC LABORATORY AND 330 00:12:55,080 --> 00:12:56,960 CLINICAL RESEARCH RELATED TO 331 00:12:56,960 --> 00:12:58,000 HUMAN CANCER IMMUNOTHERAPY, 332 00:12:58,000 --> 00:13:01,440 USING A PATIENT'S OWN AUTOLOGOUS 333 00:13:01,440 --> 00:13:03,040 LYMPHOCYTES ARE THE FOLLOWING. 334 00:13:03,040 --> 00:13:04,880 THAT IS WHAT ARE THE PHENOTYPIC 335 00:13:04,880 --> 00:13:06,480 CHARACTERISTICS OF LYMPHOCYTES 336 00:13:06,480 --> 00:13:09,440 CAPABLE OF DESTROYING CANCER, IN 337 00:13:09,440 --> 00:13:11,560 PATIENTS, AND WHAT DO THESE 338 00:13:11,560 --> 00:13:12,920 ANTI-CANCER LYMPHOCYTES 339 00:13:12,920 --> 00:13:14,040 RECOGNIZE WHEN WE ARE USING 340 00:13:14,040 --> 00:13:17,280 T-CELL RECEPTORS, THEY ARE 341 00:13:17,280 --> 00:13:17,800 RECOGNIZING INTRACELLULAR 342 00:13:17,800 --> 00:13:20,240 PROTEINS THAT ARE THEN PRESENTED 343 00:13:20,240 --> 00:13:25,720 ON THE CELL SURFACE. SO HERE IS 344 00:13:25,720 --> 00:13:27,280 A CARTOON THAT TALKS HOW 345 00:13:27,280 --> 00:13:31,840 ADOPTIVE CELL THERAPY WORKS WE 346 00:13:31,840 --> 00:13:33,160 EXCISE A THANK YOU NO, IF YOU 347 00:13:33,160 --> 00:13:36,920 FOLLOW ALONG CLOCKWISE WE EXCISE 348 00:13:36,920 --> 00:13:38,480 A TUMOR, IDENTIFY WITHIN THE 349 00:13:38,480 --> 00:13:40,880 TUMOR LYMPHOCYTES, THAT WE CAN 350 00:13:40,880 --> 00:13:44,320 GROW IN VITRO TO LARGE NUMBERS, 351 00:13:44,320 --> 00:13:45,920 WE ASSAY FOR ANTITUMOR 352 00:13:45,920 --> 00:13:48,920 REACTIVITY WHEN WE CAN. AND 353 00:13:48,920 --> 00:13:51,960 SELECT CELLS EXPAND TO LARGE 354 00:13:51,960 --> 00:13:54,600 AMOUNTS AND REINFUSE BACK TO 355 00:13:54,600 --> 00:13:56,920 PATIENT AFTER ADMINISTERING 356 00:13:56,920 --> 00:13:58,280 LYMPHODEPLETING CHEMOTHERAPY 357 00:13:58,280 --> 00:13:59,960 THAT ELIMINATES THE BODY'S 358 00:13:59,960 --> 00:14:01,320 NATURAL IMMUNE LYMPHOCYTES TO 359 00:14:01,320 --> 00:14:03,680 MAKE ROOM FOR THE CELLS THAT WE 360 00:14:03,680 --> 00:14:11,400 THEN ADMINISTER. WE TREATED 192 361 00:14:11,400 --> 00:14:15,400 PATIENTS WITH ADVANCE CANCER, 362 00:14:15,400 --> 00:14:19,960 ADVANCE ME MELANOMA USING 363 00:14:19,960 --> 00:14:21,920 AUTOLOGOUS TUMOR LYMPHOCYTES AND 364 00:14:21,920 --> 00:14:24,680 PATIENTS NAIVE TO CHECK POINT 365 00:14:24,680 --> 00:14:25,400 MODULATORS, 192 CONSECUTIVE 366 00:14:25,400 --> 00:14:27,360 PATIENTS YOU CAN SEE A COMPLETE 367 00:14:27,360 --> 00:14:30,680 RESPONSE RATE OF 25% WITH A 368 00:14:30,680 --> 00:14:32,600 PARTIAL RESPONSE RATE OF 31% 369 00:14:32,600 --> 00:14:37,280 MANY OF THESE ONGOING BEYOND TEN 370 00:14:37,280 --> 00:14:39,480 YEARS FOR OBJECTIVE OVERALL 371 00:14:39,480 --> 00:14:41,600 RESPONSE RATE OF 56%. NOTICE 372 00:14:41,600 --> 00:14:43,640 PATIENT HAS A COMPLETE 373 00:14:43,640 --> 00:14:44,680 REGRESSION ONLY TWO PATIENTS 374 00:14:44,680 --> 00:14:46,920 HAVE EVER RECURRED AT 26 AND 19 375 00:14:46,920 --> 00:14:50,400 MONTHS, REMAINING PATIENTS HAVE 376 00:14:50,400 --> 00:14:56,560 ONGOING DISEASE. SO WHEN 377 00:14:56,560 --> 00:14:58,480 ADMINISTERING NORMAL TUMOR 378 00:14:58,480 --> 00:15:00,800 INFILTRATING LYMPHOCYTES FROM A 379 00:15:00,800 --> 00:15:02,360 PATIENT THAT GROWING THEM IN 380 00:15:02,360 --> 00:15:03,880 VITRO AND TO LARGE NUMBERS AND 381 00:15:03,880 --> 00:15:06,040 THEN READMINISTERRING THEM, IT 382 00:15:06,040 --> 00:15:08,800 APPEARS AS IF THIS ADOPTIVE CELL 383 00:15:08,800 --> 00:15:10,400 THERAPY IS CAPABLE OF 384 00:15:10,400 --> 00:15:12,040 ELIMINATING A LAST MELANOMA CELL 385 00:15:12,040 --> 00:15:15,040 IF YOU CAN SEE COMPLETE 386 00:15:15,040 --> 00:15:16,440 RESPONDERS HAVE NOT RECURRED NOW 387 00:15:16,440 --> 00:15:19,320 WELL BEYOND TEN YEARS AND 388 00:15:19,320 --> 00:15:24,520 ONGOING TO 15 YEARS. SO BECAUSE 389 00:15:24,520 --> 00:15:26,320 WE HAD PATIENTS THAT HAD 390 00:15:26,320 --> 00:15:27,680 RESPONDED AND SOME THAT HAD NOT 391 00:15:27,680 --> 00:15:29,160 RESPONDED WE WERE ABLE TO ASK 392 00:15:29,160 --> 00:15:30,960 WHAT WERE THE PHENOTYPIC 393 00:15:30,960 --> 00:15:32,080 CHARACTERISTICS OF THE CELLS 394 00:15:32,080 --> 00:15:33,720 THAT MEDIATE HUMAN CANCER 395 00:15:33,720 --> 00:15:35,640 REGRESSION IN VIVO? WHAT KIND OF 396 00:15:35,640 --> 00:15:39,080 CELL DO WE HAVE TO DEVELOP IF WE 397 00:15:39,080 --> 00:15:41,080 ATTACK SOLID EPITHELIAL CANCER 398 00:15:41,080 --> 00:15:43,160 THAT RESULT IN SO MANY CANCER 399 00:15:43,160 --> 00:15:45,320 DEATHS. TO DO THIS WE USED A 400 00:15:45,320 --> 00:15:47,280 HIGH DIMENSIONAL SINGLE CELL 401 00:15:47,280 --> 00:15:50,880 TRANSCRIPTOME ANALYSIS OF UP TO 402 00:15:50,880 --> 00:15:52,840 10,000 INDIVIDUAL CELLS FROM 403 00:15:52,840 --> 00:15:57,680 EACH PATIENT AND THEN CAN USE 404 00:15:57,680 --> 00:16:00,720 ANALYSIS TSNE ANALYSIS, A T 405 00:16:00,720 --> 00:16:01,600 DISTRIBUTED O STOCHASTIC 406 00:16:01,600 --> 00:16:04,320 NEIGHBOR EMBEDDING TECHNIQUE, TO 407 00:16:04,320 --> 00:16:07,080 LOOK AT DIFFERENT TYPES OF 408 00:16:07,080 --> 00:16:12,880 LYMPHOCYTES THAT EXIST IN ANY 409 00:16:12,880 --> 00:16:15,120 POPULATION. WHEN WE DID THIS 410 00:16:15,120 --> 00:16:17,280 ANALYSIS, BY BREAKING LYMPHOCYTE 411 00:16:17,280 --> 00:16:19,840 POPULATIONS IN OUR INFUSION 412 00:16:19,840 --> 00:16:21,960 SAMPLES, THEY CAN DIVIDE TO 22 413 00:16:21,960 --> 00:16:24,880 DIFFERENT LYMPHOCYTES TYPES AND 414 00:16:24,880 --> 00:16:29,680 WHEN SRI KRISHNA AND FRANK 415 00:16:29,680 --> 00:16:30,680 LOWERY DOING THIS WORK IN 416 00:16:30,680 --> 00:16:31,840 SURGERY BRANCH COMPARED 417 00:16:31,840 --> 00:16:33,080 RESPONDERS TO NON-RESPONDERS 418 00:16:33,080 --> 00:16:33,920 THEY IDENTIFIED A PARTICULAR 419 00:16:33,920 --> 00:16:35,280 CLUSTER THAT APPEARED VERY 420 00:16:35,280 --> 00:16:37,760 DIFFERENT IN RESPONDERS AND 421 00:16:37,760 --> 00:16:41,600 NON-RESPONDERS. WE LOOK AT THESE 422 00:16:41,600 --> 00:16:43,960 22 CLUSTERS, IT WAS ONLY CLUSTER 423 00:16:43,960 --> 00:16:46,080 NUMBER 1 THAT SEPARATED 424 00:16:46,080 --> 00:16:56,840 RESPONDER -- (LOST AUDIO) CANCER 425 00:16:56,840 --> 00:16:59,800 IN THESE AUTOLOGOUS PATIENTS. 426 00:16:59,800 --> 00:17:04,960 IF WE STUDY THE CHARACTERISTICS 427 00:17:04,960 --> 00:17:08,880 OF CELLS IN THIS CLUSTER 1, WE 428 00:17:08,880 --> 00:17:12,320 CAN SEE THESE CELLS HAVE A HIGH 429 00:17:12,320 --> 00:17:15,640 CONCENTRATION OF CD 39 CD 69 430 00:17:15,640 --> 00:17:17,040 NEGATIVE CELLS INDICATIVE OF 431 00:17:17,040 --> 00:17:18,920 STEM LINE LYMPHOCYTE POPULATION 432 00:17:18,920 --> 00:17:20,880 THAT APPEARED TO BE THE EFFECTOR 433 00:17:20,880 --> 00:17:22,040 CELLS RESPONSIBLE FOR MELANOMA 434 00:17:22,040 --> 00:17:24,480 TREATMENT. IN FACT IF WE LOOK 435 00:17:24,480 --> 00:17:26,000 AT THE TOTAL NUMBER OF CELLS 436 00:17:26,000 --> 00:17:27,960 THAT WE ADMINISTER TO PATIENTS, 437 00:17:27,960 --> 00:17:29,320 THERE WAS NO DIFFERENCE BETWEEN 438 00:17:29,320 --> 00:17:31,880 PATIENTS GETTING HIGH OR LOW 439 00:17:31,880 --> 00:17:34,680 NUMBERS OF THESE CELLS IN TERMS 440 00:17:34,680 --> 00:17:39,880 OF THEIR ABILITY TO RESPOND. 441 00:17:39,880 --> 00:17:41,440 WHEN WE LOOK AT NUMBER OF DOUBLE 442 00:17:41,440 --> 00:17:42,560 NEGATIVE CELLS ADMINISTERED WE 443 00:17:42,560 --> 00:17:46,160 CAN SEE A DRAMATIC DIFFERENCE 444 00:17:46,160 --> 00:17:48,560 BETWEEN RESPONDERS AND 445 00:17:48,560 --> 00:17:49,280 NON-RESPONDERS SEPARATING THEM 446 00:17:49,280 --> 00:17:51,440 AT THE POINT 001 LEVEL 447 00:17:51,440 --> 00:17:54,080 INDICATING IT WAS THESE CD 3969 448 00:17:54,080 --> 00:17:56,600 DOUBLE NEGATIVE CELLS THAT WERE 449 00:17:56,600 --> 00:17:57,640 RESPONSIBLE FOR CAUSING TUMOR 450 00:17:57,640 --> 00:17:59,520 REGRESSION. THEY HAD THE 451 00:17:59,520 --> 00:18:01,160 APPROPRIATE PROPERTIES NECESSARY 452 00:18:01,160 --> 00:18:04,800 TO RECOGNIZE AND DESTROY THIS 453 00:18:04,800 --> 00:18:06,960 MELANOMA MET TA STATIC DEPOSITS 454 00:18:06,960 --> 00:18:10,200 IN VIVO. -- METASTATIC DEPOSITS 455 00:18:10,200 --> 00:18:11,680 IN VIVO. USING THIS INFORMATION 456 00:18:11,680 --> 00:18:14,720 WE WENT BACK TO THE LABORATORY 457 00:18:14,720 --> 00:18:17,080 IN ANIMAL STUDIES AND COMPARED 458 00:18:17,080 --> 00:18:19,680 THE CD 3969 DOUBLE NEGATIVE 459 00:18:19,680 --> 00:18:21,480 CELLS AT TWO CONCENTRATIONS WITH 460 00:18:21,480 --> 00:18:23,080 THEIR ABILITY THE TREAT AND 461 00:18:23,080 --> 00:18:24,240 ESTABLISH VASCULARIZED TUMOR. 