Okay I think we should get started I'm
David Spector I'm director of research
at Cold Spring Harbor Laboratory and
it's my great pleasure to welcome you to
the laboratory and to tonight's lectures
on immunotherapy and cancer the latest
research Cold Spring Harbor Laboratory
is one of 69 National Cancer Institute
designated cancer centers throughout the
United States and the laboratory has
been a leader in cancer research for
more than 40 years and has a very long
history of both innovative discoveries
and major breakthroughs in cancer
research a little over two years ago the
laboratory entered into a strategic
affiliation with Northwell Health
bringing together their state-of-the-art
healthcare system and large patient
population with our world-class
scientists and together we hope to move
basic science being conducted here at
Cold Spring Harbor Laboratory to the
clinic more rapidly to help patients
directly and we have a lot of exciting
collaborations going on together with
Northwell Health and I'm sure that over
the next few years you're going to hear
a number of lectures from scientists
both from Cold Spring Harbor and
Northwell who are working together to
make new advances and better treatment
options for individuals with a variety
of cancers this evening you'll be
hearing from two outstanding clinician
scientists on a topic that has been in
the news quite frequently in fact on the
front page of the New York Times
yesterday and it this this approach
takes advantage of your body's immune
system to launch an attack on cancer
cells and so it's a very powerful
approach and tonight you'll be hearing
about how this approach works what the
caveats of this approach are and how
these
issues can be improved to make this
approach more valuable to a larger
population of patients so our first
speaker this evening is Professor Doug
Fearon Doug received his MD degree from
Johns Hopkins University School of
Medicine he's been a professor at
Harvard Medical School John Hopkins
University and he's been a group leader
at Cancer Research UK in Cambridge
England he currently holds a joint
faculty appointment as professor at Cold
Spring Harbor Laboratory and Weill
Cornell Medical College in New York City
his laboratory has made major
contributions to various aspects of
immunity including cancer immunotherapy
Doug has received numerous awards
including being a member of the National
Academy of Sciences a fellow of the
Royal Society and a member of the Royal
Society of physicians and so it's my
great pleasure to introduce Doug Fearon
to give it the first lecture this evening
Thank you David David's kind of given you
my background and I thought since this
is a somewhat informal occasion I would
sort of relate the curious nature of my
research career as a clinician I was a
Rheumatologist and I was dealing with
autoimmune diseases and of course in
autoimmune disease you're trying to turn
the immune system off because the immune
system is damaging normal tissues and in
attempt to do that I felt I needed to
know more basic immunology so I became
more more of a basic immunologist and
it's actually been some time since I've
seen a patient but I as I learned more
more about immunology it actually became
apparent to me that perhaps it's easier
to turn the immune system on than it is
to turn it off once the immune system
decides it wants to attack something
it sort of hard wires that it's what
we call immulogical memory so it's hard
to turn the immune system off and that
realization occurred at a time when I was
serving on a scientific advisory board
of a Cancer Research Foundation and I
said Oh in cancer we want to turn the
immune system on and so that led to a
change in my career about ten years ago
and I became interested in cancer
immunology and so I'd like to discuss
with you today cancer immunotherapy
rapidly evolving clinical science...
I apologize for a slide having lots of
words on it but I'd like to at least
logically break down the talk into four
elements immune system can control
cancer because cells and immune system
call T lymphocytes or T cells have the
ability to kill cancer cells they have
this ability because
cancer cells invariably almost
invariably we think perhaps look like
they're foreign and as you all know the
immune system can reject foreign tissue
an ability it has because this is the
way it actually attacks virally infected
cells so in really we're not asking the
immune system to do anything that it
cannot do when we ask it to kill cancer
cells T-cells have the ability to do
that I'm going to show you a really nice
video done by my colleague at University
Cambridge Gillian Griffiths now in order
for t-cells to do this they must contact
the cancer cell they must contact a
cancer cell in order to kill it and that
in that contact the t-cell has a
receptor that recognizes a structure on
the cancer cell or virally infected cell
that triggers the T cell and elicits
it's killing activity so I'm going to
show you a video done by Gillian
Griffiths
as I said who is a colleague and a close
friend at the University of Cambridge I
think this will show us strikingly what
the immune system can do to the lymphocytes
so this short movie short video is of
cytotoxic T cells in tissue culture it has
some dramatic music associated with it
these are immune cells called cytotoxic
T cells cytotoxic T cells are able to
recognize and kill virally infected and
cancerous cells in the body these T
cells are on patrol searching for their
targets let's take a closer look at how
they move cytotoxic T cells are
constantly migrating around your body
they move through your tissues by
pushing out the membrane at the leading
edge of the cell and pulling themselves forward
when a t-cell encounters a cancer cell
an explosion of membrane fusion explore
the surface of the target
this is when T cell receptors are
getting engaged cytotoxic T cells 
kill their targets with toxic
chemicals the chemicals are housed in
these red structures called lytic
granules you can see the lytic granules
polarized from the rear of the t-cell to
the blue cancer cell those granules
these toxic granules secrete
specifically toward the target
protecting innocent bystanders which may
be nearby as the membrane of the target
is compromised by the toxins and the
granules our indicator flashes bright
red signalling the impending death of
the cancerous cell movies like these
allow us to study the efficiency with
which cytotoxic T cells operate and this
is literally what will happen when we
have successfully I will leave you with
a few more movies of T cells doing what
they do best
killing cancer.
