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>> WE'RE ALL GOOD NOW.

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I'M MATT WOLFE.

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WELCOME TO CCG R.

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A BIG WELCOME TO DAVE MOONEY

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FROM HARVARD UNIVERSITY. 

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PLEASE TAKE IT AWAY.

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[APPLAUSE]

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>> THANK YOU VERY MUCH FOR
THE

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INVITATION AND OPPORTUNITY.

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I'LL TALK ABOUT RESEARCH IN THE

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CONTEXT OF USING BIOMATERIALS TO

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IMPACT T CELL IMMUNITY, THIS IS

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AN IMAGE FROM ONE OF THE

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TECHNOLOGIES I'LL TALK ABOUT

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TODAY, T CELLS COLORIZED IN

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YELLOW ENGAGING WITH RED

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MICROPARTICLES, ANTIGEN

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REPRESENTING CELLS.

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GOOD, THIS WORKS.

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THE LAB HAS A VARIETY OF

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COMMERCIAL ENGAGEMENTS, RELATIVE

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TODAY THERE ARE A FEW, NOVARTIS

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AND ATTIVARE AND LYELL, FUNDED

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IN PART BY THE NCI ONCOLOGY 

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NETWORK, PART OF THE CANCER

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MOONSHOT, PART OF THE NCI BILL

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AND MELINDA GATES FOUNDATION AND

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EARLY PARTS OF A LOT OF RESEARCH

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FUNDED BY NIBIB.

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SO, AS I MENTIONED, WE'RE

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INTERESTED IN USING MATERIALS TO

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CONTROL T CELL BIOLOGY, WE'RE

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INTERESTED IN THIS OVER THE

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ENTIRE LIFE CYCLE OF A T CELL IN

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THE CONTEXT OF CANCER DEVELOPING

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STRATEGIES MIMICKING KEY

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FEATURES OF BONE MARROW TO TRY

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TO DRIVE T CELL DIFFERENTIAL

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FROM HEMATOPOIETIC STEM CELLS,

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ENGINEERING HUMAN THYMIC TISSUE

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TO CONTROL POSITIVE AND NEGATIVE

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SELECTION, INTERESTED IN THE

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IDEA OF -- THIS IS INTERESTING.

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THE IMAGES ON THE BOTTOM ARE NOT

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THE REAL IMAGES BUT THAT'S OKAY.

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A LITTLE BIT MIXED UP.

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THAT'S WHAT HAPPENS

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TRANSITIONING FROM MAC AND PC,

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USING BIOMATERIALS TO ADAPT AND

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FINALLY IN THE CONTEXT OF

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MODELING TUMORS.

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I'LL TALK ABOUT THE LAST THREE

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AND NOT THE FIRST TWO TODAY.

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TO GET STARTED I'LL TALK ABOUT A

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TECHNOLOGY WE'VE BEEN DEVELOPING

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THAT WE HOPE WILL ENABLE US TO

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HAVE AN IMPACT IN ADOPTIVE

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T-CELL THERAPIES.

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HERE AT THE NCI YOU'RE FAMILIAR

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IN THE CONTEXT OF CANCER

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THERAPY.

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THE QUESTION WE BECAME

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INTERESTED IN A FEW YEARS AGO

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WHETHER WE COULD IMPROVE T CELL

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MANUFACTURING AND IMPORTANTLY

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CONTROL THE ACTIVITY OF THE

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00:02:56,565 --> 00:02:57,433
TRANSFERRED T CELLS.

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THE APPROACH WE CAME AT THIS

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FROM WAS TO TRY TO DEVELOP A

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BETTER ANTIGEN-PRESENTING CELL

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MIMIC.

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YOU'RE FAMILIAR WITH USE OF

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DYNABEADS TO EXPAND AND

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MANUFACTURE T CELLS.

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THESE PRESENT A LOT OF CUES IN

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NON-PHYSIOLOGIC MANNER, BECAME

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INTERESTED IN THE ANTIGEN

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PRESENTING CELL MEMETIC SCAFFOLD

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TO MIMIC NATURAL ANTIGEN

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PRESENTATION AND OTHER CUES T

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CELLS GET FROM APCs TO HAVE

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BETTER CONTROL OVER T CELL

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BIOLOGY.

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THE SYSTEM WE DEVELOPED IS SHOWN

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HERE.

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THIS IS THE WORK OF ALEX CHUNG,

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NOW AT LYELL, AND DAVID ZHANG

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WHO FINISHED HIS Ph.D. IN THE

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LAB AS WELL, STARTING WITH

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MICROPARTICLES OF A SILICA THAT

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DISSOLVES BY HYDROLYSIS, IT GOES

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AWAY INSIDE OR OUTSIDE THE BODY,

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00:03:53,489 --> 00:03:56,859
THIS IS AN IMAGE OF WHAT

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00:03:56,859 --> 00:03:58,961
PARTICLES LOOK LIKE, LONG

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00:03:58,961 --> 00:04:00,362
ALIGNED NANOPORES DOWN THE

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00:04:00,362 --> 00:04:01,597
LENGTH OF THE PARTICLE PROVIDING

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A REALLY USEFUL PLACE TO PUT

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00:04:03,932 --> 00:04:04,967
BIOLOGICAL CARGOES.

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00:04:04,967 --> 00:04:09,104
FOR EXAMPLE, WE CAN ABSORB

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00:04:09,104 --> 00:04:11,407
CYTOKINES KEY MEDIATORS OF

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00:04:11,407 --> 00:04:12,207
INTERACTION BETWEEN ANTIGEN

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PRESENTING CELLS AND T CELLS IN

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THE BODY.

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00:04:15,044 --> 00:04:16,545
HAD THESE RELEASED IN A

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00:04:16,545 --> 00:04:17,713
SUSTAINED AND LOCALIZED MANNER

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00:04:17,713 --> 00:04:18,981
TO INTERACTING T CELLS.

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I'M JUST SHOWING DATA WITH A FEW

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CUES HERE, IL-2, IL-21,

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TGF-BETA, TYPICALLY ABOUT A WEEK

110
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TO TWO WEEKS OF SUSTAINED

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00:04:28,524 --> 00:04:30,592
PRESENTATION OF CUES DIRECTLY

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FROM THE MATERIALS.

113
00:04:32,761 --> 00:04:35,164
NOW, TO ENGAGE THE T CELLS

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DIRECTLY WITH T CELL

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STIMULATION, CO-STIMULATION, WE

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COAT THE MICROPARTICLES FIRST

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WITH SUPPORTED LIPID BILAYER, AN

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INTERFACE CONNECTED TO THAT

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NORMAL THE T CELL IS SEEING IN

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ANTIGEN PRESENTING CELL, INSTEAD

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OF RIDGE IMPARTICLE IS A MIMIC

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00:04:54,483 --> 00:04:57,986
OF A CELL MEMBRANE, FRET STUDIES

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00:04:57,986 --> 00:04:59,221
SHOWING IT'S INDEED IT HAS

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FLUIDITY AND THAT AFTER WE

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00:05:00,189 --> 00:05:04,326
BLEACH WE CAN GET RECOVERY

126
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FOLLOWING BLEACHING.

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WE CAN THEN CONJUGATE VARIOUS

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TYPES OF SIGNALS WE WANT TO

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PROVIDE DIRECT STIMULATION OR

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CO-STIMULATION TO THE T CELLS,

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AND KEY FEATURE HERE IS UNLIKE

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NORMAL ANTIGEN PRESENTING CELL,

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HERE WE CAN PRECISELY CONTROL

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THE DENSITY AND NUMBER OF THESE

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CUES WE PRESENT TO THE CELLS.

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00:05:20,909 --> 00:05:23,479
THIS WILL END UP BEING IMPORTANT

137
00:05:23,479 --> 00:05:25,514
LATER, HERE WE'RE JUST SHOWING,

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FOR EXAMPLE, WE CAN CONTROL

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AMOUNT OF IgG, STIMULATORY 

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ANTIBODY PRESENTED FROM LIPID

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MEMBRANES, COMBINE WITH T CELLS,

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HERE A VIDEO SHOWING THE

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MICROPARTICLES WE'VE INCLUDED

144
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GREEN FLUORESCENT TAG IN LIPID

145
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BILAYER, T CELLS IN RED.

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NOW, THE FIRST THING I NEED TO

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MENTION ABOUT THE SYSTEM IS THAT

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WE CAN DO BOTH KIND OF

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POLYCLONAL T CELL EXPANSION BY

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PRESENTING ANTIBODIES THAT

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ENGAGE TCR AS WELL AS

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CO-STIMULATION OR WE CAN DO

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STIMULATION IN ANTIGEN SPECIFIC

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MANNER CONJUGATING, PRESENTING

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THE RIGHT PEPTIDE ANTIGEN TO THE

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CELLS AND I'LL DESCRIBES STUDIES

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WITH BOTH OVER THE NEXT FEW

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MINUTES.

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THE FIRST STUDY ALEX DID WAS

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SIMPLE EXPANSION STUDY TO USE

161
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THESE TO MANUFACTURE LARGE

162
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QUANTITIES OF T CELLS.

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HE DID A SIMPLE COMPARISON OF

164
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EXPANSION COMPARING APCMS TO

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INDUSTRY STAND ART, DYNABEADS,

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FOR THOSE NOT FAMILIAR THESE ARE

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PLASTIC BEADS THAT HAVE

168
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ANTIBODIES CONJUGATED TO THEIR

169
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SURFACE.

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WHAT ALEX DEMONSTRATED THESE

171
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MORE METIC PARTICLES COULD LEAD

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TO EXPANSION OF T CELLS QUITE

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ROBUST T CELL EXPANSION,

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ACTUALLY SIGNIFICANTLY

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OUTPERFORMING DYNABEADS, THE

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INDUSTRY STANDARD, IN TERMS OF

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EXPANSION OF THE CELLS AND THIS

178
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CAME WITHOUT THE COST OF

179
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INDUCING EXHAUSTION, AS

180
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INDICATED HERE BY PD-1 LAG3

181
00:07:07,015 --> 00:07:08,016
STAINING ON T CELLS.

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IT LOOKED LIKE A PROMISING

183
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SYSTEM IN TERMS OF ENSURING WE

184
00:07:14,690 --> 00:07:15,991
DID NOT LOSE FUNCTIONALITY WHEN

185
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EXPANDING WITH THE SYSTEM, THE

186
00:07:18,393 --> 00:07:23,131
CLASSIC EXPERIMENT HERE, 

187
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ADAPTIVE CELL THERAPY,

188
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IMMUNOCOMPROMISED ANIMALS,

189
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INTRODUCED HUMAN MODEL OF

190
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CANCER, INTRODUCED CAR-T CELLS

191
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THAT WE EXPANDED WITH DYNABEADS

192
00:07:33,242 --> 00:07:34,543
OR APCMS SYSTEM AND TRANSFERRED

193
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THE SAME NUMBER.

194
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FROM THE GRAPHS ON THE BOTTOM IN

195
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TERMS OF THE NORMALIZED TOTAL

196
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FLUX WHICH GIVES AN INDICATION

197
00:07:41,783 --> 00:07:46,488
OF THE TUMOR BURDEN IN THE

198
00:07:46,488 --> 00:07:49,124
ANIMALS, THE SURVIVAL, UNTREATED

199
00:07:49,124 --> 00:07:50,626
ANIMALS RAPIDLY SUCCUMBED, BOTH

200
00:07:50,626 --> 00:07:53,896
THE DOSE OF DYNABEAD EXPANDED T

201
00:07:53,896 --> 00:07:55,464
CELLS AND APCMS EXPANDED T CELLS

202
00:07:55,464 --> 00:07:57,432
WERE FUNCTIONAL IN TERMS OF

203
00:07:57,432 --> 00:08:02,271
BEING ABLE TO SLOW TUMOR

204
00:08:02,271 --> 00:08:05,440
PROGRESSION AND APC-MS CELLS

205
00:08:05,440 --> 00:08:10,178
WHICH WE HAD NOT MADE EFFORT,

206
00:08:10,178 --> 00:08:11,546
OUTPERFORMED DYNABEADS, CELLS

207
00:08:11,546 --> 00:08:14,316
MORE FAST, MORE CELLS MORE

208
00:08:14,316 --> 00:08:16,051
RAPIDLY, WENT COMPROMISING TERMS

209
00:08:16,051 --> 00:08:17,019
OF THEIR FUNCTION.

210
00:08:17,019 --> 00:08:18,120
THIS WAS INTERESTING.

211
00:08:18,120 --> 00:08:19,788
BUT WHAT WE WERE WANTING TO GET

212
00:08:19,788 --> 00:08:23,258
AT IS COULD WE USE THIS KIND OF

213
00:08:23,258 --> 00:08:25,127
SYSTEM, ENGINEERED SYSTEM TO

214
00:08:25,127 --> 00:08:26,662
CONTROL THE FUNCTIONS OF T CELL

215
00:08:26,662 --> 00:08:31,366
POPULATIONS THAT WE WANTED TO 

216
00:08:31,366 --> 00:08:33,735
DELIVER INTO THE BODY.

217
00:08:33,735 --> 00:08:35,370
WHEN WE STARTED, WE'RE NOT SURE

218
00:08:35,370 --> 00:08:39,241
AS A FIELD WHAT ARE OPTIMAL

219
00:08:39,241 --> 00:08:40,542
CHARACTERISTICS OF A PRODUCT WE

220
00:08:40,542 --> 00:08:42,511
WANT TO TREAT A PATIENT WITH.

221
00:08:42,511 --> 00:08:45,414
THE APPROACH WAS A NON-BIASED

222
00:08:45,414 --> 00:08:46,815
APPROACH, WHERE WITH THIS SYSTEM

223
00:08:46,815 --> 00:08:50,085
WE CAN CONTROL FEATURES OF THE

224
00:08:50,085 --> 00:08:51,086
MSRs, CONTROL THEIR PHYSICAL

225
00:08:51,086 --> 00:08:53,255
DIMENSIONS, FOR EXAMPLE, WE CAN

226
00:08:53,255 --> 00:08:57,759
CONTROL WHAT CUES, WHAT

227
00:08:57,759 --> 00:08:59,428
PERACRINE ACCOUNT AING SIGNALS

228
00:08:59,428 --> 00:09:01,697
WE PUT IN, CAN CONTROL

229
00:09:01,697 --> 00:09:02,331
MECHANOTRANSDIGS BY CONTROLLING

230
00:09:02,331 --> 00:09:06,868
LIPIDS THAT PRESENT THE CUES,

231
00:09:06,868 --> 00:09:09,371
INSTEAD I'M GOING TO TALK ABOUT

232
00:09:09,371 --> 00:09:09,938
SIMPLE EXPERIMENTS WITH

233
00:09:09,938 --> 00:09:12,107
CONTROLLING THE AMOUNT OF

234
00:09:12,107 --> 00:09:14,943
STIMULATION BY VARYING QUANTITY

235
00:09:14,943 --> 00:09:17,312
OF T CELL LIGANDS.

236
00:09:17,312 --> 00:09:19,414
THE APPROACH WAS VERY

237
00:09:19,414 --> 00:09:20,048
NON-BIASED.

238
00:09:20,048 --> 00:09:23,986
WE CREATED A LARGE LIBRARY OF

239
00:09:23,986 --> 00:09:26,288
DIFFERENT APC-MS, VARY THE

240
00:09:26,288 --> 00:09:27,356
AMOUNT OF STIMULATION, EXPAND T

241
00:09:27,356 --> 00:09:31,860
CELLS AND LOOK AT A PANEL OF

242
00:09:31,860 --> 00:09:33,428
MARKERS FROM T CELL

243
00:09:33,428 --> 00:09:34,830
DIFFERENTIATION STATUS AND

244
00:09:34,830 --> 00:09:35,263
PHENOTYPE.

245
00:09:35,263 --> 00:09:37,366
AND AS MENTIONED WE VARIED T

246
00:09:37,366 --> 00:09:39,434
CELL LIGANDS, WE WOULD COMPARE

247
00:09:39,434 --> 00:09:42,104
ALL THESE DIFFERENT END RESULTS,

248
00:09:42,104 --> 00:09:48,410
T CELL PRODUCTS, AND DO TYPICAL

249
00:09:48,410 --> 00:09:49,177
PRINCIPAL COMPONENT APPROACH TO

250
00:09:49,177 --> 00:09:50,379
LOOK AT FEATURES WE COULD

251
00:09:50,379 --> 00:09:51,480
GENERATE IN T CELLS.

252
00:09:51,480 --> 00:09:53,882
EACH ONE OF THE DOTS IS A

253
00:09:53,882 --> 00:09:55,283
SEPARATE MANUFACTURING RUN, WITH

254
00:09:55,283 --> 00:10:00,055
A SLIGHTLY DIFFERENT OR MAYBE 

255
00:10:00,055 --> 00:10:01,456
MAJORLY DIFFERENT VERSION OF

256
00:10:01,456 --> 00:10:03,425
APC-MS SYSTEM, WE VARIED OVER A

257
00:10:03,425 --> 00:10:05,527
BROAD RANGE, GENERATED LOTS OF T

258
00:10:05,527 --> 00:10:07,662
CELL PRODUCTS WE CHARACTERIZED A

259
00:10:07,662 --> 00:10:11,400
VARIETY OF WAYS, WHEN WE USED K

260
00:10:11,400 --> 00:10:13,135
CLUSTER APPROACH TO BEND THEM

261
00:10:13,135 --> 00:10:17,305
INTO GROUPS, YOU CAN SEE HERE WE

262
00:10:17,305 --> 00:10:19,841
HAD ABOUT 8 GROUPS WE BEND THESE

263
00:10:19,841 --> 00:10:21,376
INTO FOR SIMPLICITY, AND IF WE

264
00:10:21,376 --> 00:10:23,678
STARTED TO LOOK AT PHENOTYPE OF

265
00:10:23,678 --> 00:10:25,847
THESE DIFFERENT CLUSTERS WHAT WE

266
00:10:25,847 --> 00:10:27,716
SEE IS THAT DEPENDING ON THE

267
00:10:27,716 --> 00:10:29,051
SPECIFIC STIMULATION WE PROVIDE

268
00:10:29,051 --> 00:10:31,186
WE CAN HAVE A DRAMATICALLY

269
00:10:31,186 --> 00:10:32,254
DIFFERENT IMPACT ON THE

270
00:10:32,254 --> 00:10:33,655
EXPANSION OF THE T CELLS.

