I'm Gina Vild.
I'm the Associate Dean for Communications and External
Relations from Harvard Medical School.
And welcome to our grand finale of the 2017 Longwood Seminars.
As you know, we had a snow date for the first one.
So we're thrilled that all of you decided to come back.
May I ask if there is anyone here who has attended all four
of the Longwood Seminars Wow, fabulous.
Before we actually begin our program tonight,
I'd like to ask Belinda Davis to come forward.
Belinda, this is her first year organizing the Longwood
Seminars And I believe she's done an extraordinary job.
And it's an awful lot of work that goes into this.
And so just please join me in thanking her.
And it's her birthday.
So if you see her on the way out--
The Longwood Seminars, we initiated them
about 16 years ago.
And the concept behind them was to share
the knowledge of Harvard Medical School
and our extraordinary faculty with the Boston neighborhoods.
But we soon grew far beyond that.
And in the last few years, we've been Livestreaming.
And tonight, again, we are Livestreaming around the world.
And I want to welcome all of our visitors
who are joining us from afar.
In fact, I thought you'd be interested to know
that, in the first three seminars,
they were viewed in 93 countries and watched
by more than 638,000 people.
So those in the room tonight represent just a small number
of who are enjoying these seminars around the world.
Some of the top viewing countries
are India, Taiwan, South Korea, Mexico, Singapore, and the UK.
In addition, we stream live on Facebook.
And the first three seminars were
viewed by 33,400 on Facebook, and another 5,000 on YouTube.
So to all of you, welcome.
And thank you for being a part of this very special program.
Before we get started with our program, An Answer to Cancer,
I just have a few announcements.
If you've earned a certificate of completion
or professional development points,
you can pick up your certificate in the lobby following the Q&A.
If you've earned the certificate and are not here tonight,
you can contact us via email.
We also invite you to complete an evaluation form.
We have those in the lobby.
And your ideas are really an important way
of how we can infuse some really good, new ideas
into these programs so that we keep
them vital and interesting.
So please take some time and do that.
We also will be collecting your questions.
You all know this because you're veterans.
And we will have people strolling up and down
the aisles, so please turn your questions over to them.
If you're part of our audience watching through Livestreaming,
you, too, can send us questions.
Join us and send your questions by using the hashtag
So this evening, we have four of the world's leading
And they truly are four of the world's leading authorities,
both scientists and clinicians, here to talk with you.
They'll share with you the strategy
of using the body's own defenses to combat cancer.
First, we have our moderator, Dr. Arlene Sharpe.
Dr. Sharpe is the George Fabyan Professor
of Comparative Pathology.
She is the Interim Co-Chair of the Department
of Microbiology and Immunology at Harvard Medical School.
And she's a member of the Department of Pathology
at Brigham and Women's Hospital, an Associate Member
of the Broad Institute of Harvard and MIT,
a leader of the Cancer Immunology
Program at the Dana-Farber Harvard Cancer Center,
and Co-Director of the Evergrande
Center for Immunologic Diseases at HMS and Brigham
and Women's Hospital.
Dr. Sharpe's lab focuses on new therapies
for autoimmune diseases and cancer.
And she'll be our moderator.
Dr. David McDermott is the Director of the Melanoma Skin
Cancer Program and the Biologic Therapy Program at Beth Israel
Deaconess Medical Center.
As a medical oncologist and clinical investigator,
he has a particular interest in therapies that enhance
the immune response to cancer.
Dr. McDermott is an Associate Professor of Medicine at HMS
and a member of the editorial board for the Journal
of Clinical Oncology.
Dr. Jerry Ritz is the Executive Director
of the Connell-O'Reilly Cell Manipulation Core Facility
at the Dana-Farber Harvard Cancer Center and an HMS
professor of medicine.
He's a recipient of the prestigious Stahlman Scholar
Award given by the Leukemia and Lymphoma Society of America.
Dr. Ritz is an expert whose lab focuses
on hematologic malignancies, bone marrow transplantation,
and cancer immunology.
Dr. Catherine Wu is an HMS Associate professor of medicine
and a staff physician at Dana-Farber and Brigham
and Women's Hospital.
