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00:00:03
okay thank you so much for the invitation to come here it's a great pages to be in bed for the first time
00:00:10
so i'm i'm gonna talk to about hepatitis b. which as you know hijacked to regenerate live in each
00:00:16
and still current infects an estimated in these two hundred forty million people worldwide
00:00:22
i'm killing at least seven hundred thousand people a day so an estimated two thousand people a day
00:00:29
i'm from the complications of services and of accounts and sit together with
00:00:34
hepatitis c. viral hepatitis is now um as common the cause of death as
00:00:39
h. i. v. t. b. and malaria these other infections
00:00:42
which of received a lot more attention and funding of ideas
00:00:46
um and in fact which rule now coming down um
00:00:49
in terms of prevalence what else well hepatitis debts austin increasing
00:00:55
um as i mentioned the infection takes advantage of the unique nations eleven
00:01:01
um and one of the key features that i will tell you
00:01:03
about is how very specific t. cells the picture it assistance by there
00:01:09
inadequate responses and so most of my uh working map is focused on how to cover
00:01:15
adequate t. cell responses to an initial control of
00:01:19
hepatitis b. and also um to help with hepatitis c.
00:01:23
even if there be uh but i'm gonna start with the uh slightly broader
00:01:27
approach to the whole idea of why do we want even if they're p.
00:01:32
um because you i i'm not gonna talk today about new empty bottles five types the that would be another whole election
00:01:38
but i'm sure you're aware that there's a whole raft of exciting new drugs
00:01:43
being developed for hepatitis b. um and several of these uh starting to reach trials
00:01:49
um say why do we need to worry about the mean system why don't
00:01:51
we just do what we've done with hepatitis c. entry distraught them to borrow
00:01:56
well the problem is that hepatitis b. forms this episode
00:02:00
will activate it because security in a. c. c. c. d.
00:02:04
um hidden in any case which is very difficult to attack with
00:02:08
with jocks and so far then no convincing drugs that we we
00:02:12
i'm never gonna be able to really tackle that and even if it's
00:02:16
possible to reduce levels of c. c. c. d. n. a. with some
00:02:19
of the new therapies looks very unlikely we'll be able to eliminate every
00:02:23
last trace of c. c. c. d. maybe and all the paths like
00:02:28
and on top of that this increasing recognition that integration of the virus
00:02:34
i'm into the into the crime is a multi in a is quite common and the covers quite early in the disease
00:02:39
and again this is gonna be incredibly difficult to tackle with anti vowels
00:02:45
and so having intact immune response can provide a affective immune surveillance of
00:02:51
these residual forms of the boss is a key part of a strategy
00:02:56
for a full curing will controlling kept i'd be
00:03:01
um and what we really trying to mimic with the mini therapy is what
00:03:04
we see in most adults you get this infection which is very effective long term
00:03:08
control of hepatitis b. they very rarely eliminate the virus completely but they maintain a under very good you mean
00:03:15
control we know that because if we you mean i suppress them for transplantation of chemotherapy there's a risk yet which
00:03:22
um and so um we know that also have to speed does remain susceptible to
00:03:28
me control even one screen cities established we've seen that in cases where for example
00:03:33
there's been primer transplantation from somebody who's result type type speech
00:03:37
with chronic carrier and they have managed to solve the infection
00:03:43
so there's a good question now that for a minute there you
00:03:46
we can divide the goals of the mini therapy into shortened long time
00:03:51
in the short term uh in a therapeutic approaches would be aiming
00:03:55
to act in tandem with the best possible anti borrows that we develop
00:04:00
um you know just to clear as many if in fact that's that's
00:04:02
as possible and this could be either by citing the sticker it's a killing
00:04:07
infected about sites which is the traditional well for example of c. d. a.
00:04:10
t. so in case of but also by non slices decay rates that so
00:04:16
um c. d. a. t. cells are able to clear infected paths let's without killing them which is
00:04:21
of course very valuable if you've gotten large numbers back to the paths lets you want to preserve it
00:04:28
but then in the long term as i've already lead you
00:04:30
to the impulses of immunity therapy would be to try to
00:04:34
provide the past it means abatement so that the traces of
00:04:38
residual interaction will be kept under tight control and prevented from reactivated
00:04:43
um and also to provide means surveillance for early costner genesis which
00:04:47
is remains an ongoing risking patients um even once it was all accepted
00:04:55
so how can we go back to covering immune response um so
00:04:59
i've done a a an analogy with cause say i am we can
00:05:03
uh and we can think about revving up the immune response reviving
00:05:07
a over casing it that's a very simplistic division of the different approaches
00:05:12
the revving up would be saying okay there's some parts of
00:05:14
the response which is just not being adequately triggered by hepatitis b.