271
00:10:33,655 --> 00:10:36,658
IF WE LOOK AT THINGS LIKE CD4 TO

272
00:10:36,658 --> 00:10:40,328
CD8 RATIO, BELIEVED TO BE AN

273
00:10:40,328 --> 00:10:41,563
IMPORTANT METRIC, WE CAN VARY

274
00:10:41,563 --> 00:10:42,764
THAT OVER A WIDE RANGE.

275
00:10:42,764 --> 00:10:46,068
IF YOU LOOK AT EXHAUSTION, AGAIN

276
00:10:46,068 --> 00:10:47,035
THESE CLUSTERS SHOW VERY

277
00:10:47,035 --> 00:10:47,769
DIFFERENT PROPERTIES.

278
00:10:47,769 --> 00:10:50,639
IF WE WANTED TO THINK ABOUT

279
00:10:50,639 --> 00:10:51,206
CONTROLLING DIFFERENTIATION

280
00:10:51,206 --> 00:10:52,507
STATUS BY LOOKING AT MARKERS

281
00:10:52,507 --> 00:10:54,576
THAT ARE INDICATIVE OF MEMORY

282
00:10:54,576 --> 00:10:55,477
STATUS OF THESE POPULATIONS,

283
00:10:55,477 --> 00:10:57,546
AGAIN WE CAN VARY THIS QUITE

284
00:10:57,546 --> 00:10:59,614
DRAMATICALLY SHOWN IN THE LOWER

285
00:10:59,614 --> 00:11:01,249
RIGHT WITH DIFFERENT COLORS

286
00:11:01,249 --> 00:11:01,817
THERE.

287
00:11:01,817 --> 00:11:04,653
THE POINT OF THIS IS, THIS

288
00:11:04,653 --> 00:11:08,056
PROVIDES A REALLY SIMPLE AND I

289
00:11:08,056 --> 00:11:08,690
THINK FACILE APPROACH THAT

290
00:11:08,690 --> 00:11:10,325
ALLOWS US TO TUNE THE TYPES OF T

291
00:11:10,325 --> 00:11:12,327
CELL PRODUCTS THAT YOU GET FROM

292
00:11:12,327 --> 00:11:14,229
A STARTING POPULATION.

293
00:11:14,229 --> 00:11:15,797
WE CAN DO THIS GENERATE LARGE

294
00:11:15,797 --> 00:11:17,099
NUMBERS OF CELLS WITH WIDE

295
00:11:17,099 --> 00:11:18,834
VARIETY OF DIFFERENT TYPES OF

296
00:11:18,834 --> 00:11:19,067
METRICS.

297
00:11:19,067 --> 00:11:21,369
WE HAVE SOME IDEAS WHAT METRICS

298
00:11:21,369 --> 00:11:22,671
MIGHT BE USEFUL FOR T CELL

299
00:11:22,671 --> 00:11:23,772
PRODUCTS BUT AS THAT EVOLVES

300
00:11:23,772 --> 00:11:26,174
THIS COULD BE A USEFUL SYSTEM TO

301
00:11:26,174 --> 00:11:27,242
ALLOW US TO GENERATE DIFFERENT

302
00:11:27,242 --> 00:11:28,043
KINDS OF PROPERTIES.

303
00:11:28,043 --> 00:11:30,579
ONE OF THE INTERESTING FEATURES

304
00:11:30,579 --> 00:11:34,716
IF WE COLOR CODE BASICALLY EACH 

305
00:11:34,716 --> 00:11:36,351
OF THESE INDIVIDUAL RUNS BY

306
00:11:36,351 --> 00:11:39,754
ABSOLUTE AMOUNT OF STIMULATION

307
00:11:39,754 --> 00:11:41,056
PROVIDING FROM CO-STIMULATORY

308
00:11:41,056 --> 00:11:43,091
CUES, DARKER MEANS MORE, YOU CAN

309
00:11:43,091 --> 00:11:44,693
SEE THE GENERAL TREND HERE WITH

310
00:11:44,693 --> 00:11:48,396
THESE CELLS ALL DERIVED FROM

311
00:11:48,396 --> 00:11:51,266
HEALTHY INDIVIDUALS, MORE

312
00:11:51,266 --> 00:11:52,134
STIMULATION GENERALLY DOMINATED

313
00:11:52,134 --> 00:11:52,868
PC 1.

314
00:11:52,868 --> 00:11:53,969
NOW, WE BECAME INTERESTED IN

315
00:11:53,969 --> 00:11:56,838
SAYING WHAT HAPPENS IF WE TAKE

316
00:11:56,838 --> 00:11:58,740
CELLS FROM PATIENTS INSTEAD OF

317
00:11:58,740 --> 00:11:59,574
HEALTHY INDIVIDUALS?

318
00:11:59,574 --> 00:12:02,344
SO THIS WORK WAS DONE WITH KATHY

319
00:12:02,344 --> 00:12:04,479
WU AND JERRY RITZ AT

320
00:12:04,479 --> 00:12:06,681
DANA-FARBER, A LOT IN

321
00:12:06,681 --> 00:12:07,883
COLLABORATION WITH NIKO, THE

322
00:12:07,883 --> 00:12:11,720
POSTDOC IMAGE ON THE TOP, ON THE

323
00:12:11,720 --> 00:12:14,489
LEFT, AND A Ph.D. STUDENT IN

324
00:12:14,489 --> 00:12:17,893
THE LABORATORY, SO WE TAKE CELLS

325
00:12:17,893 --> 00:12:19,961
FROM PATIENTS, WOULD LOOK TO

326
00:12:19,961 --> 00:12:23,798
EXPAND THEM, AGAIN WITH INDUSTRY

327
00:12:23,798 --> 00:12:27,302
STANDARD, DYNABEADS, OR APC-MS

328
00:12:27,302 --> 00:12:29,504
SYSTEM AND CHARACTERIZE

329
00:12:29,504 --> 00:12:30,605
FUNCTIONAL PROPERTIES WE GOT.

330
00:12:30,605 --> 00:12:33,542
THIS GIVES A SENSE OF THE RANGE

331
00:12:33,542 --> 00:12:38,380
OF STIMULATION WE PROVIDED.

332
00:12:38,380 --> 00:12:40,248
FOR DIRECT COMPARISON, DYNABEAD

333
00:12:40,248 --> 00:12:42,884
3:1 PROVIDES THE SAME CUES AS

334
00:12:42,884 --> 00:12:44,152
APC-MS, AS A COMPARISON.

335
00:12:44,152 --> 00:12:46,721
WHEN WE LOOK AT THE EXPANSION OF

336
00:12:46,721 --> 00:12:48,156
THESE CELLS, YOU CAN SEE FIRST

337
00:12:48,156 --> 00:12:49,624
OF ALL WE DON'T GET NEARLY THE

338
00:12:49,624 --> 00:12:52,394
LEVEL OF EXPANSION WITH THE

339
00:12:52,394 --> 00:12:53,962
PRIMARY CELLS FROM THE HEALTHY

340
00:12:53,962 --> 00:12:55,997
DONORS, WE ALSO SEE A DIFFERENT

341
00:12:55,997 --> 00:12:57,232
RESULT WHERE GENERALLY SPEAKING

342
00:12:57,232 --> 00:12:58,767
WITH THE CELLS FROM HEALTHY

343
00:12:58,767 --> 00:13:01,836
DONORS AS YOU INCREASE AMOUNT OF

344
00:13:01,836 --> 00:13:03,271
STIMULATION YOU DRIVE MORE AND

345
00:13:03,271 --> 00:13:04,172
MORE EXPANSION.

346
00:13:04,172 --> 00:13:06,041
WITH THESE CELLS THAT'S NOT

347
00:13:06,041 --> 00:13:06,341
ACCURATE.

348
00:13:06,341 --> 00:13:08,977
AND INDEED IF YOU LOOK AT

349
00:13:08,977 --> 00:13:10,412
DYNABEAD CONDITIONS AS WE GO

350
00:13:10,412 --> 00:13:12,714
MORE DYNABEAD STIMULATION WE

351
00:13:12,714 --> 00:13:14,015
DIMINISH THE EXPANSION WHILE

352
00:13:14,015 --> 00:13:16,751
WITH APC-MS SYSTEM THERE'S

353
00:13:16,751 --> 00:13:18,253
OPTIMAL, TOO LITTLE STIMULATION

354
00:13:18,253 --> 00:13:20,589
DON'T GET A LOT, TOO MUCH WE

355
00:13:20,589 --> 00:13:21,656
LOSE PROLIFERATION AS WELL.

356
00:13:21,656 --> 00:13:24,859
NOW, IF YOU LOOK AT THE 

357
00:13:24,859 --> 00:13:29,864
FUNCTION OF THESE CELLS BY

358
00:13:29,864 --> 00:13:32,400
LOOKING AT CYTOTOXIC ABILITY,

359
00:13:32,400 --> 00:13:33,101
SIGNIFICANTLY DIFFERENT

360
00:13:33,101 --> 00:13:34,369
CYTOTOXIC FUNCTIONALITY OF THESE

361
00:13:34,369 --> 00:13:37,072
CELLS DEPENDING HOW WE

362
00:13:37,072 --> 00:13:38,740
MANUFACTURE THEM.

363
00:13:38,740 --> 00:13:39,741
ACTUALLY, THE ORANGE HERE, .1 IS

364
00:13:39,741 --> 00:13:42,811
THE ONE THAT ALSO LED TO MAXIMAL

365
00:13:42,811 --> 00:13:43,678
STIMULATION, OR MAXIMAL

366
00:13:43,678 --> 00:13:44,079
EXPANSION.

367
00:13:44,079 --> 00:13:46,081
SO IT'S NOT JUST WE'RE HAVING

368
00:13:46,081 --> 00:13:46,715
INVERSE RELATIONSHIP BETWEEN

369
00:13:46,715 --> 00:13:49,451
SUBSTANTIAL AND FUNCTION; WE CAN

370
00:13:49,451 --> 00:13:50,218
ACTUALLY CREATE THESE SYSTEMS

371
00:13:50,218 --> 00:13:54,956
WHERE WE CAN GET OPTIMAL

372
00:13:54,956 --> 00:13:56,458
EXPANSION AND ALSO OPTIMIZE

373
00:13:56,458 --> 00:13:57,993
FUNCTION SIMULTANEOUSLY.

374
00:13:57,993 --> 00:13:59,527
NOW, TO DEMONSTRATE THIS HAD

375
00:13:59,527 --> 00:14:01,730
RELEVANCE IN VIVO IN TERMS OF

376
00:14:01,730 --> 00:14:04,566
TRUE FUNCTIONALITY, WE THEN WENT

377
00:14:04,566 --> 00:14:06,334
AHEAD AND COMPARED CELLS

378
00:14:06,334 --> 00:14:09,271
MANUFACTURED BASICALLY AT THREE

379
00:14:09,271 --> 00:14:10,171
LEVELS OF STIMULATION, IN THE

380
00:14:10,171 --> 00:14:11,406
SAME MODEL.

381
00:14:11,406 --> 00:14:13,108
AGAIN USING CAR T CELL APPROACH.

382
00:14:13,108 --> 00:14:16,711
AND WHAT YOU CAN APPRECIATE IS

383
00:14:16,711 --> 00:14:17,812
EVEN THOUGH WE'RE DELIVERING THE

384
00:14:17,812 --> 00:14:19,648
SAME NUMBER OF CELLS EXPANDED

385
00:14:19,648 --> 00:14:20,782
WITH THE SAME MICROPARTICLE

386
00:14:20,782 --> 00:14:22,484
SYSTEM, THAT DEPENDING ON THE

387
00:14:22,484 --> 00:14:23,852
LEVEL OF STIMULATION WE PROVIDE

388
00:14:23,852 --> 00:14:25,487
WE GET DRAMATIC CHANGES IN THE

389
00:14:25,487 --> 00:14:25,920
FUNCTION.

390
00:14:25,920 --> 00:14:27,789
AND YOU CAN APPRECIATE, FOR

391
00:14:27,789 --> 00:14:29,257
EXAMPLE, THE CELLS STIMULATED AT

392
00:14:29,257 --> 00:14:30,191
THE HIGH ARE MUCH LESS

393
00:14:30,191 --> 00:14:32,193
FUNCTIONAL IN TERMS OF BEING

394
00:14:32,193 --> 00:14:33,728
ABLE TO BASICALLY CLEAR THE

395
00:14:33,728 --> 00:14:35,930
CANCER CELLS FROM THESE ANIMALS

396
00:14:35,930 --> 00:14:37,899
AND HERE YOU JUST SEE SOME OF

397
00:14:37,899 --> 00:14:41,403
THE SURVIVAL DATA AND SOME OF

398
00:14:41,403 --> 00:14:42,771
THE BASICALLY TUMOR BURDEN LOAD.

399
00:14:42,771 --> 00:14:50,378
SO WE CAN HAVE  DRAMATIC IMPACT

400
00:14:50,378 --> 00:14:52,013
IN CELL CULTURE AND THE ANIMAL

401
00:14:52,013 --> 00:14:52,981
IN THESE TYPE OF SYSTEMS.

402
00:14:52,981 --> 00:14:54,649
ONE OF THE CHALLENGES YOU CAN

403
00:14:54,649 --> 00:14:56,384
APPRECIATE FROM THAT LAST SLIDE

404
00:14:56,384 --> 00:14:58,920
IS EACH OF THOSE DOTS WAS AN

405
00:14:58,920 --> 00:15:00,255
INDIVIDUAL PATIENT'S CELLS.

406
00:15:00,255 --> 00:15:01,556
THERE'S GREAT VARIABILITY.

407
00:15:01,556 --> 00:15:02,757
WE ALL APPRECIATE THAT WHEN WE

408
00:15:02,757 --> 00:15:04,492
START GETTING TO REAL PATIENTS.

409
00:15:04,492 --> 00:15:05,827
THERE'S A LOT OF VARIABILITY.

410
00:15:05,827 --> 00:15:07,228
WE BEGAN TO WONDER HOW COULD WE

411
00:15:07,228 --> 00:15:09,998
TRY TO DEAL WITH THIS AND MAYBE

412
00:15:09,998 --> 00:15:11,066
MAKE A MORE HOMOGENOUS PRODUCT

413
00:15:11,066 --> 00:15:11,766
AT THE END.

414
00:15:11,766 --> 00:15:17,005
AND SO WE CAME UP WITH A CONCEPT

415
00:15:17,005 --> 00:15:18,173
THAT MANY PEOPLE PURSUING

416
00:15:18,173 --> 00:15:20,041
SIMILAR THINGS TODAY WHERE WE

417
00:15:20,041 --> 00:15:21,810
COULD START WITH SOME

418
00:15:21,810 --> 00:15:24,179
PHENOTYPING OF THE STARTING T

419
00:15:24,179 --> 00:15:26,948
CELL POPULATION, SO WHAT ARE THE

420
00:15:26,948 --> 00:15:27,148
CELLS.

421
00:15:27,148 --> 00:15:29,217
IF WE SAID WHAT PRODUCT WE WANT

422
00:15:29,217 --> 00:15:31,453
AT THE END, AND THEN WE

423
00:15:31,453 --> 00:15:33,188
BASICALLY USE A.I. APPROACH, TO

424
00:15:33,188 --> 00:15:34,456
FEED IN A LOT OF DATA, TO CREATE

425
00:15:34,456 --> 00:15:40,295
A PRE- PREDICTIVE ALGORITHM HOW

426
00:15:40,295 --> 00:15:41,730
DO WE STIMULATE CELLS FROM GIVEN

427
00:15:41,730 --> 00:15:44,566
POPULATION TO GET TO ENDPOINT WE

428
00:15:44,566 --> 00:15:44,799
WANT?

429
00:15:44,799 --> 00:15:46,601
AND THIS SYSTEM AS I MENTIONED

430
00:15:46,601 --> 00:15:49,137
IS EASY FOR US TO MANIPULATE.

431
00:15:49,137 --> 00:15:52,374
WE TOOK THIS APPROACH, HAD

432
00:15:52,374 --> 00:15:52,974
REASONABLE ACCURACY, 76% IN

433
00:15:52,974 --> 00:15:55,610
TERMS OF BEING ABLE TO PREDICT

434
00:15:55,610 --> 00:15:56,211
FUNCTIONAL CHARACTERISTICS OF

435
00:15:56,211 --> 00:15:58,046
THE CELLS AT THE END, DEPENDING

436
00:15:58,046 --> 00:16:00,348
ON THE INPUT APPROACH AND

437
00:16:00,348 --> 00:16:01,416
MODULATING APC-MS STIMULATION.

438
00:16:01,416 --> 00:16:05,820
SO WE THINK THIS CREATES A PATH

439
00:16:05,820 --> 00:16:07,722
TO BE ABLE TO DEFINE AHEAD OF

440
00:16:07,722 --> 00:16:14,696
TYPE WHAT CAR  CAR T PRODUCTS OR

441
00:16:14,696 --> 00:16:16,064
ADOPTIVE CELL WE WANT AND

442
00:16:16,064 --> 00:16:17,999
PREDICT HOW WE NEED TO STIMULATE

443
00:16:17,999 --> 00:16:20,402
WITH APC-MS TO GET TO CONSISTENT

444
00:16:20,402 --> 00:16:22,604
PRODUCT IN THE END INDEPENDENTLY

445
00:16:22,604 --> 00:16:23,505
OF INPUT PATIENT PROPERTIES,

446
00:16:23,505 --> 00:16:26,007
THIS COULD BE USEFUL POTENTIALLY

447
00:16:26,007 --> 00:16:27,008
FROM THAT PERSPECTIVE.