She's a member of the American Society of Clinical
Investigation, a recipient of a 2011
Stand Up to Cancer Innovative Research Grant
from the American Association of Cancer Research,
and a scholar of the Leukemia and Lymphoma Society
Her laboratory focuses on dissecting the underlying
mechanisms of pathobiology of chronic lymphocytic leukemia,
which is a common adult leukemia,
as a means to generate more effective therapies.
Particularly immune-based treatments.
This is truly an illustrious panel
that we bring to our final Longwood Seminars.
So thank you, Dr. Sharpe.
Well, thank you very much for that very kind introduction.
In my talk this evening, I'm going
to be introducing the topic of cancer immunology and cancer
We all think of the immune system as a way that
defends us against infections.
For example, the immune system exists to defend us against
the diversity of the microbial world,
viruses which we cannot see with the naked eye.
This is an electron micrograph of influenza virus,
which causes the flu, as well as bacteria, shown here.
Cancer immunotherapy is designed to boost
the body's own immune defenses.
In this case, to fight cancer.
Now, white blood cells in the body
are cells that are important in the immune system.
And a particular type of white blood cell,
called a T cell is able to kill microbes that cause infection
and also cancer cells.
We have-- whoops.
Is it possible to go back one slide?
We have a very limited number of cells
that can recognize a particular microbe or cancer.
But once these cells are activated, they can expand.
And one can get large numbers of these cells that
then can function to help us fight infection or cancer.
Now, a key function of the immune system
is to distinguish normal cells in the body from foreign cells,
such as infected cells or cancer cells.
And the immune system uses proteins
that are on the surface of, for example, T cells
shown here, that need to be either activated
to promote an immune response or inhibited
to prevent an immune response at certain checkpoints.
These checkpoints are important for proper functioning
of the immune response.
And one needs to distinguish infected cells, for example,
or cancer cells from normal cells.
And these immune checkpoints lead
to responses against infected cells,
but not to our own bodies or self.
Now, cancer cells are very clever.
And they've figured out many different ways
to block immune responses.
And one of the ways that cancers do this
are to use these inhibitory checkpoints that
normally are used to prevent responses
against our own bodies.
In this case, we have an immune response,
and the tumor has put up a blockade
against the immune system.
And this system, called checkpoint blockade,
that you've heard about, essentially
blocks pathways that the tumors are using
to inhibit anti-tumor immunity.
So the tumor prevents an effective immune response.
And one type of immunotherapy called checkpoint blockade
blocks pathways that the tumors are using
to inhibit the immune response.
Now, the tumor cells themselves can
make a variety of substances that
can prevent immune responses.
And essentially, they're able to use
many of these inhibitory checkpoints
to their own devices.
Two of these checkpoints that are important and have
been translated into therapy are cell surface receptors
called PD-1 and CTLA-4.
These cell surface receptors can be
expressed on T-lymphocytes, these T-cells,
as well as some other cell types.
And when they interact with their ligands,
or binding partners, these cells then
can deliver inhibitory signals into the T-cells
and prevent their responses.
Cancer cells themselves can send signals through PD-1
into a T-cell, essentially tricking the immune system
into seeing these cells as healthy normal cells.
And checkpoint inhibition blocks these pathways
that then can expose these cells to immune attack.
This is a picture showing you two different types of tumors,
A kidney tumor on the left and the non-small cell lung
cancer on the right.
And we've used an antibody to PD-L1, one of the molecules
that combine to PD-1.
And this brown staining here is an antibody
that can visualize PD-L1 on the surface of the tumor cells,
and showing you in this brown stain
here that tumor cells can express
high levels of the ligand for PD-1.
So simply put, then, in a tumor microenvironment,
we can have T-cells that express high levels of PD-1,
And these cells then can interact with PD-L1
on a tumor cell.
When this happens, the T-cell cannot function and kill
But the drug that's used in this case
is an antibody either to PD-1 or PD-L1.
And when this is given, this prevents PD-L1
from interacting with PD-1 and blocks this inhibitory signal.
So now the T-cell can function and is
able to kill tumor cells, and make certain protein
hormones called cytokines that also can work together
to boost anti-tumor immunity.
There are now a number of checkpoint inhibitors
that are approved by the FDA that
are targeting these receptors.