00:05:19
um and so we just need to put a foot down on
00:05:21
that um accelerator all that gas that'll with the within the state
00:05:25
and trigger it properly so that would be for example the um
00:05:29
seven should is a community which have test these very bad triggering
00:05:34
it's known as a stealth virus which creates into the body without the netting many parts
00:05:39
of the innate immune response and so if we can just it's ted trigger there is
00:05:44
uh i mean sponsors artificially we might be able to have some activity against one
00:05:50
another perches is to try to revive and realise responses which should be in
00:05:54
either dampen down too much become exhausted all i've held in too tight control
00:06:01
um and so that's things like using the checkpoint inhibitors it would just
00:06:04
talking about p. d. one blockade to try to realise i existing response
00:06:09
and finally there's the possibility of completely replacing immune responses saying what what we've
00:06:14
got in the patients is just inadequate let's bring in some totally new responses
00:06:20
um and the case that i'll just go through some more detail about these different approaches
00:06:25
um so first for just a sort of um summarise this approach again
00:06:29
what we're looking at in the setting of chronic infection is a very depleted immune response
00:06:35
here i'm i'm focusing mainly on the cellular component the same is true but
00:06:39
a soluble components and selling shoes a community got very deficient
00:06:43
h. p. v. specific t. cells and be so for example
00:06:47
um you've got highly inhibited immune responses tending towards
00:06:50
exhaustion what we're trying to achieve with the minister p.
00:06:54
is some sort of strategy which i'll talk about the different ways of doing this of we're covering
00:07:00
in resisting that response to try mimic what we see in in a patient to result hepatitis b.
00:07:06
so by starting those people who've got an actual control of ours we know that
00:07:10
this is associated with a very strong robust and highly functional um adaptive immune response
00:07:17
um so it's not just the numbers of the cells that increases
00:07:20
but their ability to reduce all the key immune mediated scissor cup but
00:07:26
how could we go about doing this so this can be
00:07:28
divided into tackling said intrinsic community put some approaches that um
00:07:34
struggle between the nation adaptive and some which are really concentrating on
00:07:38
the adaptive on the response now talk about most of these briefly today
00:07:45
um the key points to take home from all this is that it's unlikely that any
00:07:50
one single approach is going to work and it's going to need rational combinations for the future
00:07:55
and offer to these immune modulator is will be need to
00:07:58
be used in combination with potent anti browse for maximum africans
00:08:04
uh_huh system is just very briefly set engines a community
00:08:07
i i just mentioned already that active speech very bad triggering
00:08:12
uh innate immunity so does it and use type one interfere
00:08:15
on you cheat stages infection in a way that most viruses do
00:08:19
um and then you therefore what downstream sell intrinsic immune responses that
00:08:24
in no way to get back to it when it from the defect
00:08:27
but the important thing is they have to speed does seem to really main susceptible
00:08:31
to these mediated um so for example type and film although it does it in jesus
00:08:38
it it up and fin also doesn't repress it and it's not politically resistant to save
00:08:43
that's why you know it is partially response if if we treat patients time and
00:08:48
so um one solution to this is to say well let's just directly activate
00:08:54
sunshine to community and that's being done for example with the re
00:08:58
kayaking list which is the phase two trials achieve at the moment
00:09:02
i'm too jeez uh interfere and get a lambda and there's a couple of other approaches which should be looked
00:09:07
at which just by cost the lack of tight went
00:09:10
through in attracting g. sell intrinsic unity within the hat sign
00:09:16
then looking at other native info affects the cells that could be hahn said the live is actually really in which there in a
00:09:23
i'm immune mediated it's um we've got is a far more n. k. cells for example in the liver than
00:09:29
the blond um and that's partly because we have specialised resident n. k. cells that live in the late but
00:09:35
um that optically adapted environment however they're very bad a p. g. c. intern
00:09:40
common the setting of h. b. and so could we somehow rescue that ability
00:09:46
we've also got a make cells that i'm happy
00:09:49
move recently identified to be highly enriched in got
00:09:52
live the gamma delta t. sell c. d.'s and
00:09:55
they like t. cells also potential important antiviral cell type
00:10:01
which might be able to be harnessed in future types be
00:10:05
and cover the um taylor seventy larry hygienist orange trial and
00:10:11
uh uh thought a partially work by and by triggering d. cell type
00:10:19
um okay i just mentioned that so so one problem with trying to
00:10:22
harness encase else they seem to have a dual role in hepatitis b.