448
00:16:27,008 --> 00:16:28,743
THE OTHER THING I WANT TO SPEND

449
00:16:28,743 --> 00:16:30,712
A FEW MINUTES TALKING ABOUT IN

450
00:16:30,712 --> 00:16:34,449
THE CONTEXT OF NOT POLYCLONAL T

451
00:16:34,449 --> 00:16:35,517
CELL EXPANSION BUT

452
00:16:35,517 --> 00:16:36,384
ANTIGEN-SPECIFIC T CELL

453
00:16:36,384 --> 00:16:38,486
EXPANSION, MCI HAS BEEN A REAL

454
00:16:38,486 --> 00:16:40,021
PIONEER AND HOME FOR TIL

455
00:16:40,021 --> 00:16:41,990
STRATEGIES, WE'VE BEEN

456
00:16:41,990 --> 00:16:42,991
INTERESTED IN ANTIGEN-SPECIFIC

457
00:16:42,991 --> 00:16:44,292
T-CELL THERAPIES AS WELL.

458
00:16:44,292 --> 00:16:46,027
AND ONE OF THE LIMITATIONS THERE

459
00:16:46,027 --> 00:16:49,063
IS ABILITY TO REALLY EXPAND

460
00:16:49,063 --> 00:16:50,231
THESE CELLS, PARTICULARLY WITH

461
00:16:50,231 --> 00:16:51,566
THE APCs THAT COME FROM THE

462
00:16:51,566 --> 00:16:54,502
SAME PARTICIPANT-CENTERED. --

463
00:16:54,502 --> 00:16:54,836
PATIENT.

464
00:16:54,836 --> 00:16:56,604
WE THOUGHT THAT MIGHT BE USEFUL

465
00:16:56,604 --> 00:16:58,406
FROM THAT PERSPECTIVE.

466
00:16:58,406 --> 00:17:00,575
FIRST WORK WAS WE LOOKED FOR

467
00:17:00,575 --> 00:17:02,444
BASICALLY EXPANSION IN THIS CASE

468
00:17:02,444 --> 00:17:05,613
MART 1 SPECIFIC T CELLS.

469
00:17:05,613 --> 00:17:07,248
WHICH ARE BASICALLY COMMON T

470
00:17:07,248 --> 00:17:09,050
CELL ANTIGEN, CONTEXT OF

471
00:17:09,050 --> 00:17:10,552
MELANOMA, THAT EXISTS OFTENTIMES

472
00:17:10,552 --> 00:17:11,886
IN OTHERWISE HEALTHY PATIENTS.

473
00:17:11,886 --> 00:17:15,123
SO HERE WE'RE LOOKING AT ABILITY

474
00:17:15,123 --> 00:17:21,496
TO EXPAND AND ENRICH MART1 CELLS

475
00:17:21,496 --> 00:17:22,530
CELLS FROM PATIENT SAMPLES.

476
00:17:22,530 --> 00:17:27,735
SIMP 

477
00:17:27,735 --> 00:17:29,504
 DEPENDING ON AMOUNT OF

478
00:17:29,504 --> 00:17:32,540
STIMULATION FROM ANTIGEN

479
00:17:32,540 --> 00:17:33,541
PRESENTING MIMICS, .1, .5, 1%

480
00:17:33,541 --> 00:17:35,510
RELATES TO HOW MUCH SUBSTITUTION

481
00:17:35,510 --> 00:17:36,644
WE PUT IN ANTIBODIES ON THE

482
00:17:36,644 --> 00:17:38,580
ARTICLES, YOU CAN SEE WE HAVE

483
00:17:38,580 --> 00:17:40,782
DRAMATIC EFFECT ON EXPANSION AND

484
00:17:40,782 --> 00:17:42,183
ENRICHMENT, AND WE GUT UP TO 10

485
00:17:42,183 --> 00:17:43,618
TO THE 4th EXPANSION OF CELLS

486
00:17:43,618 --> 00:17:46,154
OVER THE TIME COURSE OF A COUPLE

487
00:17:46,154 --> 00:17:47,989
WEEKS WITH THE OPTIMIZED SYSTEM.

488
00:17:47,989 --> 00:17:52,727
THIS WORK IS BEING DONE BY NIKO

489
00:17:52,727 --> 00:17:57,198
IN CATHY'S LAB, AND A PEDIATRIC

490
00:17:57,198 --> 00:17:58,800
HEMATOLOGIST/ONCOLOGIST AT

491
00:17:58,800 --> 00:17:59,400
CHILDREN'S HOSPITAL, AND

492
00:17:59,400 --> 00:18:01,336
DANA-FARBER DOING RESEARCH IN

493
00:18:01,336 --> 00:18:01,736
THE LABORATORY.

494
00:18:01,736 --> 00:18:05,607
NOW, ONE OF THE QUESTIONS IS HOW

495
00:18:05,607 --> 00:18:08,476
DOES THIS FUNCTION RELATIVE TO

496
00:18:08,476 --> 00:18:09,244
TYPICAL MONOCYTE DERIVED TCs

497
00:18:09,244 --> 00:18:11,546
USED FOR EXPANSION OF THESE

498
00:18:11,546 --> 00:18:12,547
CELLS?

499
00:18:12,547 --> 00:18:13,848
WE'VE DONE DIRECT HEAD-TO-HEAD

500
00:18:13,848 --> 00:18:15,817
COMPARISON, BOTH AGAIN IN TERMS

501
00:18:15,817 --> 00:18:18,119
OF THEIR ABILITY TO ENRICH THE

502
00:18:18,119 --> 00:18:19,554
POPULATION, AND ACTUALLY TO

503
00:18:19,554 --> 00:18:20,321
EXPAND THE CELLS.

504
00:18:20,321 --> 00:18:21,823
WHAT YOU CAN APPRECIATE FROM

505
00:18:21,823 --> 00:18:23,825
BOTH THESE METRICS ON THE GRAPHS

506
00:18:23,825 --> 00:18:26,628
ON THE LEFT THAT WE'RE ABLE TO

507
00:18:26,628 --> 00:18:28,530
GET MUCH GREATER ENRICHMENT, AND

508
00:18:28,530 --> 00:18:29,931
ABOUT, YOU KNOW, LOG, LOG AND A

509
00:18:29,931 --> 00:18:32,267
HALF MORE EXPANSION OF THE MART1

510
00:18:32,267 --> 00:18:34,202
SPECIFIC CELLS WITH THIS SYSTEM

511
00:18:34,202 --> 00:18:35,537
THAN IS POSSIBLE WITH BASICALLY

512
00:18:35,537 --> 00:18:39,240
THE NATURAL CELL ONE WOULD USE.

513
00:18:39,240 --> 00:18:40,008
THERE'S GREAT VARIABILITY

514
00:18:40,008 --> 00:18:41,109
DEPENDING ON SPECIFIC PATIENT

515
00:18:41,109 --> 00:18:48,483
FROM  FROM WHICH WE OBTAIN THE

516
00:18:48,483 --> 00:18:48,683
CELLS.

517
00:18:48,683 --> 00:18:50,118
WE'VE LOST A LOT OF PARTS ON THE

518
00:18:50,118 --> 00:18:52,120
GRAFT BUT ON THE RIGHT YOU CAN

519
00:18:52,120 --> 00:18:54,422
GET A SENSE OF THE DOT ON THE

520
00:18:54,422 --> 00:18:58,159
LEFT, AND CIRCLE ON THE RIGHT,

521
00:18:58,159 --> 00:19:01,229
IS CONNECTING INITIAL POPULATION

522
00:19:01,229 --> 00:19:03,531
OF MART1 CELLS IN THAT SAMPLE,

523
00:19:03,531 --> 00:19:04,599
THE BUBBLE ON THE RIGHT IS END

524
00:19:04,599 --> 00:19:06,234
OF THE EXPANSION.

525
00:19:06,234 --> 00:19:07,635
THERE'S A GREAT VARIABILITY

526
00:19:07,635 --> 00:19:10,138
BETWEEN THE INDIVIDUAL PATIENT

527
00:19:10,138 --> 00:19:12,073
SAMPLES, IN ALL CASES APC-MS LED

528
00:19:12,073 --> 00:19:14,242
TO MUCH MORE DRAMATIC EXPANSION

529
00:19:14,242 --> 00:19:17,111
OF THESE ANTIGEN-SPECIFIC CELLS

530
00:19:17,111 --> 00:19:18,846
THAN DID THE MONOCYTE-DERIVED

531
00:19:18,846 --> 00:19:19,414
DENDRITIC CELLS.

532
00:19:19,414 --> 00:19:20,715
NOW, IN TERMS OF FUNCTION OF

533
00:19:20,715 --> 00:19:22,050
THESE CELLS, WE'RE ALSO VERY

534
00:19:22,050 --> 00:19:23,017
INTERESTED OBVIOUSLY NOT JUST IN

535
00:19:23,017 --> 00:19:25,320
THE NUMBERS BUT ALSO THE

536
00:19:25,320 --> 00:19:26,521
FUNCTION, AND WE'VE DEMONSTRATED

537
00:19:26,521 --> 00:19:28,356
WE CAN GENERATE CELLS THAT LOOK

538
00:19:28,356 --> 00:19:29,891
LIKE THEY HAVE A BETTER

539
00:19:29,891 --> 00:19:32,860
PHENOTYPE IN TERMS OF ADOPTIVE

540
00:19:32,860 --> 00:19:33,861
CELL THERAPY.

541
00:19:33,861 --> 00:19:37,465
IN THIS WE'RE LOOKING AT GREEN

542
00:19:37,465 --> 00:19:41,135
BASICALLY APC-MS-EXPANDED CELLS,

543
00:19:41,135 --> 00:19:41,869
LIGHT BLUE MONOCYTE DERIVED, ON

544
00:19:41,869 --> 00:19:48,810
THE LEFT A FEW MARKERS, IL7

545
00:19:48,810 --> 00:19:52,380
RECEPTOR HLA-DR, PD-1, BETTER

546
00:19:52,380 --> 00:19:53,047
PHENOACTIVIC CHARACTERISTICS, ON

547
00:19:53,047 --> 00:19:54,983
THE RIGHT WE BRING TOGETHER A

548
00:19:54,983 --> 00:19:56,618
LOT OF THE DATA WITH ALL THE

549
00:19:56,618 --> 00:19:58,152
DIFFERENT MARKERS AND WHAT YOU

550
00:19:58,152 --> 00:20:01,122
CAN APPRECIATE IS THE KIND OF

551
00:20:01,122 --> 00:20:02,757
PHENOTYPE WE RESULT WITH APC-MS

552
00:20:02,757 --> 00:20:04,092
SYSTEM IS PROBABLY ONE THAT

553
00:20:04,092 --> 00:20:06,160
WOULD BE BENEFICIAL IN TERMS OF

554
00:20:06,160 --> 00:20:07,362
OUTCOMES AND IN TERMS OF PATIENT

555
00:20:07,362 --> 00:20:10,164
TREATMENTS WITH THESE CELLS AS

556
00:20:10,164 --> 00:20:10,965
COMPARED TO MONOCYTE-DERIVED

557
00:20:10,965 --> 00:20:11,199
DCs.

558
00:20:11,199 --> 00:20:15,003
WE CAN EXPAND THE CELLS MORE

559
00:20:15,003 --> 00:20:16,537
RAPIDLY, ENRICH THEM FOR

560
00:20:16,537 --> 00:20:17,438
SIGNIFICANTLY AND GET CELLS THAT

561
00:20:17,438 --> 00:20:18,973
LOOK LIKE THEY HAVE GREATER

562
00:20:18,973 --> 00:20:20,642
FUNCTIONALITY AT THE SAME TIME.

563
00:20:20,642 --> 00:20:24,846
NOW, WE ALSO HAVE LOOKED AT THE

564
00:20:24,846 --> 00:20:27,582
FUNCTION AFFINITY OF THE T CELLS

565
00:20:27,582 --> 00:20:29,651
BASICALLY FOR THE PEPTIDE

566
00:20:29,651 --> 00:20:31,586
ANTIGEN, AND WE SEE

567
00:20:31,586 --> 00:20:32,520
STATISTICALLY SIGNIFICANT

568
00:20:32,520 --> 00:20:36,324
ENHANCEMENT IN TERMS OF MART1

569
00:20:36,324 --> 00:20:37,325
TCR AFFINITY, ALL THE METRICS

570
00:20:37,325 --> 00:20:39,193
THAT WE'VE BEEN ABLE TO LOOK AT,

571
00:20:39,193 --> 00:20:40,728
AT THIS POINT IN TIME WE THINK

572
00:20:40,728 --> 00:20:42,363
THIS COULD BE A NICE TECHNOLOGY

573
00:20:42,363 --> 00:20:44,766
FOR EXPANSION OF TILs AND

574
00:20:44,766 --> 00:20:46,634
OTHER ANTIGEN-SPECIFIC T CELLS

575
00:20:46,634 --> 00:20:47,602
POPULATIONS FOR ADOPTIVE

576
00:20:47,602 --> 00:20:47,835
THERAPY.

577
00:20:47,835 --> 00:20:51,739
WE'VE STARTED TO DO A LITTLE BIT

578
00:20:51,739 --> 00:20:53,608
OF WORK WITH BASICALLY MELANOMA

579
00:20:53,608 --> 00:20:55,543
PATIENTS, IN THIS CASE TREATMENT

580
00:20:55,543 --> 00:20:56,844
NAIVE MELANOMA PATIENTS.

581
00:20:56,844 --> 00:21:00,948
WHERE WE BASICALLY HAVE DONE

582
00:21:00,948 --> 00:21:03,117
BLOOD DRAWS, WE'VE SCREENED

583
00:21:03,117 --> 00:21:05,219
BASICALLY FOR HLA2, BASICALLY

584
00:21:05,219 --> 00:21:07,922
THE MHC THAT WE'RE BASICALLY

585
00:21:07,922 --> 00:21:10,191
PRESENTING FROM THE APC-MS, AND

586
00:21:10,191 --> 00:21:12,060
THEN BASICALLY EXPLORING WHETHER

587
00:21:12,060 --> 00:21:14,562
WE CAN EXPAND MART1 CELLS FROM

588
00:21:14,562 --> 00:21:15,797
THEIRS THESE PATIENTS.

589
00:21:15,797 --> 00:21:20,368
ABOUT 5 OF THE 8 CELLS, 5 OF 8

590
00:21:20,368 --> 00:21:21,703
PATIENTS FROM WHO WE RECEIVE

591
00:21:21,703 --> 00:21:25,973
SAMPLES TO DATE WE SAW

592
00:21:25,973 --> 00:21:26,841
SIGNIFICANT EXPANSION, GREATER

593
00:21:26,841 --> 00:21:34,148
THAN 5% OF C  -- T CELL

594
00:21:34,148 --> 00:21:41,255
ENRICHMENT, A FEW GAVE DRAMATIC

595
00:21:41,255 --> 00:21:42,356
RESULTS, PATIENT 11, 55% WERE

596
00:21:42,356 --> 00:21:43,191
MART1 SPECIFIC.

597
00:21:43,191 --> 00:21:45,727
THE GRAPH ON THE RIGHT SHOWS

598
00:21:45,727 --> 00:21:47,395
DISTRIBUTION WHERE WE HAD A

599
00:21:47,395 --> 00:21:48,496
PRETTY GOOD RESPONSE FROM THE

600
00:21:48,496 --> 00:21:49,630
MAJORITY OF PATIENTS, WE THINK

601
00:21:49,630 --> 00:21:50,932
THE STRATEGY WILL BE USEFUL

602
00:21:50,932 --> 00:21:53,201
BROADLY, NOT JUST FROM THE

603
00:21:53,201 --> 00:21:55,303
CONTEXT OF HEALTHY T CELLS BUT

604
00:21:55,303 --> 00:21:57,338
ALSO THOSE FROM PATIENTS WITH

605
00:21:57,338 --> 00:21:58,973
DISEASE, AND WE HAVE SOME

606
00:21:58,973 --> 00:22:01,175
ONGOING EFFORTS NOW TO TAKE SOME

607
00:22:01,175 --> 00:22:04,812
OF THE PATIENT SAMPLES FROM SOME

608
00:22:04,812 --> 00:22:06,647
OF CATHY WU'S NEW ANTIGEN

609
00:22:06,647 --> 00:22:10,017
VACCINE TRIALS AND SEE IF KEY

610
00:22:10,017 --> 00:22:11,319
CAN EXPAND OUT SPECIFIC

611
00:22:11,319 --> 00:22:13,521
POPULATIONS IN THE SAMPLES FROM

612
00:22:13,521 --> 00:22:15,923
PATIENT CLINICAL TRIALS.

613
00:22:15,923 --> 00:22:17,892
SO, THE LAST THING I WANT TO

614
00:22:17,892 --> 00:22:20,061
MENTION ABOUT THIS SYSTEM, WE'RE

615
00:22:20,061 --> 00:22:21,295
ALSO THINKING THAT, WELL, MAYBE

616
00:22:21,295 --> 00:22:23,564
WE COULD USE IT BEYOND IN CELL

617
00:22:23,564 --> 00:22:25,099
CULTURE TO EXPAND T CELL

618
00:22:25,099 --> 00:22:26,334
POPULATIONS IN TERMS OF

619
00:22:26,334 --> 00:22:27,168
MANUFACTURING, MAYBE WE COULD

620
00:22:27,168 --> 00:22:29,470
ALSO USE IT TO ACTUALLY BOOST T

621
00:22:29,470 --> 00:22:31,572
CELLS THAT ARE ALREADY IN THE

622
00:22:31,572 --> 00:22:32,673
BODY.

623
00:22:32,673 --> 00:22:38,246
AND SO THE FIRST FORAY INTO THIS

624
00:22:38,246 --> 00:22:40,882
WAS WORK BY DAVID DANE, AND

625
00:22:40,882 --> 00:22:45,353
JOSHUA MOVED TO HIS OWN FACULTY

626
00:22:45,353 --> 00:22:46,821
POSITION, UNIVERSITY OF

627
00:22:46,821 --> 00:22:48,356
WISCONSIN, JOSH BROCKMAN.