okay
so that's an in vitro study but we think
essentially the same things go on in
vivo when a t-cell encounters a cancer
cell for which that t-cell is specific
now there are two ways the tumors escape
t-cell killing and I think these are
have naturally evolved to protect normal
tissues from t-cell attack if the cancer
didn't invent anything new
these were protective mechanisms that
evolved to protect normal tissues from
t-cell attack and the two ways are
inhibiting t-cell stimulation by cancer
cells and that it will inhibit the
signaling that the T cell receptor
imparts into inside the cells to lead
the secretion of the cytolytic granules
it's a signaling process and there are
ways that cancer cells have of
inhibiting that signaling process and
the other way that tumors escape t-cell
killing is they can prevent the
accumulation of T cells in the tumor so
it's called T cell exclusion so that's
pretty straightforward if you if a
tissue wants to protect itself from T
cell attack it can do it by two ways and
maybe tumors do it by both ways and some
tumors do it by more one way or the other you
prevent the T cells from even getting
into the tumor and that obviously needs
to escape immune control or if T cells
get in you turn off the signaling
through the T cell receptor so current
immunotherapy is directed at these two
ways that tumors escape immune
controlled by T cells it's perfectly
logical
and the current immunotherapy that you
have been reading about and hearing
about that's very exciting is ways to
block the so called t-cell checkpoints
ways to block that those inhibitory
molecules that prevent t-cell receptor
signaling now there are two people's two
scientists that have contributed to
these approaches Jim Allison on the left
and Lieping Chen on the right I put
the dates up here to let you know kind
of what is a pace of translational
research
Jim published his paper on a membrane
protein on T cells called CTLA-4 showing
that if you block the activity CTLA-4 on
T cells you could promote tumor killing
in a mouse model in 1996
it wasn't until 2010 that the first
report of a clinical trial using
antibody to block CTLA-4 function
reported that melanoma patients about 10
to 15% of melanoma patients had long
term cures well long term remissions so
that's the 1996 to 2010 timespan
in fact the molecule of CTLA-4 was
discovered by Pierre Goldstein in 1987
so the membrane protein in t-cell CTLA-4
was discovered nine years before Jim
discovered that it could have a role in
t-cell killing of cancer cells
Lieping Chen work worked on another
protein on the lymphocyte surface that
inhibits t-cell receptor signaling
called PD-1
and he published his first paper showing
it in PD one was inhibiting t-cell
killing in cancer cells in 2002 Honjo
actually discovered PD-1 molecule in
1992 again a ten-year gap between the
initial discovery of a protein and its
understanding that it may have a role in
cancer and the clinical publications
that antibody at the PD-1 so-called
checkpoint inhibitors was published in
2012 now I'm sure that some aspects of
this we can speed up but it may be an
irreducible stupidity on our part to
account for the slow progress I just
would let you know the logic of PD-1 so
here's the T cell and the T cell
receptor is what recognizes a tumor cell
so call MHC peptide and that imparts of
positive signals for activations of the
philological leading to killing of the
tumor cell PD-1 was engaged by a
ligand called B7-H1 on a tumor cell
actually leads to a negative signal that
turns off T cell receptor signaling and
immunotherapy is an antibody called anti
PD-1 specific for the PD-1 it binds
a PD-1 and blocks the binding of PD-1
by B7-H1 on the tumor cell so now the T
cell receptor actually can be stimulated
by the tumor itself and it can kill it
and to show you the glass is half-full
glass is half emply nature of clinical
research here is the first reports of
anti PD-1 blocking in anti PD-L1
unblocking antibody or blocking antibody
PD-1 in 2012 New England Journal of
Medicine paper both from Johns Hopkins
here the cancer types, the number of
patients and a number of responders of
those patients so you can see melanoma
patients respond to both anti PD-L1
and at the PD-1 about 1/5 renal
cell carcinoma some patients respond NSCLC
so lung cancer some patients respond
but these so this may look like you know
not much but these patients would have
died of their cancers there was no
therapy for these patients
so the amino therapy really was a
dramatic advance for clinical
oncologists but then there are tumors
that do not respond at all
colorectal cancer, pancreatic cancer,
prostate cancer I have an asterisk for
colorectal there is a subset of
colorectal cancer patients that respond
so our challenge is to try to figure out
how can we get these tumors to respond so
maybe those tumors are not responding to
so-called t-cell checkpoint inhibitors
which enhance t-cell receptor signaling
because these are tumors maybe the
t-cells don't get into the tumors so
enhancing t-cell activation
isn't going to help because the t-cells
aren't even encountering cancer
cells so the challenge at least from my
lab is developing immunotherapy to
overcome this t-cell exclusion so and
and we wonder whether or not this is
actually a more fundamental way that
tumors escape immunity the t-cells can
you getting into the tumor that's the
most effective way to protect yourself
from cancer killing these are biopsies
of human pancreatic cancer the cancer
cells are colored in red and you can see
the tumor is comprised of cancer cells
and regions in between cancer cells
called stroma the T cells are staying
these are the green white whitish dots
these are T cells and you notice that in
this tumor all almost all the T cells
are the stroma not in amongst the cancer cells
it's a non retina distribution
