Using Immunotherapy to Treat Cancer

Dr. Richard Edelson, Using Immunotherapy to Treat
Cancer
December 19, 2010Welcome to Yale Cancer Center Answers with doctors Francine
Foss and Lynn Wilson.  I am Bruce Barber.  Dr. Foss is a
Professor of Medical Oncology and Dermatology, specializing in the
treatment of lymphomas.  Dr. Wilson is a Professor of
Therapeutic Radiology and an expert in the use of radiation to
treat lung cancers and cutaneous lymphomas.  If you would like
to join the conversation, you can contact the doctors
directly.  The address is canceranswers@yale.edu and
the phone number is 1-888-234-4YCC.  This evening, Francine
and Lynn are pleased to welcome Dr. Richard Edelson.  Dr.
Edelson is Aaron and Marguerite Lerner Professor of Dermatology and
Chair and Professor of the Department of Dermatology at Yale School
of Medicine.  Here is Francine Foss.Foss
Since we are talking about immunotherapy, let us start off by
defining immunotherapy for the audience.Edelson
Immunotherapy is really one of those relatively few aptly named
terms.  It actually involves manipulation of the immune system
to the benefit of patients.  It can be an important tool in
the defense against cancer, even in the prevention of cancer, but
it can also be a valuable tool when the immune system is an enemy
in autoimmunity.Foss
Your interest in immunotherapy dates way back and the first disease
that you addressed with immunotherapy was a disease called
cutaneous T-cell lymphoma.  Could you take us back and tell us
how this all got started?Edelson
Thank you for saying that it goes way, way back, but it does, and
it goes back to the time when very early in my career I was at the
National Cancer Institute and it was the year that human T-cells,
the cells that are at the actual center of immune responses, were
first identified.  So it first became possible, all the way
back as you say in 1972, to apply the new principles of immune cell
recognition and demonstrate that the first malignancy of white
blood cells shown to be a malignancy of T-cells, was cutaneous
T-cell lymphoma, which was named cutaneous because it involves the
skin, and because the cells that are malignant are T-cells.Foss
It really is interesting when you think about it that we really did
not understand much about immunology until the 1970s when the
T-cell was identified and that so much has happened since that
time.Edelson
Right, if you take cutaneous T-cell lymphoma, here was a disease
which was a malignancy starting as all malignancies do, from a
normal counterpart cell.  So a single normal T-cell, which has
a propensity to circulate from the blood to the skin and back,
becomes malignant and many, many copies of that cell wind up
amplifying the localization patterns of the cell.  So a cell
that normally helps defend against infections in the skin, for
example, when it becomes malignant, shows up as tumors in the
skin.Wilson
 Tell our listeners a little bit about the thought process you had
in the development of photopheresis and what photopheresis is and
what was happening during this exciting time.3:48 into mp3 file 
http://yalecancercenter.org/podcast/dec1910-cancer-answers-edelson.mp3Edelson       
 Photopheresis was introduced by our group when I was still at
Columbia University School of Medicine in 1982, and first became
FDA approved as a therapy for cutaneous T-cell lymphoma in
1988.  I am happy to say we were on our toes because it
certainly was not discovered on purpose and I would actually make
the point that relatively few really important therapies are
discovered on purpose, but the idea behind photopheresis at the
beginning was not as immunotherapy but as what we thought was neat
at the time, maybe trivial in retrospect, a chemotherapeutic drug
that could be turned on by a light switch and only have its
activity exactly where the light and the drug came together. 
The goal was to be palliative, not curative but help patients
decrease severe symptomatology.  In the absence of systemic
side effects, the very first patients with a leukemic form of the
disease, which is really devastating, had not responded to
conventional chemotherapy and had total skin infiltration. 