628
00:22:48,356 --> 00:22:50,124
IF IT'S NOT PROVING TO BE

629
00:22:50,124 --> 00:22:52,627
EFFECTIVE COULD WE JUST DO A

630
00:22:52,627 --> 00:22:54,028
SIMPLE SUBCUTANEOUS INJECTION OF

631
00:22:54,028 --> 00:22:55,463
PARTICLES, HAVE THE CELLS HOME

632
00:22:55,463 --> 00:22:58,199
SO THE PARTICLES GET A I

633
00:22:58,199 --> 00:23:00,401
APPROPRIATE STIMULATION AND

634
00:23:00,401 --> 00:23:02,603
EXPAND AND ALTER PHENOTYPE OF

635
00:23:02,603 --> 00:23:03,771
THESE CELLS, STRAIGHTFORWARD

636
00:23:03,771 --> 00:23:04,639
IDEA.

637
00:23:04,639 --> 00:23:06,407
THE FIRST EXAMPLE WE'VE JUST

638
00:23:06,407 --> 00:23:06,774
COMPLETED.

639
00:23:06,774 --> 00:23:11,879
THIS IS IN CONTEXT OF POLYCLONAL

640
00:23:11,879 --> 00:23:13,581
T CELL EXPANSION USING THE SAME

641
00:23:13,581 --> 00:23:16,918
MODEL WITH T-CELL THERAPY IN

642
00:23:16,918 --> 00:23:20,655
IMMUNOCOMPROMISED ANIMALS.

643
00:23:20,655 --> 00:23:21,956
UNTREATED ANIMALS SUCCUMB

644
00:23:21,956 --> 00:23:22,590
RAPIDLY.

645
00:23:22,590 --> 00:23:25,426
IF WE PROVIDE CAR T AND

646
00:23:25,426 --> 00:23:26,727
PURPOSELY DELIVER SUBTHERAPEUTIC

647
00:23:26,727 --> 00:23:29,897
DOSE TO CAR-T CELLS, SO IT WOULD

648
00:23:29,897 --> 00:23:34,368
BE PARTIALLY EFFECTIVE LOSING

649
00:23:34,368 --> 00:23:36,671
EFFECTIVENESS WITH TIME AND

650
00:23:36,671 --> 00:23:37,538
INJECTED WITHOUT STIMULATORY

651
00:23:37,538 --> 00:23:40,942
CUES THEY WERE ALSO INEFFECTIVE.

652
00:23:40,942 --> 00:23:45,112
IF WE DELIVERED CUES WITH THE T

653
00:23:45,112 --> 00:23:47,148
CELL, TCR STIMULATION AND

654
00:23:47,148 --> 00:23:49,083
CO-STIMULATION, ALSO RELEASING

655
00:23:49,083 --> 00:23:50,785
SMALL AMOUNT OF IL-2 WE GOT

656
00:23:50,785 --> 00:23:52,954
GREATER RESPONSE, I'M NOT

657
00:23:52,954 --> 00:23:54,622
SHOWING DATA, BUT DUE TO THE

658
00:23:54,622 --> 00:23:57,892
FACT WE GOT RESTIMULATION OF T

659
00:23:57,892 --> 00:23:58,793
CELLS, EXPANSION OF DELIVERED

660
00:23:58,793 --> 00:24:01,028
CAR-T CELLS, AND THAT SEEMED TO

661
00:24:01,028 --> 00:24:02,196
UNDERLIE EFFECTIVENESS IN THIS

662
00:24:02,196 --> 00:24:03,464
KIND OF MODEL.

663
00:24:03,464 --> 00:24:06,100
SO WE THINK THIS COULD

664
00:24:06,100 --> 00:24:06,701
POTENTIALLY BE INTERESTING IN

665
00:24:06,701 --> 00:24:14,075
THE FUTURE FROM  POTENTIAL OF

666
00:24:14,075 --> 00:24:15,743
DIRECT IN VIVO EXPANSION IN

667
00:24:15,743 --> 00:24:16,310
POPULATIONS OF INTEREST AS

668
00:24:16,310 --> 00:24:20,681
WEVMENT  -- WELL.

669
00:24:20,681 --> 00:24:22,850
HOPEFULLY, HOW WE CAN PROVIDE A

670
00:24:22,850 --> 00:24:26,153
VARIETY OF CUES, WITH THESE

671
00:24:26,153 --> 00:24:28,890
PARTICLES, WITH THIS WE CAN MORE

672
00:24:28,890 --> 00:24:31,125
RAPIDLY EXPAND T CELLS, WE CAN

673
00:24:31,125 --> 00:24:32,627
TUNE THE PRODUCTS, WE CAN

674
00:24:32,627 --> 00:24:33,494
GENERATE HIGHER FUNCTIONALITY,

675
00:24:33,494 --> 00:24:34,528
AND WE THINK THIS COULD BE

676
00:24:34,528 --> 00:24:36,697
RELEVANT IN A NUMBER OF

677
00:24:36,697 --> 00:24:37,632
CONTEXTS.

678
00:24:37,632 --> 00:24:40,534
BEYOND T CELL BIOLOGY, OR THIS

679
00:24:40,534 --> 00:24:43,604
PART OF T CELL BIOLOGY WE'VE

680
00:24:43,604 --> 00:24:44,472
BEEN EXPLORING ALTERNATIVE

681
00:24:44,472 --> 00:24:45,673
INPUTS, VARIETY OF DIFFERENT

682
00:24:45,673 --> 00:24:48,709
TYPES OF SIGNALS WE COULD

683
00:24:48,709 --> 00:24:49,510
PROVIDE FROM THESE MATERIALS,

684
00:24:49,510 --> 00:24:50,811
AND THEN WE'RE ALSO BEGINNING TO

685
00:24:50,811 --> 00:24:53,314
THINK ABOUT THIS AS BEING A

686
00:24:53,314 --> 00:24:53,981
BROADLY USEFUL PLATFORM FOR

687
00:24:53,981 --> 00:24:56,517
EXPANSION OF A VARIETY OF CELL

688
00:24:56,517 --> 00:25:00,121
TYPES BEYOND T CELLS, SO, FOR

689
00:25:00,121 --> 00:25:01,756
EXAMPLE, IN COLLABORATION WITH A

690
00:25:01,756 --> 00:25:03,891
LABORATORY AT THE DANA-FARBER

691
00:25:03,891 --> 00:25:05,293
WE'VE BEEN LOOKING AT NK CELL

692
00:25:05,293 --> 00:25:08,763
EXPANSION, MANY OF YOU ARE QUITE

693
00:25:08,763 --> 00:25:10,231
FAMILIAR, THEY ARE OF GREAT

694
00:25:10,231 --> 00:25:11,866
INTEREST TODAY, EXPANSION OF

695
00:25:11,866 --> 00:25:13,067
THESE CELLS IS PROBLEMATIC.

696
00:25:13,067 --> 00:25:14,702
BUT WHAT WE'VE BEEN ABLE TO

697
00:25:14,702 --> 00:25:17,238
DEMONSTRATE WITH THIS SYSTEM IN

698
00:25:17,238 --> 00:25:21,275
THIS CASE PRESENTING IL-21 AND

699
00:25:21,275 --> 00:25:25,713
4-1BBL, JOHN CUE -- CONJUGATED

700
00:25:25,713 --> 00:25:28,015
TO THE MEMBRANE CAN GET UP TO

701
00:25:28,015 --> 00:25:28,816
2,000-FOLD EXPANSION OVER THE

702
00:25:28,816 --> 00:25:30,518
TIME COURSE OF A FEW WEEKS AND

703
00:25:30,518 --> 00:25:32,253
CELLS WE'VE EXPANDED AGAIN STAY

704
00:25:32,253 --> 00:25:33,487
HIGHLY FUNCTIONAL.

705
00:25:33,487 --> 00:25:35,156
WE THINK THIS KIND OF STRATEGY,

706
00:25:35,156 --> 00:25:36,324
THIS KIND OF APPROACH MIGHT BE

707
00:25:36,324 --> 00:25:39,593
USEFUL IN A VARIETY OF CONTEXTS

708
00:25:39,593 --> 00:25:41,195
BEYOND T CELLS.

709
00:25:41,195 --> 00:25:41,395
OKAY.

710
00:25:41,395 --> 00:25:43,898
SO I'D LIKE TO CHANGE GEARS NOW

711
00:25:43,898 --> 00:25:45,866
AND TALK ABOUT ANOTHER ASPECT OF

712
00:25:45,866 --> 00:25:47,935
THE TECHNOLOGY, AGAIN RELATED TO

713
00:25:47,935 --> 00:25:48,936
T CELL BIOLOGY.

714
00:25:48,936 --> 00:25:52,406
BUT HERE THE IDEA OF TRYING TO

715
00:25:52,406 --> 00:25:53,874
DEGENERATE T-CELL RESPONSES

716
00:25:53,874 --> 00:25:55,309
USING THERAPEUTIC VACCINATION.

717
00:25:55,309 --> 00:25:56,477
THE GENERAL STRATEGY WE FOLLOW

718
00:25:56,477 --> 00:25:59,547
IN THE LABORATORY SHOWN IN THIS

719
00:25:59,547 --> 00:26:01,549
SLIDE, WHICH WE FIRST PROPOSED

720
00:26:01,549 --> 00:26:03,017
NOW 15 YEARS AGO.

721
00:26:03,017 --> 00:26:04,318
AND WHAT WE PROPOSED AT THAT

722
00:26:04,318 --> 00:26:06,187
POINT IN TIME IS THAT ONE COULD

723
00:26:06,187 --> 00:26:07,855
TAKE A BIOMATERIAL AND ONE COULD

724
00:26:07,855 --> 00:26:13,227
PLACE IT IN THE BODY, AND IF IT

725
00:26:13,227 --> 00:26:15,629
RELEASED WHAT WE CALL RECRUITING

726
00:26:15,629 --> 00:26:21,435
FACTORS, IN THE CONTEXT OF MY

727
00:26:21,435 --> 00:26:28,509
COMMENTS TODAY THAT WILL BE

728
00:26:28,509 --> 00:26:30,277
GMC-MS, COULD DRAW IN

729
00:26:30,277 --> 00:26:31,779
POPULATIONS BY CHEMOTAXIS,

730
00:26:31,779 --> 00:26:39,887
AIMING TO BRING IN IMMATURE

731
00:26:39,887 --> 00:26:42,223
DENDRITIC CELLS, PROVIDE

732
00:26:42,223 --> 00:26:43,391
APPROPRIATE AGENTS, IN THE

733
00:26:43,391 --> 00:26:46,193
CONTEXT OF CANCER AND ADJUVANTS

734
00:26:46,193 --> 00:26:48,029
TO ACTIVATE CELLS, LOAD THEM

735
00:26:48,029 --> 00:26:49,563
WITH ANTIGENS, AND INDUCE THEM

736
00:26:49,563 --> 00:26:51,065
TO ACTUALLY THEN RETURN TO THE

737
00:26:51,065 --> 00:26:52,133
DRAINING LYMPH NODES.

738
00:26:52,133 --> 00:26:55,436
A KEY FEATURE HERE IS THAT THIS

739
00:26:55,436 --> 00:26:57,405
IS NOT A ONE SHOT.

740
00:26:57,405 --> 00:26:59,373
THIS IS A CONTINUOUS PROCESS.

741
00:26:59,373 --> 00:27:02,243
WE THOUGHT OF THIS AS A CELL

742
00:27:02,243 --> 00:27:04,111
FACTORY IN THE BODY, YOU'RE

743
00:27:04,111 --> 00:27:04,712
CONTINUOUSLY BRINGING IN CELLS

744
00:27:04,712 --> 00:27:06,747
FOR A PERIOD OF TIME, ACTIVATING

745
00:27:06,747 --> 00:27:07,715
THEM, LOADING WITH ANTIGEN,

746
00:27:07,715 --> 00:27:09,116
SENDING THEM TO THE DRAINING

747
00:27:09,116 --> 00:27:13,721
LYMPH NODES, TO THEN INDUCE

748
00:27:13,721 --> 00:27:14,255
ADAPTIVE IMMUNE RESPONSE.

749
00:27:14,255 --> 00:27:19,126
THAT WAS THE GENERAL IDEA.

750
00:27:19,126 --> 00:27:26,867
FIRST GENERATION DEVICE WAS

751
00:27:26,867 --> 00:27:27,701
WD-VAK FROM POLYMERS USED TO

752
00:27:27,701 --> 00:27:31,906
MAKE SUTURES.

753
00:27:31,906 --> 00:27:34,442
A LYSATE OBTAINED FROM BIOPSY OF

754
00:27:34,442 --> 00:27:36,243
TUMORS, AN ADJUVANT, A SMALL

755
00:27:36,243 --> 00:27:39,246
TABLET ABOUT THE SIZE OF A BABY

756
00:27:39,246 --> 00:27:40,548
ASPIRIN UNDER THE SKIN OF A

757
00:27:40,548 --> 00:27:41,482
PATIENT.

758
00:27:41,482 --> 00:27:43,918
WE DID ALL THE PRE-CLINICAL

759
00:27:43,918 --> 00:27:46,687
STUDIES, PHASE 1 CLINICAL TRIAL

760
00:27:46,687 --> 00:27:49,557
RUN BY STEVE HODE AT THE

761
00:27:49,557 --> 00:27:54,495
DANA-FARBER, THIS IS STEVE WITH 

762
00:27:54,495 --> 00:27:55,763
ONE OF THE FIRST PATIENTS THAT

763
00:27:55,763 --> 00:27:57,298
RECEIVED THE PLASTIC UNDER THE

764
00:27:57,298 --> 00:27:59,600
SKIN TO TREAT MELANOMA.

765
00:27:59,600 --> 00:28:00,968
I'LL LEAVE IT TO STEVE TO

766
00:28:00,968 --> 00:28:03,104
PRESENT THE OUTCOME IN TERMS OF

767
00:28:03,104 --> 00:28:05,840
CLINICALLY THE OUTCOME BUT FROM

768
00:28:05,840 --> 00:28:06,941
AN ENGINEERING PERSPECTIVE

769
00:28:06,941 --> 00:28:09,110
THERE'S TWO KEY OBSERVATIONS WE

770
00:28:09,110 --> 00:28:09,343
MADE.

771
00:28:09,343 --> 00:28:12,746
THAT WERE LIMITATIONS OF THIS

772
00:28:12,746 --> 00:28:13,047
TECHNOLOGY.

773
00:28:13,047 --> 00:28:16,650
ONE IS THAT WE HAD TO DO A SMALL

774
00:28:16,650 --> 00:28:18,152
INCISION, PLACE OUT UNDER THE

775
00:28:18,152 --> 00:28:18,452
SKIN.

776
00:28:18,452 --> 00:28:20,654
THAT WAS OKAY BUT NOT IDEAL.

777
00:28:20,654 --> 00:28:22,723
YOU'D RATHER HAVE A MINIMALLY

778
00:28:22,723 --> 00:28:24,024
INVASIVE DELIVERY.

779
00:28:24,024 --> 00:28:27,228
THE SECOND LIMITATION IS THAT WE

780
00:28:27,228 --> 00:28:28,496
COULDN'T ACTUALLY FABRICATE THIS

781
00:28:28,496 --> 00:28:29,830
VACCINE, UNTIL WE HAD THE

782
00:28:29,830 --> 00:28:32,466
ANTIGEN OF INTEREST FROM THE

783
00:28:32,466 --> 00:28:32,700
PATIENT.

784
00:28:32,700 --> 00:28:35,569
WHICH MEANS WE DO A BIOPSY, WE

785
00:28:35,569 --> 00:28:37,204
WOULD BASICALLY MORE OR LESS

786
00:28:37,204 --> 00:28:39,573
FREEZE DRY IT, AND THEN MAKE THE

787
00:28:39,573 --> 00:28:39,807
VACCINE.

788
00:28:39,807 --> 00:28:41,442
SO THIS RESULTED IN DELAY OF

789
00:28:41,442 --> 00:28:43,043
MULTIPLE WEEKS BEFORE WE COULD

790
00:28:43,043 --> 00:28:44,245
TREAT A PATIENT.

791
00:28:44,245 --> 00:28:46,113
SO, WE THOUGHT WE NEEDED TO MOVE

792
00:28:46,113 --> 00:28:48,549
ON TO A NEXT GENERATION SYSTEM

793
00:28:48,549 --> 00:28:51,519
THAT WOULD OVERCOME THESE

794
00:28:51,519 --> 00:28:51,819
LIMITATIONS.

795
00:28:51,819 --> 00:28:53,287
I SHOULD ALSO MENTION THIS

796
00:28:53,287 --> 00:28:55,890
TECHNOLOGY WAS LICENSED BY

797
00:28:55,890 --> 00:29:02,897
NOVARTIS AND IN PART BY A SMALL

798
00:29:02,897 --> 00:29:03,164
START-UP.

799
00:29:03,164 --> 00:29:03,864
ATAVARE.

800
00:29:03,864 --> 00:29:05,299
ONE OF THE SYSTEMS IS SHOWN

801
00:29:05,299 --> 00:29:05,766
HERE.

802
00:29:05,766 --> 00:29:07,601
WE DECIDED TO USE THE SAME TYPE

803
00:29:07,601 --> 00:29:09,703
OF MICROPARTICLES THAT I JUST

804
00:29:09,703 --> 00:29:12,406
DESCRIBED THAT WE'RE USING FOR

805
00:29:12,406 --> 00:29:13,174
ARTIFICIAL ANTIGEN-PRESENTING

806
00:29:13,174 --> 00:29:15,376
CELLS HERE WITHOUT A LIPID

807
00:29:15,376 --> 00:29:16,710
COATING, USING THESE AS MICRO

808
00:29:16,710 --> 00:29:27,087
PARTICLES TO WHICH WE CAN ABSORB

809
00:29:27,087 --> 00:29:28,656
DIFFERENT CARGOES ON DIFFERENT

810
00:29:28,656 --> 00:29:35,829
SETS OF MICROPARTICLES, ALTERING

811
00:29:35,829 --> 00:29:37,898
THE CHEMISTRY, MIX AND MATCH

812
00:29:37,898 --> 00:29:40,734
DIFFERENT PARTICLES THAT MAYBE

813
00:29:40,734 --> 00:29:44,471
ONE WOULD HAVE ADJUVANT, ONE

814
00:29:44,471 --> 00:29:45,573
GCM-MS, ANOTHER AN ANTIGEN OF

815
00:29:45,573 --> 00:29:46,006
INTEREST.