they're being excluded from the vicinity
of the cancer cells it's the same thing
in this biopsy of a pancreatic cancer
this one, this one, this one doesn t have
any T cells even in stroma but we know
that occasionally
we know that can happen because
occasionally have a biopsy like this
where you have T cells under months of
cancer cells
you see the same phenomenon in
colorectal cancers most colorectal
cancers look like this and occasionally
about 10% of colorectal cancer
patients will look like that and that's
because those cancer cells have many
more mutations because of a genetic
abnormality of cancer cells and the
same thing happens in pancreatic cancer
and these patients do respond to
checkpoint antagonist therapy but none
of these do so can we overcome that
t-cell exclusion I'm not going to go
into the basic research that led up to
this approach but we chose a target
called CXCR4 which is a receptor that
directs the migration of immune cells
and we had some evidence that CXCR4
signaling was somehow inhibiting T cell
included accumulation in tumors there is
a small molecule called AMD3100
which actually blocks CXCR4 signaling so
just to show you what preclinical
research can do this is a mouse model of
human pancreatic cancer actually
developed by David Tuveson who's here
at Cold Spring Harbor he developed it when
he was a postdoc to a fellow Tyler
Jacks at MIT and I've stained here
the cancer cells are staining in green
and a t-cells are in red and you can see
in this mouse model pancreatic cancer
t-cells are excluded from the vicinity
cancer cells just like you saw in human
biases they're in the stroma but not
among the cancer cells if we treat the
mice for 24 hours with a AMD3100 this
inhibitor of CXCR4 you see T cells amongst
the cancer cells and furthermore this
tumor now responds to the checkpoint
antagonist anti PD-L1 where it didn't
here and you actually come combining
AMD3100 + anti-PD-L1 you have elimination of 
cancer cells within 24 hours now we can
objectively quantitate the
redistribution of T cells with AMD3100
by sectioning the car crossing to the
tumor staining it and using a computer
to measure the distance between each
cancer cell in green and the nearest T
cell in red and you get a histogram and
this is the frequency of those cancer
cells and their distance from a t cell
and you can see PBS treated might it the
T cells are far away from the cancer
cells you do not alter that with anti
PD-L1 the red histogram but with AMD3100
 you make the T cells come closer to
the cancer cells and now they're engaged
able to engage the cancer cells and
potentially kill them and that killing
process can be enhanced with anti
PD-L1
so what is the purpose of all this
preclinical research it is to say is the
mouse giving us a clue for what might
happen in human cancer so we're
conducting a phase 1 trial of AMD 3100
in colorectal and pancreatic cancer to
ask a question whether or not CXCR4
inhibition will promote the inter-tumoral T
cell immunity and this is funded by the
Lustgarten Foundation which many of you
may know funds a lot of pancreatic
cancer research and Stand Up to Cancer I
just would let you know that this cannot
occur without a clinical research group
and these are the individuals at the
University of Cambridge engaged in the
clinical research and this is my
preclinical group here at Cold Spring
Harbor and I want to give you some
of the results that we are getting in early
results of the Phase one clinical trial
to allow you to get into my shoes and
and to say you know
is there a hint is something going on is
inhibiting CXCR4 and human cancers
having the same effect as it did in a
mouse so the protocol is that we give
one week infusion of AMD 3100 in
patients with metastatic cancer disease
either colorectal or pancreatic cancer
we're limited to one week because it's
it's a phase one trial whose real
purpose is for toxicity we're into
dose escalation phase where we start out
a low dose and we have a target dose and
we enroll patients at lower doses and if things
are alright we higher dose things are
alright higher dose til we get to the
target dose and so we're in the dose
escalation phase and all the patients
I'll be discussing 11 colorectal
cancer patients now how we're assessing
what happens is we're taking biopsies of
metastases in the liver before we start
treatment and at the end of treatment
and we'll do various assays of those
biopsies of tumor metastasis to say have
we changed the immune reaction in the
tumor our one-week readout precludes the
test of therapy we do not expect to cure
any cancer which also means were
terribly great for these patients
participating in the trial because it's
very unlikely that they will receive
benefit from their participation
we hope that benefit will come for
patients in the future and we ask a
question does AMD3100 or CXCR4 inhibition 
enhance expression of immune
related genes in those biopsies and so we
measure the expression of immune genes using
a technique called RNA-Seq in the
biopsies now I'll show you some striking
results so the first thing that was sent
to me by the team in Cambridge was a
biophragmatic analysis of the genes that
were upregulated with the post-treatment
biopsy compared to the pretreatment
biopsy and then you have program to say
well that pattern of related genes
what is it most resemble what biological
process
is it most resemble and the top hit was
allograft rejection in which it's called
a false discovery rate of .006
so 6 out of 10,000
times this will pop up by chance
allograft rejection is precisely the
biological process we want to get going
in the tumor T cells mediate allograft
rejection transplant rejection so this
came to about a month ago that was
terribly exciting and for the other
significantly up pathways in which genes