Your listeners can imagine what that would be like of these
malignant cells.  As well as the malignant cells in the blood,
we treated only 2% of the patient's malignant cells by passing the
blood through an apparatus to see that it was safe, and the goal
was, if we could show that those cells could be safely returned and
then removed by the filtration in the body, the liver, spleen,
lymph nodes, then we would go ahead and treat the patient more
frequently and simply try to decrease the number of cells by
removing them faster than they were being made.  The
astonishing thing was that by treating such a small percentage of
the cells and returning them, the other cells disappeared.  So
it was clear, all the way back in the first patient, that somehow,
mysteriously, this was fortuitously causing an immune reaction that
was treating the rest of the disease and one could argue that we're
not that good because it took from 1982 all the way until 2010, 28
years, to gain a handle on many of the clues which I must say, came
from my two interviewers, Lynn Wilson and Francine Foss, but we
have got a pretty good handle on this now.Wilson
Can you elaborate on that a little bit for our listeners, and some
of the mechanisms or the understanding of how this works in terms
the listeners could understand?Edelson
The drug that was used, and is used, has a name that is abbreviated
to 8-MOP, because we do not even have to bother your listeners with
the real long name.  That drug is actually a naturally
occurring substance found in small quantities in figs, lime, and in
larger quantities in the root of a weed that grows in most of our
backyards called Queen Anne's lace.  It does nothing by
itself, but if you take it, as dermatologist have known for a long
time, by mouth, although it's excreted without any activity, any
effect in 24 hours, if you shine light on any tissue that
temporarily have it in it, which is usually two hours after a
person has ingested the drug, this inactive drug gets
instantaneously converted to a very potent chemotherapeutic agent
which binds in an active H-DNA.  So the mechanism, as we fast
forward, does relate to the original suggestion that it is such a
finely tunable drug because it only is active where the light and
the drug come together for literally a millionth of a second, but
what actually happens is something very surprising, which is why it
was not discovered on purpose.  As the blood is passed from
one arm vein through a machine where the light is shined on the
blood, as we had always planned, before it is returned to another
arm vein, a very abundant protein in the blood, generally involved
in blood clotting, fibrinogen, sticks to the plastic in the
ultraviolet exposure system and within seconds completely coats
that plastic surface.  So the cells that are passed through
that surface including the leukemic cells and 8:58 into mp3 file 
http://yalecancercenter.org/podcast/dec1910-cancer-answers-edelson.mp3
                     
cutaneous T-cell lymphoma, never actually encounter the plastic
surface.  Those that are closest to the surface encounter the
platelets, also typically involved in clotting, which have stuck to
the fibrinogen just as they do in clotting, and now a white blood
cell called a monocyte which was also not the cell we were
targeting at first, but a so-called antigen-presenting cell but not
that good an antigen-presenting cell in the form that it circulates
in the blood as a monocyte, now sticks and unsticks and literally
jumps from platelet to platelet on that plate, and it is that
interaction with the platelets, probably just as happens in wound
healing and in sites of inflammation, converts these monocytes to
dendritic cells within a single day and those dendritic cells,
named because of their shape, normally are only one-tenth of 1% of
the circulating white blood cells, but 70% of the monocytes that
pass through this apparatus within one day become dendritic cells,
which are the most potent trigger of immune reaction.  So to
very briefly summarize that, this treatment has had its impact on
the immune system because all these years, secretly, by mechanisms
that had not been recognized before, this treatment is converting
monocytes into dendritic cells that stimulate immune reactions,
probably because that is the way it really happens.Foss
You recently published this in the highest-tier journal in the
field of hematologic malignancies, the journal Blood, and
this paper elucidates this mechanism that you described to us. Can
you talk a little bit about the impact of those findings,
particularly with respect to the fact that there are other ways to
view these antigen-presenting cells and to prepare these
antigen-presenting cells, and there are other immunotherapies out
there?  Can you talk a little bit about the impact of your
findings in this paper?Edelson
One of the really puzzling and even disappointing features of
immunotherapy for cancer, which has always had so much promise
because it is really such a powerful intricate system, and we know
that the immune system, even as we speak is protecting us against
cancers we will never see.  We know that people that get
immunosuppressed as part of an organ transplant have a much higher
incidence particularly of cancers of the skin.  They
presumably are normally being destroyed before they ever get to
that point of being clinically evident.  So the question has
always been, why can't immunotherapy in the face of clinical cancer
do just as well?  It does often induce clinical responses, but
they have been generally disappointing.  Then why would a
treatment that was not even designed as an immunotherapy turn out
to have such as good record?  Part of it is that the immune
system is incredibly complicated and in a way, certainly we in our
own group fall prey to this, we tend to think that we can create
immunologic responses because we are smart enough to do that. 