00:10:26
although they could be antiviral 'cause they can produce infrared camera for example
00:10:31
they can also have pathogenic effect because we show that they can express deck
00:10:36
um ligands which allow them to kill the h. p. v. specific t. so it's
00:10:41
if you lose the n. k. cells you might paradoxically actually reduce the antiviral t. sociable
00:10:48
you have to be very careful with beneath or piece of targeting in case
00:10:54
so overall will be considering using innate immune modulation modulation
00:11:00
um there's some advances some disadvantages advantage would be that you might go
00:11:04
to bypass the exhausted adaptive immune response which is very difficult to rescue
00:11:10
um but most in a remote mediate is uh quite short lived um
00:11:14
see probably need repeated demonstration we might use them in conjunction with adaptive
00:11:19
i mean he's doing a lot of them i'm not going to be directed exclusively gets infected pats
00:11:24
light so there'd be quite nonspecific in their activity
00:11:27
in there for the efficacy toxicity pants could be problematic
00:11:32
um and then moving full what the model systems the testing
00:11:35
or efficacy or or quite of a problem as well so
00:11:39
there's a lot of differences between the happy tame a cell
00:11:42
lines are often used to test them and primary apart sites
00:11:45
this differences between mice and humans protectively in an eight mean
00:11:49
populations and between the periphery and the cats and it but
00:11:55
what about human immunity inhabitants people about the cells so they've been
00:12:00
winning detected in in terms of the search and appetite is b.
00:12:04
and um we all know the antibodies important protection weaned use them with
00:12:08
the vaccine as a way of protecting against re infection or new infection
00:12:14
but what about ongoing control but be so well it's become obvious um in recent years from a number of
00:12:21
chronic about infections that b. cells can actually play a major role in control of chronic infections this is
00:12:26
coming out in the h. i. v. h. to we seen in hepatitis b. because of a texan so
00:12:32
um one of the key jokes that can cause h. p. v. act yet to
00:12:35
patients with tax map which is not affecting your t. cells it's affecting all be so
00:12:39
so that tells us that b. cells applying an ongoing role in the control of hepatitis b.
00:12:45
and such try to to look at that bit more we've been studying the cells a bit in the last few years
00:12:50
um we show no one subset b. cells it's expanded titus b. is
00:12:55
actually even as oppressive produces i attend which can again down regulate t. cells
00:13:01
i mean recent you'll see started to study this the specific t. cells that recognise hepatitis b.
00:13:07
and the way that it's possible to do that is i'm using a pate
00:13:10
reagent which basically just the hepatitis b. surface antigen labelled with the floor crime
00:13:16
i'm i'm with that i'm i'm just that might be is able to identify
00:13:20
only those b. cells that are able to recognise h. p. v. surface antigen
00:13:25
and you can see that small population of them here which if you sold those cells you can show that
00:13:30
in an alley spot um they are reactive we can't surface antigen
00:13:35
and a producer for sound body from a back sunny and if you look at
00:13:38
the faction that doesn't stain with this bait you have no exemptions specific pieces that
00:13:44
a specific um reagent you can use the phrase like some trees it means you stop
00:13:48
for the first time we have to crack tries the antigen specific t. cells in patients
00:13:56
so um what alice found was when she identified and source it
00:14:00
just the small numbers of cells that are specific to f. antigen
00:14:04
well neither cells that were from vaccinated healthy controls could produce lots of anti h. b.
00:14:09
s. and see what we saw this population from chronic hepatitis
00:14:13
b. patients although there was some of these piece of that
00:14:17
and said that they're not completely lost that present but just take a dysfunctional because they don't produce the antibody
00:14:24
uh_huh and when he starts try to understand what's wrong with them we notice that they have this atypical phenotype
00:14:31
so where is if you look at these vaccinated healthy controls most
00:14:35
of their um surface tension piece of have a classical memory phenotype
00:14:39
when you look in the chronic hepatitis c. patients large proportion of the
00:14:44
s. n. should be sells uh taken over by these red cells which are
00:14:47
of down regulated she sickening molecules required for the some memory funk
00:14:54
um and we see this a typical be so uh expansion also in the global the cell compartment
00:15:00
looking at those cells they have quite a lot of features like the
00:15:04
axle c. t. cell response that's been described for number of using chronic barn
00:15:09
have high levels of p. d. one classical exhaustion market it got high levels of somebody's
00:15:15
um uh receptors which combine for example to new complex is
00:15:19
um and this tells you give us some targets which might mean we could actually
00:15:24
therapeutic to manipulate the pisa response to rescue
00:15:28
a good antibody response in chronic hepatitis b.
00:15:32
so just to um some of the b. so study
00:15:36
um it we found that assesses pass shape about affection drives
00:15:40
an accumulation of atypical both antigen specific kind global peace
00:15:44
holes in the plot and also in that eventually knew that
00:15:47
and which haven't patented bark nasty have wanted sickening wilted homey
00:15:53
very bad differentiating and passed the cells um and
00:15:56
have even produce row impaired production of antiviral sites kinds
00:16:01
and by a by study nice those by direct x. p. that
00:16:05
by free site how much we can start to identify molecular target
00:16:08
that could be used for the sting more effective human unity in the function to of h. p. v.