462 00:18:24,240 --> 00:18:26,480 YOU CAN SEE THE DOUBLE POSITIVE 463 00:18:26,480 --> 00:18:29,000 CELLS HAD SOME STRONG, SOME 464 00:18:29,000 --> 00:18:32,520 SLIGHT IMPROVEMENT COMPARED TO 465 00:18:32,520 --> 00:18:33,920 NO TREATMENT BUT DOUBLE NEGATIVE 466 00:18:33,920 --> 00:18:36,960 CELLS HAD A SIGNIFICANT 467 00:18:36,960 --> 00:18:37,600 IMPROVEMENT SHOWING IN ONLY IN 468 00:18:37,600 --> 00:18:39,840 HUMAN BUT ANIMAL MODELS IT WAS 469 00:18:39,840 --> 00:18:43,080 THIS STEM LIKE POPULATION OF 470 00:18:43,080 --> 00:18:43,920 3969 DOUBLE NEGATIVE CELLS THAT 471 00:18:43,920 --> 00:18:49,000 HAD THE PROPERTIES NECESSARY TO 472 00:18:49,000 --> 00:18:52,040 DESTROY CANCER. THAT LED US TO A 473 00:18:52,040 --> 00:18:53,480 SECOND QUESTION, THAT IS, WHAT 474 00:18:53,480 --> 00:18:56,680 DO THESE TUMOR INFILTRATING 475 00:18:56,680 --> 00:18:57,920 LYMPHOCYTES RECOGNIZE THAT 476 00:18:57,920 --> 00:19:00,800 ENABLES THE IN VIVO CONTROL OF 477 00:19:00,800 --> 00:19:02,680 THE LAST MELANOMA CELL AND CAN 478 00:19:02,680 --> 00:19:04,800 WE USE THIS INFORMATION THEN TO 479 00:19:04,800 --> 00:19:07,480 ATTEMPT TO FIND THESE ANTIGENS 480 00:19:07,480 --> 00:19:09,160 IN THE SOLID EPITHELIAL CANCERS 481 00:19:09,160 --> 00:19:13,520 THAT ARE THE MAJOR KILLERS. OUR 482 00:19:13,520 --> 00:19:18,520 CLUE TO THE KIND OF ANTIGEN THAT 483 00:19:18,520 --> 00:19:19,760 MIGHT BE RECOGNIZED CAME FROM 484 00:19:19,760 --> 00:19:21,880 OBSERVATION IN MELANOMA PATIENTS 485 00:19:21,880 --> 00:19:22,880 THAT THERE WAS SPECIFIC CANCER 486 00:19:22,880 --> 00:19:26,400 REGRESSION IN ABSENCE OF ANY OFF 487 00:19:26,400 --> 00:19:27,640 TUMOR ON TARGET TOXICITIES IN 488 00:19:27,640 --> 00:19:30,880 THESE PATIENTS. THAT LED US TO 489 00:19:30,880 --> 00:19:35,400 STUDY THE ROLE OF THE MOST 490 00:19:35,400 --> 00:19:36,120 SIGNIFICANT DIFFERENCE BETWEEN 491 00:19:36,120 --> 00:19:37,200 CANCER CELLS AND NORMAL CELLS 492 00:19:37,200 --> 00:19:40,920 AND THAT IS THE DEVELOPMENT OF 493 00:19:40,920 --> 00:19:42,920 SPECIFIC CANCER MUTATIONS THAT 494 00:19:42,920 --> 00:19:48,640 LEADS TO THE MALIGNANT PHENE 495 00:19:48,640 --> 00:19:50,560 TYPE, SO WE LOOK AT MUTATIONS AS 496 00:19:50,560 --> 00:19:55,160 POSSIBLE TARGETTERS BECAUSE OFS BECAUSE OF THIS 497 00:19:55,160 --> 00:19:56,360 HIGHLY SELECTED REACTIVITY. TO 498 00:19:56,360 --> 00:19:58,480 DO THIS WE DEVELOPED AN ASSAY 499 00:19:58,480 --> 00:20:00,920 THAT WE FIRST REPORTED ABOUT 500 00:20:00,920 --> 00:20:03,840 FOUR AND A HALF YEARS AGO. AND 501 00:20:03,840 --> 00:20:05,520 TO IDENTIFY NATURE OFFER THESE 502 00:20:05,520 --> 00:20:07,160 ANTIGENS AND YOU CAN SEE THAT IN 503 00:20:07,160 --> 00:20:11,800 THIS CARTOON. WE IDENTIFY TUMOR 504 00:20:11,800 --> 00:20:13,880 SAMPLE THAT CAN BE RESECTED AND 505 00:20:13,880 --> 00:20:16,680 SUBJECT THAT TUMOR SAMPLE TO DNA 506 00:20:16,680 --> 00:20:19,440 AN RNA SEQUENCING TO IDENTIFY 507 00:20:19,440 --> 00:20:22,680 ALL OF THE CANCER MUTATIONS THAT 508 00:20:22,680 --> 00:20:25,120 ARE PRESENT IN THAT MALIGNANCY 509 00:20:25,120 --> 00:20:30,640 COMPARED TO NORMAL CELLS. ONCE 510 00:20:30,640 --> 00:20:31,840 WE IDENTIFY ALL MUTATIONS 511 00:20:31,840 --> 00:20:33,640 PRESENT IN THESE CANCERS AND 512 00:20:33,640 --> 00:20:36,160 MELANOMA IS ABOUT 300, MOST 513 00:20:36,160 --> 00:20:38,360 EPITHELIAL CANCER IS AROUND 514 00:20:38,360 --> 00:20:39,920 HUNDRED OF THESE MUTATIONS THAT 515 00:20:39,920 --> 00:20:42,640 RESULT IN THE CANCER. WE THEN 516 00:20:42,640 --> 00:20:44,800 TAKE EVERY ONE OF THE SEQUENCES 517 00:20:44,800 --> 00:20:46,920 SURROUNDING THE NON-SYNONYMOUS 518 00:20:46,920 --> 00:20:49,880 MUTATION IN THE CANCER, AND 519 00:20:49,880 --> 00:20:53,680 INTRODUCE THOSE MUTATIONS AS 25 520 00:20:53,680 --> 00:20:56,880 PEPTIDES OR MINI GENES INTO THE 521 00:20:56,880 --> 00:20:58,080 PATIENTS ANTIGEN PRESENTING 522 00:20:58,080 --> 00:21:00,440 CELL, WHICH CONTAINS ALL THE MHC 523 00:21:00,440 --> 00:21:02,440 MOLECULES THAT COULD POTENTIALLY 524 00:21:02,440 --> 00:21:05,280 PRESENT ANY MUTATION PRODUCT TO 525 00:21:05,280 --> 00:21:07,920 T-CELLS. WE THEN TAKE T-CELLS 526 00:21:07,920 --> 00:21:11,280 AND ISOLATE FROM THE TUMOR, OR 527 00:21:11,280 --> 00:21:13,120 NOW FROM BLOOD. WE CO-CULTURE 528 00:21:13,120 --> 00:21:14,360 THAT WITH ANTIGEN PRESENTING 529 00:21:14,360 --> 00:21:15,720 CELLS FROM THAT SAME PATIENT, 530 00:21:15,720 --> 00:21:19,080 WHICH CONTAIN ALL OF THE TUMOR 531 00:21:19,080 --> 00:21:20,800 MUTATIONS TO SEE IF ANY OF THE 532 00:21:20,800 --> 00:21:22,120 LYMPHOCYTES THAT MEDIATED 533 00:21:22,120 --> 00:21:23,480 COMPLETE TUMOR REGRESSION 534 00:21:23,480 --> 00:21:26,680 RECOGNIZE ANY OF THESE ANTIGENS. 535 00:21:26,680 --> 00:21:29,880 WE CAN THEN IDENTIFY EXACT 536 00:21:29,880 --> 00:21:32,320 ANTIGEN BY USING CYTOKINE 537 00:21:32,320 --> 00:21:35,360 ELISPOT ASSAY ELISA ASSAYS OR 538 00:21:35,360 --> 00:21:39,240 CYTOKINE SECRETIONS TO IDENTIFY 539 00:21:39,240 --> 00:21:40,800 THE ANTIGEN. THIS ASSAY DOESN'T 540 00:21:40,800 --> 00:21:42,480 REQUIRE ANY PREDICTION OF 541 00:21:42,480 --> 00:21:44,600 PEPTIDE BINDING. EVERY CANDIDATE 542 00:21:44,600 --> 00:21:47,400 MUTATION AND ALL OF THE MHC LOCI 543 00:21:47,400 --> 00:21:50,840 OF ANY OF THAT PARTICULAR 544 00:21:50,840 --> 00:21:52,920 PATIENT ARE INCLUDED IN THE 545 00:21:52,920 --> 00:21:55,240 SCREEN AND THERE'S NO TUMOR CELL 546 00:21:55,240 --> 00:21:56,120 LINES NECESSARY WHICH HAS 547 00:21:56,120 --> 00:21:57,640 INHIBITED RESEARCH IN THIS AREA 548 00:21:57,640 --> 00:21:59,600 BECAUSE IT IS VERY DIFFICULT TO 549 00:21:59,600 --> 00:22:02,480 ESTABLISH EPITHELIAL CANCER 550 00:22:02,480 --> 00:22:06,040 LINES FROM MOST PATIENTS. WE 551 00:22:06,040 --> 00:22:07,920 UTILIZE THIS TECHNIQUE FIRST TO 552 00:22:07,920 --> 00:22:10,000 LOOK AT PATIENTS WITH METASTATIC 553 00:22:10,000 --> 00:22:13,080 MELANOMA. AND THEN OTHER MORE 554 00:22:13,080 --> 00:22:15,320 COMMON EPITHELIAL CANCERS AND 555 00:22:15,320 --> 00:22:18,680 THESE 76 CONSECUTIVE PATIENTS 556 00:22:18,680 --> 00:22:22,640 THEY HAD 44,000 PLUS MUTATIONS 557 00:22:22,640 --> 00:22:25,000 COLLECTIVELY, WE ONLY SCREENED 558 00:22:25,000 --> 00:22:26,520 13,400 OR 30% BECAUSE THOSE WERE 559 00:22:26,520 --> 00:22:28,960 THE ONES THAT WERE EXPRESSED IN 560 00:22:28,960 --> 00:22:35,240 THE CANCER BY RNA SEQ ANALYSIS. 561 00:22:35,240 --> 00:22:37,400 IF YOU LOOK AT THE NUMBER OF 562 00:22:37,400 --> 00:22:38,120 IMMUNOGENIC MUTATIONS THAT TURN 563 00:22:38,120 --> 00:22:40,080 OUT RECOGNIZED BY A PATIENT'S 564 00:22:40,080 --> 00:22:42,080 LYMPHOCYTES, TUMOR ANTIGENS, IT 565 00:22:42,080 --> 00:22:44,760 TURNED OUT TO BE 1.3% AND 566 00:22:44,760 --> 00:22:47,880 MELANOMA PATIENTS THESE WERE 567 00:22:47,880 --> 00:22:51,560 LARGELY IDENTIFIED BY CD8 568 00:22:51,560 --> 00:22:53,560 POSITIVE CELLS. SURPRISING 569 00:22:53,560 --> 00:22:56,840 OBSERVATION WAS THAT IN THESE 570 00:22:56,840 --> 00:22:58,240 PATIENTS EVERY ANTIGEN RECOGNIZE 571 00:22:58,240 --> 00:23:02,920 WAS UNIQUE TO THE INDIVIDUAL 572 00:23:02,920 --> 00:23:04,120 PATIENT, NONE SHARED BETWEEN TWO 573 00:23:04,120 --> 00:23:06,040 PATIENTS AND THERE IS A WIDE 574 00:23:06,040 --> 00:23:07,400 VARIETY OF THE ACCUMULATION OF 575 00:23:07,400 --> 00:23:09,960 CANCER MUTATIONS THAT CAN RESULT 576 00:23:09,960 --> 00:23:16,680 IN A MALIGNANT PHENOTYPE. WE 577 00:23:16,680 --> 00:23:18,040 THEN LOOKED AT VARIETY OF 578 00:23:18,040 --> 00:23:18,960 DIFFERENT EPITHELIAL CANCERS, 579 00:23:18,960 --> 00:23:21,080 THIS STUDY FROM BREAST CANCER IS 580 00:23:21,080 --> 00:23:25,760 NOW IMPRESS BY NIKOS ZAKARAKIS A 581 00:23:25,760 --> 00:23:28,080 FELLOW IN THE SURGERY BRANCH WHO 582 00:23:28,080 --> 00:23:28,880 STUDIED 43 CONSECUTIVE PATIENTS 583 00:23:28,880 --> 00:23:30,480 WITH METASTATIC BREAST CANCER 584 00:23:30,480 --> 00:23:33,720 WITH A MEDIAN NUMBER OF 585 00:23:33,720 --> 00:23:39,200 MUTATIONS ABOUT 119. THERE WERE 586 00:23:39,200 --> 00:23:42,080 7900 PLUS MUTATIONS IN THESE 43 587 00:23:42,080 --> 00:23:45,280 PATIENTS, WE SCREENED 4722, AND 588 00:23:45,280 --> 00:23:48,080 COULD IDENTIFY 100 DIFFERENT 589 00:23:48,080 --> 00:23:52,680 IMMUNOGENIC EPITOPES. 67% OF 590 00:23:52,680 --> 00:23:54,320 THESE METASTATIC BREAST CANCER 591 00:23:54,320 --> 00:23:56,600 PATIENTS HAD MUTATIONS, THAT 592 00:23:56,600 --> 00:24:00,480 COULD BE RECOGNIZED BY THE 593 00:24:00,480 --> 00:24:02,200 PATIENTS ON AUTOLOGOUS 594 00:24:02,200 --> 00:24:05,440 LYMPHOCYTES, ABOUT 2.1% OF THESE 595 00:24:05,440 --> 00:24:07,520 MUTATIONS WERE RECOGNIZED BY 596 00:24:07,520 --> 00:24:10,480 T-CELLS, BUT IN BREAST CANCER, 597 00:24:10,480 --> 00:24:12,400 EPITHELIAL CANCER PATIENTS, 598 00:24:12,400 --> 00:24:13,880 ABOUT THREE QUARTERS OF THESE 599 00:24:13,880 --> 00:24:15,760 ANTIGENS ARE RECOGNIZED BY CD4 600 00:24:15,760 --> 00:24:18,680 CELLS AND NOT CD8 CELLS AND ONCE 601 00:24:18,680 --> 00:24:20,280 AGAIN, ALL OF THESE 100 602 00:24:20,280 --> 00:24:22,280 IMMUNOGENE EPITOPES WERE UNIQUE 603 00:24:22,280 --> 00:24:25,560 TO THE INDIVIDUAL PATIENT NONE 604 00:24:25,560 --> 00:24:30,240 SHARED AMONG PATIENTS. NOW 605 00:24:30,240 --> 00:24:32,920 STUDIED 195 PATIENTS WITH A 606 00:24:32,920 --> 00:24:34,360 VARIETY OF DIFFERENT CANCER FROM 607 00:24:34,360 --> 00:24:36,440 THE GASTRO INTESTINAL CANCER YOU 608 00:24:36,440 --> 00:24:37,680 MENTIONED BREAST CANCER, LUNG 609 00:24:37,680 --> 00:24:39,800 CANCER, OVARIAN AND PROSTATE 610 00:24:39,800 --> 00:24:41,560 CANCER, AND IF YOU LOOK HERE AT 611 00:24:41,560 --> 00:24:43,880 THE NUMBER OF PATIENTS THAT HAVE 612 00:24:43,880 --> 00:24:44,560 NEOANTIGEN REACTIVITY, 613 00:24:44,560 --> 00:24:48,160 IDENTIFIED BY THESE ASSAYS, YOU 614 00:24:48,160 --> 00:24:51,480 CAN SEE IT IS ABOUT 77% ON 615 00:24:51,480 --> 00:24:52,880 AVERAGE BUT YOU CAN SEE 616 00:24:52,880 --> 00:24:56,200 VIRTUALLY EVERY HISTOLOGY HAS -- 617 00:24:56,200 --> 00:24:57,480 EVERY PATIENT WITH DIFFERENT 618 00:24:57,480 --> 00:25:00,520 HISTOLOGIC TYPES OF CANCER HAVE 619 00:25:00,520 --> 00:25:02,120 T-CELLS, THAT CAN RECOGNIZE 620 00:25:02,120 --> 00:25:05,240 THEIR TUMORS. ABOUT THREE 621 00:25:05,240 --> 00:25:06,640 QUARTERS OF THESE PATIENTS ARE 622 00:25:06,640 --> 00:25:09,240 INCLUDED. THEY RECOGNIZE ABOUT 623 00:25:09,240 --> 00:25:12,080 363 DIFFERENT NEOANTIGENS. LET 624 00:25:12,080 --> 00:25:13,680 ME EMPHASIZE THIS POINT AGAIN, 625 00:25:13,680 --> 00:25:14,600 BECAUSE IT HAS A LOT OF 626 00:25:14,600 --> 00:25:16,160 IMPLICATIONS FOR THE DEVELOPMENT 627 00:25:16,160 --> 00:25:19,880 OF CANCER TREATMENTS. AMONG 628 00:25:19,880 --> 00:25:21,440 THESE 363 ANTIGENS RECOGNIZED BY 629 00:25:21,440 --> 00:25:25,040 PATIENT OWN T-CELLS, ALL WERE 630 00:25:25,040 --> 00:25:26,760 UNIQUE EXCEPT TWO PATIENTS WHO 631 00:25:26,760 --> 00:25:30,520 SHARED THE SAME KRAS MUTATION 632 00:25:30,520 --> 00:25:34,200 RESTRICTED BY RELATIVELY RARE 633 00:25:34,200 --> 00:25:40,160 CLASS 1 ANTIGEN CW 0802. AN 634 00:25:40,160 --> 00:25:41,320 ADVANTAGE OF TARGETING 635 00:25:41,320 --> 00:25:42,680 MUTATIONS, IS POTENTIAL 636 00:25:42,680 --> 00:25:44,480 APPLICABILITY TO TARGET MULTIPLE 637 00:25:44,480 --> 00:25:45,880 CANCER TYPES BECAUSE VIRTUALLY 638 00:25:45,880 --> 00:25:47,920 ALL CANCERS HAVE MUTATIONS THAT 639 00:25:47,920 --> 00:25:50,600 RESULTED IN THE MALIGNANT 640 00:25:50,600 --> 00:25:52,280 PHENOTYPE. SO THESE -- THIS KIND 641 00:25:52,280 --> 00:25:54,360 OF APPROACH TO TREATMENT IS NOT 642 00:25:54,360 --> 00:25:55,280 UNIQUE TO ANY INDIVIDUAL 643 00:25:55,280 --> 00:25:56,600 HISTOLOGY. LET ME JUST PRESENT A 644 00:25:56,600 --> 00:25:58,680 FEW EXAMPLES BEFORE I SHOW YOU 645 00:25:58,680 --> 00:26:02,480 OVERALL RESULTS. THE FIRST 646 00:26:02,480 --> 00:26:03,480 PATIENT TREAT WITH HIGHLY 647 00:26:03,480 --> 00:26:04,760 SELECTED CELLS AGAINST MUTATIONS 648 00:26:04,760 --> 00:26:06,880 IS A PATIENT WITH METASTATIC 649 00:26:06,880 --> 00:26:10,640 BILE DUCT TUMOR, FA LAIN JOEL 650 00:26:10,640 --> 00:26:15,600 CARCINOMA. THAT KARAT HAD A 651 00:26:15,600 --> 00:26:18,680 RIGHT HEAPECTOMY, RECEIVED 652 00:26:18,680 --> 00:26:20,400 MULTIPLE CHEMOTHERAPY REGIMENS 653 00:26:20,400 --> 00:26:21,520 RECEIVED UNSELECTED TIL AS WE 654 00:26:21,520 --> 00:26:23,960 DID IN PATIENTS WITH MELANOMA 655 00:26:23,960 --> 00:26:26,280 BUT DIDN'T WORK, MELANOMA IS THE 656 00:26:26,280 --> 00:26:27,800 ONLY HISTOLOGY UNSELECTED CELLS 657 00:26:27,800 --> 00:26:29,080 CAN CAUSE REGRESSION WHEN GROWN 658 00:26:29,080 --> 00:26:33,960 IN VITRO. IN THIS PATIENT WE 659 00:26:33,960 --> 00:26:35,480 UTILIZED OUR PEPTIDE POOL 660 00:26:35,480 --> 00:26:39,120 APPROACH TO IDENTIFY CELLS THAT 661 00:26:39,120 --> 00:26:44,480 REACT WITH UNIQUE ANTIGEN IN ERB 662 00:26:44,480 --> 00:26:47,720 TRANSMUTATION AND ERIC TRAN 663 00:26:47,720 --> 00:26:49,280 REPORTED RESULTS OF COMPLETE 664 00:26:49,280 --> 00:26:50,520 TUMOR REGRESSION IN THIS 665 00:26:50,520 --> 00:26:52,880 PARTICULAR PATIENT. YOU CAN SEE 666 00:26:52,880 --> 00:26:54,880 THE TUMORS THAT ARE PRESENT IN 667 00:26:54,880 --> 00:26:58,680 THE LUNG OF PATIENTS, SHE 668 00:26:58,680 --> 00:26:59,960 PROGRESSED ONCE AND RECEIVED A 669 00:26:59,960 --> 00:27:01,240 SECOND TREATMENT A FEW MONTHS 670 00:27:01,240 --> 00:27:03,080 LATER, RESULTING IN THE COMPLETE 671 00:27:03,080 --> 00:27:04,280 DISAPPEARANCE OF ALL OF HER 672 00:27:04,280 --> 00:27:05,960 TUMOR AS WELL AS THREE DIFFERENT 673 00:27:05,960 --> 00:27:08,440 LIVER METASTATIC DEPOSITS AS 674 00:27:08,440 --> 00:27:11,480 WELL AND SHE REMAINS NOW DISEASE 675 00:27:11,480 --> 00:27:13,280 FREE OVER EIGHT YEARS. OVER 676 00:27:13,280 --> 00:27:15,720 EIGHT YEARS LATER. THIS IS A 677 00:27:15,720 --> 00:27:18,520 PATIENT WITH METASTATIC BREAST 678 00:27:18,520 --> 00:27:24,080 CANCER REPORTED BY DR. ZAKARAKIS 679 00:27:24,080 --> 00:27:26,680 WHO HAS ER POSITIVE BREAST 680 00:27:26,680 --> 00:27:27,600 CANCER, WITH SEVEN TREATMENTS 681 00:27:27,600 --> 00:27:28,160 AND PROGRESSED THROUGH UNTIL 682 00:27:28,160 --> 00:27:31,640 COMING TO THE NIH FOR TREATMENT 683 00:27:31,640 --> 00:27:33,000 WITH CELLS THAT RECOGNIZE FOUR 684 00:27:33,000 --> 00:27:35,280 DIFFERENT CANCER MUTATIONS IN 685 00:27:35,280 --> 00:27:37,280 HER TUMOR. THESE ARE NOT 686 00:27:37,280 --> 00:27:40,280 NECESSARILY DRIVER MUTATIONS, 687 00:27:40,280 --> 00:27:42,960 AND YOU CAN SEE THEIR FUNCTIONS 688 00:27:42,960 --> 00:27:46,720 HERE, 23% INFUSED CELLS CONTAIN 689 00:27:46,720 --> 00:27:48,200 NEOANTIGEN REACTIVITY AND THIS 690 00:27:48,200 --> 00:27:50,520 PATIENT UNDERWENT COMPLETE 691 00:27:50,520 --> 00:27:51,640 RESPONSE AFTER THIS TREATMENT 692 00:27:51,640 --> 00:27:52,960 YOU CAN SEE TUMOR BEGINNING TO 693 00:27:52,960 --> 00:27:55,080 GROW THROUGH THE CHEST WALL, 694 00:27:55,080 --> 00:27:57,120 MULTIPLE LIVER METASTATIC 695 00:27:57,120 --> 00:27:58,680 DEPOSITS DISAPPEARED COMPLETELY 696 00:27:58,680 --> 00:28:00,960 AND SHE REMAINS DISEASE FREE NOW 697 00:28:00,960 --> 00:28:02,560 OVER FIVE YEARS LATER. THIS 698 00:28:02,560 --> 00:28:05,440 PATIENT WITH VERY AGGRESSIVE 699 00:28:05,440 --> 00:28:08,440 METASTATIC CERVICAL CANCER HAD A 700 00:28:08,440 --> 00:28:09,080 FUN GATING SEARCHCAL MASS WITH 701 00:28:09,080 --> 00:28:11,960 MULTIPLE DEPOSITS IN THE LUNG 702 00:28:11,960 --> 00:28:13,200 INTRAPERITONEALLY, SHE HAD 703 00:28:13,200 --> 00:28:15,120 UNDERGONE RADIATION THERAPY, 704 00:28:15,120 --> 00:28:17,160 CHEMOTHERAPY, PROGRESSED 705 00:28:17,160 --> 00:28:19,600 UNDERWENT FURTHER SURGE RITES, 706 00:28:19,600 --> 00:28:21,440 DEVELOPED LIVER LYMPH NODE 707 00:28:21,440 --> 00:28:22,280 INTRAABDOMINAL MA TA STATIC 708 00:28:22,280 --> 00:28:24,080 DISEASE, SHE WAS TREATED OVER 709 00:28:24,080 --> 00:28:27,560 SEVEN YEARS, TREATED WITH OUR 710 00:28:27,560 --> 00:28:30,440 OWN TUMOR REACTIVE CELLS, 711 00:28:30,440 --> 00:28:32,480 EXPERIENCED COMPLETE REGRESSION 712 00:28:32,480 --> 00:28:34,840 OF ALL HER DISEASE, AND I SHOW 713 00:28:34,840 --> 00:28:38,080 YOUR X-RAY HERE YOU CAN SEE 714 00:28:38,080 --> 00:28:39,680 THESE YELLOW ARROWS POINTING TO 715 00:28:39,680 --> 00:28:41,600 MULTIPLE DEPOSITS, THIS WAS A 716 00:28:41,600 --> 00:28:43,880 LYMPH NODE BLOCKING HER URETER, 717 00:28:43,880 --> 00:28:45,000 UNDERWENT COMPLETE REGRESSION 718 00:28:45,000 --> 00:28:46,280 BUT FIRST YEAR AFTER TREATMENT 719 00:28:46,280 --> 00:28:48,280 WE CAN REMOVE THAT CATHETER AND 720 00:28:48,280 --> 00:28:49,280 AGAIN SHE REMAINS DISEASE FREE 721 00:28:49,280 --> 00:28:53,480 NOW. OVER SEVEN YEARS LATER. 722 00:28:53,480 --> 00:28:55,640 FINALLY A PATIENT WITH A COLON 723 00:28:55,640 --> 00:29:03,040 CANCER, WHO HAD SIGMOID 724 00:29:03,040 --> 00:29:05,680 COLONECTOMY, RECEIVED CHEM 725 00:29:05,680 --> 00:29:06,600 CHEMOTHERAPY, TREATED, SHE HAS 726 00:29:06,600 --> 00:29:08,040 SEVERAL LUNG DEPOSITS 727 00:29:08,040 --> 00:29:10,520 PROGRESSING, SIX OF SEVEN 728 00:29:10,520 --> 00:29:11,160 DISAPPEARED, ONE GREW HOWEVER, 729 00:29:11,160 --> 00:29:13,080 AND WE RESECTED THAT ONE LESION, 730 00:29:13,080 --> 00:29:14,000 LEAVING HER DISEASE FREE AND 731 00:29:14,000 --> 00:29:16,440 SHE'S REMAINED DISEASE FREE NOW 732 00:29:16,440 --> 00:29:18,360 OVER FIVE YEARS AFTER TREATMENT. 733 00:29:18,360 --> 00:29:20,360 THAT ONE LESION WHEN WE LOOK AT 734 00:29:20,360 --> 00:29:22,960 COPY NUMBER OF OUR CHROMOSOMES, 735 00:29:22,960 --> 00:29:24,840 HAD LOST ONE COPY OF CHROMOSOME 736 00:29:24,840 --> 00:29:30,120 6. WHICH ENCODES THE MAJOR 737 00:29:30,120 --> 00:29:31,000 COMPATIBILITY ANTIGENS THAT HAVE 738 00:29:31,000 --> 00:29:32,080 TO PRESENT ANTIGENS TO 739 00:29:32,080 --> 00:29:33,280 LYMPHOCYTES AND THAT EXPLAINS 740 00:29:33,280 --> 00:29:36,200 WHY THAT ONE LESION DIDN'T 741 00:29:36,200 --> 00:29:38,640 RESPOND TO REPRESENTS ESCAPE 742 00:29:38,640 --> 00:29:40,480 MECHANISM POTENTIALLY USED BY 743 00:29:40,480 --> 00:29:44,280 TUMOR TO ESCAPE THIS KIND OF 744 00:29:44,280 --> 00:29:46,520 TREATMENT. WE NOW COMPLETE THREE 745 00:29:46,520 --> 00:29:48,480 SMALL PILOT STUDIES FIRST 746 00:29:48,480 --> 00:29:50,680 LOOKING AT BULK UNSELECTED TIL 747 00:29:50,680 --> 00:29:53,000 FOR TREATMENT, WE SAW NO 748 00:29:53,000 --> 00:29:54,840 RESPONSES. EXCEPT PATIENTS WITH 749 00:29:54,840 --> 00:29:57,040 MEL MONA, ONLY TALKING 750 00:29:57,040 --> 00:29:59,280 EPITHELIAL CANCER. IF WE SELECT 751 00:29:59,280 --> 00:30:01,200 TIL WE ADD THREE OUT OF FIRST 25 752 00:30:01,200 --> 00:30:02,800 PATIENTS RESPOND, 12% WHEN WE 753 00:30:02,800 --> 00:30:07,080 ADDED PEMBROLIZAMAB TO TREATMENT 754 00:30:07,080 --> 00:30:08,360 BECAUSE WE HAD SHOWN SUBMITTED 755 00:30:08,360 --> 00:30:13,640 CELLS INFUSED REEXPRESS PD 1, 756 00:30:13,640 --> 00:30:14,960 THIS CHECK POINT MODULATOR WHEN 757 00:30:14,960 --> 00:30:17,400 WE CAN ELIMINATE THAT, NOW IN 758 00:30:17,400 --> 00:30:18,480 THESE HOYLY PRE-TREATED PATIENTS 759 00:30:18,480 --> 00:30:22,200 SIX OUT OF 26 OR 23% RESPONDED 760 00:30:22,200 --> 00:30:25,680 AND WE ARE NOW RESUMING TO TREAT 761 00:30:25,680 --> 00:30:26,440 OUR STUDIES TO TREAT LARGE 762 00:30:26,440 --> 00:30:29,600 NUMBERS OF PATIENTS WITH THIS 763 00:30:29,600 --> 00:30:31,080 LAST REGIMEN AS WE CONTINUE TO 764 00:30:31,080 --> 00:30:34,720 TRY TO IMPROVE IT. THERE ARE 765 00:30:34,720 --> 00:30:36,560 TWO HYPOTHESES ONE TAKES FROM 766 00:30:36,560 --> 00:30:38,080 THIS WORK. FIRST IT IS A 767 00:30:38,080 --> 00:30:39,960 RECOGNITION OF RANDOM SOMATIC 768 00:30:39,960 --> 00:30:41,160 MUTATIONS WHICH REPRESENTS A 769 00:30:41,160 --> 00:30:43,440 FINAL COMMON PATHWAY THAT 770 00:30:43,440 --> 00:30:44,880 EXPLAINS CANCER REGRESSION FOR 771 00:30:44,880 --> 00:30:47,400 MOST IMMUNOTHERAPIES FOR SOLID 772 00:30:47,400 --> 00:30:49,640 CANCERS, IT IS SHOWN FOR AND PD 773 00:30:49,640 --> 00:30:53,480 1, ANTI-CTLA 4 AS WELL AS TUMOR 774 00:30:53,480 --> 00:30:54,280 INFILTRATING LYMPHOCYTES. 775 00:30:54,280 --> 00:30:57,680 THAT'S GOOD NEWS AND BAD NEWS. 776 00:30:57,680 --> 00:30:59,440 WE HAVE SHOWN ANY INTRACELLULAR 777 00:30:59,440 --> 00:31:01,240 PROTEIN CAN POTENTIALLY BE A 778 00:31:01,240 --> 00:31:03,320 CANCER ANTIGEN IF MUTATED IN 779 00:31:03,320 --> 00:31:05,200 PROCESS INTRACELLULARLY TO A 780 00:31:05,200 --> 00:31:06,680 PEPTIDE THAT CAN BIND TO THAT 781 00:31:06,680 --> 00:31:09,120 PATIENT MHC MOLECULES, THE BAD 782 00:31:09,120 --> 00:31:10,120 NEWS IS TREATMENT THEREFORE HAS 783 00:31:10,120 --> 00:31:13,680 TO BE HIGHLY INDIVIDUALIZED AND 784 00:31:13,680 --> 00:31:15,080 THUS COMPLEX BECAUSE EACH 785 00:31:15,080 --> 00:31:16,960 PATIENT IS RECOGNIZING UNIQUE 786 00:31:16,960 --> 00:31:19,160 ANTIGEN BUT THE GOOD NEWS SINCE 787 00:31:19,160 --> 00:31:21,480 ALL CANCER HAVE MUTATIONS, LARGE 788 00:31:21,480 --> 00:31:23,520 NUMBERS OF CANCER PATIENTS ARE 789 00:31:23,520 --> 00:31:24,800 POTENTIALLY WITH VARIETY OF 790 00:31:24,800 --> 00:31:26,760 HISTOLOGIC TYPES OF CANCER COULD 791 00:31:26,760 --> 00:31:30,680 POTENTIALLY BE ELIGIBLE FOR THIS 792 00:31:30,680 --> 00:31:32,880 TREATMENT. THERE IS ANOTHER 793 00:31:32,880 --> 00:31:34,160 CLASS OF ANTIGENS WE MIGHT LOOK 794 00:31:34,160 --> 00:31:36,680 LIKE IN ADDITION TO THE UNIQUE 795 00:31:36,680 --> 00:31:37,960 MUTATIONS, THAT IS THE TINY 796 00:31:37,960 --> 00:31:39,960 NUMBER OF SHARED DRIVER 797 00:31:39,960 --> 00:31:43,600 ONCOGENES OR TUMOR SUPPRESSER 798 00:31:43,600 --> 00:31:45,480 GENES SHARED AMONG PATIENTS. 