816
00:29:46,006 --> 00:29:48,876
WE CAN MAKE THE SYSTEM, AND WE

817
00:29:48,876 --> 00:29:51,045
HAVE THEM READY TO BE USED IN A

818
00:29:51,045 --> 00:29:52,346
PATIENT AND IF WE'RE OBTAINING

819
00:29:52,346 --> 00:29:54,215
ANTIGEN FROM A PATIENT WE CAN

820
00:29:54,215 --> 00:29:55,249
JUST ABSORB TO THESE PARTICLES

821
00:29:55,249 --> 00:29:57,718
AFTER THEY HAVE BEEN FULLY

822
00:29:57,718 --> 00:29:58,919
MANUFACTURED, AND I'LL SHOW YOU

823
00:29:58,919 --> 00:30:00,754
NEXT DATA FROM THAT APPROACH.

824
00:30:00,754 --> 00:30:03,724
ABSORB IT FOR A COUPLE HOURS AND

825
00:30:03,724 --> 00:30:05,359
INJECT, MAKE IT NEEDLE

826
00:30:05,359 --> 00:30:06,460
INJECTABLE AND MINIMIZE THE WAIT

827
00:30:06,460 --> 00:30:09,830
BEFORE WE CAN ACTUALLY MOVE TO

828
00:30:09,830 --> 00:30:10,097
TREATMENT.

829
00:30:10,097 --> 00:30:14,168
THIS IDEA WAS FIRST BROUGHT TO

830
00:30:14,168 --> 00:30:18,872
FRUITION BY KIM AND LEE IN THE

831
00:30:18,872 --> 00:30:21,842
LABORATORY, NOW RUNNING A

832
00:30:21,842 --> 00:30:25,012
LABORATORY IN SOUTH KOREA,

833
00:30:25,012 --> 00:30:30,551
EILEEN IS WORKING FOR LYELL.

834
00:30:30,551 --> 00:30:31,285
LONG ALIGNED NANOPARTICLES,

835
00:30:31,285 --> 00:30:33,354
NANOPORES, WE PUT THE CARGO, AND

836
00:30:33,354 --> 00:30:36,657
THE IDEA HERE IN CONTEXT OF

837
00:30:36,657 --> 00:30:39,293
VACCINE WE COULD HAVE THESE IN

838
00:30:39,293 --> 00:30:40,694
SUSPENSION IN SALINE, WOULD

839
00:30:40,694 --> 00:30:45,065
INJECT THEM, AND AFTER INJECTION

840
00:30:45,065 --> 00:30:48,469
THE SALINE DISSIPATE, PARTICLES

841
00:30:48,469 --> 00:30:52,640
COLLAPSE AND CREATE MICROPOROUS

842
00:30:52,640 --> 00:30:55,042
MATERIAL SCAFFOLDING SIMILAR TO

843
00:30:55,042 --> 00:30:58,012
WDVAX, IN THE BODY, CELLS WITH

844
00:30:58,012 --> 00:31:06,186
CRAWL INTO THE PORES AS OPPOSED 

845
00:31:06,186 --> 00:31:08,422
TO WDVAX OUTSIDE THE BODY.

846
00:31:08,422 --> 00:31:10,591
WE COULD RECRUIT LARGE NUMBERS

847
00:31:10,591 --> 00:31:13,327
OF CELLS, COMPARED TO THE SAME

848
00:31:13,327 --> 00:31:14,094
MATERIAL WITHOUT BLUE.

849
00:31:14,094 --> 00:31:16,463
WE GET HIGH NUMBERS OF

850
00:31:16,463 --> 00:31:18,565
ANTIGEN-PRESENTING CELLS AS

851
00:31:18,565 --> 00:31:20,301
INDICATED BY CD11 STAINING, WE

852
00:31:20,301 --> 00:31:21,835
GET A COUPLE MILLION

853
00:31:21,835 --> 00:31:24,138
ANTIGEN-PRESENTING CELLS TO THAT

854
00:31:24,138 --> 00:31:24,338
SITE.

855
00:31:24,338 --> 00:31:29,310
AND IF WE RELEASE AN ADJUVANT,

856
00:31:29,310 --> 00:31:33,247
CpG, KEY INCREASE SURFACE

857
00:31:33,247 --> 00:31:36,617
EXPRESSION OF CD86, 82,

858
00:31:36,617 --> 00:31:37,518
ACTIVATING DENDRITIC CELLS

859
00:31:37,518 --> 00:31:38,585
SIMULTANEOUSLY LOADING WITH

860
00:31:38,585 --> 00:31:38,919
ANTIGEN.

861
00:31:38,919 --> 00:31:40,554
BOTTOM SHOWS THE IDEA THAT WE

862
00:31:40,554 --> 00:31:42,356
CAN USE THESE AS A SUSTAINED

863
00:31:42,356 --> 00:31:44,725
RELEASE SYSTEM, AS I MENTIONED

864
00:31:44,725 --> 00:31:49,496
BEFORE, WE'RE WE LOADED WITH

865
00:31:49,496 --> 00:31:51,665
FLUORESCENTLY LABELED ALBUMIN,

866
00:31:51,665 --> 00:31:52,333
INJECTION SUBCUTANEOUS, FOLLOWED

867
00:31:52,333 --> 00:31:53,200
THE SIGNAL OVER TIME.

868
00:31:53,200 --> 00:31:55,069
YOU CAN APPRECIATE A COUPLE

869
00:31:55,069 --> 00:31:56,804
WEEKS OF CONTINUOUS PRESENTATION

870
00:31:56,804 --> 00:31:59,440
OF ANTIGEN WITH THIS SYSTEM.

871
00:31:59,440 --> 00:32:01,642
NOW, WHEN WE LOOKED AT THE

872
00:32:01,642 --> 00:32:02,276
RESULTING RESPONSE WE'VE

873
00:32:02,276 --> 00:32:03,811
PUBLISHED THIS IN A NUMBER OF

874
00:32:03,811 --> 00:32:05,379
FORMATS, SO I'M GOING TO GIVE A

875
00:32:05,379 --> 00:32:06,780
COUPLE PIECES OF DATA TO GIVE A

876
00:32:06,780 --> 00:32:09,249
SENSE OF THE PERFORMANCE OF THE

877
00:32:09,249 --> 00:32:09,483
SYSTEM.

878
00:32:09,483 --> 00:32:13,120
IN THIS CASE WHEN WE'RE USING

879
00:32:13,120 --> 00:32:15,189
GnRH, A SMALL PEPTIDE, AS THE

880
00:32:15,189 --> 00:32:18,559
ANTIGEN WHAT YOU CAN APPRECIATE

881
00:32:18,559 --> 00:32:22,629
WITH SINGLE INJECTION, SINGLE

882
00:32:22,629 --> 00:32:25,566
VACCINATION, THERE'S NO BOOST.

883
00:32:25,566 --> 00:32:28,635
WITH THREE SYSTEMS, THE ORIGINAL

884
00:32:28,635 --> 00:32:31,171
ONE WDVAX, A GEL SYSTEM I WON'T

885
00:32:31,171 --> 00:32:33,273
DESCRIBE DATE GENERATED HIGH AND

886
00:32:33,273 --> 00:32:35,242
QUITE DURABLE TITERS THAT LAST

887
00:32:35,242 --> 00:32:37,211
THE FOR WELL OVER A YEAR WITH

888
00:32:37,211 --> 00:32:39,113
SINGLE VACCINATION, AND ALSO

889
00:32:39,113 --> 00:32:41,482
ABLE TO GENERATE PRETTY ROBUST

890
00:32:41,482 --> 00:32:43,450
T-CELL RESPONSES.

891
00:32:43,450 --> 00:32:45,185
HERE AS INDICATED BY T-CELL

892
00:32:45,185 --> 00:32:48,889
RESPONSES WHEN USING OVA AS THE

893
00:32:48,889 --> 00:32:50,324
ANTIGEN, e-7 PEPTIDE, AND

894
00:32:50,324 --> 00:32:52,993
BASICALLY THE RED IS THE

895
00:32:52,993 --> 00:32:55,396
OPTIMIZED VACCINE, ALSO WHEN WE

896
00:32:55,396 --> 00:32:59,566
LOOK AT TILs B 16S 10 MODEL

897
00:32:59,566 --> 00:33:01,201
USING NEOANTIGENS AS SOURCE TO

898
00:33:01,201 --> 00:33:02,503
GENERATE THE RESPONSE, AGAIN YOU

899
00:33:02,503 --> 00:33:05,572
SEE WE GET A SIGNIFICANT

900
00:33:05,572 --> 00:33:06,573
INCREASE IN BASICALLY TILs

901
00:33:06,573 --> 00:33:11,945
WITHIN THE TUMORS IN ANIMALS.

902
00:33:11,945 --> 00:33:22,489
SO SYSTEM WORKS WELL GENERATING

903
00:33:23,490 --> 00:33:25,659
HUMORAL RESPONSES, EFFECTIVE IN

904
00:33:25,659 --> 00:33:26,527
MURINE MODELS, SIGNIFICANT

905
00:33:26,527 --> 00:33:30,697
ADVANTAGE, FOR EXAMPLE, IN

906
00:33:30,697 --> 00:33:32,366
CONVEX OF BASICALLY TC 1

907
00:33:32,366 --> 00:33:35,269
SUPPRESSING MODEL OF CERVICAL

908
00:33:35,269 --> 00:33:40,007
CANCER AND NICE  EFFECTIVENESS

909
00:33:40,007 --> 00:33:42,676
IN B 16, SYNERGISTIC EFFECT WITH

910
00:33:42,676 --> 00:33:44,445
CHECKPOINT BLOCKADE THERAPY, AS

911
00:33:44,445 --> 00:33:47,114
ONE WOULD EXPECT FROM REASONABLE

912
00:33:47,114 --> 00:33:47,347
VACCINE.

913
00:33:47,347 --> 00:33:49,817
SO THE SYSTEM BASICALLY HAS

914
00:33:49,817 --> 00:33:51,118
WORKED NICELY.

915
00:33:51,118 --> 00:33:54,488
AND WE'VE BEEN EXPLORING IT A

916
00:33:54,488 --> 00:33:56,790
NUMBER OF CONTEXTS, ONE CONTEXT

917
00:33:56,790 --> 00:33:59,092
MORE RECENTLY IS THAT MANY OF

918
00:33:59,092 --> 00:34:00,861
YOU MAY BE FAMILIAR WITH THE

919
00:34:00,861 --> 00:34:02,930
FACT THAT MANY TYPES OF CANCER

920
00:34:02,930 --> 00:34:05,332
CELLS WHEN THEY ARE STRESSED

921
00:34:05,332 --> 00:34:10,237
THEY WILL BEGIN TO EXPRESS NK

922
00:34:10,237 --> 00:34:11,138
G2D LIGANDS, TARGETS FOR

923
00:34:11,138 --> 00:34:17,478
CLEARANCE FROM A VARIETY OF

924
00:34:17,478 --> 00:34:20,013
CYTOTOXIC LYMPHOCYTES INCLUDING

925
00:34:20,013 --> 00:34:21,882
NK CELLS, MANY DEVELOPED AN

926
00:34:21,882 --> 00:34:25,185
ESCAPE MECHANISM TO SHED LIGANDS

927
00:34:25,185 --> 00:34:28,755
BINDING TO RECEPTORS ON

928
00:34:28,755 --> 00:34:30,524
LYMPHOCYTES AND DOWNREGULATE THE

929
00:34:30,524 --> 00:34:30,791
FUNCTION.

930
00:34:30,791 --> 00:34:31,525
A COMMON MECHANISM OF ESCAPE

931
00:34:31,525 --> 00:34:33,293
FROM MANY TYPES OF HUMAN

932
00:34:33,293 --> 00:34:34,795
CANCERS, THIS HAS BEEN

933
00:34:34,795 --> 00:34:35,229
DOCUMENTED.

934
00:34:35,229 --> 00:34:37,197
SO KAI CAME TO THE LAB A FEW

935
00:34:37,197 --> 00:34:38,966
YEARS AGO AND SAID HE WAS

936
00:34:38,966 --> 00:34:39,733
COLLABORATING WITH DEVELOPMENT

937
00:34:39,733 --> 00:34:41,335
OF THE SYSTEM AND PROPOSED WE

938
00:34:41,335 --> 00:34:44,104
COULD USE THIS AS EFFECTIVE

939
00:34:44,104 --> 00:34:45,205
MEANS OF VACCINATING

940
00:34:45,205 --> 00:34:48,141
SPECIFICALLY AGAINST THE SITE AT

941
00:34:48,141 --> 00:34:49,443
WHICH THESE LIGANDS ARE SHED

942
00:34:49,443 --> 00:34:51,512
FROM THE SURFACE OF THE CANCER

943
00:34:51,512 --> 00:34:52,980
CELLS WHICH HAD BEEN PREVIOUSLY

944
00:34:52,980 --> 00:34:54,481
DESCRIBED IN THE LITERATURE.

945
00:34:54,481 --> 00:34:59,353
SO WE BASICALLY USED THAT DOMAIN

946
00:34:59,353 --> 00:35:03,357
OF MYC A, MYC B AS ANTIGEN IN

947
00:35:03,357 --> 00:35:05,325
THE SYSTEM.

948
00:35:05,325 --> 00:35:08,028
BASICALLY WE SHOWED IN THIS

949
00:35:08,028 --> 00:35:09,596
PAPER THAT THIS ACTUALLY

950
00:35:09,596 --> 00:35:11,732
DIMINISHED THE ABILITY OF THE

951
00:35:11,732 --> 00:35:13,400
CELLS TO SHED MICA AND B.

952
00:35:13,400 --> 00:35:20,641
THEY MAINTAINED IT ON THEIR

953
00:35:20,641 --> 00:35:21,074
SURFACE.

954
00:35:21,074 --> 00:35:22,009
SIGNIFICANTLY INCREASED

955
00:35:22,009 --> 00:35:23,710
CROSS-PRESENTATION OF TUMOR

956
00:35:23,710 --> 00:35:25,579
ANTIGENS BY CDCs, TARGETING OF

957
00:35:25,579 --> 00:35:32,252
TUMORS BY NK CELLS AND T CELLS.

958
00:35:32,252 --> 00:35:34,655
POTENTIAL POTENCY, THIS IS TWO

959
00:35:34,655 --> 00:35:37,424
SETS OF DATA, BASICALLY

960
00:35:37,424 --> 00:35:39,893
VACCINATING AFTER PRIMARY TUMOR

961
00:35:39,893 --> 00:35:41,762
REMOVAL LOOKING TO PREVENT

962
00:35:41,762 --> 00:35:42,896
METASTASES, THE TOP IN THE

963
00:35:42,896 --> 00:35:46,466
CONTEXT OF B 16 MODEL, BOTTOM

964
00:35:46,466 --> 00:35:49,169
WITH A 4T 1 OR BREAST CANCER

965
00:35:49,169 --> 00:35:53,740
MODEL, VACCINATION HERE HAS A

966
00:35:53,740 --> 00:35:55,342
SIGNIFICANT REDUCTION IN

967
00:35:55,342 --> 00:35:56,710
METASTASES AFTER PRIMARY TUMOR

968
00:35:56,710 --> 00:35:58,445
REMOVAL SUGGESTING THE SYSTEM IS

969
00:35:58,445 --> 00:36:01,481
POTENT ABLE TO GENERATE ROBUST

970
00:36:01,481 --> 00:36:01,949
RESPONSES.

971
00:36:01,949 --> 00:36:05,319
WHAT WE'VE BEEN LOOKING AT THE

972
00:36:05,319 --> 00:36:06,420
LAST COUPLE YEARS, WE'RE TRYING

973
00:36:06,420 --> 00:36:07,421
TO UNDERSTAND HOW THIS SYSTEM

974
00:36:07,421 --> 00:36:09,723
WORKS AND WHY IT'S SO EFFECTIVE.

975
00:36:09,723 --> 00:36:12,993
AND ONE OF THE THINGS WE THOUGHT

976
00:36:12,993 --> 00:36:15,062
AND THAT DATA SUPPORTS IS THAT

977
00:36:15,062 --> 00:36:18,565
IT'S PARTLY JUST A NUMBERS GAME.

978
00:36:18,565 --> 00:36:22,336
THAT THIS VACCINE BY ATTRACTING

979
00:36:22,336 --> 00:36:22,970
LOTS OF ANTIGEN-PRESENTING CELLS

980
00:36:22,970 --> 00:36:25,839
GETTING THEM TO MOVE TO DRAINING

981
00:36:25,839 --> 00:36:27,107
LYMPH NODE CARRYING ANTIGEN,

982
00:36:27,107 --> 00:36:29,142
OVER SOME SUSTAINED PERIOD OF

983
00:36:29,142 --> 00:36:31,411
TIME WE GET A LOT MORE CELLS,

984
00:36:31,411 --> 00:36:37,417
MOVING TO DRAINING  LYMPH NODE,

985
00:36:37,417 --> 00:36:38,518
MORE ACTIVITY, MORE ROBUST

986
00:36:38,518 --> 00:36:38,919
RESPONSE.

987
00:36:38,919 --> 00:36:41,588
WE'VE LOOKED WITH A VARIETY OF

988
00:36:41,588 --> 00:36:43,190
METRICS, ALEX JUST FINISHED UP

989
00:36:43,190 --> 00:36:45,392
IN THE LAB FOR EXAMPLE HAS SHOWN

990
00:36:45,392 --> 00:36:45,726
THIS.

991
00:36:45,726 --> 00:36:47,094
YOU CAN APPRECIATE THIS GROSSLY.