00:16:15
um so that study was published back to back with the study for
00:16:18
mentally but select description with very similar findings i'm using a different bait reagent
00:16:24
and um there's been a as of now uh a number of studies coming out starting to look at
00:16:29
both b. cells and if t. fit to help uh cells which of the c. d. four t. cells
00:16:34
and needed to help the piece of response i think this is a really exciting area of features a show
00:16:42
but as i mentioned at the beginning most file works concentrating on t. cells which are really
00:16:46
critical for recognising interest cellular viruses like hepatitis b.
00:16:51
and a markedly depleted exhausted in in chronic infection
00:16:55
um we see it's become clear that is quite sort of heterogeneity within chronic hepatitis b.
00:17:01
in terms of the t. cell exhaustion it varies according to the antigen specificity the t. cells
00:17:06
you might be able to define different subsets in different patients in order to pick out those ones who could
00:17:12
respond better to mean modulation and which type of immune modulator therapies needed
00:17:20
um i i as you probably know there's been a number of therapeutic
00:17:23
vaccines try hepatitis b. of the u. s. unable failed miserably save file
00:17:28
um but that doesn't mean that approaches is in a completely
00:17:32
useless going forward it just means that we need to think much
00:17:35
i'm more carefully about the right strategy in how to combine it with other approaches
00:17:40
um i'm a card sort of working optimal ideas about going
00:17:45
forward with therapeutic vaccines is to select the right patient great
00:17:49
who at the moment should be with vi reno well suppressed on you
00:17:54
it's earlier on in the course of disease 'cause we know that younger patients of got less damaged immune responses
00:18:01
an interesting group going for what might be um patients you had treatment interruption
00:18:05
and mark nine involved in the treatment interruption but it maybe which marks leading um
00:18:11
there is some reports showing the t. cells of these did when you interrupt treatment and so if you got a
00:18:17
little bit boosting might be a good time to come in with a therapeutic vaccine to for the old man response
00:18:24
um but most exciting me when you jerks become available that can really reduce the antigen dated hepatitis b.
00:18:30
as opposed to just the by reading yeah there's a better chance that back therapeutic vaccines will start somewhere
00:18:36
and the vaccines themselves h. b. well designed in the past they've often just targeted surface
00:18:41
tension that should really talk will keep our luncheons they have to be highly minute janet
00:18:46
um then each chime in jesus multi specific broadly cross reactivity so's we need to
00:18:51
focus now on wall saint using could be self finance bodies not just t. cells
00:18:56
and we may have to keep some additional immune modulation as
00:18:59
well as the vaccine to allow the mean response to respond properly
00:19:04
and in order to work to do that i mean uh modulation we need to do with
00:19:08
different defects a. t. seven don't worry i'm gonna take you through this very quickly step by step
00:19:14
um so one thing i've mentioned already is that the um
00:19:19
chronic antigen load drives to send exhaustion so because the t. cell receptor
00:19:25
on t. cells it's been calls the exposed to pack ted image c. complexes
00:19:30
yep drives um t. said exhaustion if we can reduce the amount of antigen
00:19:36
by bringing down really not just the levels of
00:19:39
circulating virus but the levels of the surface antigen
00:19:43
and and c. c. d. n. a. we may be able to reduce the stimulation of t. cells allow them to cover a bit
00:19:51
i've also when he told about fat n. k. cells might be limiting the t. cell response
00:19:57
i'm here isn't any cases that we've been taking pictures of with an electron microscopy guy ever
00:20:02
collaborating with that and when they become activated big it is lovely folder that you know whether pretty
00:20:08
um but anyway they can express this deftly can try another
00:20:12
molecules to allow them to delete when he bit t. cells and
00:20:16
so um it may be that some sort of manipulation of
00:20:19
the interaction between encase in t. cells allows better t. so risky
00:20:26
a checkpoint in which is the thing which are most
00:20:29
likely to uh to move into clinic in combination with um
00:20:33
a therapeutic vaccines 'cause of that they've already been tried in a very small trodden hepatitis b.
00:20:39
um and of course that being used a lot in counts including in h. c. c.
00:20:44
um and you know that the nobel prizes awarded full that discovery this year or last year um
00:20:51
so the question is i mean we have a lot of data from in the church studies from
00:20:56
occupant others and from animal models suggesting they will
00:21:00
be able to beast h. p. v. specific t. cells
00:21:03
um however um you know will they be safe enough for use in chronic hepatitis b.