799 00:31:45,480 --> 00:31:48,040 KRAS IS AN EXAMPLE OF 30% OF 800 00:31:48,040 --> 00:31:49,960 CANCER, P53 IS PRESENT IN ALMOST 801 00:31:49,960 --> 00:31:51,960 50% OF ALL CANCER, AND BY USING 802 00:31:51,960 --> 00:31:54,960 A SERIES OF INTENSIVE SCREENING 803 00:31:54,960 --> 00:31:58,080 TECHNIQUES AS WELL AS IN VITRO 804 00:31:58,080 --> 00:31:59,400 SENSITIZATION, TWO FELLOWS IN 805 00:31:59,400 --> 00:32:01,080 THE SURGERY BRANCH HAVE NOW BE 806 00:32:01,080 --> 00:32:04,160 ABLE TO IDENTIFY T-CELL 807 00:32:04,160 --> 00:32:06,200 RECEPTOR, FIRST AGAINST RAS HOT 808 00:32:06,200 --> 00:32:09,160 SPOT MUTATIONS, SERIES OF 809 00:32:09,160 --> 00:32:12,520 STUDIES BY NOEM LEVIN WHO 810 00:32:12,520 --> 00:32:16,280 IDENTIFIED T-CELL RECEPTORS THAT 811 00:32:16,280 --> 00:32:17,360 CAN RECOGNIZE SPA VARIETY OF 812 00:32:17,360 --> 00:32:20,400 KRAS RECEPTORS ON A VARIETY OF 813 00:32:20,400 --> 00:32:21,880 RESTRICTION ELEMENTS AS WELL AS 814 00:32:21,880 --> 00:32:23,360 PETER KIM WHO IDENTIFIED A LARGE 815 00:32:23,360 --> 00:32:25,280 NUMBER OF T-CELL RECEPTORS THAT 816 00:32:25,280 --> 00:32:29,720 CAN RECOGNIZE P53 MUTATIONS, IN 817 00:32:29,720 --> 00:32:31,360 PATIENTS, SO THAT POTENTIALLY 818 00:32:31,360 --> 00:32:33,160 THESE T-CELL RECEPTOR CAN BE 819 00:32:33,160 --> 00:32:34,680 USED FOR TREATMENT. WE JUST 820 00:32:34,680 --> 00:32:36,240 STARTED THOSE STUDIES, AND 821 00:32:36,240 --> 00:32:39,560 TREATED A SINGLE PATIENT WITH 822 00:32:39,560 --> 00:32:41,280 BREAST CANCER WHO HAD RECEIVED 823 00:32:41,280 --> 00:32:42,680 MULTIPLE TREATMENT WITH 824 00:32:42,680 --> 00:32:44,840 PROGRESSIVE DISEASE, AS WELL AS 825 00:32:44,840 --> 00:32:50,080 EXTENSIVE DISEASE IN OUR MEDIA 826 00:32:50,080 --> 00:32:51,640 STINUM, FIRST PATIENT TREATED 827 00:32:51,640 --> 00:32:53,480 WITH T-CELL RECEPTORS FROM 828 00:32:53,480 --> 00:32:55,760 DIFFERENT PATIENT THAT RECOGNIZE 829 00:32:55,760 --> 00:32:58,680 P53 MUTATIONS, A DRAMATIC 830 00:32:58,680 --> 00:33:00,840 REGRESSION OF EXTENSIVE DISEASE 831 00:33:00,840 --> 00:33:03,520 SURROUNDING PERICARDIUM, 832 00:33:03,520 --> 00:33:05,000 INVADING INTO BREAST AND 833 00:33:05,000 --> 00:33:06,960 UNDERWENT A DRAMATIC REGRESSION 834 00:33:06,960 --> 00:33:08,640 THAT LASTED SIX MONTHS BEFORE 835 00:33:08,640 --> 00:33:12,560 SHE DID RECUR. HOWEVER, 836 00:33:12,560 --> 00:33:13,760 REPRESENTING PATIENT WHO COULD 837 00:33:13,760 --> 00:33:17,680 BE TREATED BY T-CELL RECEPTOR, 838 00:33:17,680 --> 00:33:18,320 MODIFIED AUTOLOGOUS LYMPHOCYTES. 839 00:33:18,320 --> 00:33:19,680 YOU CAN SEE HERE IN BREAST EVERY 840 00:33:19,680 --> 00:33:21,520 ONE OF THESE IS A CANCER NO 841 00:33:21,520 --> 00:33:24,000 DUAL, A BIG MASS -- NODULE, A 842 00:33:24,000 --> 00:33:25,800 BIG MASS UNDER NECROTIC LESION 843 00:33:25,800 --> 00:33:30,680 THAT WENT AWAY ALMOST COMPLETELY 844 00:33:30,680 --> 00:33:33,440 LASTING SIX MONTHS. SO IN 845 00:33:33,440 --> 00:33:35,480 CONCLUSION I WOULD LIKE TO JUST 846 00:33:35,480 --> 00:33:36,800 EMPHASIZE THAT CELL TRANSFER 847 00:33:36,800 --> 00:33:39,560 THERAPY CAN MEDIATE DURABLE 848 00:33:39,560 --> 00:33:41,120 COMPLETE REGRESSION IN PATIENTS 849 00:33:41,120 --> 00:33:42,560 WITH METASTATIC CANCER 850 00:33:42,560 --> 00:33:44,640 REFRACTORY TO OTHER TREATMENTS. 851 00:33:44,640 --> 00:33:47,160 TIL RECOGNIZE UNIQUE SOMATIC 852 00:33:47,160 --> 00:33:48,720 MUTATIONS CAN BE FOUND IN 853 00:33:48,720 --> 00:33:50,320 PERIPHERAL BLOOD THAT 854 00:33:50,320 --> 00:33:52,120 IDENTIFYING THESE CAN RESULT IN 855 00:33:52,120 --> 00:33:54,280 CANCER REGRESSION AND THAT GENE 856 00:33:54,280 --> 00:33:57,920 SIGNATURES CAN BE GENERATED TO 857 00:33:57,920 --> 00:34:01,160 IDENTIFY ANTI-T-CELL RECEPTORS 858 00:34:01,160 --> 00:34:03,120 THAT RECOGNIZE A CANCER. SURGERY 859 00:34:03,120 --> 00:34:04,600 BRANCH WILL BE MOVING AS JUST 860 00:34:04,600 --> 00:34:06,280 MOVED IN THE PAST MONTH INTO A 861 00:34:06,280 --> 00:34:08,640 NEW FACILITY TO CELL TRANSFER 862 00:34:08,640 --> 00:34:09,720 GENEROUSLY SUPPORTED BY THE 863 00:34:09,720 --> 00:34:12,680 NATIONAL CANCER INSTITUTE. 864 00:34:12,680 --> 00:34:14,200 BEFORE I FINISH I WOULD LIKE TO 865 00:34:14,200 --> 00:34:15,480 THANK DR. ANNA LAU THE NEXT 866 00:34:15,480 --> 00:34:20,520 SPEAKER WHO IS RESPONSIBLE FOR 867 00:34:20,520 --> 00:34:22,080 ALL STERILITY PROCEDURES AND 868 00:34:22,080 --> 00:34:25,360 DEVELOPMENT SO THAT WE COULD 869 00:34:25,360 --> 00:34:27,160 DEVELOP HE CANTIVE GOOD 870 00:34:27,160 --> 00:34:27,960 MANUFACTURING PRODUCT -- 871 00:34:27,960 --> 00:34:29,400 EFFECTIVE GOOD MANUFACTURING 872 00:34:29,400 --> 00:34:30,440 PRODUCT CELLS FOR TREATMENT. MY 873 00:34:30,440 --> 00:34:31,880 THANKS TO DR. LAU FOR HER 874 00:34:31,880 --> 00:34:34,080 EFFORTS IN THIS. THANK YOU, VERY 875 00:34:34,080 --> 00:34:34,960 MUCH FOR YOUR VERY KIND 876 00:34:34,960 --> 00:34:37,160 ATTENTION. 877 00:34:37,160 --> 00:34:38,720 >>HI, THANK YOU SO 878 00:34:38,720 --> 00:34:42,160 MUCH FOR JOINING IN TO TODAY'S 879 00:34:42,160 --> 00:34:43,200 GRAND ROUNDS. IT IS A PLEASURE 880 00:34:43,200 --> 00:34:46,800 TO BE SHARING A STAGE WITH DR. 881 00:34:46,800 --> 00:34:47,760 ROSENBERG, AND HAVE THIS 882 00:34:47,760 --> 00:34:50,800 PLATFORM TO SHOWCASE THE GMP 883 00:34:50,800 --> 00:34:53,280 PROGRAM AVAILABLE AT THE NIH TO 884 00:34:53,280 --> 00:34:53,920 SUPPORT PATIENT CARE 885 00:34:53,920 --> 00:35:00,360 INNOVATIONS. NO DISCLOSURES AND 886 00:35:00,360 --> 00:35:01,960 EVERYTHING I SAY IS MY OWN 887 00:35:01,960 --> 00:35:02,680 OPINION AND NOT THE VIEWS OF 888 00:35:02,680 --> 00:35:06,080 NIH. SO CLEARLY THE INTRAMURAL 889 00:35:06,080 --> 00:35:08,760 PROGRAM AT THE NIH HAS A VERY 890 00:35:08,760 --> 00:35:11,160 LONG HISTORY AND MASSIVE IMPACT 891 00:35:11,160 --> 00:35:12,640 ON GLOBAL PUBLIC HEALTH. MANY 892 00:35:12,640 --> 00:35:15,160 SUCCESS STORIES, THE DISCOVERY 893 00:35:15,160 --> 00:35:18,080 OF NEW DRUGS AND PIONEERING OF 894 00:35:18,080 --> 00:35:21,440 NEW METHODS AS DR. ROSENBERG 895 00:35:21,440 --> 00:35:22,680 EXEMPLIFIED, IMPACT OF HUMAN 896 00:35:22,680 --> 00:35:25,560 HEALTH CANNOT BE UNDERESTIMATED 897 00:35:25,560 --> 00:35:27,400 AND CLEARLY HAVE BEEN MANY 898 00:35:27,400 --> 00:35:29,280 FIRSTS THAT HAVE COME EXACTLY 899 00:35:29,280 --> 00:35:31,360 FROM THIS BETHESDA CAMPUS AND 900 00:35:31,360 --> 00:35:34,520 INTRAMURAL PROGRAM. IN FACT, IN 901 00:35:34,520 --> 00:35:37,400 NATURE ARTICLE PUBLISHED IN 902 00:35:37,400 --> 00:35:38,760 2014, WE CAN SEE HERE IN THIS 903 00:35:38,760 --> 00:35:40,960 FIGURE, THE NUMBER OF 904 00:35:40,960 --> 00:35:43,160 APPLICATIONS OF NEW DRUGS AND 905 00:35:43,160 --> 00:35:46,160 NEW BIOLOGICS THAT THE FDA 906 00:35:46,160 --> 00:35:48,760 APPROVED BETWEEN 1991 AND 2006. 907 00:35:48,760 --> 00:35:52,960 AND WHAT YOU CAN SEE HERE TOTAL 908 00:35:52,960 --> 00:35:54,560 NUMBER OF APPROVED APPLICATIONS 909 00:35:54,560 --> 00:35:57,040 AN BLUE BARS ARE REPRESENTING 910 00:35:57,040 --> 00:35:58,560 THOSE THAT ORIGINATED 911 00:35:58,560 --> 00:36:01,760 SPECIFICALLY FROM THE INTRAMURAL 912 00:36:01,760 --> 00:36:04,760 PROGRAM INVENTIONS AT THE NIH. 913 00:36:04,760 --> 00:36:06,960 SO IF THERE ARE INVESTIGATORS 914 00:36:06,960 --> 00:36:09,040 LISTENING IN ON THIS TALK AND IT 915 00:36:09,040 --> 00:36:12,120 MAY FEEL LIKE OVER THE LAST FEW 916 00:36:12,120 --> 00:36:16,560 YEARS THERE'S BEEN EXTREMELY 917 00:36:16,560 --> 00:36:17,840 CUMBERSOME AND AMOUNT OF 918 00:36:17,840 --> 00:36:19,360 PAPERWORK AND UPHILL BATTLE WITH 919 00:36:19,360 --> 00:36:20,960 REGARDS TO REGULATIONS TO GET 920 00:36:20,960 --> 00:36:23,200 NEW PROTOCOLS UNDERWAY, I FEEL 921 00:36:23,200 --> 00:36:27,160 YOUR PAIN AND I AGREE, IT HAS 922 00:36:27,160 --> 00:36:28,600 QUITE A TIRE SOME PROCESS. 923 00:36:28,600 --> 00:36:30,400 HOWEVER, IT IS IMPORTANT TO 924 00:36:30,400 --> 00:36:32,160 REMEMBER THAT THE REGULATIONS 925 00:36:32,160 --> 00:36:35,480 THAT ACTUALLY ALWAYS EXISTED, 926 00:36:35,480 --> 00:36:37,360 AND IN FACT WHAT HAS CHANGED 927 00:36:37,360 --> 00:36:39,960 OVER THE LAST FEW YEARS IS 928 00:36:39,960 --> 00:36:42,840 LANDSCAPE AND CULTURE THAT THE 929 00:36:42,840 --> 00:36:46,760 NIH ADOPTED IN RESPONSE TO 930 00:36:46,760 --> 00:36:49,160 CERTAIN EVENTS OVER LAST DECADE. 