were upregulated was interfering gamma
response and immune response two types
interferon immune response IL2 signaling
inflammatory response so the
treatment is promoting immune reactions
in the cancer biopsies one other
thing this is the level of RNA levels
for the two chains of the T cell
receptor T receptor and each T cell has
an alpha chain and a beta chain this is
the way that T cells so the number of T
cells in the tumor will will be
reflected by the amount of message for
those T cell receptors and you can see
some patients I circled pre versus post
treatment increase the message for T
cell receptor alpha and T cell receptor
beta so we interpret that as potentially
meaning there are actually more T cells
in a tumor post treatment with the AMD
3100 which we had predicted and what's
interesting about that is we can switch
it and say well what genes are inversely
correlated with expression of T cell
receptors so we have up regulation T
cell receptors what what's down
regulated in a tumor that have increased
some our T cells and what you have is a
bunch of biological processes all of
which relate to cancer cell replication
mitotic cell process cell cycle
process etc
so this is incremental evidence that the
increased t-cells of the tumor are
decreasing the number of cancer cells
it's inferential, it's a hit, it's a clue
and furthermore these are all colorectal
cancers and it's interesting the tissues
which tissues express these
downregulated genes that are inversely
correlated with increased t-cell
receptors with colorectal tissue so it
makes sense
finally I just want to show you one last
thing so so we really pour over these
data saying what hints can we get and
this is another interesting correlation
it's a negative correlation between the
full changes of immune markers and the
two immune markers are called fas
ligand and granzyme A and these are
proteins expressed by the cytolytic
t-cells that actually kill cancer cells
fas ligand and granzyme A and what we've
plotted here is keratin 19 which is a
marker of the cancer cells it's only
expressed in cancer cells in the biopsies
and so you have decrease in keratin 19
with increasing fas ligand a negative
correlation a more fas ligand message
you have it a tumor the less message you
have for keratin 19 suggesting again
that the killer that the tumors that
have the T cell killer molecules are
losing cancer cells and the same thing
with granzyme A so I'll finish with
that on advances immunotherapy depend on
understanding basic immunology you don't
want to go into this guessing you want
to have some mechanistic concepts that
you're actually testing Jim Allison
identified CTLA-4 as a target for
immunotherapy in 1996 but the first
clinical evidence for his efficacy was
2010 Lieping Chen identified PD-1 as a
target for immunotherapy in 2002 those
papers have published that it was true in
2012 and what we are in the midst of
wondering whether or not we will have
any clinical evidence for efficacy but
again we started on this pathway in 2010
okay well I think Bob will go next and
then we'll have questions after that
Thank you Doug for a very exciting
presentation and we're all looking
forward to hearing how these studies go
and hopefully in a very positive way in
the next few years our next speaker is
Professor Robert Mackey Bob received his
MD and Ph.D. degrees from Cornell
University Medical College he has been
on the faculty of Morial sloan-kettering
Cancer Center, Weill Cornell Medical
College and Mount Sinai Medical Center
where he was a professor and section
chief of pediatric hematology oncology
currently he is a professor of medicine
at Hofstra Northwell Medical School and
director of experimental therapeutics at
the Don Monte division of medical
oncology and hematology at Northwell
Health's Monter Cancer Center
he is also a
professor at Cold Spring Harbor
Laboratory Bob's specialty is in the
area of sarcoma where he is a world
leading clinician and he has been
involved in clinical trials including
immunotherapies and new drug development
Bob has received numerous awards
including being a fellow of the American
College of Physicians and he's been
named Clinician of the Year by the Life
Raft Group it's my pleasure to introduce
Dr. Robert Mackey
Thanks everybody thanks for the
opportunity to speak tonight thanks for
coming out to hear a little bit about
cancer immunology I'm going to really
reiterate a lot of things Doug was
saying as well but coming from a
different perspective and what I'd like
to do is get after some of the issues
that that I deal with as a clinician as
well everyday I'm going to actually
discuss that a little bit first in terms
of immunity and what it means to have
immunity against infection against
cancer I do my disclosures I do consult
for a number of companies and we do
research with these people and just so we
have idea of the different companies
that I do work with but the big question
I'm always asked I get this at least
twice a clinic a couple times
today in fact is how can i boost my
immune system and pretty clearly
the answer is you just call a cardiac
surgeon Dr. Oz will be happy to tell you
all the good things that you can do to
boost your immunity and really it's a
matter of definitions when it comes to -
all of these things and just your
ability to fight off illness like I used
to refer that to that as your
Constitution you just you're somebody
who just doesn't get ill very much
or you're always somebody has a runny
nose or something like that that's it
could be cellular barriers to infection
our skin and the mucous lining of our
gut and and up here in our sinuses all
of those things stomach acid all these
things help prevent prevent us from
getting infections and this another
group of cells that don't really have a
specific way of attacking an infection