One is against CTLA-4, a molecule called Yervoy.
And there are several antibodies to PD-1, one called Opdivo,
and the other is Keytruda.
And then antibodies to PD-L1 as well.
And there are, in addition, about 20 agents
that are present in ongoing clinical trials.
These antibodies have been approved by the FDA
for several tumors, shown in green here.
And one of the remarkable things about the PD-1
pathway is that it's been used over and over again
by a variety of types of tumors to inhibit anti-tumor immunity.
And so antibodies that inhibit the PD-1 pathway
have been FDA-approved for melanoma, for bladder cancer,
non-small cell lung cancer, head and neck tumors, kidney tumors,
Hodgkin's disease, and Merkel cell tumors.
And what this is showing you is overall response rates, showing
you the overall response rate ranges from 20% to 30%
in many tumors.
Up to 87% in Hodgkin's disease.
Now, why is there such enthusiasm for immunotherapy?
This slide illustrates one of the major reasons.
If we first look at this graph on the left, what we're
looking at are patients whose tumors
have been treated with blockers of CTLA-4 or PD-1.
The experience is longer with blockers of CTLA-4.
And what you can see is that there are about 20%
of the patients who respond.
But the benefit is durable, lasting for at least a decade.
The experience with PD-1 is more recent.
But in addition, in this situation,
blockers of the PD-1 pathway, also
can lead to durable benefit.
So the enthusiasm for immunotherapy
is that it can lead to a long-term benefit,
but a moderate number of patients respond.
And I'll come back to that point.
In contrast, patients who receive chemotherapy,
or other types of therapies such as kinase blockade,
there is a higher percentage of patients who initially respond.
But, unfortunately, the response is short-lived.
So the great enthusiasm for immunotherapy
is the durability of response that's seen.
Now, what is it the immune system
sees in a tumor to attack?
Tumors have a variety of changes in protein coding regions.
And these are [INAUDIBLE] mutations.
And as a result of this, these changes
that occur in the tumor cell can be recognized
by the immune system.
And these protein coding changes are called tumor neoantigens.
And so, in cancer, there are two types of evolutionary processes
that are driving the tumor.
The first are the mutations that are occurring.
And there are two types of mutations.
There are so-called driver mutations
that initiate the tumor-forming process.
And then there are these protein coding changes
called neoantigens that the immune system can recognize.
In addition, there are a number of immune evasion pathways
that we're learning more and more about.
The PD-1 pathway is one, and there are many others as well.
And one of the reasons why the immune system is
the perfect approach to use against the tumor
is that, as the tumor continues to evolve,
so can the immune system.
So the immune system can keep up with the tumor.
We're just beginning to understand
how to identify those groups of patients
who benefit from PD-1 therapy.
Understanding of immunology, as well as cancer genetics,
has identified several groups who are responders.
One are groups of people who have highly mutated tumors,
where there's defects in DNA repair.
These patients have a high response rate to PD-1.
In addition, there are certain tumors,
such as Hodgkin's disease, where the tumors have
many, many copies of the ligands for PD-1.
And so when you then block this pathway,
there is a very high response rate
to PD-1 pathway inhibitors.
In addition, certain tumors of viral origin,
such as those caused by papilloma viruses,
this can lead to head neck tumors, for example,
or Merkel cell tumors, one can see in those settings
that there also is a high response rate.
But we're really just beginning to understand these responses,
and further work is needed to identify biomarkers
that we can correlate broadly with responses
to PD-1 immunotherapy.
But this is really just the beginning.
And really, we're at the beginning
of a revolution in cancer therapy
because there are many more cancer immunotherapy targets
than PD-1 and CTLA-4.
This is a diagram showing you here that these T-lymphocytes
can express many of these inhibitory receptors.
And all of these receptors have become druggable targets
for cancer immunotherapy.
And so while we now have therapies
to CTLA-4 and the PD-1 pathway, many of these other targets
are also now, molecules are being made for therapies.
And there are clinical trials that are ongoing.
And so the PD-1 pathway is really
becoming a foundational building block
to combine with other types of therapies.
And right now, there is great interest
in combination therapy.
How to increase the benefit to PD-1 pathway blockade.