931 00:36:49,160 --> 00:36:50,760 SO IT IS IMPORTANT TO REMEMBER 932 00:36:50,760 --> 00:36:52,760 BIOLOGICS CELL THERAPIES, ET 933 00:36:52,760 --> 00:36:55,200 CETERA, HAVE EMERGED RAPIDLY ON 934 00:36:55,200 --> 00:36:57,480 TO THE SCENE OVER THE LAST 10 TO 935 00:36:57,480 --> 00:36:59,760 20 YEARS. IT IS DIFFICULT FOR 936 00:36:59,760 --> 00:37:02,640 REGULATORY AGENCIES SUCH AS THE 937 00:37:02,640 --> 00:37:05,960 FDA TO KEEP ON PACE WITH THAT. 938 00:37:05,960 --> 00:37:07,880 THERE IS INCREASE AWARENESS ON 939 00:37:07,880 --> 00:37:10,320 THE NIH CAMPUS WITH REGARD TO 940 00:37:10,320 --> 00:37:14,560 THESE REGULATIONS OF GMP, 941 00:37:14,560 --> 00:37:16,240 PARTICULARLY AFTER THE RED TEAM 942 00:37:16,240 --> 00:37:19,080 REPORT WAS RELEASED IN 2016 943 00:37:19,080 --> 00:37:20,560 FOLLOWING TWO HYPERCONTAMINATION 944 00:37:20,560 --> 00:37:24,240 EVENTS IN 2015. THE FDA IS ALSO 945 00:37:24,240 --> 00:37:25,160 CHANGING ITS CURRENT WAY OF 946 00:37:25,160 --> 00:37:27,920 THINKING. SO WHILE THE 947 00:37:27,920 --> 00:37:29,240 REGULATIONS MAY EXIST IN BLACK 948 00:37:29,240 --> 00:37:31,080 AND WHITE, THE FDA'S COMMITTED 949 00:37:31,080 --> 00:37:32,680 TO CHANGE THAT YOU ARE WAY OF 950 00:37:32,680 --> 00:37:34,840 THINKING, AND THAT IS BECAUSE 951 00:37:34,840 --> 00:37:37,240 THERE IS INCREASED LEVEL OF 952 00:37:37,240 --> 00:37:39,360 MANUFACTURING THAT IS NOW DONE 953 00:37:39,360 --> 00:37:41,560 AT ACADEMIC CENTERS WHERE 954 00:37:41,560 --> 00:37:43,200 PREVIOUSLY BEFORE MANY OF THE 955 00:37:43,200 --> 00:37:46,040 FOCUS OF THE FDA WAS ON BIG 956 00:37:46,040 --> 00:37:48,160 PHARMA AND ITS GLOBAL IMPACT ON 957 00:37:48,160 --> 00:37:50,360 PUBLIC HEALTH. CELL AND GENE 958 00:37:50,360 --> 00:37:52,160 THERAPIES NOW CONSIDERED FRONT 959 00:37:52,160 --> 00:37:53,760 LINE TREATMENT FOR MANY DISEASE 960 00:37:53,760 --> 00:37:55,800 STATES. AND ACADEMIC CENTERS ARE 961 00:37:55,800 --> 00:37:58,320 NOW DRAWK FOCUS FROM THE FDA 962 00:37:58,320 --> 00:38:03,920 WITH REGARD TO GMP. THERE HAVE 963 00:38:03,920 --> 00:38:06,480 BEEN THIS PERCEIVED GRAY ZONE 964 00:38:06,480 --> 00:38:09,480 REFERS TO EARLY PHASE STUDIES SO 965 00:38:09,480 --> 00:38:11,440 EXACTLY HOW MUCH GMP MUST BE 966 00:38:11,440 --> 00:38:12,920 APPLIED FOR PHASE 1 AND PHASE 2 967 00:38:12,920 --> 00:38:15,920 STUDIES. SO IT IS A SLIDING 968 00:38:15,920 --> 00:38:19,760 SCALE, OF RISK BENEFIT, AND 969 00:38:19,760 --> 00:38:21,640 RECENTLY LAST YEAR THE FDA 970 00:38:21,640 --> 00:38:23,040 RELEASED A GUIDANCE DOCUMENT FOR 971 00:38:23,040 --> 00:38:26,120 HOW TO ASSESS THAT BENEFIT AND 972 00:38:26,120 --> 00:38:27,480 RISK FOR NEW DRUGS AND 973 00:38:27,480 --> 00:38:29,440 BIOLOGICAL PRODUCTS. SO WHAT I 974 00:38:29,440 --> 00:38:30,880 WOULD LIKE TO DO OVER THE NEXT 975 00:38:30,880 --> 00:38:33,360 20 MINUTES OR SO IS TELL YOU OUR 976 00:38:33,360 --> 00:38:35,560 STORY. FROM A MICROBIOLOGICAL 977 00:38:35,560 --> 00:38:38,040 PERSPECTIVE AND HOW THE GMP 978 00:38:38,040 --> 00:38:39,280 PROGRAM AT THE NIH BEGAN TO 979 00:38:39,280 --> 00:38:39,760 EMERGE. 980 00:38:39,760 --> 00:38:42,520 SO WHAT I'M SHOWING IN THIS 981 00:38:42,520 --> 00:38:45,840 FIGURE HERE IS TAKING FROM A 982 00:38:45,840 --> 00:38:47,720 TECHNICAL REPORT, PHARMACEUTICAL 983 00:38:47,720 --> 00:38:48,640 DRUG ASSOCIATION AND WHAT YOU 984 00:38:48,640 --> 00:38:53,080 CAN SEE HERE IS THE NIH IS VERY 985 00:38:53,080 --> 00:38:54,160 GOOD SUCH AS RESEARCH 986 00:38:54,160 --> 00:38:55,400 DEVELOPMENT AND PRE-CLINICAL 987 00:38:55,400 --> 00:38:56,960 STUDIES WHICH GOOD DOCUMENTATION 988 00:38:56,960 --> 00:38:59,320 PRACTICES, GOOD LABORATORY 989 00:38:59,320 --> 00:39:01,160 PRACTICE, ARE ALL THAT IS 990 00:39:01,160 --> 00:39:04,000 REQUIRED. CALIBRATED EQUIPMENT 991 00:39:04,000 --> 00:39:06,000 AND QUALIFIED TESTING METHODS. 992 00:39:06,000 --> 00:39:09,040 HOWEVER AS WE START TO MOVE 993 00:39:09,040 --> 00:39:10,480 TOWARDS CLINICAL TRIALS STARTING 994 00:39:10,480 --> 00:39:12,480 AT PHASE 1 AND 2, THERE IS 995 00:39:12,480 --> 00:39:16,160 EXPECTATION BY THE FDA THAT GMP 996 00:39:16,160 --> 00:39:17,160 PRACTICES ARE STARTING TO BE 997 00:39:17,160 --> 00:39:18,960 APPLIED AND IN FACT THOSE 998 00:39:18,960 --> 00:39:21,160 EXPECTATIONS START TO INCREASE, 999 00:39:21,160 --> 00:39:23,160 AS THE PHASE OF THE STUDY 1000 00:39:23,160 --> 00:39:24,600 INCREASE INTO PRODUCT 1001 00:39:24,600 --> 00:39:27,960 COMMERCIALIZATION. AS PART OF 1002 00:39:27,960 --> 00:39:29,960 THE GMP PROCESS REQUIRES USE OF 1003 00:39:29,960 --> 00:39:31,800 QUALIFIED VALIDATED EQUIPMENT, 1004 00:39:31,800 --> 00:39:34,280 VALIDATED TESTING METHODS, AS 1005 00:39:34,280 --> 00:39:36,040 WELL AS MICROBIAL CONTROLS TO 1006 00:39:36,040 --> 00:39:38,800 LOOK FOR CONTAMINATION. AS I 1007 00:39:38,800 --> 00:39:41,160 SAID WE WILL FOCUS ONLY ON THE 1008 00:39:41,160 --> 00:39:43,160 MICROBIOLOGICAL PORTION OF THAT. 1009 00:39:43,160 --> 00:39:46,240 SO CLEARLY STERILITY ASSURANCE 1010 00:39:46,240 --> 00:39:47,920 IS OBVIOUS, AND THE REGULATION 1011 00:39:47,920 --> 00:39:49,400 FOR THAT HAVE EXISTED FOR A 1012 00:39:49,400 --> 00:39:51,560 VERY, VERY LONG TIME AND WHAT I 1013 00:39:51,560 --> 00:39:53,760 AM SHOWING HERE IS A SHIP PET 1014 00:39:53,760 --> 00:39:55,160 FROM THE CODE OF FEDERAL 1015 00:39:55,160 --> 00:39:56,960 REGULATIONS ABOUT 6, 10, 12, ITS 1016 00:39:56,960 --> 00:39:59,000 TALKS ABOUT STERILITY TESTING. 1017 00:39:59,000 --> 00:40:01,600 CLEARLY THE POINTS OF STERILITY 1018 00:40:01,600 --> 00:40:03,000 TESTING IS TO ENSURE THE PRODUCT 1019 00:40:03,000 --> 00:40:04,760 IS SAFE FOR HUMAN USE, WE WANTS 1020 00:40:04,760 --> 00:40:07,360 TO MAKE SURE THERE IS AN ABSENCE 1021 00:40:07,360 --> 00:40:09,560 OF VIABLE MICROORGANISMS USING A 1022 00:40:09,560 --> 00:40:11,880 VALIDATED TEST METHOD. HOWEVER 1023 00:40:11,880 --> 00:40:13,240 THERE ARE SOME ISSUES THAT 1024 00:40:13,240 --> 00:40:15,440 SURROUND THE TYPE OF TESTS THAT 1025 00:40:15,440 --> 00:40:18,360 THE FDA CURRENTLY REFERS TO AS 1026 00:40:18,360 --> 00:40:19,760 THE COME PENDIAL OR GOLD 1027 00:40:19,760 --> 00:40:23,320 STANDARD TEST. THE TEST LISTED 1028 00:40:23,320 --> 00:40:24,280 HERE FORESTER RILLTY IN 1029 00:40:24,280 --> 00:40:26,720 MICROPLASM THEY DEVELOP BACK 1030 00:40:26,720 --> 00:40:28,480 MANY THE 1930s. THEY ARE 1031 00:40:28,480 --> 00:40:31,200 EXTREMELY OLD SCHOOL, AND 1032 00:40:31,200 --> 00:40:33,200 ADOPTION OF MORE MODERN METHODS 1033 00:40:33,200 --> 00:40:36,160 MAKES IT A LITTLE DAUNTING FOR 1034 00:40:36,160 --> 00:40:38,880 MOST LABORATORIES GIVEN THE 1035 00:40:38,880 --> 00:40:40,240 VALIDATION WORK REQUIRED. 1036 00:40:40,240 --> 00:40:41,520 HOWEVER ADOPTION OF THESE GOLD 1037 00:40:41,520 --> 00:40:44,760 STANDARD METHODS FOR TESTING OF 1038 00:40:44,760 --> 00:40:48,000 BIOLOGIC IS FLAWED. THESE 1039 00:40:48,000 --> 00:40:52,440 STERILITY TESTING METHODS WERE 1040 00:40:52,440 --> 00:40:53,360 DEVELOPED ON STERILE DRUG 1041 00:40:53,360 --> 00:40:54,920 PRODUCTS NOT FOR BIOLOGICS SO 1042 00:40:54,920 --> 00:40:57,440 THEY DEVELOP ORIGINALLY FOR DRUG 1043 00:40:57,440 --> 00:40:58,800 PRODUCTS THAT COULD BE 1044 00:40:58,800 --> 00:41:00,560 TERMINALLY STERILIZED. THEY 1045 00:41:00,560 --> 00:41:02,920 ALSO HAVE AN EXTREMELY SLOW TURN 1046 00:41:02,920 --> 00:41:05,240 AROUND TIME OF 14 TO 28 DAYS 1047 00:41:05,240 --> 00:41:09,640 CULTURE AND THIS CLEARLY IS NOT 1048 00:41:09,640 --> 00:41:10,800 CONDUCIVE TO FRESH PRODUCT FOR 1049 00:41:10,800 --> 00:41:12,440 INFUSION AND CELL THERAPIES THAT 1050 00:41:12,440 --> 00:41:14,240 HAVE A SHORT SHELF LIFE FOR CELL 1051 00:41:14,240 --> 00:41:17,480 VIABILITY. WE ALSO RUN INTO THE 1052 00:41:17,480 --> 00:41:19,960 ISSUE OF TEST INTERFERENCE 1053 00:41:19,960 --> 00:41:24,160 CAUSED BY THE BIOLOGICAL BECAUSE 1054 00:41:24,160 --> 00:41:26,560 OF NATURAL CELL AVIDITY SO THERE 1055 00:41:26,560 --> 00:41:29,560 IS A VERY LONG HISTORY OF 1056 00:41:29,560 --> 00:41:32,320 STERILITY TESTING AT NIH. FIRST 1057 00:41:32,320 --> 00:41:34,360 AND FOREMOST TESTING IS 1058 00:41:34,360 --> 00:41:36,560 CONDUCTED IN THE CLINICAL 1059 00:41:36,560 --> 00:41:38,400 LABORATORY WITHIN DLM STARTING 1060 00:41:38,400 --> 00:41:40,840 BACK IN IN 1980s AND 1990s 1061 00:41:40,840 --> 00:41:43,640 WERE FIRST IN HUMAN TRIALS 1062 00:41:43,640 --> 00:41:44,720 STARTED, CLINICAL MICRODIRECTOR 1063 00:41:44,720 --> 00:41:46,360 AT THE THAT TIME AGREED TO DO 1064 00:41:46,360 --> 00:41:49,160 STERILITY TESTING FOR THESE 1065 00:41:49,160 --> 00:41:52,120 PRODUCTS, USING OLD SCHOOL GOLD 1066 00:41:52,120 --> 00:41:53,560 STANDARD METHOD EXTREMELY 1067 00:41:53,560 --> 00:41:55,440 TEDIOUS, LABOR INTENSIVE AND 1068 00:41:55,440 --> 00:41:59,240 VERY SLOW. FORTUNATELY THEN IN 1069 00:41:59,240 --> 00:42:01,960 THE EARLY 2000s THERE WAS A 1070 00:42:01,960 --> 00:42:03,280 CHANGE IN THE CLINICAL 1071 00:42:03,280 --> 00:42:05,880 MICRODIRECTOR AND HE APPLIED A 1072 00:42:05,880 --> 00:42:06,600 VERY INNOVATIVE APPROACH WHICH 1073 00:42:06,600 --> 00:42:10,400 IS TO USE AUTOMATED BLOOD 1074 00:42:10,400 --> 00:42:14,080 CULTURE SYSTEMS THAT WE USE FOR 1075 00:42:14,080 --> 00:42:15,720 PATIENT CARE, AND TO USE THAT 1076 00:42:15,720 --> 00:42:18,240 INSTEAD FOR PRODUCT STERILITY 1077 00:42:18,240 --> 00:42:19,480 TESTING. MAKING THE ENTIRE 1078 00:42:19,480 --> 00:42:21,120 PROCESS AUTOMATE AND LESS 1079 00:42:21,120 --> 00:42:25,360 ONEROUS ON THE LAB IRTO. THESE 1080 00:42:25,360 --> 00:42:27,320 HERE TWO PAPERS PUBLISHED IN 1081 00:42:27,320 --> 00:42:29,520 COLLABORATION OF LABORATORY 1082 00:42:29,520 --> 00:42:30,720 MEDICINE AND TRANSFUSION MEDS 1083 00:42:30,720 --> 00:42:33,120 SIN AT THAT TIME IN THE EARLY 1084 00:42:33,120 --> 00:42:34,360 2000s AND THESE ARE THE 1085 00:42:34,360 --> 00:42:37,840 FOUNDATIONAL STUDIES, THAT WERE 1086 00:42:37,840 --> 00:42:40,200 ACCEPTD BY THE FDA FOR 15 YEARS 1087 00:42:40,200 --> 00:42:42,160 OR SO THAT SHOWED THAT THE 1088 00:42:42,160 --> 00:42:44,720 AUTOMATED BLOOD CULTURE SYSTEMS, 1089 00:42:44,720 --> 00:42:48,360 WERE EQUIVALENT METHOD TO THE 1090 00:42:48,360 --> 00:42:50,560 TRADITIONAL TESTING METHOD AND 1091 00:42:50,560 --> 00:42:51,680 COMPLIANT TO MEET THE FDA 1092 00:42:51,680 --> 00:42:54,720 STANDARDS. SO ESSENTIALLY 1093 00:42:54,720 --> 00:42:57,400 PRODUCT STERILITY TESTING WHAT 1094 00:42:57,400 --> 00:42:58,480 HAPPENING IN CLIP MICRO USING 1095 00:42:58,480 --> 00:42:59,840 THE BLOOD CULTURE SYSTEM FOR 1096 00:42:59,840 --> 00:43:01,080 MANY YEARS WITH NO DEDICATED 1097 00:43:01,080 --> 00:43:06,760 