00:21:09
still remains a concern as mark mentioned side effects are not trivial for chronic wound infection
00:21:15
um and in addition that they're very complex the checkpoint in its its multiple
00:21:20
layers of checkpoints is not just p. d. one and so if you've got one
00:21:24
um you may have then other ones compensating and so you then in can't seek
00:21:29
and then think about combination trials uh but that's again much more problematic in hepatitis b.
00:21:38
so what about going deep into the t. cell to understand what the underlying defects on so
00:21:43
there's a lot of work going on looking at um the mike to congealed effects in exhaustion
00:21:49
the and the metabolic defects to see whether we can do some that metabolic manipulation to rescue t. cells
00:21:55
um so for example a colour for always
00:21:58
keep ashamed that by using mind control and antioxidant
00:22:02
you can get some reversal of the on the line much
00:22:05
control defects and some recovery if t. select solution hepatitis b.
00:22:09
um and we show in if you are in the chief you give 'em i'll twelve
00:22:14
in combination with p. d. one blockade you can get some uh cover your might control defect
00:22:20
um this other metabolic checkpoints that could be of interest
00:22:23
um we've we've shown a argentine um can regulate t.
00:22:27
so perforation and that's something that could be supplemented relatively
00:22:31
easily um i'm currently working on a role for class struggle
00:22:37
so just something not how we could try to revival release and don't just adaptive immunity
00:22:42
we need a very um effective code to grow what's their piece it
00:22:46
back see we may need to inhibit some of these regulate three populations
00:22:50
or um you know regulates recites kinds all checkpoint inhibits is
00:22:55
and then try to see if we can recover both h. p. v. specific b. and t. cells
00:23:02
but finally if we can't do that come we replace the new response quickly with anyone
00:23:08
this is obviously quite a radical approach um it's unlikely
00:23:11
i would say to be sieve ever ever a sort
00:23:14
of suitable for reaching use in of widespread chronic about
00:23:17
infection hepatitis b. but it is being tried in um
00:23:21
h. c. c. and and it could be very exciting in selected cases and of h. c. c.
00:23:27
and the idea here is to say um it's too difficult to get an adequate response from the intelligence
00:23:33
uh exhausted every response so we'll engine a new t. o. b. cells to do the job instead
00:23:40
um and so you can do that in a number of different ways um
00:23:44
i'm sure you've heard about the success of car t. cells which are being quite
00:23:48
widely used nine counts the and you can do the same thing in hepatitis b.
00:23:52
because you're basically using an antibody fragment you inserted into t. cells which recognises um
00:23:58
uh uh an antigen lot in this case we use
00:24:02
f. essential on presented on the surface of a path side
00:24:06
um the advantage of cocky sources they're not m. h. c. restricted so they
00:24:10
can be used across different patient patient groups but they do then rely on
00:24:15
on targeting the essentials on high pass let's not soluble extension which might be a problem
00:24:21
um the alternative is to use t. cells whether t. so sector has been rejected
00:24:26
um so you can you can um crisper knocked down the in duchess t. t. so
00:24:32
set on the t. seven put in a new one which is specific for h. p. v.
00:24:37
and um i i took part in this work in the early stages and we we treated in fact the first patient
00:24:43
um in the world with them uh h. p. v. specific t. c.
00:24:47
or redirected t. cells a one of case you had um but current
00:24:52
um attacks the sees a expressing the h. b. ascension
00:24:56
and that that work is now being extended by jenny personality into big trials and looks quite promising
00:25:03
um and then another waiting you can do this instead of
00:25:06
doing it genetic engineering the t. cells you can give soluble receptors
00:25:11
so this is what is being done by um even record company in
00:25:14
oxford whether developing t. so sectors that recognise h. p. v. up to
00:25:19
and then they'd given is as us only put infusion and they then have um a up a component which
00:25:26
will harness any c. d. three t. cells that are present in the lip and get them to do the job
00:25:33
and similarly with with the he will side you can do the same kind of thing you can you can give 'em
00:25:39
um either therapeutic antibody infusions which uh uh
00:25:44
some again being considered much more seriously now as a therapeutic approach
00:25:48
as they are in h. i. b. we can tailor those antibodies to
00:25:52
make them by specific notes to engage um the the local t. so
00:26:00
again with these kind of engineering perched all the sound so elegant 'cause you
00:26:04
putting in just cells of the right specificity there's cells still going to be
00:26:08
susceptible to exhaustion if they hang around and then if it's you know it's still going to be inhibited
00:26:12
by marcus like p. d. one so we've been working on what it's possible to for the op to mice
00:26:17
there's cells genetically one thing that it's your targeted in my group was to
00:26:22
put in the right t. cell receptor but then knocked down peeking once a second dual genetic modification
00:26:28
and we were able to show in collaboration with 'em under very easy and antonio
00:26:33
the the there's cells then have enhanced ability to kill ascension expressing um cheaper so
00:26:40
however what we noticed was that over time with repeated stimulation
00:26:44
baby driven towards uh it up more severe form of some lessons
00:26:49
um and uh exhaustion probably because of our regulation of alternative exhaustion market
00:26:55
and so i think this page could be useful again for short term therapy but maybe not so good long term
00:27:03
and then the thing that always comes up with a mini therapies is it