992
00:36:47,094 --> 00:36:50,664
IF YOU LOOK AT THE DRAINING

993
00:36:50,664 --> 00:36:52,332
LYMPH NODE, DOWNSTREAM FROM THE

994
00:36:52,332 --> 00:36:54,601
VACCINATION SITE, THIS IS JUST

995
00:36:54,601 --> 00:36:55,802
USING ULTRASOUND IMAGING TO LOOK

996
00:36:55,802 --> 00:36:58,972
AT DRAINING LYMPH NODE WITH PBS

997
00:36:58,972 --> 00:37:02,275
INJECTION, TYPICAL BOLUS VACCINE

998
00:37:02,275 --> 00:37:08,749
INJECTION WITH ANTIGEN,

999
00:37:08,749 --> 00:37:09,449
ADJUVANT, GMC-SF IN SOLUTION,

1000
00:37:09,449 --> 00:37:11,585
SIGNIFICANT EXPANSION OF THE

1001
00:37:11,585 --> 00:37:13,654
DOWNSTREAM DRAINING LYMPH NODE

1002
00:37:13,654 --> 00:37:15,188
AND EXPANSION THAT PERSISTS FOR

1003
00:37:15,188 --> 00:37:18,925
MULTIPLE WEEKS WITH THE VACCINE

1004
00:37:18,925 --> 00:37:19,559
SYSTEM.

1005
00:37:19,559 --> 00:37:21,862
CURRENTLY NOT SURPRISINGLY WE

1006
00:37:21,862 --> 00:37:23,730
SEE SIGNIFICANT INCREASES IN

1007
00:37:23,730 --> 00:37:25,699
DENDRITIC CELLS, T CELLS, B

1008
00:37:25,699 --> 00:37:26,700
CELLS, IN THE DRAINING LYMPH

1009
00:37:26,700 --> 00:37:26,900
NODE.

1010
00:37:26,900 --> 00:37:29,336
AND THE ORANGE HERE IS BASICALLY

1011
00:37:29,336 --> 00:37:31,605
BIOMATERIAL VACCINE, GREEN IS

1012
00:37:31,605 --> 00:37:33,507
BOLUS, AND THE OTHERS ARE SOME

1013
00:37:33,507 --> 00:37:35,175
OF THE CONTROLS.

1014
00:37:35,175 --> 00:37:37,344
SO, PARTLY A NUMBER GAME WE GET

1015
00:37:37,344 --> 00:37:39,413
A LOT MORE CELLS TRAFFICKING

1016
00:37:39,413 --> 00:37:40,781
ANTIGEN BACK TO DRAINING LYMPH

1017
00:37:40,781 --> 00:37:41,415
NODE.

1018
00:37:41,415 --> 00:37:42,783
BUT WE'VE ALSO BEGUN TO LOOK AT

1019
00:37:42,783 --> 00:37:44,785
THE GENE EXPRESSION OF THE CELLS

1020
00:37:44,785 --> 00:37:47,120
IN THE DRAINING LYMPH NODES.

1021
00:37:47,120 --> 00:37:48,955
AND STRIKINGLY WE FOUND WE JUST

1022
00:37:48,955 --> 00:37:52,359
DON'T HAVE MORE CELLS BUT WE'RE

1023
00:37:52,359 --> 00:37:53,026
DRAMATICALLY CHANGING THE

1024
00:37:53,026 --> 00:37:53,794
EXPRESSION, GENE EXPRESSION OF

1025
00:37:53,794 --> 00:37:54,928
CELLS IN THE DRAINING LYMPH

1026
00:37:54,928 --> 00:37:55,128
NODE.

1027
00:37:55,128 --> 00:37:57,564
AND SO IF WE LOOK AT JUST THE

1028
00:37:57,564 --> 00:38:02,035
MYELOID CELLS HERE AND LOOK AT 

1029
00:38:02,035 --> 00:38:04,871
THE NUMBER OF DIFFERENTIALLY

1030
00:38:04,871 --> 00:38:06,206
EXPRESSED UP OR DOWNREGULATED

1031
00:38:06,206 --> 00:38:13,513
WE'RE GETTING  CHANGES IN

1032
00:38:13,513 --> 00:38:16,183
ANTIGEN CELLS THAT ARE

1033
00:38:16,183 --> 00:38:16,817
IMPORTANT, INFLAMMATORY

1034
00:38:16,817 --> 00:38:18,151
MONOCYTES, ALSO PLASMA CELLS.

1035
00:38:18,151 --> 00:38:20,120
SO WE'VE BEEN DOING SOME MINING

1036
00:38:20,120 --> 00:38:22,656
OF DATA IN COLLABORATION WITH

1037
00:38:22,656 --> 00:38:25,392
SHANNON TURLEY AT GENENTECH, SO

1038
00:38:25,392 --> 00:38:29,329
WE FOUND INFLAMMATORY MONOCYTES

1039
00:38:29,329 --> 00:38:31,431
ARE DRAMATICALLY EXPANDED IN THE

1040
00:38:31,431 --> 00:38:32,466
MPS-BASED VACCINATION, YOU CAN

1041
00:38:32,466 --> 00:38:34,835
SEE THE NUMBERS ON THE TOP, ON

1042
00:38:34,835 --> 00:38:40,173
THE BOTTOM BASICALLY A UMAP

1043
00:38:40,173 --> 00:38:42,342
PLOT, WITH THE MPS VACCINATION

1044
00:38:42,342 --> 00:38:44,644
WE PARTICULARLY ENRICH IN CELLS

1045
00:38:44,644 --> 00:38:46,413
IN THIS BASICALLY ZERO QUADRANT

1046
00:38:46,413 --> 00:38:47,714
OF THE POPULATION, AND IF YOU

1047
00:38:47,714 --> 00:38:49,349
LOOK AT GENE EXPRESSION OF THOSE

1048
00:38:49,349 --> 00:38:54,387
CELLS YOU SEE THAT IT'S

1049
00:38:54,387 --> 00:38:55,422
DRAMATICALLY -- DRAMATIC

1050
00:38:55,422 --> 00:38:57,057
UPREGULATION IN PROCESSING, IF

1051
00:38:57,057 --> 00:38:58,859
YOU'RE IN GAMMA RESPONSE,

1052
00:38:58,859 --> 00:38:59,493
INFLAMMATORY RESPONSE, WE THINK

1053
00:38:59,493 --> 00:39:02,329
PART OF THE REASON IT'S SO SEE

1054
00:39:02,329 --> 00:39:03,964
EFFECTIVE IS THE NUMBERS BUT

1055
00:39:03,964 --> 00:39:05,599
PARTIALLY BECAUSE WE'RE HAVING

1056
00:39:05,599 --> 00:39:06,800
SIGNIFICANT ALTERATIONS IN THE

1057
00:39:06,800 --> 00:39:09,536
BILE GENE AND DRAINING LYMPH

1058
00:39:09,536 --> 00:39:09,736
NODE.

1059
00:39:09,736 --> 00:39:12,372
PLASMA CELLS YOU CAN APPRECIATE

1060
00:39:12,372 --> 00:39:15,208
WITH THIS VACCINE SYSTEM WE GET

1061
00:39:15,208 --> 00:39:17,511
SIGNIFICANT UPREGULATION IN THE

1062
00:39:17,511 --> 00:39:18,712
CELLS WITH THE BIOMATERIAL

1063
00:39:18,712 --> 00:39:21,548
VACCINE, FOR EXAMPLE IN IgG HG

1064
00:39:21,548 --> 00:39:24,751
1, AS CONTRASTED TO MORE

1065
00:39:24,751 --> 00:39:27,687
IMMATURE RESPONSE BASICALLY WITH

1066
00:39:27,687 --> 00:39:28,822
BOLUS VACCINATION.

1067
00:39:28,822 --> 00:39:29,055
OKAY.

1068
00:39:29,055 --> 00:39:32,526
SO ALL THIS WORK THAT I'VE BEEN

1069
00:39:32,526 --> 00:39:35,328
DESCRIBING HAS BEEN PART OF

1070
00:39:35,328 --> 00:39:39,232
NIH-FUNDED CENTER, NCI AND NIA

1071
00:39:39,232 --> 00:39:41,635
FUNDED CENTER TO ACHIEVE THESE

1072
00:39:41,635 --> 00:39:41,868
THINGS.

1073
00:39:41,868 --> 00:39:42,736
MAYBE WE'LL TALK FOR A COUPLE

1074
00:39:42,736 --> 00:39:44,471
MINUTES ON THE LAST PART, I'LL

1075
00:39:44,471 --> 00:39:47,440
TRY TO END MORE OR LESS ON TIME.

1076
00:39:47,440 --> 00:39:49,209
TALK A FEW MINUTES ABOUT ONE

1077
00:39:49,209 --> 00:39:51,578
LAST ASPECT OF THE WORK.

1078
00:39:51,578 --> 00:39:55,882
SO, NONE OF WHAT I'VE  DESCRIBED

1079
00:39:55,882 --> 00:39:57,951
HOW T CELLS CAN GET INTO THE

1080
00:39:57,951 --> 00:39:58,952
SOLID TUMOR ENVIRONMENT WHICH WE

1081
00:39:58,952 --> 00:40:00,687
KNOW IS A CHALLENGE.

1082
00:40:00,687 --> 00:40:02,656
THIS IS JUST A REVIEW WE WROTE

1083
00:40:02,656 --> 00:40:04,758
LAST YEAR THAT HIGHLIGHTED A FEW

1084
00:40:04,758 --> 00:40:07,594
OF THE KNOWN BARRIERS TO T CELL

1085
00:40:07,594 --> 00:40:08,028
TRAFFICKING.

1086
00:40:08,028 --> 00:40:10,363
BUT WHAT WE BECAME INTERESTED IN

1087
00:40:10,363 --> 00:40:12,098
BEYOND ALL OF THESE THAT HAVE

1088
00:40:12,098 --> 00:40:13,967
BEEN PREVIOUSLY PROPOSED OR LAST

1089
00:40:13,967 --> 00:40:15,101
COUPLE YEARS WE'VE BECOME

1090
00:40:15,101 --> 00:40:17,337
INTERESTED IN CHANGES IN THE

1091
00:40:17,337 --> 00:40:19,339
PHYSICAL PROPERTIES OF THE

1092
00:40:19,339 --> 00:40:20,207
TUMORS THEMSELVES MIGHT ALSO

1093
00:40:20,207 --> 00:40:21,975
CREATE CHANGES IN T CELL BIOLOGY

1094
00:40:21,975 --> 00:40:24,344
THAT COULD BE RELEVANT IN TERMS

1095
00:40:24,344 --> 00:40:26,313
OF MEDIATED ABILITY TO PROVIDE

1096
00:40:26,313 --> 00:40:27,747
EFFECTIVE THERAPY.

1097
00:40:27,747 --> 00:40:29,316
NOW, THE RATIONALE HERE THAT

1098
00:40:29,316 --> 00:40:30,584
YOU'RE QUITE FAMILIAR WITH IS

1099
00:40:30,584 --> 00:40:33,320
THAT IN THE CONTEXT OF SOLID

1100
00:40:33,320 --> 00:40:35,288
TUMOR DEVELOPMENT, WE ALL

1101
00:40:35,288 --> 00:40:36,623
APPRECIATE THAT BASICALLY THE

1102
00:40:36,623 --> 00:40:38,692
TISSUE BECOMES STIFFER AND MORE

1103
00:40:38,692 --> 00:40:39,793
FIBROSED, AND THERE'S BEEN A LOT

1104
00:40:39,793 --> 00:40:41,995
OF INTEREST IN TRYING TO

1105
00:40:41,995 --> 00:40:44,297
UNDERSTAND IMPACT OF CHANGES IN

1106
00:40:44,297 --> 00:40:46,132
STIFFNESS THAT MAY ACCOMPANY

1107
00:40:46,132 --> 00:40:48,869
CANCER AND TUMOR PROGRESSION ON

1108
00:40:48,869 --> 00:40:50,003
BIOLOGY OF CELL TYPES.

1109
00:40:50,003 --> 00:40:52,372
AND PART OF THIS IS DUE TO THE

1110
00:40:52,372 --> 00:40:55,876
FACT THAT WHEN CELLS ENGAGE WITH

1111
00:40:55,876 --> 00:40:57,611
THE EXTRACELLULAR MATRIX IT'S A

1112
00:40:57,611 --> 00:40:58,345
MECHANICALLY ACTIVE ENGAGEMENT

1113
00:40:58,345 --> 00:41:01,047
WHERE THEY ARE CONSTANTLY

1114
00:41:01,047 --> 00:41:03,550
PUSHING AND PULLING AS SHOWN BY

1115
00:41:03,550 --> 00:41:06,419
THE VIDEO OF THE HUMAN IMMUNE

1116
00:41:06,419 --> 00:41:07,921
CELL THROUGH COLLAGEN SCAFFOLD,

1117
00:41:07,921 --> 00:41:08,788
ACTIVE MECHANICAL INTERACTION OF

1118
00:41:08,788 --> 00:41:11,524
CELLS WITH ENVIRONMENT, SO AS

1119
00:41:11,524 --> 00:41:12,425
MECHANICAL PROPERTIES CHANGE IT

1120
00:41:12,425 --> 00:41:14,060
MAKES SENSE THAT THE CELL

1121
00:41:14,060 --> 00:41:15,829
BEHAVIOR MIGHT CHANGE.

1122
00:41:15,829 --> 00:41:17,564
HOWEVER, THE EMPHASIS TO DATE

1123
00:41:17,564 --> 00:41:19,799
HAS BEEN ON THE IMPACT OF

1124
00:41:19,799 --> 00:41:21,401
CHANGES IN STIFFNESS OF THE

1125
00:41:21,401 --> 00:41:21,635
TISSUE.

1126
00:41:21,635 --> 00:41:23,904
BUT ALL THE TISSUES IN OUR BODY

1127
00:41:23,904 --> 00:41:26,806
AND TUMORS IN OUR BODY ARE NOT

1128
00:41:26,806 --> 00:41:28,875
PURELY ELASTIC LIKE RUBBER

1129
00:41:28,875 --> 00:41:29,075
BANDS.

1130
00:41:29,075 --> 00:41:31,511
THEY ARE A PROPERTY INTERMEDIATE

1131
00:41:31,511 --> 00:41:35,482
BETWEEN SOLID AND LIQUID. 

1132
00:41:35,482 --> 00:41:37,984
THEY ARE VISCOELASEK.

1133
00:41:37,984 --> 00:41:40,186
ONE DEMONSTRATION, MAPPING OF

1134
00:41:40,186 --> 00:41:50,597
SKELETAL TISSUES, SOFT TISSUES, 

1135
00:41:50,597 --> 00:41:52,565
RECONSTITUTED EXTRACELLULAR

1136
00:41:52,565 --> 00:41:55,168
MATRICES, THEY ALL EXHIBIT

1137
00:41:55,168 --> 00:41:56,169
INTERMEDIATE BEHAVIOR.

1138
00:41:56,169 --> 00:41:59,906
ANOTHER WAY TO DEMONSTRATE IS IF

1139
00:41:59,906 --> 00:42:03,677
YOU PUSH ON A VISCOELASTIC

1140
00:42:03,677 --> 00:42:08,181
TISSUE, IT PLASTICALLY  DEFORMS

1141
00:42:08,181 --> 00:42:09,282
AND DISSIPATES ENERGY, STRESS

1142
00:42:09,282 --> 00:42:10,050
DIMINISHES WITH TIME.

1143
00:42:10,050 --> 00:42:11,384
YOU CAN SEE A VARIETY OF TISSUES

1144
00:42:11,384 --> 00:42:15,088
IN THE BODY DO THIS, IN CONTRAST

1145
00:42:15,088 --> 00:42:17,590
A PURELY ELASTIC MATERIAL LIKE

1146
00:42:17,590 --> 00:42:19,159
RUBBER BAND WOULD STAY CONSTANT

1147
00:42:19,159 --> 00:42:24,130
FROM THE LINE ACROSS THE TOP. 

1148
00:42:24,130 --> 00:42:25,365
I WON'T GO DETAIL BUT A SENSE OF

1149
00:42:25,365 --> 00:42:27,767
WHAT IT LOOKS LIKE THIS IS A

1150
00:42:27,767 --> 00:42:30,637
VIDEO OF A PURELY ELASTIC

1151
00:42:30,637 --> 00:42:30,904
MATERIAL.

1152
00:42:30,904 --> 00:42:32,439
PRESS DOWN, IT DEFORMS.

1153
00:42:32,439 --> 00:42:34,341
WHEN YOU REMOVE, IT JUMPS BACK

1154
00:42:34,341 --> 00:42:35,442
TO ORIGINAL DIMENSIONS.

1155
00:42:35,442 --> 00:42:38,712
IN CONTRAST ON THE BOTTOM WE'RE

1156
00:42:38,712 --> 00:42:42,482
LOOKING AT VISCOELASTIC

1157
00:42:42,482 --> 00:42:43,616
MATERIAL, BRAIN TISSUE.

1158
00:42:43,616 --> 00:42:46,486
WHEN WE PULL UP THE TISSUE STAYS

1159
00:42:46,486 --> 00:42:48,288
DEFORMS, DISSIPATED SOME STRESS.

1160
00:42:48,288 --> 00:42:49,889
THE MOVIE CYCLES, IT JUMPS UP

1161
00:42:49,889 --> 00:42:53,326
BECAUSE THE MOVIE IS STARTING

1162
00:42:53,326 --> 00:42:54,194
OVER AGAIN.

1163
00:42:54,194 --> 00:42:56,363
AND SO WE BECAME INTERESTED IN

1164
00:42:56,363 --> 00:42:57,564
WHETHER TRANSITIONS THAT MAY

1165
00:42:57,564 --> 00:43:00,967
HAPPEN IN THINGS LIKE CANCER

1166
00:43:00,967 --> 00:43:02,268
BETWEEN A MORE VISCOELASTIC

1167
00:43:02,268 --> 00:43:05,505
NORMAL TISSUE AND MORE ELASTIC,

1168
00:43:05,505 --> 00:43:07,574
YOU KNOW, FIBROSED DEVELOPING

1169
00:43:07,574 --> 00:43:11,945
TUMOR MIGHT IMPACT T CELL

1170
00:43:11,945 --> 00:43:13,246
BIOLOGY.