FACULTY OVERSIGHT. THEN IN 2015 1098 00:43:06,760 --> 00:43:08,560 THE PROGRAM STARTS. THIS IS 1099 00:43:08,560 --> 00:43:09,720 BECAUSE OF THE FIRST 1100 00:43:09,720 --> 00:43:10,560 CONTAMINATION EVENT WHICH 1101 00:43:10,560 --> 00:43:15,200 OCCURRED IN APRIL, TWO VIALS OF 1102 00:43:15,200 --> 00:43:18,000 ALBUMIN, IN THE CLINICAL CENTER 1103 00:43:18,000 --> 00:43:20,480 PHARMACY. FOUND TO BE GROSSLY 1104 00:43:20,480 --> 00:43:21,240 CONTAMINATED WITH TWO DIFFERENT 1105 00:43:21,240 --> 00:43:24,880 SPECIES OF MOLD. THERE WAS A 1106 00:43:24,880 --> 00:43:26,920 FOUR INSPECTION BY THE FDA SPENT 1107 00:43:26,920 --> 00:43:28,720 SEVERAL DAYS ON CAMPUS, THEY 1108 00:43:28,720 --> 00:43:30,160 ISSUED A FORM 483 WHICH IS 1109 00:43:30,160 --> 00:43:32,280 ESSENTIALLY A LIST OF 1110 00:43:32,280 --> 00:43:33,360 OBSERVATIONS, AND HOSPITAL 1111 00:43:33,360 --> 00:43:34,200 PHARMACY WAS SHUT DOWN AT THAT 1112 00:43:34,200 --> 00:43:39,920 TIME. THESE CLOSELY FORWARDS A 1113 00:43:39,920 --> 00:43:42,880 FEW MONTHS LATER WITH SECOND CON 1114 00:43:42,880 --> 00:43:43,480 TAME NATION EVENT AND IN THIS 1115 00:43:43,480 --> 00:43:45,640 PARTICULAR CASE IT WAS A NATURAL 1116 00:43:45,640 --> 00:43:47,760 KILLER CELL PRODUCT SENT DOWN TO 1117 00:43:47,760 --> 00:43:51,480 THE MICROLAB, FOR US TO PERFORM 1118 00:43:51,480 --> 00:43:53,800 A GRAM STAIN AS PART OF 1119 00:43:53,800 --> 00:43:54,680 MICROMICROBIAL RELEASE PRODUCTS 1120 00:43:54,680 --> 00:43:57,960 TO THE PATIENT AND WHAT WE SAW 1121 00:43:57,960 --> 00:44:03,240 ON THE GRAM STAIN WAS WE WENT TO 1122 00:44:03,240 --> 00:44:05,080 THE ARABIC BOTTLE INCUBATING IN 1123 00:44:05,080 --> 00:44:06,360 THE INSTRUMENT AT THAT TIME AND 1124 00:44:06,360 --> 00:44:09,920 THERE WAS CLEARLY GROSS CON PAM 1125 00:44:09,920 --> 00:44:10,840 NATION OF MOLD THAT WAS VISIBLE 1126 00:44:10,840 --> 00:44:13,960 TO THE NAKED EYE, ACROSS 1127 00:44:13,960 --> 00:44:14,800 MULTIPLE BOTTLES OF THAT 1128 00:44:14,800 --> 00:44:18,080 PRODUCT. THAT WENT UNDETECTED BY 1129 00:44:18,080 --> 00:44:20,160 THE INSTRUMENTS SO THE 1130 00:44:20,160 --> 00:44:20,960 INSTRUMENT FAILED TO FLAG BEING 1131 00:44:20,960 --> 00:44:25,240 POSITIVE. THIS THEN WAS CLOSELY 1132 00:44:25,240 --> 00:44:26,960 FOLLOWED BY THE RED TEAM REPORT 1133 00:44:26,960 --> 00:44:29,240 WHICH WAS A REVIEW OF REDUCING 1134 00:44:29,240 --> 00:44:32,320 RISK AND PROMOTING PATIENT 1135 00:44:32,320 --> 00:44:35,840 SAFETY ACROSS THE ENTIRE NIH 1136 00:44:35,840 --> 00:44:37,160 INTRAMURAL PROGRAM, THEN CLEARLY 1137 00:44:37,160 --> 00:44:38,960 MANY SAFETY LESSONS LEARNED IN 1138 00:44:38,960 --> 00:44:42,240 THE CLINICAL CENTER. FROM A 1139 00:44:42,240 --> 00:44:43,160 MICROBIOLOGICAL PERSPECTIVE WHAT 1140 00:44:43,160 --> 00:44:44,760 DID WE DO IN LAB MEDICINE TO 1141 00:44:44,760 --> 00:44:47,240 REACT TO THESE FINDINGS? AS WE 1142 00:44:47,240 --> 00:44:49,360 STARTED RESEARCHING THE 1143 00:44:49,360 --> 00:44:51,160 REGULATIONS IT BECAME APPARENT 1144 00:44:51,160 --> 00:44:53,320 TO US THAT THE FDA EXPECTS THAT 1145 00:44:53,320 --> 00:44:56,240 THE TESTING LABORATORY SHOULD 1146 00:44:56,240 --> 00:44:57,360 EMPLOY FACILITIES AND CONTROLS 1147 00:44:57,360 --> 00:45:00,760 THAT WILL COMPARABLE TO THE USED 1148 00:45:00,760 --> 00:45:01,960 IN ASEPTIC OPERATIONS OR 1149 00:45:01,960 --> 00:45:03,520 MANUFACTURING AND CLEARLY A 1150 00:45:03,520 --> 00:45:06,040 CLINICAL DIAGNOSTIC LAB IS NOT 1151 00:45:06,040 --> 00:45:12,760 THE SAME AS A GMP LABORATORY. SO 1152 00:45:12,760 --> 00:45:14,280 CREATION OF MY LABORATORY 1153 00:45:14,280 --> 00:45:17,120 STERILITY TESTING SERVICE IN 1154 00:45:17,120 --> 00:45:19,160 2018, WHERE OUR GOAL WAS TO 1155 00:45:19,160 --> 00:45:21,880 CREATE A BRAND NEW GMP TESTING 1156 00:45:21,880 --> 00:45:24,880 LAB WHICH SERVES AS THE CORE 1157 00:45:24,880 --> 00:45:26,480 MICROBIOLOGY SUPPORT LAB FOR 1158 00:45:26,480 --> 00:45:27,800 INTRAMURAL PROGRAM, THIS IS 1159 00:45:27,800 --> 00:45:29,160 BUILDING ON NEW SYSTEMS 1160 00:45:29,160 --> 00:45:30,520 OPERATIONS FACILITIES, 1161 00:45:30,520 --> 00:45:32,280 PERSONNELS, ALL BUILDING FROM 1162 00:45:32,280 --> 00:45:34,360 THE GROUND UP WITH A CHALLENGE 1163 00:45:34,360 --> 00:45:37,440 BEING TO BUILD THAT UP, AND 1164 00:45:37,440 --> 00:45:39,960 REACH GMP COMPLIANCE ALL WHILE 1165 00:45:39,960 --> 00:45:43,160 MAINTAINING OPERATIONS AS THE 1166 00:45:43,160 --> 00:45:44,000 CLINICAL CENTER WAS STILL 1167 00:45:44,000 --> 00:45:44,920 ACCEPTING PATIENTS AT THAT TIME 1168 00:45:44,920 --> 00:45:48,640 FOR THESE INNOVATIVE THERAPIES. 1169 00:45:48,640 --> 00:45:51,160 SO SOME OF YOU MAY BE CURIOUS 1170 00:45:51,160 --> 00:45:52,840 ABOUT WHAT HAPPENED BETWEEN 2015 1171 00:45:52,840 --> 00:45:55,320 AND 2018, CLEARLY KNEW WE HAD 1172 00:45:55,320 --> 00:45:56,600 FLAWED TESTING SYSTEM THAT WAS 1173 00:45:56,600 --> 00:45:59,640 BEING OPERATED THROUGH IN DLM. 1174 00:45:59,640 --> 00:46:02,640 SO WE APPLIED CLINICAL 1175 00:46:02,640 --> 00:46:03,560 MICROKNOWLEDGE WHERE WE KNOW 1176 00:46:03,560 --> 00:46:06,680 THAT THE BLOOD CULTURE SYSTEMS 1177 00:46:06,680 --> 00:46:08,240 ARE POOR, FOR DETECTION OF MODEL 1178 00:46:08,240 --> 00:46:12,600 AND IF YOU ARE LOOKING FOR FUNGI 1179 00:46:12,600 --> 00:46:16,880 IN A PATIENT WE SENDS FUNGAL 1180 00:46:16,880 --> 00:46:18,920 CULTURE RATHER THAN BOTTLES. WE 1181 00:46:18,920 --> 00:46:20,680 ADDED A SOLID MEDIA CULTURE TO 1182 00:46:20,680 --> 00:46:23,280 INCREASE SENSITIVITY FOR FUNGAL 1183 00:46:23,280 --> 00:46:24,880 CONTAMINANTS. HOWEVER THE 1184 00:46:24,880 --> 00:46:26,200 PROBLEM EXISTED THAT TESTING WAS 1185 00:46:26,200 --> 00:46:27,400 BEING PROCESSED IN THE CLINICAL 1186 00:46:27,400 --> 00:46:30,800 LABORATORY AND NOT IN A GMP 1187 00:46:30,800 --> 00:46:32,120 SPACE. THESE CLEARLY THEN 1188 00:46:32,120 --> 00:46:34,800 INCREASE RISK OF CONTAMINATION, 1189 00:46:34,800 --> 00:46:36,800 AND BETWEEN A SIX YEAR PERIODS 1190 00:46:36,800 --> 00:46:39,280 WE HAD 54 POSITIVE FUNGAL 1191 00:46:39,280 --> 00:46:42,920 CULTURES A PERCENTAGE CONSIDERED 1192 00:46:42,920 --> 00:46:45,760 LABORATORY CONTAMINANTS TO POOR 1193 00:46:45,760 --> 00:46:46,320 LABORATORY LAND MANAGELING 1194 00:46:46,320 --> 00:46:48,160 BECAUSE WE WERE IN UNCONTROLLED 1195 00:46:48,160 --> 00:46:51,960 NON-GMP ENVIRONMENT. IN A STUDY 1196 00:46:51,960 --> 00:46:54,520 IN COLLABORATION BETWEEN DLM AND 1197 00:46:54,520 --> 00:46:56,360 THE CENTER FOR ENGINEERING, THE 1198 00:46:56,360 --> 00:46:58,640 GROUP LOOKED AT A ONE YEAR 1199 00:46:58,640 --> 00:47:04,080 REVIEW OF POSITIVE STERILITY FOR 1200 00:47:04,080 --> 00:47:04,720 CELL MANUFACTURING AND WHAT YOU 1201 00:47:04,720 --> 00:47:07,960 CAN SEE HERE IS THERE WERE 13 1202 00:47:07,960 --> 00:47:09,560 POSITIVES OF WHICH EIGHT OF 1203 00:47:09,560 --> 00:47:12,880 THOSE 13 WERE CONTRIBUTED TO 1204 00:47:12,880 --> 00:47:14,680 POSSIBLE OR PROBABLE LABORATORY 1205 00:47:14,680 --> 00:47:15,800 CONTAMINANTS. THESE CULTURES 1206 00:47:15,800 --> 00:47:17,400 PERFORMED IN A CLINICAL SETTING 1207 00:47:17,400 --> 00:47:20,720 NOT IN GMP BUT THIS LEADS TO 1208 00:47:20,720 --> 00:47:22,360 CHALLENGING TIME CONSUMING RISK 1209 00:47:22,360 --> 00:47:23,200 ASSESSMENT TO WHETHER THE 1210 00:47:23,200 --> 00:47:26,000 PRODUCT IS SAFE OR NOT, WHEN YOU 1211 00:47:26,000 --> 00:47:28,560 HAVE CLEARLY A TERMINALLY ILL 1212 00:47:28,560 --> 00:47:30,160 PATIENT WHO MAY BENEFIT 1213 00:47:30,160 --> 00:47:31,520 SIGNIFICANTLY FROM RECEIVING A 1214 00:47:31,520 --> 00:47:34,200 TREATMENT. MAYBE DUE TO A FALSE 1215 00:47:34,200 --> 00:47:36,560 POSITIVE STERILITY TEST. THIS 1216 00:47:36,560 --> 00:47:41,880 LED TO A LARGE STUDY CONDUCTED 1217 00:47:41,880 --> 00:47:44,600 BY ONE OUR CLINICAL MICROFELLOWS 1218 00:47:44,600 --> 00:47:46,560 TO RE-EVALUATE THE BLOOD CULTURE 1219 00:47:46,560 --> 00:47:47,520 SYSTEMS BEING APPLIED AT THE 1220 00:47:47,520 --> 00:47:54,080 NIH. SO THIS WAS A LARGE STUDY 1221 00:47:54,080 --> 00:47:56,800 LARGEST THE DATE, AND WHEN YOU 1222 00:47:56,800 --> 00:48:00,480 LOOK AT STUDY RESULTS IF WE 1223 00:48:00,480 --> 00:48:02,400 NARROW TESTING TO THE GOLD 1224 00:48:02,400 --> 00:48:03,960 STANDARD METHOD AND TWO 1225 00:48:03,960 --> 00:48:06,360 AUTOMATED BLOOD CULTURE SYSTEMS 1226 00:48:06,360 --> 00:48:10,120 LOOKING ONLY AT SIX QC ORGANISM, 1227 00:48:10,120 --> 00:48:12,520 THE MINIMUM REQUIREMENT THE FDA 1228 00:48:12,520 --> 00:48:15,040 EXPECTS, WE SEE 100% DETECTION 1229 00:48:15,040 --> 00:48:17,080 ACROSS THE BOARDS AND IT GIVES A 1230 00:48:17,080 --> 00:48:18,800 FALSE SENSE OF SECURITY WHAT WE 1231 00:48:18,800 --> 00:48:20,240 WERE DOING WAS ABSOLUTELY FINE 1232 00:48:20,240 --> 00:48:21,960 BUT WE KNOW IN REALITY WE HAVE 1233 00:48:21,960 --> 00:48:25,400 PROBLEMS. IF THE ORGANISM TEST 1234 00:48:25,400 --> 00:48:28,760 SET WAS EXPANDED TO 118 1235 00:48:28,760 --> 00:48:30,480 ORGANISMS AND WE EXTEND 1236 00:48:30,480 --> 00:48:32,160 INCUBATION TO 14 DAYS YOU CAN 1237 00:48:32,160 --> 00:48:35,400 SEE IN THE GRAY BAR REPRESENTED 1238 00:48:35,400 --> 00:48:36,840 AT THE BACK TECH SYSTEM WHICH 1239 00:48:36,840 --> 00:48:40,720 WAS THE SYSTEM THAT FAILED TO 1240 00:48:40,720 --> 00:48:43,360 DETECT MOLD CONTAMINANTS IN THE 1241 00:48:43,360 --> 00:48:44,960 PRODUCT IN 2015. YOU CAN SEE THE 1242 00:48:44,960 --> 00:48:46,480 GRAY BARLOWER THAN THE GOLD 1243 00:48:46,480 --> 00:48:48,400 STANDARD AND ALSO LOWER THAN ITS 1244 00:48:48,400 --> 00:48:51,960 ALTERNATIVE METHOD HERE. 1245 00:48:51,960 --> 00:48:55,160 CLEARLY DETECTION OF FUNGI 1246 00:48:55,160 --> 00:48:58,360 CONTINUES TO BE PROBLEM MORE 1247 00:48:58,360 --> 00:48:59,400 IMAGES OF MOLD BALLS THAT FAILED 1248 00:48:59,400 --> 00:49:01,360 