00:27:07
is it gonna be safe orbits trade off between immunity in a minute pathology
00:27:11
because of course the virus itself is non psychopathic the liver disease is immune mediated
00:27:17
i'm an most components of the new response that could be
00:27:20
protective like the c. d. t. cells can also immediate giver injury
00:27:24
and so is it going to be inevitable that we'll have to have a degree of live a flare if we're gonna have effectively mean be sitting
00:27:31
one thing we can do is try to promote the non sighted
00:27:34
basically mean responses say the fact that for example c. d. t. cells
00:27:38
can clear interface to pass sites without killing them is
00:27:41
attractive if we can tailor that side of t. cells on
00:27:45
but on the other hand we probably need some control degree of the path site license if we want to eliminate
00:27:51
um paths that surgical integrated d. n. a. that we probably need to actually them kill some of them
00:27:57
um and also we know that if we eliminate path sites in fact surpass sites
00:28:01
that will encourage the c. c. d. nails because of them pat pat side division
00:28:08
um uh and it's obviously important first minimise and
00:28:12
she loaded we need more statistics that i'm stand extent
00:28:16
of in fact paths lights could be really don't know when a lot of cases how widespread the infection is
00:28:21
and how much liver was the they'll be if we get a very effective immune response
00:28:26
um hum ideally want immune responses that remain very much focused within the leave it
00:28:31
to avoid side effects in the rest of the body and focused on the right component
00:28:36
i mean we need to really develop some junked approaches to limit collateral damage
00:28:43
so i'm fine i just want to engage by talking about
00:28:47
the needful monitoring within the live uh as well as the plot
00:28:50
uh because you have to just because a lot of compartments
00:28:54
lies ration of both by roland g. and immunology within the liver
00:28:58
um the bar reservoirs like c. c. c. d. inane integrated d. n. a. up best measured from the live that
00:29:04
we have a number of immune responses that are really resident and then live and don't come out into the
00:29:10
plot and socially any dual army monitoring of new therapies in the plot begin to miss a lot of the action
00:29:17
um so every dimension that um some encase sells a resident of uh
00:29:23
a lot of the of the cell types that may be important might make it sells a main be present in the back
00:29:29
most h. p. v. specific t. cells and then have a very few than commands
00:29:34
the plot and find a um we've recently described liver resident faction t. cells which scenes
00:29:40
very well adapted to the live environment highly functional associated
00:29:44
with h. p. v. control but copy sampled in the plot
00:29:49
um and that's the work of of your palate um she
00:29:52
showed the cells um maintain very rapid functionality in the liver
00:29:57
um and um it's mainly non socialistic which as i said would be attractive um
00:30:04
the question is is it possible to use the cells for functional q.
00:30:10
and how we gonna test for that because as you all know the diagnostic
00:30:14
biopsies of being useless unless i don't know what situations like here in switzerland but
00:30:19
um in the u. k. and many other countries very few diagnostic boxes are being done in hepatitis b. now
00:30:26
um and so with of pete gill what's apache can idiot button on the we've recently asked is it
00:30:32
possible to turn to using fine needle aspiration instead of
00:30:36
a biopsy as a wave reliably sampling the little compartment
00:30:41
um so that finally last grits with first time need for you
00:30:44
to have to speed by harry ounces creepy in two thousand five
00:30:48
um and they had been used also for long which you know monitoring of hepatitis c. um
00:30:54
by um id got can screw 'em because they needed is is is is the same even a useful number
00:31:01
punctures a very fine needle patience hockey feed it a
00:31:05
tool and a happy to have it done repeatedly which obviously
00:31:08
most people are not with uh but see i'm so in in um and a
00:31:13
coke can study some of them had it up to ten times um and um
00:31:18
what what we wanted to ask was can you actually get the
00:31:22
same immune composition with the findings last but you get with a biopsy
00:31:27
and so what we did was we we we did a number of cases where we've got a lot
00:31:32
finally last but i'm biopsy or together and pound out
00:31:35
from the same individuals and then compared and mean profiles
00:31:39
i'm just looking at what different mean parameters that looked at one principal components analysis
00:31:44
you can see that the plot is casting here the little
00:31:47
biopsy here and uh finally last spring is in the middle so
00:31:52
look at different the button never are really dramatically spaced apart
00:31:56
and the final last is a kind of compromise between the two
00:31:59
i'm just some i mean pronounces it actually correlates really well so if you plot
00:32:04
be percent over protective parameter in the biopsy versus the fine you can ask for it
00:32:09
you see that is quite nice correlation for these parameters
00:32:12
global c. d. a. t. cells may itself be so
00:32:15
um you know a a patient who has a high number on the of make
00:32:19
cells on that but see we'll have a high number on their f. in a
00:32:23
so that's quite reassuring but instead we need tend to um some of the things like
00:32:29
um the uh h. p. v. specific t. cells and the and the um tissue resident t. cells
00:32:36
we see that there are they are present in the finer
00:32:39
aspects they are slightly lower numbers than in the uh biopsies
00:32:44
um but then not there in the plot tools so his the tissue resident subset was telling about
00:32:50
just um it's march by these two parameters here it's there in the asp
00:32:55