1171
00:43:13,246 --> 00:43:15,015
A TALENTED Ph.D. STUDENT WITH

1172
00:43:15,015 --> 00:43:17,417
ANOTHER TALENTED Ph.D. STUDENT

1173
00:43:17,417 --> 00:43:20,687
IN THE LAB TO BEGIN TO EXPLORE

1174
00:43:20,687 --> 00:43:23,189
THIS FIRST OF ALL, WELL, LET'S

1175
00:43:23,189 --> 00:43:25,492
GET SOME REALITY CHECK, LET'S

1176
00:43:25,492 --> 00:43:27,260
LOOK AT PUBLISHED SINGLE CELL

1177
00:43:27,260 --> 00:43:28,628
RNAseq DATA OF T CELLS FROM

1178
00:43:28,628 --> 00:43:30,897
CANCER PATIENTS AND SEE IF THE

1179
00:43:30,897 --> 00:43:32,732
GENE EXPRESSION REALLY CHANGES

1180
00:43:32,732 --> 00:43:34,601
BETWEEN VISCOUS ENVIRONMENT IN

1181
00:43:34,601 --> 00:43:35,702
THE BLOOD, VISCOELASTIC

1182
00:43:35,702 --> 00:43:38,204
ENVIRONMENT IN NORMAL TISSUE,

1183
00:43:38,204 --> 00:43:39,973
AND MORE ELASTIC ENVIRONMENT IN

1184
00:43:39,973 --> 00:43:41,274
BASICALLY A SOLID TUMOR.

1185
00:43:41,274 --> 00:43:45,712
THEY COLLECTED DATA FOR  A FEW

1186
00:43:45,712 --> 00:43:48,381
TYPES OF CANCER, T CELLS IN

1187
00:43:48,381 --> 00:43:49,082
DIFFERENT ENVIRONMENTS DID

1188
00:43:49,082 --> 00:43:51,351
SEGREGATE FROM EACH OTHER AND IF

1189
00:43:51,351 --> 00:43:55,688
YOU DEFINE BASICALLY GENE SETS,

1190
00:43:55,688 --> 00:43:58,558
FOR THE CELLS BASICALLY TUMORS,

1191
00:43:58,558 --> 00:44:00,427
STIFF ELASTIC TUMORS, YOU SEE

1192
00:44:00,427 --> 00:44:02,362
THEIR EXPRESSION VARIES BY

1193
00:44:02,362 --> 00:44:03,096
LOCATION.

1194
00:44:03,096 --> 00:44:06,032
THIS WASN'T CAUSE AND EFFECT,

1195
00:44:06,032 --> 00:44:06,533
SIMPLY CORRELATION, BUT

1196
00:44:06,533 --> 00:44:08,168
SUGGESTED POSSIBILITY.

1197
00:44:08,168 --> 00:44:10,270
I'M GOING TO SKIP THAT SLIDE

1198
00:44:10,270 --> 00:44:12,338
WHICH SHOWS THE MATERIAL SYSTEM

1199
00:44:12,338 --> 00:44:16,376
THAT ALLOWS US TO CLEANLY

1200
00:44:16,376 --> 00:44:16,876
REGULATE VISCOELASTICITY

1201
00:44:16,876 --> 00:44:20,447
SEPARATELY FROM STIFFNESS OR

1202
00:44:20,447 --> 00:44:20,880
VARIABLES.

1203
00:44:20,880 --> 00:44:24,050
WE CAN CLEANLY SEPARATE THE

1204
00:44:24,050 --> 00:44:26,252
VARIABLES BUT THIS MODEL SYSTEM

1205
00:44:26,252 --> 00:44:31,091
IN CELL CULTURE, WHICH ALLOWS US

1206
00:44:31,091 --> 00:44:31,991
TO CLEANLY SEPARATE

1207
00:44:31,991 --> 00:44:33,827
VISCOELASTICITY, PUT HUMAN T

1208
00:44:33,827 --> 00:44:34,894
CELLS, THEY LOOK PHENOTYPICALLY

1209
00:44:34,894 --> 00:44:35,328
DIFFERENT.

1210
00:44:35,328 --> 00:44:37,130
LOOK AT HEAT MAP ON THE BOTTOM,

1211
00:44:37,130 --> 00:44:43,770
T CELLS IN THE SLOWLY RELAXING

1212
00:44:43,770 --> 00:44:45,004
MORE VISCOELASTICITY MATERIAL

1213
00:44:45,004 --> 00:44:47,173
HAVE MORE ACTIVATION AND

1214
00:44:47,173 --> 00:44:47,774
EXHAUSTION MARKER EXPRESSION

1215
00:44:47,774 --> 00:44:52,612
WHILE THOSE IN THE FAST RELAXING

1216
00:44:52,612 --> 00:44:53,913
GELS HAVE -- EXPRESSION MORE

1217
00:44:53,913 --> 00:44:57,250
MARKERS RELATED TO MEMORY TYPES

1218
00:44:57,250 --> 00:44:57,717
OF PHENOTYPES.

1219
00:44:57,717 --> 00:44:59,686
FURTHERMORE IF YOU DO SOME

1220
00:44:59,686 --> 00:45:01,654
SINGLE CELL RNAseq ON THESE

1221
00:45:01,654 --> 00:45:03,089
CELLS, WHAT YOU FIND IS

1222
00:45:03,089 --> 00:45:06,993
EXPRESSION OF A WIDE VARIETY OF

1223
00:45:06,993 --> 00:45:10,530
GENES RELEVANT TO T CELL

1224
00:45:10,530 --> 00:45:13,366
FUNCTION SIGNIFICANTLY ALTERED 

1225
00:45:13,366 --> 00:45:14,501
TRANSITION FROM ELASTIC TO

1226
00:45:14,501 --> 00:45:15,335
VISCOELASEK ENVIRONMENT.

1227
00:45:15,335 --> 00:45:17,337
IF YOU DO SOME ANALYSIS OF

1228
00:45:17,337 --> 00:45:22,575
PATHWAYS, YOU SEE AGAIN YOU HAVE

1229
00:45:22,575 --> 00:45:23,710
SIGNIFICANT ALTERATIONS IN

1230
00:45:23,710 --> 00:45:24,978
PATHWAYS BASICALLY T CELL

1231
00:45:24,978 --> 00:45:26,646
BIOLOGY IN THESE TWO PHYSICAL

1232
00:45:26,646 --> 00:45:27,947
ENVIRONMENTS AND A LOT OF THESE

1233
00:45:27,947 --> 00:45:29,349
ARE HIGHLY RELEVANT TO WHAT YOU

1234
00:45:29,349 --> 00:45:30,683
MIGHT EXPECT TO LEAD TO CHANGES

1235
00:45:30,683 --> 00:45:32,552
IN FUNCTION OF THE T CELLS.

1236
00:45:32,552 --> 00:45:35,855
NOW, TO SEE WHETHER OR NOT THIS

1237
00:45:35,855 --> 00:45:41,728
HAD ANY REALITY CHECK HERE, HE

1238
00:45:41,728 --> 00:45:44,597
TOOK THE GENE SETS HE IDENTIFIED

1239
00:45:44,597 --> 00:45:46,232
IN CELL CULTURE MODEL, NOW USED

1240
00:45:46,232 --> 00:45:51,604
THOSE AND WENT BACK TO 

1241
00:45:51,604 --> 00:45:52,605
PATIENT-DERIVED DATA,

1242
00:45:52,605 --> 00:45:54,107
DIFFERENTIAL EXPRESSION IN T

1243
00:45:54,107 --> 00:45:58,011
CELLS IN PATIENTS, YOU

1244
00:45:58,011 --> 00:45:59,913
SIGNIFICANTLY MORE EXPRESSION IN

1245
00:45:59,913 --> 00:46:01,247
T CELLS AND PATIENT TUMORS

1246
00:46:01,247 --> 00:46:02,682
CONTRASTED TO OTHER

1247
00:46:02,682 --> 00:46:03,249
ENVIRONMENTS, DOESN'T PROVE

1248
00:46:03,249 --> 00:46:05,051
ANYTHING BUT SUGGESTS MAYBE

1249
00:46:05,051 --> 00:46:05,718
THERE'S RELEVANCE.

1250
00:46:05,718 --> 00:46:09,222
IN CASE YOU'RE WORRIED IT'S DUE

1251
00:46:09,222 --> 00:46:11,391
TO DIFFERENT T CELL POPULATION,

1252
00:46:11,391 --> 00:46:12,492
ACTUALLY HE THEN FURTHER LOOKED

1253
00:46:12,492 --> 00:46:13,927
AT OTHER SETTINGS WHERE WE KNOW

1254
00:46:13,927 --> 00:46:18,631
WE GET CHANGES FROM MORE

1255
00:46:18,631 --> 00:46:20,833
VISCOELASTIC TO ELASTIC

1256
00:46:20,833 --> 00:46:22,168
BACKGROUND, LIVER CIRRHOSIS,

1257
00:46:22,168 --> 00:46:23,570
PULMONARY FIBROSIS, SAW SAME

1258
00:46:23,570 --> 00:46:25,638
ENRICHMENT IN THESE GENES OF THE

1259
00:46:25,638 --> 00:46:28,274
T CELLS IN THESE MORE DISEASED

1260
00:46:28,274 --> 00:46:28,808
SETTINGS.

1261
00:46:28,808 --> 00:46:34,380
I'M GOING TO SKIP THIS DATA, WE

1262
00:46:34,380 --> 00:46:35,715
LOOKED AT THE PATHWAY, I'LL

1263
00:46:35,715 --> 00:46:37,483
FINISH WITH THIS LAST PIECE OF

1264
00:46:37,483 --> 00:46:39,319
DATA, WHICH IS WE THINK THIS

1265
00:46:39,319 --> 00:46:40,720
MIGHT BE RELEVANT TO UNDERSTAND

1266
00:46:40,720 --> 00:46:43,790
WHAT HAPPENS TO T CELLS IN SOLID

1267
00:46:43,790 --> 00:46:44,023
TUMORS.

1268
00:46:44,023 --> 00:46:45,024
ALSO THEN OPEN TO THE

1269
00:46:45,024 --> 00:46:46,092
POSSIBILITY MAYBE THIS IS

1270
00:46:46,092 --> 00:46:47,727
SOMETHING THAT WE COULD EXPLOIT

1271
00:46:47,727 --> 00:46:49,162
IN TERMS OF T CELL MANUFACTURING

1272
00:46:49,162 --> 00:46:50,396
TO CHANGE THEIR PHYSICAL

1273
00:46:50,396 --> 00:46:52,131
ENVIRONMENT TO GET DIFFERENT

1274
00:46:52,131 --> 00:46:54,334
TYPES OF FUNCTIONAL T CELLS OUT.

1275
00:46:54,334 --> 00:46:58,271
SO TO LOOK AT THIS, A SIMPLE

1276
00:46:58,271 --> 00:47:00,139
EXPERIMENT, TOOK CAR-T CELLS

1277
00:47:00,139 --> 00:47:02,075
THEY WERE MANUFACTURING, HAD

1278
00:47:02,075 --> 00:47:03,309
THEM MANUFACTURED IN A MORE

1279
00:47:03,309 --> 00:47:07,647
ELASTIC GEL OR A MORE

1280
00:47:07,647 --> 00:47:08,114
VISCOELASTIC GEL, AND

1281
00:47:08,114 --> 00:47:09,849
TRANSFERRED INTO THE SAME KINDS

1282
00:47:09,849 --> 00:47:11,517
OF MODELS, WHAT THEY

1283
00:47:11,517 --> 00:47:13,820
DEMONSTRATED WAS THE CELLS THAT

1284
00:47:13,820 --> 00:47:15,888
THEY HAD EXPANDED IN THE MORE

1285
00:47:15,888 --> 00:47:17,757
SLOWLY RELAXING GELS WERE MUCH

1286
00:47:17,757 --> 00:47:19,626
MORE EFFECTIVE IN THIS CONTEXT

1287
00:47:19,626 --> 00:47:21,361
IN TERMS OF CANCER CELL

1288
00:47:21,361 --> 00:47:22,695
CLEARANCE BACK IN THE BODY.

1289
00:47:22,695 --> 00:47:24,864
SO WE THINK THAT THIS MAY HAVE

1290
00:47:24,864 --> 00:47:25,898
RELEVANCE FOR CANCER BIOLOGY,

1291
00:47:25,898 --> 00:47:27,300
SOME RELEVANCE IN TERMS OF HOW

1292
00:47:27,300 --> 00:47:29,702
WE THINK ABOUT TRYING TO MAGNIFY

1293
00:47:29,702 --> 00:47:30,336
CELLS.

1294
00:47:30,336 --> 00:47:33,640
SO, I'M GOING TO STOP HERE AND

1295
00:47:33,640 --> 00:47:35,708
IF THIS IDEA OF CHANGING

1296
00:47:35,708 --> 00:47:36,576
PHYSICAL PROPERTIES AND

1297
00:47:36,576 --> 00:47:38,344
VISCOELASTICITY IS OF INTEREST

1298
00:47:38,344 --> 00:47:40,546
TO YOU, WE'VE SHOWN NOW IT'S NOT

1299
00:47:40,546 --> 00:47:44,350
JUST T CELLS THAT ARE

1300
00:47:44,350 --> 00:47:47,086
DRAMATICALLY IMPACTS, EPITHELIAL

1301
00:47:47,086 --> 00:47:48,521
TO MESENCHYMAL TRANSITION IS

1302
00:47:48,521 --> 00:47:52,158
INTACTED BY CHANGES IN

1303
00:47:52,158 --> 00:47:53,359
VISCOELASTICITY AND MONOCYTE,

1304
00:47:53,359 --> 00:47:54,994
ABILITY TO DO ANTIGEN

1305
00:47:54,994 --> 00:47:55,862
PRESENTATION ALSO DRAMATICALLY

1306
00:47:55,862 --> 00:47:57,397
IMPACTED BY THESE CHANGES IN

1307
00:47:57,397 --> 00:47:58,731
VISCOELASTICITY AS WELL.

1308
00:47:58,731 --> 00:48:00,033
SO I'LL STOP THERE.

1309
00:48:00,033 --> 00:48:01,567
I'D BE HAPPY TO TAKE ANY

1310
00:48:01,567 --> 00:48:02,101
QUESTIONS.

1311
00:48:02,101 --> 00:48:05,371
[APPLAUSE]

1312
00:48:05,371 --> 00:48:10,209
 

1313
00:48:10,209 --> 00:48:15,915
 

1314
00:48:15,915 --> 00:48:19,986
>> IF YOU EXPOSE THE T
CELLS TO

1315
00:48:19,986 --> 00:48:22,388
GIVEN VISCOELASTIC PROPERTIES IS

1316
00:48:22,388 --> 00:48:23,556
THERE SOME MECHANICAL

1317
00:48:23,556 --> 00:48:24,791
(INDISCERNIBLE) DOES IT LAST?

1318
00:48:24,791 --> 00:48:27,527
>> THAT'S A REALLY
IMPORTANT

1319
00:48:27,527 --> 00:48:27,960
QUESTION.

1320
00:48:27,960 --> 00:48:28,928
YES, THERE DOES SEEM TO BE --

1321
00:48:28,928 --> 00:48:33,199
YOU KNOW, T CELL MEMORY IS

1322
00:48:33,199 --> 00:48:35,401
DIFFERENT THAN -- THE TERM

1323
00:48:35,401 --> 00:48:36,035
MECHANICAL MEMORY, VERY

1324
00:48:36,035 --> 00:48:38,071
DIFFERENT, THERE SEEMS TO BE A

1325
00:48:38,071 --> 00:48:39,005
MECHANICAL MEMORY, DEPENDENT ON

1326
00:48:39,005 --> 00:48:40,239
TIME SCALE THE CELLS WERE

1327
00:48:40,239 --> 00:48:40,673
EXPOSED.

1328
00:48:40,673 --> 00:48:44,277
IF WE HAVE THE CELLS EXPOSED TO

1329
00:48:44,277 --> 00:48:45,812
THE DIFFERENT PHYSICAL

1330
00:48:45,812 --> 00:48:48,181
ENVIRONMENT FOR 24 HOURS, IT'S

1331
00:48:48,181 --> 00:48:49,949
MORE TRANSIENT AND YOU TEND TO

1332
00:48:49,949 --> 00:48:51,284
START LOSING THE PHENOTYPE

1333
00:48:51,284 --> 00:48:53,453
WITHIN ABOUT 2 OR 3 DAYS OF

1334
00:48:53,453 --> 00:48:53,886
REMOVING THEM.

1335
00:48:53,886 --> 00:48:55,755
IN CONTRAST IF THEY ARE IN THE

1336
00:48:55,755 --> 00:48:58,591
ENVIRONMENT FOR 3 DAYS, THEN WE

1337
00:48:58,591 --> 00:48:59,659
SEE THEM MAINTAINING

1338
00:48:59,659 --> 00:49:00,660
DIFFERENTIAL PHENOTYPE AND GENE

1339
00:49:00,660 --> 00:49:01,794
EXPRESSION FOR AT LEAST A WEEK,

1340
00:49:01,794 --> 00:49:03,429
WHICH IS AS FAR AS WE'VE LOOKED.

1341
00:49:03,429 --> 00:49:04,664
THEY CAN MAINTAIN IT.

1342
00:49:04,664 --> 00:49:06,966
IT DEPENDS ON HISTORY OF

1343
00:49:06,966 --> 00:49:07,266
EXPOSURE.

1344
00:49:07,266 --> 00:49:09,836
>> AND IF I COULD ADD A

1345
00:49:09,836 --> 00:49:11,604
FOLLOW-UP.

1346
00:49:11,604 --> 00:49:16,109
SO IF YOU TIME BASED ON NORMAL

1347
00:49:16,109 --> 00:49:17,744
ORGAN HOMOSTASIS DO YOU SEE

1348
00:49:17,744 --> 00:49:19,479
BETTER RESULT FOR YOUR CAR T

1349
00:49:19,479 --> 00:49:19,979
EXPANSION?