or let's say a cancer or this is these are
assaults that are involved what's called
innate immunity and these respond very
quickly to infections that are trying to
bother us but Dr. Fearon was discussing
though is the adaptive immune system
which involves both these t-cells that
you saw attacking a cancer cell as well
as other cells such as B cells which
make antibodies in your body against
again against infections and allow for
this memory response to reside in your
body in case you recognize
and get exposed to the same infection
again later and really to fight off
infection well and technically cancer as
well you need both of these things to
work well otherwise you're going to have
a problem and get infections that that
dead is a defective immune system and we
see this people have these genetic
syndromes where one thing is missing or
another and they are predisposed in
particular to two infections
what are the cells that are involved in
this process these are many of the white
blood cells in our body these are all
made by the bone marrow and they
circulate around or reside in the
different tissues of our bodies and some
of them have this nonspecific function
where they're trying to kill off things
as they're trying to invade your skin
like a bacteria or virus or things that
that float around our bloodstream the B
cells and the T cells here on the right
which are responsible for infections and
watching things that actually make it
into the interior of the body once the
infections have breached these initial
forces that are trying to prevent us
from from getting infected all right so
the key cells that are involved here
are the B cells again which make
antibodies and the T cells like the
cytotoxic T lymphocytes which kill can
some cancer cells and you just saw and
also killed virus infected cells all
right so how do you boost your immunity
in terms of the innate immunity how do
you make those nonspecific cells work
better how do you improve these barriers
these are things that we really don't
understand very much now certainly
probiotics and yogurts if you've gotten
exposed to taking a series of
antibiotics you completely change the
bacteria that are in your gut perhaps
that's the sort of thing that you need
to help protect the you against
infection in the future but we really
don't understand the details of that one
thing I will recommend is that a lot of
people do take supplements of some sort
Memorial sloan-kettering have put
together a very nice website called
about herbs and this can tell you a lot
about all these natural products that
people are taking and what is purported
to be useful about them and what the
actual data are regarding that process
so for example for ginkgo biloba it says
the ginkgo does not improve memory your
cognitive funk
in healthy people and it goes into the
details based on surveying the
literature for each of these compounds
so if you have a question about you know
CoQ10 or whatever the supplement may
be this is really a nice resource and
it's been curated over the last 10 or 15
years they've done a really nice job
with it in terms of adapting immunity
what can you do to boost your
immune system well is vaccination and and
we talked about using hepatitis B
vaccinations to prevent you from getting
hepatitis B which leads to cirrhosis
which leads to liver cancer but the the
vaccine that we have access to now that
we should be getting as young people
between age ten and thirteen is a good
old HPV vaccination because human
papillomavirus is responsible for not
just cervical cancer of the uterus but
also for an increasing number of throat
cancers as well as penile and anal
cancers now just about everybody who's
sexually active has HPV so we're going
to make a dent in some forms of
preventable cancer this is one way to do
that so this is one way to technically
boost your immunity against cancer so in
terms of the approaches that are used
today against cancer these are some of
them and Dr. Fearon already discussed
these to some degree we've been trying
to use cancer vaccines for a very long
time they really have not been very
effective in a largely experimental
perhaps the one exception for this is
this Provenge vaccine where you take
some of the white blood cells out of
your body you train them to recognize
proteins that are found in prostate
cancer and give those cells the vaccine
back to people it helps a little bit but
profoundly expensive over a hundred
thousand dollars for three vaccinations
and the benefit that people get it's
relatively marginal antibodies these are
made by the b-cells the special white
blood cells this technology that after
having recognized the structure of these
proteins and what they can do in the
body against infections especially
bacteria we now use these very specific
tools as cancer drugs and it's probably
the most commonly
used approach in cancer now beyond the
regular toxic chemotherapy medications
themselves immune checkpoint inhibitors
you just heard Dr. Fearon discuss these
I'll talk about these a little bit more
as I will discuss some of these car
t-cell chimeric antigen receptor t-cells
genetic therapy that's been discussed in
The New York Times and on CBS Sunday
morning there's this past weekend as
well
some of the new approaches that are
being taken to trigger an immune
response against cancer a lot of these
do involve t-cells to be sure Provenge
eventually does stimulate T cells to
attack prostate cancer these immune
checkpoint inhibitors stimulate t-cells
that were otherwise being too lazy and
not activating themselves against the
cancer cells if they were there already
and these car t-cells are engineered
versions of T cells that can recognize
and kill cancer cells by themselves I
wanted to show you a little picture here
this is just a molecular structure of an
antibody molecule and this structure