TO BE DECKED BY INSTRUMENT 1249 00:49:01,360 --> 00:49:03,080 THOUGH VISIBLE TO NAKED EYE AND 1250 00:49:03,080 --> 00:49:08,800 CLEARLY IF WE ADD ON THE MANUAL 1251 00:49:08,800 --> 00:49:10,320 FUNGAL CULTURE WE HAVE 100% 1252 00:49:10,320 --> 00:49:11,760 SENSITIVITY FOR DETECTING THE 1253 00:49:11,760 --> 00:49:13,760 CAN CONTAMINANTS SUPERIOR TO 1254 00:49:13,760 --> 00:49:14,720 THAT OF THE GOLD STANDARDS 1255 00:49:14,720 --> 00:49:17,600 METHOD. SO THIS REALLY LED TO A 1256 00:49:17,600 --> 00:49:19,760 REBACK OF THE ENTIRE STERILITY 1257 00:49:19,760 --> 00:49:21,080 TESTING PROGRAM OFFERED AT THE 1258 00:49:21,080 --> 00:49:22,600 NIH. WHAT YOU CAN SEE IN THE 1259 00:49:22,600 --> 00:49:24,720 BLUE BAR ARE RESULTS OF A GOLD 1260 00:49:24,720 --> 00:49:26,280 STANDARD METHOD AS OPPOSED TO 1261 00:49:26,280 --> 00:49:28,080 THE ALTERNATIVE METHOD THAT WAS 1262 00:49:28,080 --> 00:49:31,040 NOW OFFERED STARTING BACK IN 1263 00:49:31,040 --> 00:49:32,960 2019. HOWEVER WE STILL HAVE THE 1264 00:49:32,960 --> 00:49:36,320 SAME ISSUE OF PRODUCT BEING 1265 00:49:36,320 --> 00:49:37,840 MANIPULATED IN THE LABORATORY IN 1266 00:49:37,840 --> 00:49:40,480 TERMS OF THE ADDITIONAL FUNGAL 1267 00:49:40,480 --> 00:49:42,160 CULTURE. SO THEN THIS LED TO 1268 00:49:42,160 --> 00:49:46,240 ANOTHER STUDY CONDUCTED BY ANY 1269 00:49:46,240 --> 00:49:47,120 KY PUTNAM, ONE OF OUR 1270 00:49:47,120 --> 00:49:51,480 MICROFELLOWS LAST YEAR WHERE SHE 1271 00:49:51,480 --> 00:49:53,200 EVALUATED A NEW TYPE OF MEDIA 1272 00:49:53,200 --> 00:49:55,240 CALLED ILYM, ORIGINAL HI 1273 00:49:55,240 --> 00:49:56,480 MARKETED FOR THE FOOD AND 1274 00:49:56,480 --> 00:50:00,000 BEVERAGE INDUSTRY TO LOOK FOR 1275 00:50:00,000 --> 00:50:02,160 CONTAMINANTS IN THINGS LIKE CANS 1276 00:50:02,160 --> 00:50:03,320 TOMATOES B, ORANGE JUICE, EGG, 1277 00:50:03,320 --> 00:50:05,800 WHAT SHE FOUND WAS POTENTIAL 1278 00:50:05,800 --> 00:50:10,120 SOLUTION, TO MINIMIZE LABORATORY 1279 00:50:10,120 --> 00:50:12,400 HANDLING OF PRODUCTS WHICH IS A 1280 00:50:12,400 --> 00:50:15,360 LOW RISK CLOSE SYSTEM MODEL TO 1281 00:50:15,360 --> 00:50:17,160 IMPROVE FUNGAL CONTAMINATION. SO 1282 00:50:17,160 --> 00:50:18,600 ESSENTIALLY THIS IS THE SUMMARY 1283 00:50:18,600 --> 00:50:20,200 OF HER RESULTS HERE, AND WHAT 1284 00:50:20,200 --> 00:50:23,760 YOU CAN SEE GOING DOWN THE Y ACT 1285 00:50:23,760 --> 00:50:26,480 SEIZE IS 51 DIFFERENT FUNGAL 1286 00:50:26,480 --> 00:50:27,800 ISOLATES AND ACROSS THE TOP ON 1287 00:50:27,800 --> 00:50:29,560 THE X ARE JUST DIFFERENT CULTURE 1288 00:50:29,560 --> 00:50:31,160 CONDITIONS. SO DIFFERENT MEDIA, 1289 00:50:31,160 --> 00:50:33,440 DIFFERENT INCUBATION, 1290 00:50:33,440 --> 00:50:36,440 TEMPERATURES. WHAT YOU CAN 1291 00:50:36,440 --> 00:50:39,280 APPRECIATE IS THAT ALONG COLUMNS 1292 00:50:39,280 --> 00:50:42,800 ON THE RIGHT HAND SIDE OF THE 1293 00:50:42,800 --> 00:50:44,960 HEAT MAP YOU SEE RED BARS SO 1294 00:50:44,960 --> 00:50:46,400 BEHOLD DOESN'T LIKE TO GROW AT 1295 00:50:46,400 --> 00:50:47,800 HIGH TEMPERATURE AND THESE 1296 00:50:47,800 --> 00:50:49,560 SYSTEMS FAIL TO DETECT HIGH 1297 00:50:49,560 --> 00:50:52,360 PERCENTAGE OF FUNGI. AS WE MOVE 1298 00:50:52,360 --> 00:50:55,280 TOWARDS AUTOMATED SYSTEMS AT A 1299 00:50:55,280 --> 00:50:57,360 LOWER TEMPERATURE IT PERFORMS 1300 00:50:57,360 --> 00:51:00,040 MODERATELY BETTER BUT STILL HAS 1301 00:51:00,040 --> 00:51:01,840 SOME ISSUES AND CLEARLY AGAIN 1302 00:51:01,840 --> 00:51:05,560 THE MANUAL CULTURE HAS ALL GREEN 1303 00:51:05,560 --> 00:51:06,800 FOR EXCELLENT DETECTION, THE 1304 00:51:06,800 --> 00:51:08,520 GOLD STANDARD METHOD IS MOSTLY 1305 00:51:08,520 --> 00:51:10,560 GREEN, FAILING TO DETECT ONLY 1306 00:51:10,560 --> 00:51:12,560 TWO ORGANISMS. SO WIDE 1307 00:51:12,560 --> 00:51:13,960 VARIABILITY ACROSS ICE RATES IN 1308 00:51:13,960 --> 00:51:16,360 CULTURE CONDITIONS. HOWEVER, 1309 00:51:16,360 --> 00:51:18,560 WHAT NIKKI WAS ABLE TO FIND WAS 1310 00:51:18,560 --> 00:51:21,920 IF SHE COMBINED THE RESULTS OF 1311 00:51:21,920 --> 00:51:24,040 TWO DIFFERENT AUTOMATED METHODS 1312 00:51:24,040 --> 00:51:28,080 AND MEDIA, WE WERE ABLE TO 1313 00:51:28,080 --> 00:51:32,000 ACHIEVE A SENSITIVITY THAT WAS 1314 00:51:32,000 --> 00:51:34,400 NOT SIGNIFICANTLY INFERIOR TO 1315 00:51:34,400 --> 00:51:38,160 THE GOLD STANDARD. SO THIS 1316 00:51:38,160 --> 00:51:40,400 PROVIDES AN OPTION OR 1317 00:51:40,400 --> 00:51:42,560 POTENTIALLY CLOSE SYSTEM MODEL 1318 00:51:42,560 --> 00:51:44,920 THAT IMPROVES FUNGAL DETECTION 1319 00:51:44,920 --> 00:51:47,360 BEYONDS WHAT WAS ORIGINALLY 1320 00:51:47,360 --> 00:51:50,000 OFFERED AT THE NIH SO IT IS AN 1321 00:51:50,000 --> 00:51:51,000 EXCITING AREA TO EXPLORE 1322 00:51:51,000 --> 00:51:52,760 FURTHER. SO CLEARLY LESS SONS 1323 00:51:52,760 --> 00:51:56,800 LEARNED FROM THE MICROBIOLOGICAL 1324 00:51:56,800 --> 00:51:57,880 PERSPECTIVE IS CLINICAL IS NOT 1325 00:51:57,880 --> 00:52:00,400 SAME AS GMP. UNFORTUNATELY WHAT 1326 00:52:00,400 --> 00:52:02,960 STORY WE WENT THROUGH IN DLM IS 1327 00:52:02,960 --> 00:52:05,960 NOT UNUSUAL. WHAT I'M SHOWING 1328 00:52:05,960 --> 00:52:08,640 YOU HERE ARE SCREEN SHOTS OF 1329 00:52:08,640 --> 00:52:09,600 DISCUSSIONS THAT HAPPEN EITHER 1330 00:52:09,600 --> 00:52:12,280 THROUGH EMAIL OR ON LIST SERVE 1331 00:52:12,280 --> 00:52:14,960 FROM THE AMERICAN SOCIETY OF 1332 00:52:14,960 --> 00:52:18,520 MICROBIOLOGY, WHERE REQUEST 1333 00:52:18,520 --> 00:52:19,760 FORESTER RILLTY TESTING ON 1334 00:52:19,760 --> 00:52:21,480 CLINICAL MICROLABS IS INCREASING 1335 00:52:21,480 --> 00:52:22,560 AND THERE ARE QUESTIONS BEING 1336 00:52:22,560 --> 00:52:25,960 RAISED ABOUT THE ROLE OF 1337 00:52:25,960 --> 00:52:28,440 CLINICAL MICROBE MICROBE. WE HAVE 1338 00:52:28,440 --> 00:52:30,240 SOMEONE ASKING ABOUT THEY HAVE A 1339 00:52:30,240 --> 00:52:32,200 CELL THERAPY FACILITY, IS ANYONE 1340 00:52:32,200 --> 00:52:34,560 USING A BLOOD CULTURE SYSTEM, IS 1341 00:52:34,560 --> 00:52:36,160 IT DONE IN THE CLINICAL LAB, IF 1342 00:52:36,160 --> 00:52:37,640 NOT WHO PERFORMS STERILITY 1343 00:52:37,640 --> 00:52:40,280 TESTING. I RECEIVED AN EMAIL 1344 00:52:40,280 --> 00:52:41,920 FROM A COLLEAGUE COUPLE OF 1345 00:52:41,920 --> 00:52:45,160 MONTHS AGO WHO WANTS TO START 1346 00:52:45,160 --> 00:52:46,360 ISLET CELL TRANSPLANT PROGRAM, 1347 00:52:46,360 --> 00:52:49,320 THEY WANT TO ALLOW THE LAB TO DO 1348 00:52:49,320 --> 00:52:50,680 STERILITY TESTING AND WHAT 1349 00:52:50,680 --> 00:52:52,960 REGULATIONS APPLY. AN EMAIL FROM 1350 00:52:52,960 --> 00:52:55,080 ANOTHER COMPLYING ABOUT BONE 1351 00:52:55,080 --> 00:52:57,920 MARROW TRANSPLANT AND AGAINST 1352 00:52:57,920 --> 00:52:59,560 HARVEST ITSELF. THESE GO BACK 1353 00:52:59,560 --> 00:53:01,320 YEARS, ANOTHER IN 2018, COUPLE 1354 00:53:01,320 --> 00:53:03,360 MORE IN 2015 NOW TALKING ABOUT 1355 00:53:03,360 --> 00:53:06,520 PHARMACIES, AS WELL AS SOME OF 1356 00:53:06,520 --> 00:53:07,800 THE SETTLING PLACE AND MEDIA 1357 00:53:07,800 --> 00:53:10,320 BILLS ALL COMPONENTS THAT FORM 1358 00:53:10,320 --> 00:53:15,360 PART OF GMP THAT DON'T 1359 00:53:15,360 --> 00:53:16,480 NECESSARILY IN CLINICAL 1360 00:53:16,480 --> 00:53:18,360 MICROBIOLOGY SO WHY ARE CLINICAL 1361 00:53:18,360 --> 00:53:20,280 MICROLABS ASKED TO ASSIST, 1362 00:53:20,280 --> 00:53:21,960 CLEARLY PROXIMITY OF LABS TO 1363 00:53:21,960 --> 00:53:25,160 MANUFACTURING SUITES AS CELL 1364 00:53:25,160 --> 00:53:26,520 THERAPY CONTINUES TO BE FRONT 1365 00:53:26,520 --> 00:53:28,440 LINE TREATMENT AND MORE AND MORE 1366 00:53:28,440 --> 00:53:29,400 ACADEMIC SENORS BRING THIS ON 1367 00:53:29,400 --> 00:53:31,520 BOARD. -- CENTERS BRING ON 1368 00:53:31,520 --> 00:53:33,400 BOARD. THIS ON SITE BIOLOGICAL 1369 00:53:33,400 --> 00:53:35,440 EXPERTISE AND IN HOUSE TESTING 1370 00:53:35,440 --> 00:53:37,640 IS MORE CONVENIENT FROM A COST 1371 00:53:37,640 --> 00:53:38,560 AND RESULT TURN AROUND TIME 1372 00:53:38,560 --> 00:53:43,040 PERSPECTIVE. SO REALLY WHERE I 1373 00:53:43,040 --> 00:53:44,760 SAY OUR ROLE WITHIN STERILITY 1374 00:53:44,760 --> 00:53:46,960 TESTING SERVICE IS TO HELP 1375 00:53:46,960 --> 00:53:48,840 EDUCATE MY CLINICAL 1376 00:53:48,840 --> 00:53:50,320 MICROCOLLEAGUES AS TO THE 1377 00:53:50,320 --> 00:53:52,760 LESSONS LEARNED FROM THE NIH AND 1378 00:53:52,760 --> 00:53:55,560 WHAT THE ROLE IS FOR CELLULAR 1379 00:53:55,560 --> 00:53:59,000 THERAPY TESTING IN CLINICAL 1380 00:53:59,000 --> 00:54:01,960 MICROLABS. HELPING THEM WELCOME 1381 00:54:01,960 --> 00:54:03,440 AWARE OF REGULATIONS IN 1382 00:54:03,440 --> 00:54:04,720 STERILITY TESTING WITH END GOAL 1383 00:54:04,720 --> 00:54:07,480 OF PATIENT SAFETY. SO WITH THAT, 1384 00:54:07,480 --> 00:54:10,200 I JUST WANTED TO END BY 1385 00:54:10,200 --> 00:54:12,160 INTRODUCING THE GMP PROGRAM. 