And there are a number of approaches
that are being undertaken.
The first is to combine PD-1 blockade
with blocking other inhibitory pathways to release the brakes
on the immune system.
The other is to block PD-1, and then stimulate
the immune system in some way.
Another is to block PD-1, and then give chemotherapies
or certain types of kinase inhibitors or radiation
Or give PD-1 blockade, along with a cancer vaccine,
a cellular or engineered T-cell.
And you'll be hearing much more about these
in the subsequent talks.
And so hopefully over the next decade,
we're going to have tremendous progress because there's
so much work ongoing now.
So the future of cancer therapy and decisions
may look something like this.
One will have sequencing of the genome.
So one can identify what genes are causing the tumor,
and these can be drug targets.
In addition, one can identify those protein coding mutations
and identify neoantigens, which also can
service targets for therapy.
In addition, one can develop a so-called tumor immunoevasion
score, identify which ways the tumor is
using what pathways to evade the immune system,
and then target these.
So this would lead to choosing the best immunotherapy, and how
to combine immunotherapy with the best
targeted therapy or vaccine.
So to summarize, then, the success of checkpoint blockade
therapy has led to incredible change
in the strategy for cancer therapy.
We're beginning to appreciate that tumor immunity is
limited by natural regulatory mechanisms
that the immune system is using.
And by boosting the body's immune defenses,
we can fight cancer.
The future is in combination therapy
to extend the benefit of cancer immunotherapy,
to build on the success we have with checkpoint blockade
and combine it with a variety of other approaches.
And in the next talks, you'll be hearing about some
of these other approaches, taking basic discoveries
in immunology and translating them to therapy.
The appreciation that there are many pathways that
inhibit tumor immunity has translated
to checkpoint blockade.
And you're going to hear from Cathy Wu about approaches that
are leading to t-cell vaccines, from Dr. Jerry
Ritz about T-cell engineering and stem cell approaches,
and from Dr. David McDermott about clinical trials
in combination therapies.
Thank you very much for your attention.
And I'll turn it over to Dr. Wu.
So great, happy to be here.
And just to follow Arlene's talk, as she said,
we have a very complex number of different types of cells that
comprise the immune system.
There are specialized organs.
They have the ability to travel and go and survey
the whole entire body to make sure that we're safe.
And just to remind ourselves that as hardwiring,
the immune system is hardwired to recognize
these external pathogens, so protect us
from these external evaders.
They're really a mixed and motley group of different types
Bacteria, fungi, viruses and parasites.
But also to reiterate that, as a system,
the immunity responses, the function
to survey all the interfaces that our body interfaces
with the environment, detect whether or not
these pathogens are present.
If so, mount an immune response.
For example, traffic to the lymph
node, where robust responses can be generated.
And there's another very important function
that happens which, is memory is developed.
So there may be, first, the initial encounter
with a pathogen. And once an immune response
is developed, if there is a secondary encounter,
there is a very swift and high amplitude response.
And again, this serves to protect us in the long term.
Now, the Danish physiologist Peter Panum, back in the 1800s,
was called to the Faroe Islands to investigate
a measles outbreak, and was able to study this phenomena
of immunologic memory.
Because certainly what he found was
there had been already a measles outbreak many years before,
some several decades before.
No measles for 65 years.
And when there was this new outbreak that came out,
those that were infected earlier were not affected again, back
So this really demonstrated this long-lived immune protection
that exposure to this infectious agent had caused.
Now, one question you might ask, all of us
are well-acquainted with the flu.
So why, for example, do we get flu pandemics?
And it gets back to the idea of antigen and antigen exposure.
Because influenza, as a wily organism,
it can avoid immunologic memory by changing its molecules
every so often.
So mechanistically, this is how we
can understand why these outcroppings of flu pandemics
come from time to time.
Now, what about cancer?
We all know that cancer arises because of DNA mutations that
can lead to altered proteins.
And there is quite a bit of different types of mutations
per different cancer.
Many of you know that there's been a technological revolution
that's happened over the last couple of years,
with the availability of broad sequencing
that allows us to systematically sequence
the coding genomes of cancers.
And many of these large-scale studies
have had the goal of understanding the mutation
spectrum of tumor cells, putting that all together
with other layers of information so
that we can come to understand what
are prognostic markers related to that cancer.