which has places for proteins to bind on
in two places in this particular version
of an immunoglobulin this is a sort of
structure that's been used to raise
basically vaccines antibodies against a
variety of proteins and these proteins
are found on tumor cells and then we
give these antibodies which are
schematized here they recognize the
protein of interest so for Bevacizumab
this is something called VEGF -
Vascular endothelial growth factor
something that prevents this antibody
then would prevent the growth of blood
vessels into tumors and you also can
starve tumor cells in different ways by
blocking special signals that keep the
cells alive whether they are solid
tumors such as breast cancer or things
like lymphoma in which Rituximab is an
active compound so these are exquisitely
specific molecules they don't bind to
other molecules even if they have a very
small genetic difference and as a result
they become become really useful tools
for cancer because the side effects are
something that we can control much
better than we can with the regular
chemotherapy drugs
so very very nice approach and this is
commonly used now for for cancer therapy
as Doug was getting getting getting at
before
what are these immune checkpoint
inhibitors do they basically take the
brakes off the immune system and they're
relatively nonspecific because these
same molecules which turn off immune
responses are found on both the cells
that might fight a cancer as well as
those fight that fight infection as well
as those that might just by happenstance
that may attack a normal organ of your
body so good risk good immune responses
if you get an infection with flu let's
say you have this up regulation a larger
number of T cells that recognize the
flu virus and it's proteins and kills
off the infected cells but then you want
those things to calm down and go away
and that's where these molecules exists
in T cells to turn off an immune
response if they stay to active well
then you end up with autoimmunity where
the body is being attacked by these T
cells that are chronically turned on so
it's important for T cells to be both
turned on and turned off so
either one of these if you have too much
of one or the other it's not good energy
where you don't get their immune
response at all this is what viruses
have been trying to do throughout
evolution so EBV epstein-barr virus
which causes mononucleosis it's been
engineered itself it's been selected
against being seen by the immune system
it's really very much a stealth virus
that has many ways of preventing the immune
system from seeing it for example so
these are either these are
counter-productive of what we want are
these responses that you can control and
the immune checkpoint inhibitors do give
us some degree of control that we've
never had before for for for cancer
therapy so if you've been unfortunate to
watch commercial TV news
you've been assaulted by commercials for
this is a bizarre one irritable bowel
syndrome and diabetes and arthritis and
well you know what
and but now I'm sure you've seen the
advertisements now for these direct to
patient ads for treatments for lung
cancer Nivolumab Opdivo which is
approved for I'll show you some of the
diagnosis for which it's now approved or
to give it equal time the other big drug
that's used most frequently these days
pembrolizumab or Keytruda and as Doug
was referring to already and has
discussed how do you how do these drugs
work again you're taking the brakes off
the immune system normally the immune
system is turned on and then turned off
again these t-cells are turned on and
turned off and in fact the tumor cells
have a means of turning off that immune
response by the presence of these
special molecules they figured it out
that we want to negate or neutralize
that immune response so by taking away
that negative signal sort of a double
negative by taking away the blocking
response taking your foot off the brake
you allow the immune response to go
forward but again it's a nonspecific
event it turns on every T cell in the
body which is great if you're trying to
fight cancer but bad if you have Crohn's
disease let's say all right there very
nice graphic anyway so I'm going to show
you another thing that make you a bit of
a clinical statistician as well and
we're going to review a few of the
clinical trials data this requires an
understanding of the so-called survival
curves these are morbid actuarial
devices of that allows to discuss who's
doing well and who's not basically who's
alive and who's dead and as you see time
pass well things happen if everybody
survives with this does may happen in a
normal population over time then you'll
see no change in the fact that 100% of
people are still alive if everybody dies
from something really bad like an
advanced cancer you'll see this curve
crashed down to the zero point and if
people have metastatic cancer people
died at some rate and we'll see that
over time some number people are still
alive and we compare these curves to
determine how good one treatment is
versus the other and this is the the
bread and butter of
randomized phase two and phase three
clinical trials which have led to all
the advances all the approvals of the
drugs we use so for some examples of
that one of the first ones it doesn't
look that impressive because there is
there isn't that much space between the
curve this is a as Dr. Fearon was
mentioning a little while ago melanoma
that these were the first people to show
signs of benefit from one of these
immune checkpoint inhibitors Jim Allison
and the discovery the CTLA-4 molecule
led to the development of Ipilimumab
also called Yervoy and this is
the first study that showed that
immunotherapy with chemotherapy was
better than just giving the chemotherapy
alone not a huge difference but you can