1350
00:49:19,979 --> 00:49:21,247
>> THAT'S A REALLY
INTERESTING

1351
00:49:21,247 --> 00:49:21,447
IDEA.

1352
00:49:21,447 --> 00:49:21,848
DON'T KNOW.

1353
00:49:21,848 --> 00:49:24,217
WE HAVEN'T TRIED TO CAREFULLY

1354
00:49:24,217 --> 00:49:28,254
LOOK AT THAT YET.

1355
00:49:28,254 --> 00:49:30,256
YEAH, THE -- YEAH, WE DON'T KNOW

1356
00:49:30,256 --> 00:49:31,457
YET.

1357
00:49:31,457 --> 00:49:32,892
>> THANK YOU.

1358
00:49:32,892 --> 00:49:34,627
REALLY FASCINATING TALK.

1359
00:49:34,627 --> 00:49:36,529
MY QUESTION IS ABOUT YOUR --

1360
00:49:36,529 --> 00:49:38,531
SOMETHING YOU COVERED AT THE

1361
00:49:38,531 --> 00:49:39,799
BEGINNING WITH THE PROGRAMMING

1362
00:49:39,799 --> 00:49:44,203
KIND OF -- OR TRYING TO USE AN

1363
00:49:44,203 --> 00:49:46,239
A.I. ALGORITHM TO PREDICT HOW

1364
00:49:46,239 --> 00:49:47,673
LIKE WHEN YOU TOGGLE T CELL

1365
00:49:47,673 --> 00:49:49,976
INPUT IN TERMS OF TYPES OF T

1366
00:49:49,976 --> 00:49:51,344
CELL POPULATIONS YOU GET OUT,

1367
00:49:51,344 --> 00:49:55,281
WHEN YOU DO THAT HOW DO YOU

1368
00:49:55,281 --> 00:49:57,784
QUANTIFY LIKE WHAT CONSTITUTES A

1369
00:49:57,784 --> 00:49:59,419
DIFFERENT T CELL ENVIRONMENT?

1370
00:49:59,419 --> 00:50:00,520
AT LEAST FROM THE PROCESS YOU

1371
00:50:00,520 --> 00:50:02,588
SHOWED IT WAS A GRADIENT, IT'S

1372
00:50:02,588 --> 00:50:05,224
NOT LIKE -- HOW DO YOU KIND OF

1373
00:50:05,224 --> 00:50:07,760
FIGURE OUT WHICH T CELL

1374
00:50:07,760 --> 00:50:09,195
ENVIRONMENTS ARE SIMILAR OR NOT.

1375
00:50:09,195 --> 00:50:10,930
I KNOW YOU USED KIND OF

1376
00:50:10,930 --> 00:50:11,697
CLUSTERING, RIGHT?

1377
00:50:11,697 --> 00:50:15,101
HOW DO YOU KIND OF -- IS THAT --

1378
00:50:15,101 --> 00:50:17,970
YOU GO FROM THERE TO AN ERROR

1379
00:50:17,970 --> 00:50:20,706
FUNCTION OR SOME WAY OF THINKING

1380
00:50:20,706 --> 00:50:22,108
WHAT'S DIFFERENT OR NOT?

1381
00:50:22,108 --> 00:50:23,443
>> I'M NOT SURE I
COMPLETELY

1382
00:50:23,443 --> 00:50:23,743
UNDERSTAND.

1383
00:50:23,743 --> 00:50:24,844
I'LL TRY.

1384
00:50:24,844 --> 00:50:25,945
SO WE BASICALLY COLLECTED DATA

1385
00:50:25,945 --> 00:50:29,282
ON A NUMBER OF DIFFERENT

1386
00:50:29,282 --> 00:50:29,882
PHENOTYPIC AND DIFFERENTIATION

1387
00:50:29,882 --> 00:50:32,718
STATUS MARKERS FOR THE T CELLS.

1388
00:50:32,718 --> 00:50:36,656
WE THEN BASICALLY FOR THE

1389
00:50:36,656 --> 00:50:38,024
STARTING CELL POPULATION, WE

1390
00:50:38,024 --> 00:50:41,160
THEN SUBJECTED A NUMBER OF

1391
00:50:41,160 --> 00:50:42,195
DIFFERENT PATIENT-DERIVED CELLS

1392
00:50:42,195 --> 00:50:43,763
TO DIFFERENT LEVELS OF

1393
00:50:43,763 --> 00:50:45,331
STIMULATION, AND KIND OF

1394
00:50:45,331 --> 00:50:48,734
FIGURED, OKAY, WHAT'S THE ENDING

1395
00:50:48,734 --> 00:50:49,001
PHENOTYPE.

1396
00:50:49,001 --> 00:50:50,403
AND THEN WE DEFINED -- SAID,

1397
00:50:50,403 --> 00:50:54,006
OKAY, IF WE WANT PHENOTYPE X, AT

1398
00:50:54,006 --> 00:50:55,308
THE END OF DIFFERENTIATION

1399
00:50:55,308 --> 00:50:59,045
PROCESS HOW DO WE NEED TO CHANGE

1400
00:50:59,045 --> 00:51:00,346
APC-MS TO GET US THERE AS A

1401
00:51:00,346 --> 00:51:01,581
FUNCTION OF THE STARTING

1402
00:51:01,581 --> 00:51:02,381
POPULATION?

1403
00:51:02,381 --> 00:51:03,082
>> THAT MAKES SENSE.

1404
00:51:03,082 --> 00:51:04,450
MY QUESTION WAS HOW DID YOU

1405
00:51:04,450 --> 00:51:06,486
FIGURE OUT LIKE WHEN YOU SAY

1406
00:51:06,486 --> 00:51:08,221
PHENOTYPE X, HOW DID YOU

1407
00:51:08,221 --> 00:51:12,492
IDENTIFY LIKE PHENOTYPE X AND Y

1408
00:51:12,492 --> 00:51:13,860
AS OPPOSED TO --

1409
00:51:13,860 --> 00:51:16,095
>> YEAH, WE BASICALLY KIND
OF

1410
00:51:16,095 --> 00:51:17,396
TOOK WHAT WE THOUGHT REPRESENTED

1411
00:51:17,396 --> 00:51:18,764
THE CURRENT STATE OF KNOWLEDGE

1412
00:51:18,764 --> 00:51:19,966
FOR WHAT PEOPLE ARE BELIEVING

1413
00:51:19,966 --> 00:51:22,268
YOU WANT TO AIM FOR IN TERMS OF

1414
00:51:22,268 --> 00:51:23,736
ADOPTIVE CAR T THERAPY.

1415
00:51:23,736 --> 00:51:27,106
SO IF THIS IS WHAT PEOPLE THINK

1416
00:51:27,106 --> 00:51:28,875
IS THE OPTIMAL PROPERTIES, BUT

1417
00:51:28,875 --> 00:51:30,142
KIND OF THE APPROACH AND

1418
00:51:30,142 --> 00:51:31,077
ALGORITHM IS INDEPENDENT OF

1419
00:51:31,077 --> 00:51:31,644
THAT.

1420
00:51:31,644 --> 00:51:33,746
SO IF TWO YEARS FROM NOW WE AS A

1421
00:51:33,746 --> 00:51:36,048
FIELD DECIDE THERE IS A

1422
00:51:36,048 --> 00:51:38,417
DIFFERENT PHENOTYPE THAT WOULD

1423
00:51:38,417 --> 00:51:41,521
BE IDEAL OR DIFFERENTIATION

1424
00:51:41,521 --> 00:51:42,522
STATUS THAT'S IDEAL WE COULD

1425
00:51:42,522 --> 00:51:44,390
PLUG THAT IN INSTEAD AND

1426
00:51:44,390 --> 00:51:45,258
BASICALLY HAVE THIS BASICALLY

1427
00:51:45,258 --> 00:51:50,263
SPIT OUT TO US, OKAY, HOW DO WE 

1428
00:51:50,263 --> 00:51:51,697
NEED -- WHAT APC-MS TO WE NEED

1429
00:51:51,697 --> 00:51:53,065
TO GIVE PATIENTS TO GET US

1430
00:51:53,065 --> 00:51:53,699
THERE.

1431
00:51:53,699 --> 00:51:54,567
>> THANK YOU.

1432
00:51:54,567 --> 00:51:55,034
>> YEP.

1433
00:51:55,034 --> 00:51:56,369
>> EXCELLENT TALK.

1434
00:51:56,369 --> 00:51:58,104
I STUDY MIGRATION OF T CELLS

1435
00:51:58,104 --> 00:51:59,438
FROM PERIPHERY TO CENTRAL

1436
00:51:59,438 --> 00:52:02,408
NERVOUS SYSTEM IN THE CONTEXT OF

1437
00:52:02,408 --> 00:52:03,576
AUTOIMMUNE NEUROINFLAMMATION.

1438
00:52:03,576 --> 00:52:05,344
THIS PROCESS IS HIGHLY

1439
00:52:05,344 --> 00:52:05,611
REGULATED.

1440
00:52:05,611 --> 00:52:08,848
ONE OF THE TOP PATHWAYS THAT'S

1441
00:52:08,848 --> 00:52:10,316
COME UP BEING DIFFERENTIALLY

1442
00:52:10,316 --> 00:52:13,452
REGULATED IN T CELLS IS EMT

1443
00:52:13,452 --> 00:52:21,527
PATHWAY SO INTRIGUED BY THE LAST

1444
00:52:21,527 --> 00:52:22,061
PART.

1445
00:52:22,061 --> 00:52:25,064
AP-1 PATHWAY, HAVE YOU TRIED TO

1446
00:52:25,064 --> 00:52:26,165
MANIPULATE THE PATHWAY IN CAR-T

1447
00:52:26,165 --> 00:52:27,800
CELLS BECAUSE IT'S ALSO THE

1448
00:52:27,800 --> 00:52:29,335
BIGGEST DRAWBACK WHERE WE TRY TO

1449
00:52:29,335 --> 00:52:31,103
USE CAR-T CELLS IN TREATMENT OF

1450
00:52:31,103 --> 00:52:34,373
BRAIN TUMORS, THEY JUST HAVE

1451
00:52:34,373 --> 00:52:34,907
DIFFICULTY PENETRATING THE

1452
00:52:34,907 --> 00:52:37,009
BLOOD-BRAIN BARRIER EVEN THOUGH

1453
00:52:37,009 --> 00:52:38,411
IT'S LEAKY TO INFILTRATE THE

1454
00:52:38,411 --> 00:52:39,245
BRAIN TISSUE.

1455
00:52:39,245 --> 00:52:41,614
>> YEAH, WE'VE NOT DONE
THAT.

1456
00:52:41,614 --> 00:52:42,682
WHAT WE'VE -- ALL WE'VE DONE

1457
00:52:42,682 --> 00:52:44,784
FROM THAT RESPECT IS WE'VE

1458
00:52:44,784 --> 00:52:46,619
ACTUALLY -- WE HAVE GONE BACK TO

1459
00:52:46,619 --> 00:52:48,487
THE CELL CULTURE, 3D CELL

1460
00:52:48,487 --> 00:52:50,456
CULTURE MODEL AND HAVE

1461
00:52:50,456 --> 00:52:52,959
DEMONSTRATED IF WE INHIBIT THE

1462
00:52:52,959 --> 00:52:55,695
PATHWAY, WE INHIBIT RESPONSE TO

1463
00:52:55,695 --> 00:52:57,129
CHANGING VISCOELASTICITY, SO WE

1464
00:52:57,129 --> 00:53:00,099
DO BELIEVE WE'VE SHOWN THAT

1465
00:53:00,099 --> 00:53:01,634
PATHWAY IN CAUSATIVE IN TERMS OF

1466
00:53:01,634 --> 00:53:03,769
CELL'S ABILITY TO RESPOND BUT WE

1467
00:53:03,769 --> 00:53:06,105
HAVEN'T TAKEN THAT IN VIVO.

1468
00:53:06,105 --> 00:53:08,507
WE HAVE ACTUALLY IN THE MONOCYTE

1469
00:53:08,507 --> 00:53:11,110
WORK, WE HAVE TAKEN THAT BACK IN

1470
00:53:11,110 --> 00:53:12,244
VIVO AND DEMONSTRATED

1471
00:53:12,244 --> 00:53:14,413
INTERFERING WITH THE SPECIFIC

1472
00:53:14,413 --> 00:53:15,748
SIGNAL TO TRANSDUCTION PATHWAY

1473
00:53:15,748 --> 00:53:17,817
DOES ALLOW US TO SLOW DISEASE

1474
00:53:17,817 --> 00:53:18,918
PROGRESSION, SO IN THAT CONTEXT

1475
00:53:18,918 --> 00:53:21,554
WE HAVE BUT NOT IN THE T CELLS

1476
00:53:21,554 --> 00:53:21,821
YET.

1477
00:53:21,821 --> 00:53:22,855
>> OKAY.

1478
00:53:22,855 --> 00:53:24,924
THANK YOU VERY MUCH.

1479
00:53:24,924 --> 00:53:27,727
>> EXCELLENT TALK.

1480
00:53:27,727 --> 00:53:33,566
SO, YOU CAME FULL CIRCLE GETTING

1481
00:53:33,566 --> 00:53:37,303
BACK TO CAR T CELL PROLIFERATION

1482
00:53:37,303 --> 00:53:38,371
AND GENERATION AND

1483
00:53:38,371 --> 00:53:40,339
VISCOELASTICITY PLAYS A BIG

1484
00:53:40,339 --> 00:53:40,906
ROLE.

1485
00:53:40,906 --> 00:53:44,810
GOING BACK TO MSRs I ASSUME

1486
00:53:44,810 --> 00:53:45,945
THOSE ARE STIFF ELASTIC.

1487
00:53:45,945 --> 00:53:48,881
SO IS THAT A STRATEGY THAT YOU

1488
00:53:48,881 --> 00:53:51,183
WOULD FEED BACK INTO THAT

1489
00:53:51,183 --> 00:53:53,819
PLATFORM WHERE YOU'RE

1490
00:53:53,819 --> 00:53:55,454
CONTROLLING YOUR LIGAND DENSITY

1491
00:53:55,454 --> 00:53:56,856
AND THOSE SIGNALS?

1492
00:53:56,856 --> 00:53:59,625
>> MSRs THEMSELVES, YES,
ARE

1493
00:53:59,625 --> 00:54:06,298
RIGID AND ELASTIC BUT WITH CELLS

1494
00:54:06,298 --> 00:54:07,500
ENGAGING WITH LIPID BILAYER, A

1495
00:54:07,500 --> 00:54:09,802
SOFT COATING CELLS SEE WHEN THEY

1496
00:54:09,802 --> 00:54:12,071
ENGAGE T CR WITH CUES AND

1497
00:54:12,071 --> 00:54:14,206
PULLING ON IT, WE HAVE FOUND AS

1498
00:54:14,206 --> 00:54:16,409
WE VARY THE LIPID COMPOSITION

1499
00:54:16,409 --> 00:54:18,444
FOR EXAMPLE USING PANEL OF

1500
00:54:18,444 --> 00:54:19,879
LIPIDS AT DIFFERENT MELTING

1501
00:54:19,879 --> 00:54:22,915
POINT, SO WE HAVE DIFFERENT KIND

1502
00:54:22,915 --> 00:54:25,217
OF RIGIDITY ON THE SURFACE, WE

1503
00:54:25,217 --> 00:54:26,452
ACTUALLY HAVE A PROFOUND IMPACT

1504
00:54:26,452 --> 00:54:29,488
ON THE PHENOTYPE OF THE T CELL

1505
00:54:29,488 --> 00:54:33,893
POPULATIONS WE GENERATE WITH

1506
00:54:33,893 --> 00:54:37,363
APC-MS SO WE THINK THE LAST I

1507
00:54:37,363 --> 00:54:38,798
GOT IS CONSISTENT WITH THAT IDEA

1508
00:54:38,798 --> 00:54:40,232
AS WE CHANGE BASICALLY THE

1509
00:54:40,232 --> 00:54:41,967
MECHANICS OF THE INTERACTION WE

1510
00:54:41,967 --> 00:54:44,203
CAN INDEED CHANGE THE OUTPUT,

1511
00:54:44,203 --> 00:54:47,073
THOUGH IT'S DIFFERENT BETWEEN

1512
00:54:47,073 --> 00:54:50,176
THE TWO, THE APC-MS WE'RE

1513
00:54:50,176 --> 00:54:51,711
DIRECTLY ENGAGING TCR,

1514
00:54:51,711 --> 00:54:52,611
PRESUMABLY WHAT'S SEEING

1515
00:54:52,611 --> 00:54:53,512
DIFFERENTIAL PHYSICAL

1516
00:54:53,512 --> 00:54:55,915
ENVIRONMENT WHILE IN THE WORK

1517
00:54:55,915 --> 00:54:58,818
WITH THE GELS THE TCR ISN'T

1518
00:54:58,818 --> 00:55:02,855
ACTUALLY ENGAGED WITH THE GEL,

1519
00:55:02,855 --> 00:55:03,856
INTEGRIN LIGANDS ARE ENGAGED

1520
00:55:03,856 --> 00:55:07,093
WITH THE CELL BUT BOTH SEEM TO

1521
00:55:07,093 --> 00:55:12,465
CONVERGE HAVING A BIG IMPACT ON

1522
00:55:12,465 --> 00:55:12,965
T CELL PHENOTYPE.

1523
00:55:12,965 --> 00:55:15,468
>> THANK YOU VERY MUCH.

1524
00:55:15,468 --> 00:55:17,970
>> ANY QUESTIONS OFFLINE?

1525
00:55:17,970 --> 00:55:18,604
NOPE?

1526
00:55:18,604 --> 00:55:18,804
OKAY.

1527
00:55:18,804 --> 00:55:25,978
WELL, A BIG ROUND OF APPLAUSE

1528
00:55:25,978 --> 00:55:29,582
FOR DR. MOONEY.

1529
00:55:29,582 --> 00:55:29,849
[APPLAUSE]

1530
00:55:29,849 --> 00:55:40,159
[END OF PROGRAM]