1386 00:54:12,160 --> 00:54:15,360 WHICH IS ESSENTIALLY FORMED 1387 00:54:15,360 --> 00:54:18,080 FOLLOWING THE CONTAMINATION 1388 00:54:18,080 --> 00:54:20,560 EVENTS IN 2015. WHAT YOU CAN SEE 1389 00:54:20,560 --> 00:54:23,960 HERE ARE SEVEN BRANCHES OR 1390 00:54:23,960 --> 00:54:24,840 DEPARTMENTS ESSENTIALLY THAT 1391 00:54:24,840 --> 00:54:27,120 THESE GUYS ARE THE MANUFACTURING 1392 00:54:27,120 --> 00:54:31,440 OR THE ASEPTIC PROCESSING 1393 00:54:31,440 --> 00:54:32,720 FACILITIES. THERE'S HUNDREDS OF 1394 00:54:32,720 --> 00:54:33,600 FOLKS WITHIN EACH OF THESE 1395 00:54:33,600 --> 00:54:35,360 FACILITIES THAT FOCUS ON CELL AN 1396 00:54:35,360 --> 00:54:39,520 GENE THERAPY MANUFACTURING, KIT 1397 00:54:39,520 --> 00:54:40,360 AND RADIO PHARMACEUTICAL 1398 00:54:40,360 --> 00:54:42,160 MANUFACTURERS AS WELL AS 1399 00:54:42,160 --> 00:54:44,600 HOSPITAL PHARMACY. THERE ARE IN 1400 00:54:44,600 --> 00:54:46,600 FACT 13 FACILITIES CURRENTLY ON 1401 00:54:46,600 --> 00:54:49,400 THE NIH CAMPUS, THAT ARE DOING 1402 00:54:49,400 --> 00:54:51,680 THIS TYPE OF NOVEL DRUG 1403 00:54:51,680 --> 00:54:53,480 MANUFACTURING. WITH SIX MORE 1404 00:54:53,480 --> 00:54:55,320 FACILITIES SLATED TO ON BOARD 1405 00:54:55,320 --> 00:54:57,560 OVER THE NEXT TWO YEARS. I THINK 1406 00:54:57,560 --> 00:54:58,760 ALL OF US ARE AWARE THAT THERE 1407 00:54:58,760 --> 00:55:00,480 IS A LOT OF CONSTRUCTION 1408 00:55:00,480 --> 00:55:02,000 HAPPENING ON THE BETHESDA CAMPUS 1409 00:55:02,000 --> 00:55:03,760 AT THE MOMENT TO HELP BUILD 1410 00:55:03,760 --> 00:55:06,560 THESE NEW STATE OF THE ART 1411 00:55:06,560 --> 00:55:08,040 FACILITIES, MANY OF WHICH TAKE 1412 00:55:08,040 --> 00:55:10,280 SEVERAL YEARS TO BUILD FOUR TO 1413 00:55:10,280 --> 00:55:11,440 FIVE YEARS, IN FACT. WHAT YOU 1414 00:55:11,440 --> 00:55:15,760 CAN SEE HERE IS DR. ROSENBERG'S 1415 00:55:15,760 --> 00:55:20,040 T 30 FACILITY AND JMP FACILITY 1416 00:55:20,040 --> 00:55:21,480 FOR CLEAN ROOM ENVIRONMENTS 1417 00:55:21,480 --> 00:55:22,840 INCITE. THIS SLIDE HERE JUST 1418 00:55:22,840 --> 00:55:24,760 HELPS TO HIGHLIGHT THE WIDE 1419 00:55:24,760 --> 00:55:26,160 SCOPE OF THE PRODUCTS 1420 00:55:26,160 --> 00:55:27,760 MANUFACTURED AT THE NIH ACROSS 1421 00:55:27,760 --> 00:55:29,800 THOSE DIFFERENT FACILITIES. 1422 00:55:29,800 --> 00:55:32,000 VARYING FROM DIFFERENT TYPES OF 1423 00:55:32,000 --> 00:55:33,760 BIOLOGICS, PET RADIO LABEL 1424 00:55:33,760 --> 00:55:34,560 DRUGS, RAW MATERIALS THAT 1425 00:55:34,560 --> 00:55:36,000 REQUIRE TESTING AS WELL AS VIRAL 1426 00:55:36,000 --> 00:55:40,240 VECTORS. AND THEN TO SUPPORT 1427 00:55:40,240 --> 00:55:43,600 THESE MANUFACTURING GROUPS, WE 1428 00:55:43,600 --> 00:55:46,000 HAVE AN ENTIRE DIFFERENT SET OF 1429 00:55:46,000 --> 00:55:46,880 DEPARTMENTS THAT FOLLOW SUPPORT 1430 00:55:46,880 --> 00:55:49,720 AND REGULATORY FUNCTION. SO THIS 1431 00:55:49,720 --> 00:55:52,760 INCLUDES MY LAB FOR QUALITY 1432 00:55:52,760 --> 00:55:55,880 CONTROL TESTING, THE ORF HAS A 1433 00:55:55,880 --> 00:55:58,680 GROUP FOCUSING ON FACILITY 1434 00:55:58,680 --> 00:56:00,280 COMPLIANCE FOR CLEAN GREEN 1435 00:56:00,280 --> 00:56:01,440 SPACE, OFFICE OF RESEARCH 1436 00:56:01,440 --> 00:56:02,360 SUPPORT AND COMPLIANCE AS WELL 1437 00:56:02,360 --> 00:56:04,480 AS THE SPONSORS FROM VARIOUS 1438 00:56:04,480 --> 00:56:06,360 INSTITUTES AND CENTERS. AND 1439 00:56:06,360 --> 00:56:09,000 REALLY ALL OF US WORK TOGETHER, 1440 00:56:09,000 --> 00:56:09,960 THERE ARE HUNDREDS OF HANDS 1441 00:56:09,960 --> 00:56:14,360 INVOLVED IN THIS PROGRAM, TO 1442 00:56:14,360 --> 00:56:16,160 HELP MAKE A PRODUCT WHETHER CELL 1443 00:56:16,160 --> 00:56:17,760 THERAPY OR DRUG PRODUCT, THAT IS 1444 00:56:17,760 --> 00:56:21,280 READY TO INFUSE INTO A PATIENT. 1445 00:56:21,280 --> 00:56:23,680 SO IT HAS BEEN A VERY, VERY LONG 1446 00:56:23,680 --> 00:56:25,320 JOURNEY EVEN THOUGH THE PROGRAM 1447 00:56:25,320 --> 00:56:28,360 IS GOTTEN ONLY SEVEN YEARS OLD. 1448 00:56:28,360 --> 00:56:30,440 BUT HONESTLY BEFORE 2015 THERE 1449 00:56:30,440 --> 00:56:32,560 WAS LITTLE KNOWLEDGE OF GMP 1450 00:56:32,560 --> 00:56:34,200 ACROSS THE NIH CAMPUS AND IN 1451 00:56:34,200 --> 00:56:36,360 FACT I DOUBT THAT ACRONYM WAS 1452 00:56:36,360 --> 00:56:39,360 USED VERY READILY PRIOR TO 2015. 1453 00:56:39,360 --> 00:56:42,080 IT IS IMPORTANT REMEMBER THE 1454 00:56:42,080 --> 00:56:43,280 REGULATIONS ARE THE SAME WE ARE 1455 00:56:43,280 --> 00:56:44,560 JUST BEING HELD TO A DIFFERENT 1456 00:56:44,560 --> 00:56:46,360 STANDARD, WE HAVE CHANGED THE 1457 00:56:46,360 --> 00:56:48,560 CULTURE AND AWARENESS OF THE 1458 00:56:48,560 --> 00:56:49,920 REGULATIONS, WITH MANY, MANY 1459 00:56:49,920 --> 00:56:51,000 LESSONS LEARNED OVER SHORT 1460 00:56:51,000 --> 00:56:54,400 PERIOD OF TIME. I THINK FOR 1461 00:56:54,400 --> 00:56:57,200 MANY OF US IN INVOLVED IN THE 1462 00:56:57,200 --> 00:56:59,000 GMP PROGRAM, THE CHALLENGE COMES 1463 00:56:59,000 --> 00:57:01,040 WHEN IT COMES TO TRY TO 1464 00:57:01,040 --> 00:57:02,320 HARMONIZE THESE PROGRAMS THAT 1465 00:57:02,320 --> 00:57:05,400 HAVE EXISTED FOR MANY, MANY 1466 00:57:05,400 --> 00:57:06,960 DECADES SOMETIMES SPREAD ACROSS 1467 00:57:06,960 --> 00:57:09,160 NUMEROUS INSTITUTES AN CENTERS 1468 00:57:09,160 --> 00:57:11,600 AS WELL AS FACILITIES AND TRY TO 1469 00:57:11,600 --> 00:57:12,960 DEVELOP AN INTERDISCIPLINARY 1470 00:57:12,960 --> 00:57:15,560 APPROACH ACROSS THE NIH TO 1471 00:57:15,560 --> 00:57:17,920 IMPROVE THE GMP PROGRAM. WITH 1472 00:57:17,920 --> 00:57:19,360 END GOAL OF CLEARLY PATIENT 1473 00:57:19,360 --> 00:57:21,800 SAFETY AND OUR MISSION TO 1474 00:57:21,800 --> 00:57:23,840 CONTINUE TO SUPPORT INNOVATIVE 1475 00:57:23,840 --> 00:57:25,320 PATIENT CARE AND DRUG AND 1476 00:57:25,320 --> 00:57:26,760 BIOLOGIC DEVELOPMENT. SO WITH 1477 00:57:26,760 --> 00:57:30,120 THAT I WOULD LIKE TO END BY 1478 00:57:30,120 --> 00:57:32,200 THANKING DR. ROSENBERG SHORE 1479 00:57:32,200 --> 00:57:32,920 THEIR SHARING THE PLATFORM WITH 1480 00:57:32,920 --> 00:57:36,480 ME, THANKS TO DLM LEADERSHIP AND 1481 00:57:36,480 --> 00:57:37,920 STERILITY TESTING LAB, TAKEN 1482 00:57:37,920 --> 00:57:39,560 LAST WEEK AND THEN IT TAKES A 1483 00:57:39,560 --> 00:57:42,480 VILLAGE, THE GMP PROGRAM AT NIH 1484 00:57:42,480 --> 00:57:44,400 IS HUGE. HUNDREDS AND HUNDREDS 1485 00:57:44,400 --> 00:57:48,040 OF FOLKS WORK BEHIND THE SCENES 1486 00:57:48,040 --> 00:57:49,360 WITH MANUFACTURING FACILITY 1487 00:57:49,360 --> 00:57:53,320 SUPPORT, TESTING, AND REGULATORY 1488 00:57:53,320 --> 00:57:53,960 COMPLIANCE. THANK YOU VERY MUCH 1489 00:57:53,960 --> 00:57:55,600 FOR YOUR TIME, IF THERE IS TIME 1490 00:57:55,600 --> 00:57:59,920 WE ARE HAPPY TO TAKE QUESTIONS. 1491 00:57:59,920 --> 00:58:01,800 >> DR. ROSENBERG AND DR. LAU, I 1492 00:58:01,800 --> 00:58:04,960 WANT TO THANK YOU FOR VERY 1493 00:58:04,960 --> 00:58:06,640 POWERFUL PAIR OF TALKS. DR. 1494 00:58:06,640 --> 00:58:08,040 ROSENBERG WE ARE HONORED TO HEAR 1495 00:58:08,040 --> 00:58:09,800 ANT YOUR INCITES AND BREAK 1496 00:58:09,800 --> 00:58:11,560 THROUGHS AS PIONEER IN CELL 1497 00:58:11,560 --> 00:58:14,920 TRANSFER THERAPIES. AND PERHAPS 1498 00:58:14,920 --> 00:58:16,440 OFFERING A WINDOW WHAT THAT 1499 00:58:16,440 --> 00:58:19,120 LOOKS LIKE FUTURE BUT ALSO DR. 1500 00:58:19,120 --> 00:58:20,560 LAU FOR SHARING WITH US THE 1501 00:58:20,560 --> 00:58:23,960 COMPLEXITY WHAT IT MEANS SCALES 1502 00:58:23,960 --> 00:58:31,640 UP TO CLINICAL LEVEL OUTSIDE THE 1503 00:58:31,640 --> 00:58:33,200 WORLD. I THINK WE HAVE TIME 1504 00:58:33,200 --> 00:58:34,560 MAYBE FOR ONE QUESTION THAT CAME 1505 00:58:34,560 --> 00:58:38,680 IN, THIS MIGHT BE TO DR. 1506 00:58:38,680 --> 00:58:40,800 ROSENBERG. HUE FOR PHENOMENAL 1507 00:58:40,800 --> 00:58:42,680 TALK AND WORK. DO THESE MUTATION 1508 00:58:42,680 --> 00:58:45,760 SPECIFIC T-CELL RESPONSES 1509 00:58:45,760 --> 00:58:47,560 ULTIMATELY SPREAD B CELLS? DO 1510 00:58:47,560 --> 00:58:49,000 PATIENTS DEVELOP IGE SPECIFIC TO 1511 00:58:49,000 --> 00:58:53,960 THEIR CANCER MUTATION? 1512 00:58:53,960 --> 00:58:56,160 >> WE GENERALLY DO NOT FIND 1513 00:58:56,160 --> 00:58:57,680 ANTIBODIES CAPABLE OF 1514 00:58:57,680 --> 00:58:59,960 RECOGNIZING CANCER ANTIGENS 1515 00:58:59,960 --> 00:59:01,720 BECAUSE AGAIN THEY ARE NOT 1516 00:59:01,720 --> 00:59:03,360 PRESENTED WHEN USING 1517 00:59:03,360 --> 00:59:06,760 CONVENTIONAL T-CELLS AND T-CELL 1518 00:59:06,760 --> 00:59:08,360 RECEPTORS, THESE ARE NOT THREE 1519 00:59:08,360 --> 00:59:09,400 DIMENSIONAL PROTEINS PRESENTED 1520 00:59:09,400 --> 00:59:12,160 ON THE CELL SURFACE. BUT RATHER 1521 00:59:12,160 --> 00:59:15,440 PROCESS PEPTIDES FROM AN 1522 00:59:15,440 --> 00:59:17,400 INTRACELLULAR MOLECULE THEN 1523 00:59:17,400 --> 00:59:18,400 TRANSPORTED TO THE CELL TO THE 1524 00:59:18,400 --> 00:59:23,960 CELL SURFACE. SO IT IS VERY 1525 00:59:23,960 --> 00:59:25,920 DIFFICULT TO IDENTIFY ANTIBODIES 1526 00:59:25,920 --> 00:59:29,800 THAT ARE CAPABLE OF RECOGNIZING 1527 00:59:29,800 --> 00:59:30,960 CANCER ANTIGENS. THAT'S PART OF 1528 00:59:30,960 --> 00:59:35,880 THE REASON WHY CAR T-CELLS ARE 1529 00:59:35,880 --> 00:59:37,160 PREDOMINANTLY EFFECTIVE IN 1530 00:59:37,160 --> 00:59:39,320 PATIENTS WITH HEMATOLOGIC 1531 00:59:39,320 --> 00:59:40,000 CANCERS BECAUSE THERE ARE 1532 00:59:40,000 --> 00:59:42,640 MOLECULES SUCH AS CD 19 THAT ARE 1533 00:59:42,640 --> 00:59:44,080 EXPRESSED NOT ONLY ON NORMAL B 1534 00:59:44,080 --> 00:59:47,360 CELLS BUT ON TUMOR CELLS, AND 1535 00:59:47,360 --> 00:59:50,720 WHEN ONE ATTACKS THEM WITH A 1536 00:59:50,720 --> 00:59:54,040 CAR, AGAIN RECOGNIZING AN 1537 00:59:54,040 --> 00:59:56,080 ANTIBODY RECOGNITION, ONE 1538 00:59:56,080 --> 00:59:57,640 DESTROYS NORMAL B CELLS AS WELL 1539 00:59:57,640 --> 01:00:00,400 AS THE TUMOR CELLS, FORTUNATELY 1540 01:00:00,400 --> 01:00:01,800 THE STEM CELLS THAT GIVE RISE TO 1541 01:00:01,800 --> 01:00:05,520 B CELLS ARE SPARED Z SO AFTER 1542 01:00:05,520 --> 01:00:06,800 SEVERAL MONTHS NORMAL B CELLS 1543 01:00:06,800 --> 01:00:13,080 WILL APPEAR. 1544 01:00:13,080 --> 01:00:14,680 >> THANK YOU, DR. ROSENBERG, 1545 01:00:14,680 --> 01:00:17,360 THAT TAKES US TO HOUR. DR. 1546 01:00:17,360 --> 01:00:18,640 ROSENBERG, DR. LAU, THANK YOU 1547 01:00:18,640 --> 01:00:21,120 FOR SHARING YOUR EXPERTISE AND 1548 01:00:21,120 --> 01:00:22,240 INSIGHTS WITH US AND THE NIH 1549 01:00:22,240 --> 01:00:23,360 COMMUNITY. THANK YOU VERY MUCH, 1550 01:00:23,360 --> 01:00:24,000 I WISH EVERYONE A GREAT 1551 01:00:24,000 --> 01:03:00,720 AFTERNOON. THANK YOU AGAIN.