Well, we are generally not, and we learn from experiences like
this.  So the answer to your question in a very succinct way
is that the way the dendritic cells have been manufactured, which
has been a great advance pioneered largely originally from
Rockefeller University, were breakthroughs, but if you look closely
at them, that is not the way the body could possibly ever do
it.  The amounts of growth factors that are used over a full
week to induce the conversion is a thousand fold what is normally
present in the body.  So the question will be, since we fell
into this by actually, probably co-opting of the way it may
normally happen in one day without any added growth factors, maybe
now one can take that knowledge and try to use it in other kinds of
cancer.13:59 into mp3 file 
http://yalecancercenter.org/podcast/dec1910-cancer-answers-edelson.mp3Wilson         
 Rick, this is really a fascinating story.  We are going to
take a short break for a medical minute.  Please stay tuned to
learn more information about immunotherapy with Dr. Richard
Edelson. Wilson
Welcome back to Yale Cancer Center Answers.  This is Dr. Lynn
Wilson and I am joined by my co-host Dr. Francine Foss.  Today
we are joined by Dr. Richard Edelson and we are discussing
photopheresis and immunotherapy.  Rick, this is a fascinating
story that you were obviously spearheading during the majority of
your career, and we do a lot of photopheresis at Yale.  Is
this done at other centers, and how commonly is this done around
the world?  The second part of the question is, could you
discuss what other malignancies or other clinical problems that you
think this treatment could be applicable to?Edelson
Lynn, photopheresis, which really was started here, was used for
the first time at Yale Cancer Center.  So it is a Yale
home-grown therapy on the basis of clinical responses and an
excellent safety profile.  In fact, I am not aware of a single
patient who had to stop the treatment after responding because of
side effects.  The issue originally was, how do you explain
how this treatment works?  But here we fast forward again to
2010, the treatment is used throughout Europe and the United
States, and it has become the most widely used cellular
immunotherapy, even though the mechanism has only just now become
elucidated.  It is widely used and the question about what
other cancers it could be used for begins to become a very
interesting question, because now that we know that this simple
treatment which a patient receives over a two-hour period as an
outpatient procedure lying comfortably on a blood drawing type of
couch, even watching television, is something that might be
applicable to other kinds of cancers, solid tumors, that cannot be
cured surgically.  The key to the way photopheresis works in
T-cell lymphoma is that the drug that we mentioned damages in the
blood stream, the malignant cells, and essentially feeds them to
the new immunogenic dendritic cells that we talked about.  So
the dendritic cells loaded with digested parts or antigens that are
distinctive of the malignant T-cells, go back into the body as
essentially a cellular vaccine.  Well, if
that is the actual way that this is happening as it appears, then
other kinds of cancers become susceptible, at least in
concept.  If you can get your hands18:06 into mp3 file 
http://yalecancercenter.org/podcast/dec1910-cancer-answers-edelson.mp3
                     
surgically, for example, on a lung cancer or a breast cancer, if
that cancer is capable of stimulating an immune reaction at all,
then those cells could be damaged in a different way, and then
incubated or placed together over night with the new dendritic
cells, which then can perhaps become a vaccine for those cells in
that cancer. In collaboration with Dr. Foss, and Thomas Rutherford
in gynecologic oncology and his close colleague Dr. Gil Mor, and
several people in our group, one of the first cancers that we will
try to treat that way is ovarian cancer, because there is a cancer
that is quite severe often in an initial diagnosis because it is
already advanced, and in those cases, we will try to immunize those
patients against a cancer.  I emphasize that these kinds of
studies are very preliminary.  In fact, that study has not
even yet begun.Foss
We are talking about these antigen-loaded dendritic cells
stimulating an immune response against the tumor, is that what
normally happens in a cancer patient, is that recapitulating, say,
a normal process in the patient?Edelson
It is very tough to know and it would be very nice if that is the
case, but by the time we actually diagnose a cancer, if the immune
system had originally slowed its progression or prevented cases
like it, by the time we see that cancer, the immune system has
already been overrun.  So what really is confronting the
clinician who was attempting to then turn the immune system back
on, is that you are really trying to get the horses back into the
barn, and you are running in reverse.Foss
Do you think that these kinds of immunotherapies that we are
talking about would be most useful for patients, say after they
have received their chemotherapy and their disease is at a minimal
level, or perhaps early on in the course of  their
disease?Edelson
What you want to do, of course, if you are going to marshal the
strength of the immune system to fight cancer is you also have to
have an immune system that is fully functional.  So
chemotherapy, and the certain kinds of chemotherapy that you both
know better than I, can suppress the immune system.  So you
would not want to use a treatment like this in a patient whose
immune system could not respond, but a lot of the other more
biologic modern therapies that both of you have pioneered do not
involve suppression of the immune system.  For example, a
great way to limit the number of malignant cells it would need to
be attacked by an immune system that you turn back on, would be the
kind of radiotherapy that Lynn Wilson does, because by and large it
does not suppress the immune reactions, and several other
treatments that you developed also circumvent suppression of the
immune system.  I would favor those in association with this
treatment as opposed to conventional therapies.Wilson
Rick, you had mentioned that photopheresis is very safe for
patients and that you have not been aware of even one patient who
has had to discontinue therapy assuming they are responding because