say that it is statistically different
from from the two and this led to the
approval of Ipilimumab based on
work that was done in the late 2000s and
early 2010's there is more impressive
data as we went along
so here's instead of a CTLA-4 inhibitor
here's a PD-1 inhibitor this is
Nivolumab
and it's clearly in melanoma patients
was led recurrences was better than
Dacarbazine the plane will
chemotherapy and in fact if you look out
here you see that this curve isn't going
down to zero that means people are
staying alive longer and without disease
this as people stay on this and this
curve stays flat that's what we start
calling remissions or cures so this is
exactly what we're looking for and this
was really quite striking to see this
happen for the first time melanoma is
sort of the poster child for these
diagnoses in terms of the benefit but it
still isn't everybody and doctor Fearon
gave some really good reasons why these
drugs may not work from the lack of
penetration of the t-cells into the
tumor or other reasons to reject
the t-cells from being active within the
tumor
now again melanoma is the poster child
here's data from lung cancer and they're
one of the most common cancers it's the
most common fatal cancer in the United
States about 175,000 - 180,000
people get this a year and
it's the number one killer in terms of
cancer in the US and the data are not as
impressive this is a but this was still
a relatively revolutionary study in that
for this very common cancer we showed we
showed the community showed for the
first time that immunotherapy with this
PD-1 inhibitor was better than giving
chemotherapy so it immediately moved
immunotherapy into first place and it's
used now more and more earlier in the
treatment of people with cancer so that
you can avoid some of these poisons
which cause all kinds of side effects
yes they're all side effects with these
as well and they can be difficult to to
manage and perhaps
something we can discuss during during
the discussion I'd like to just outline
now just in the past few years now all
the diagnoses that have approvals for
one or another of these so-called immune
checkpoint inhibitors and so a number of
diagnoses were happy to have these drugs
available and we use these routinely now
in the clinic we're trying to build on
this now can you combine these drugs you
combine them with chemotherapy what new
things can you add to them such as
Dr. Fearon's study with the cytokine
inhibitor or chemo con inhibitor but
their number of diagnoses also as you
pointed out that are not responding and
in fact most people with a number of
these diagnoses are not responding for a
long time so we definitely need some
improvements and we're hopeful that the
work with Dr. Fearon will lead to things
that we can do here within our own
healthcare system as well right here in
Long Island we've got some of the brightest
lights here in cancer research and
hopefully be able to apply those to
trials now the next thing I'd like to
mention here in terms of these immuno
therapeutics if if immune checkpoint
inhibitors which you've seen now
approved that these different diagnoses
are the shotgun well the more specific
tool that we have are the so called
chimeric antigen receptor t-cells and
why is it more specific well with the
immune checkpoint inhibitors you don't
know the target whereas with the
chimeric antigen receptor t-cells you
actually engineer these things
and you know the target in the context
in which the molecule is found very very
well so how do you cook cook up one of
these things well it actually has been
trial and error and Carl June and others
down at Penn and the groups at the NCI
have really led the way in terms of
figuring of how to do this it's a
engineering a tour de force and it
involves taking out blood cells from
your body you can take out the whole
blood volume and spin it down collect
the blood cells and give the red blood
cells back to a person then just collect
the white blood cells you take those and
you select out the key cell the T cells
and you now infect them it sounds
anathema that you'd actually use a virus
to treat these cells but this is how you
introduce a special virus which now
has basically the trigger to be pulled
when the T cell encounters a cancer cell
and you then give a patient some
chemotherapy to clear out their own
immune system and now introduce these
special engineered T cells and then you
can watch what happens both in terms of
blood tests that you do for the patient
looking for the presence how long did
the cells last in the body and you can
see if they actually do something in
terms of the number of cancer cells that
remain in the body some details in terms
of what this virus entails there are
basically ways of activating the T cell
in a very methodical way again it's a
very specific molecule the CD19 molecule
this is the car-T cell so that's just been
recommended for approval by the FDA and
this recognizes the CD19 molecule CD19
is a molecule only found on the B cells
and it turns out that acute
lymphoblastic leukemia (ALL) myeloma
lymphomas those sorts of different
versions of chronic leukemias all have
this molecule on there and therefore
this kind of an approach could
theoretically be used for any tumor that
has a CD19 molecule on it it's been
tested and this approval will revolve
around acute lymphoblastic leukemia
where basically kids and young adults
who most commonly
get this who had exhausted you know
double bone-marrow transplants and
multiple rounds of chemotherapy were
treated with these drugs actually cells
and had remissions once again where they
had yeah it does sound complicated right and
and it is and it really is this could be
a limited number of centers that are
able to use these sorts of therapies but
when they're effectively used there is a
very significant survival rate this is