or it's than the but since just not there and the plot at all so
00:32:59
overall i'm you know this these data reassured us uh find us what is a good compromise instead
00:33:06
of doing biopsies if you caught you biopsies but you don't want to just from on the plot
00:33:11
to be able to sample subsets like the tissue present t. cells h. b. b. specific t. cells um
00:33:18
with with a couple of tosses the find last but you can guess enough to do three face item she panels so
00:33:24
and you can look at low flow parameters but that was very nice was it could also get viable
00:33:29
hats lights these asked for it so we need china look a concert some biopsy specimens matched up the biopsy
00:33:35
it's often very difficult to get nice staining think that's that's the from the finally last
00:33:39
but it's um because you you don't have to do any processing and matching out just
00:33:43
spin that um you couldn't get nice stains a path site so
00:33:49
it's possible and potentially look at both the lip sites any class that's in
00:33:53
the same sample for example to look at things that painting one expression that
00:33:58
um we yeah as i've mentioned we can sample tissue resident subsets by finding last but
00:34:05
we can see the h. b. b. specific t. cells and we've developed a scoring so that we can try to standardise these
00:34:14
um so just final words um to move would i think i'm in
00:34:18
this field lots happening in have ties but it's a very exciting time
00:34:22
um we need some better in feature you and in beaver models
00:34:25
for testing new you mean much energy therapies that are coming through
00:34:29
we need to make use of um opportunistic something about patients when you know when patients on
00:34:34
trial so are cheating functional too it's a great time to monitor really fair already what's happening
00:34:40
um so i think in every phase trials um we
00:34:44
should have really quite comprehensive on plastic little square analyses
00:34:48
um id all some kind of as well as plot um and then all this
00:34:53
if moving forward into big trials we'd need to have more practical um immunological by markets
00:35:00
in in the blog rather than ever that can be scaled up for knowledge chiles
00:35:06
um in terms of therapies coming towards the kinetic um the encouraging thing is that there are there are
00:35:13
multiple defects in response to have to speed but the
00:35:16
boss does remain susceptible wendy's uh approaches up east it
00:35:21
um it it looks uh so it will be essential to have some induction verb pass
00:35:27
interprets it can mean surveillance for long term functional pure and um
00:35:32
we have a sampling would be useful to try to evaluate you
00:35:35
purchase for that we may have to tolerate a degree of liver
00:35:38
damage you know just to introduce a useful anti by our immune response
00:35:42
and some of the um successful in the third piece that people have
00:35:46
been despairing about like vaccines and even the recent to last seven study
00:35:50
may in fact turn out to be efficacious when i combine respect mansion reduction
00:35:55
um so i think i think 'cause he's gonna require really
00:35:58
careful combinations of immunological of approaches in the right patient great
00:36:04
um i think that's it yes so just like two and by thanking my
00:36:08
team and um well my collaborative on this attractive staying so late to listen
00:36:24
just watch out of his room was pushed also scored closest to talk shoulder or some questions
00:36:31
uh_huh or would like to stop because those who still sort of look most focused
00:36:37
so one question regarding source controller cousins warlock on books uh_huh topics
00:36:46
so we should see what's possible to to go
00:36:52
but no i mean at the moment it's what's been done is just checking to see what happens
00:36:56
to the names points is accessing and a couple of studies an usher in a little bit of increase
00:37:02
in h. p. v. specific t. cells around the time of into treatment interruption
00:37:07
so i i was just suggesting that that might be an
00:37:10
opportunity to then come in with a therapeutic vaccines for example
00:37:14
so um i mean all i in the in the trial of it at the moment interfere on is being tried
00:37:21
it does work because of stocks and you would have those flu or also to talk on the cartons
00:37:28
virtual to one piece goes with his response was it for example because i'm considered because like what
00:37:38
you have a condom machines to each person to come to think that postmarked oh maybe yeah maybe
00:37:47
um i mean i think it was
00:37:51
i mean i think it's more likely to hell with um the b. cell recovery because that's only going to and what
00:37:58
is really going to damped down the circulating antigen but you still have the c. c. c. d. n. a. that path sites
00:38:05
producing mansion which can be within the paths that's presented to the t. cells so i'm not sure
00:38:10
what helps so much with the t. cell recovery i think it's quite exciting would be so completely
00:38:17
oh
00:38:21
okay
00:38:23
uh_huh yeah
00:38:32
all
00:38:35
yeah
00:38:40
um i it does the current have says b. was first described in only twenty
00:38:45
years ago something but it seems what was initially thought to be extremely rare adapted speak
00:38:50
even though um it's it's always endeavour prayer in virus using reverse transcript isn't it's that
00:38:56
um and lisa studies suggest that it probably is more common than we've relies
00:39:01
so it is so it's something to bear in mind i mean i think the predominant
00:39:05
problem is not that the predominant problem is the exhaustion that's the lack of t. cells
00:39:09
but it is a worry that when we if we guess they're pretty basses working well we might
00:39:15
bruce the wrong responses um which the boss so it's definitely a reason to not
00:39:19
just focus on single specificity is but a couple with several different persons things yeah
00:39:29
the s. s.