of toxicity, could you just briefly describe for our listeners what
is involved?  You had mentioned lying down on a comfortable
blood-drawing couch, venous access, what are the side effects of
the treatment, if there indeed are any, because I agree it is very
well tolerated.22:08 into mp3 file 
http://yalecancercenter.org/podcast/dec1910-cancer-answers-edelson.mp3Edelson       
 The side effects of the treatment involve the same kind of side
effects that blood drawing itself for a blood donor might
have.  If you donate a unit of blood, most people can tolerate
that very well.  That is approximately the amount of blood
which is outside the body at any given time being processed through
the apparatus and then returned to the patient, but some people
with low blood volumes or with cardiac insufficiency might have
some difficulty because of temporary volume depletion, so their
blood pressure might drop, and that would be reversed quickly by
attentive nurses and the overseeing physicians, by then returning
that blood.  The other kinds of reactions that can occur can
be in a circumstance where the treatment actually is working too
fast, where the photoactivatable drug is injuring the cells that
are particularly susceptible to it, a little too fast so that over
the first few hours when the blood goes back, a lot of the cells, a
lot of the malignant cells, might be dying and releasing their
products.  These are not very dangerous, typically, but one
has to be on their toes.Wilson
Patients get this treatment as an outpatient, is that correct, and
they go home?Edelson
That is right.Wilson
Do they have to have precautions when they leave your center in
terms of exposure to light or anything else that could happen to
them when they walk outside?Edelson
There is one very important thing, and that is as the blood passes
through the machine, it is important that it not clot in the
machine.  We certainly have many protections against it that
eliminate the possibility of accidently returning a clot so that
does not happen, but these patients have to have their blood
thinned with a drug called heparin.  That drug does not wear
off for a few hours after they leave.  We highly advise
individuals who leave not to have an automobile accident.Foss
Rick, can we go back to talk a little bit about this new technique
that you are developing to take photopheresis to the next step,
which is to try to introduce tumor cells to these
antigen-presenting cells that have gone through the machine. Are
there some new ways that you are developing now in collaboration
with other areas, or expertise, at Yale that would help us to
better deliver those tumor cells to these antigen-presenting
cells?Edelson
These are areas of very active investigation.  One area, for
example, as Lynn Wilson and other colleagues and I have discussed
over a number of years, is in areas like the lung.  One could
radiate and damage, not necessarily in a curative way, classical,
non-small cell lung cancer, and then introduce these new dendritic
cells intravenously where they then pass directly, with a very
simple introduction the same way we always do, back to the right
side of the heart which pumps blood through the lung and to the
lung.  That was a very attractive way of getting these new
dendritic cells directly to the site of damaged malignant cells,
and hoping that that encounter could accomplish the goal of
immunizing the patients.  In other kinds of solid tumors,
there are a number of different approaches that can be taken,
building on the scientific advances.  For example, one of26:03 into mp3 file 
http://yalecancercenter.org/podcast/dec1910-cancer-answers-edelson.mp3
 the most interesting and intriguing to us is, in fact, as you
know, one of the approaches that we are planning to take in ovarian
cancer for the first time, and that is to do a single photopheresis
treatment, hold on to the new dendritic cells that come out, and
there are actually typically now up to 500,000,000 of them, and
freeze them, in a way, in small test tubes, aliquots of only
10,000,000 each.  So, 500,000,000 would lead to 50 different
aliquots that could be frozen and saved, and instead of giving the
cells back to the patient after adding the ovarian cancer antigens,
have 50 different vials of such cells and immunize them by
injecting it into their skin.  So one could boost the immunity
in an oncologist's office, for example, and even tell whether the
patient has truly been immunized against a cancer by whether they
develop a little bump at that site, just like a tuberculin
reaction.  So these are the kinds of exciting new advances,
and time will tell.Foss
Basically, all of these techniques involve a patient's own tumor
cells being introduced to the antigen-presenting cells, and that is
a little bit different than say some of the other vaccine
strategies out there where they are using proteins like Mac-1, for
instance, which is a protein expressed on a number of tumors for
many different patients and trying to immunize a patient against
that.  In this case, you are immunizing a patient against
their own tumor cells.Edelson
That is right.  This is an ultimate example of personalized
therapy but it is also important to emphasize that we are always
dealing, as physicians, with practical considerations.  So
there are so-called markers or antigens that can stimulate immune
reactions against the tumor type in general, like a melanoma, like
ovarian cancer, but the most important antigens may be the ones
that are very unique to that person's malignant cells, and you
cannot have a preparation that is put into a bottle for every
single patient that really knows and identifies each patient's
individual array of antigens, but the immune system and their own
dendritic cells can do that sorting for you if you give them, as a
source, the malignant cells.  So, what you say is exactly
correct Francine, and that is that the attraction of this treatment
is that it is so unique and so simple to apply to the individual
patient.Dr. Richard Edelson is Aaron and Marguerite Lerner Professor
of Dermatology and Professor and Chair of the Department of
Dermatology at Yale School of Medicine.  If you have questions
or would like to share your comments, visit YaleCancerCenter.org,
where you can also subscribe to our podcast and find written
transcripts of past programs.  I am Bruce Barber and you are
listening to the WNPR Health Forum on the Connecticut Public
Broadcasting Network.