the initial publication of the CAR
t-cell data back from 2014 very small
number of patients being treated because
of all the engineering that's required
it takes a small army of people to grow
these cells infect them get them in
enough numbers we can give them back to
a patient to be an effective essentially
drug against that that cancer but
nonetheless it's kind of writing a
bucking bronco because of all the side
effects that happen with with these
things as well so fine it's an effective
technology why don't we use it for everybody
well number one you have to know the
target we know the target is CD19 on ALL we don't know what the target is
necessarily on let's say pancreas cancer
cell or you may have some idea but that
molecule might be found both on the
pancreas cancer cell but and also in the
normal pancreas maybe it's also on the
normal colon or in the normal stomach
well you don't want to start destroying
the normal colon and the normal stomach
along with the tumors you have to be
very careful about the molecule that you
choose to target so for example that
that speaks to one of the side effects
of CAR t-cell therapy if you wipe out
every CD19 positive cell with the
therapy you have no more b-cells and you
no longer make antibodies and you need
to get lifelong intravenous
immunoglobulin to help fight off
infections otherwise you get bad
bacterial infections but it's a price to
pay for being cured hopefully of your
illness you also have to know the
context in which these different
molecules are binding if you're bind if
you're looking at a bit of a protein it
has to bind to one of six adapter
molecules that are found on every cell
of the body and if you don't have that
adapter molecule in combination with the
right protein well the CAR t-cell is
never going to fit it's never going to
be able to do its thing it doesn't
recognize the target and that does
require a lot of work from our basic and
translational immunologists is to
find out what these adapter molecules
are sticking to and how we can find bits
and pieces of different molecules that
would be effective targets and also the
treatment is very toxic you do need ICU
intensive care unit level care for the
shock sort of very low blood
pressure that people get for prolonged
period of time for least several days
after exposure to these CAR T cells from
this massive release of hormones
cytokines as they call them that are
released into the bloodstream else we'll
see problems with delirium, confusion and
cephalopoda some people can lapse into a
coma thank goodness it's just a
temporary thing that they do come back
by them it's certainly a scary ride for
people to have to go through it doesn't
happen to everybody but as many as about
1/4 to 1/3 of people are getting very
severe side effects with the application
B cells the idea to try and treat people
and they don't have such large number of
cancer cells in their body try and get
them down in terms of the numbers of the
cells and then apply this very
aggressive approach to to uh to the
patient and it's also laborious you have
to define these new targets it does take
a lot of work and to prove that there's
specificity on one cell not that the
molecules not found on another important
cell the body brain, heart whatever it
may be that that's critical before you
move forward with this kind of an
approach and there's some other ways of
trying to get around that problem as
well about the specificity issue abusing
less specific but still active killing
cells the body such as the NK cells
natural killer cells these have also had
the potential for killing cancer cells
in a more a nonspecific way and maybe
another approach that's taken in a new
future in fact they're already doing
studies of this at several centers in
the US and worldwide but the last and
most important point is that it's not
going to be cheap so so basically these
antibodies run about $10,000 every three
weeks so one hundred and seventy
thousand dollars per year per patient so
that benefit better be pretty big for
you to justify using these drugs well I
mean it's a free country everybody gets
access
at least on Medicare let's say - to
these compounds if they are approved but
other other places like in England they
say okay well if treatment is going to
be you know several million dollars and
it only prolongs life by a few weeks
it's certainly not going to be valuable
well we have to make this decision as
society as to what's going to be worth
it and what's not so yeah who knows what
the going price is going to be for this
very very newfangled and
technically complicated approach will be
so something to keep in mind we're going
to have a limited you know amount of
these things we can actually use at some
point to choose which ones we move
forward with carefully and hopefully
find the ones that work the best and
give us the best bang for our buck
literally and figuratively
so immunotherapy now is a new way to
treat cancer effectively and along
alongside of the other treatments we use
now which are surgery and radiation
therapy and chemotherapy not all types
of cancer respond well it's sometimes as
a matter of not getting the t-cells over
there to the tumor and we'll hopefully
see that some of these approaches do
bear fruit both in terms of what he's
studying assuming this micro environment
of the tumor in other words better
looking looking at different
combinations of immunotherapies and new
agents and then also trying to find new
targets and new diagnoses for these
technologies as well and with that I'm
going to stop with a picture of this
very nice plant which gave rise to
something we call at see little phallic
silicic acid or aspirin natural products
still have a place in our armamentarium
against disease as well so with that
I'll stop and we'll move forward to
questions.