00:39:42
very little about that i have to say
00:39:45
um we'll that's not my work and i i come sir i don't actually know enough
00:39:50
about it to really comment but i mean it is being tried as a way of
00:39:54
the sting sell interns it could pass i mean see but i want to be honest i
00:39:59
can't remember exactly how it's supposed to work 'cause it's not something that is that the company
00:40:08
uh_huh
00:40:11
yeah yeah i i don't think it connected with that 'cause that's when
00:40:15
it hit cluster partisan t. cells was this is the paths like itself
00:40:19
and i think it's independent cluster but i i honestly can't remember has this work it's i think it's quite
00:40:24
early stages that way but that's or not and that you pick the one thing i really didn't know that
00:40:33
so it was just one
00:40:43
or
00:40:47
yours
00:40:51
sure
00:40:55
um
00:41:02
it's yeah
00:41:07
it's like he's fine it's a a a very small study being presented to give
00:41:13
you had not published yet it's only thirty patients with the not good vaccine um
00:41:20
uh with a single days and that's is that what we did just a single those p. d. one and at least it seems safe
00:41:27
um as it did in when it was previously given to have see patients actually
00:41:31
um surprising because i'm not you know it is a t. regulated and uh so i i find it quite
00:41:38
worrying the idea of using it but i'm safe but it does seem to be safe um
00:41:44
it only one patients are converts it but actually quite a lot of them had
00:41:48
a low production ascension and given the fact is is suboptimal vaccine and single those
00:41:55
you know it does look like promising specially going for what we would
00:41:57
have to be used yeah with a very step wise approach i use yours
00:42:06
uh_huh
00:42:08
uh_huh
00:42:11
ah
00:42:15
yeah because there's no no yeah i'm certainly no even just looking at my levels of p.
00:42:23
d. one at baseline and then doing in beach assay that doesn't predict who's going to respond so
00:42:29
i'm not too optimistic that's gonna fall below and yeah
00:42:37
uh_huh uh_huh persians one to stop who's just
00:42:47
what is so 'cause at some point now is going to look like you have to store
00:42:54
apart from talking about the conclusion to what you could so because it's just a good chance at some point
00:43:02
to stop and go to some calls yeah i mean it's a lot
00:43:06
of the pace at the moment so this whole working groups in hepatitis b.
00:43:10
talking and you know about what's safe live a flat debating about how high you shouldn't be able to go
00:43:17
and in the street interruption studies it's been quite variable different groups have had different
00:43:21
thresholds for coming back in with treatment and certainly the ones who came in very cautiously
00:43:27
well in that respect that probably they didn't give enough chance for a sort of immune recovery
00:43:33
um but obviously um first do no harm programs
00:43:49
just just use it
00:43:58
oh
00:44:10
huh
00:44:13
which is four or more
00:44:27
yes
00:44:32
ah mm
00:44:45
slows us
00:44:51
difficult area you only even when there is just would have to
00:44:55
be tested first indicate setting of our suppression all ninety miles i'm
00:45:00
i'm really thinking we can move them into that setting if we've
00:45:02
already notice safe um in the normal setting up a vile suppression
00:45:10
oh really
00:45:15
fish

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Conference Program

Progress in Alcoholic Hepatitis: Has there been any?
Prof. Mark Thursz, Head of Digestive Diseases Division, Imperial College London,Department of Surgery & Cancer, London, United Kingdom
9 May 2019 · 6:06 p.m.
Harnessing immunity for the functional cure of hepatitis B
Prof. Mala Maini, Honorary Consultant Viral Immunology, University College London, Department of Infection and Immunity, London, United Kingdom
9 May 2019 · 6:49 p.m.