And also, can we think better how
to develop novel therapeutics?
And certainly in the disease that I study, but certainly,
this could have been any cancer, we've
come a long way ever since these sequencing technologies
have been upon us, which has been a mere seven or so years.
So at least in chronic lymphocytic leukemia,
where a long-standing question has been,
can we understand why certain patients progress more rapidly?
Why do some patients have a more indolent course?
Can we understand what are the clinical or the protein
Well, I would say that since the advent
of next-generation sequencing, there's
been this explosive increase in our knowledge of the genetics,
the transcriptomics, and the epigenomics that
allow us to understand that.
And just to give you a flavor of what we've been able to find,
through the mining of all this high-dimensional data,
is that we certainly have been able to find,
for example, again, this is the example
of chronic lymphocytic leukemia.
But it certainly could have been true for any
of the many other tumors that have been characterized
in a similar fashion.
We can identify those type of molecular events
that statistically appear to be present
at a higher-than-expected frequency that suggests
that there was positive selection,
and was involved in the genesis of these tumors or leukemias.
Each column here is an individual patient.
And what I want to point out to you
is that, although there are some recurrent events that
are common amongst patients who have this type of leukemia,
for the most, part each patient has
a different genetic profile.
And that really speaks to not only the immense heterogeneity
in the genetics of individuals that have the same disease,
but also the differing evolutionary trajectories
that each patient takes as all of these alterations
And altogether, again, in the example
of chronic lymphocytic leukemia, but I
think this is extendable across the different cancers,
we have come to a picture such as this.
Which is we understand each tumor as not monolithically
all the same type of cells that are one block of population,
but rather many sub-populations within each cancer.
So there's maybe one clone that has three mutations that
define this sub-clone.
There's another group that has another five
mutations, and this one with another two mutations,
and so on and so forth.
So within individual patients' cells,
there may be different sub-populations.
What that means therapeutically is
that, as we try to start to treat patients
with different types of therapies,
be it chemotherapy or targeted therapy,
if not all the cells are eradicated, because there
is such diversity in the population already,
there are evolutionary pressures that
lead small populations then to expand
and be the cause of subsequent relapses.
So too often in cancer, we see remissions that are short,
that come back.
And we go through successive rounds of therapy.
So this really provides us with a tremendous challenge
as we think about how to eradicate cancer.
And so I would say that if we acknowledge that not only is
each individual's cancer different from the next
individual, but also within each individual's cancer,
there are many different sub-populations,
and that each of those as in aggregate, that
means that per individual, there's
a unique set of antigens per tumor per patient.
Then perhaps the solution to this conundrum
is we need to have an army of T-cells.
Because the immune system is actually,
again, hardwired to be able to have a capacity
to generate diverse T-cells that can recognize diverse antigens
and eradicate them.
So in that respect, again, along the same lines
of what Arlene mentioned, cancer vaccines
actually have perhaps a very complementary role to play.
So Arlene already talked about how
blocking immune checkpoints that have
the brakes on the immune system can now be overcome
with some therapeutics.
Perhaps we can use cancer vaccines
to help steer that response, focus the response,
raise T-cells that have the right specificity,
and guide the immune response in the anti-tumor direction.
So that together with strong adjuvants, which
are going to add strength and speed to the process,
and if we put this together with checkpoint blockade,
perhaps this is a nice, effective way
to generate highly-specific anti-tumor immunity
with fewer side effects.
So how do we generate cancer vaccine?
So I've tried to bring it down to the essential ingredients.
And I think that we would all agree
that, for a vaccine to work, we need at least
these four complements.
You need antigen, so something to target against.
You need adjuvants, so something to kickstart the system.
You need to figure out how to deliver the vaccine.
And of course, again, as Arlene mentioned, decrease that shield
around the tumor that's immunosuppressive
and inhibits the activity of cytotoxic T-lymphocytes.
So we need to block that suppression.
Do we have any evidence already that vaccines can work?
Well, it turns out this is not a new idea.
People have been kicking around the idea
of vaccines for a long time.
This is from back in the late 1890s.
There was a very renowned New York
surgeon who created what he called, his name was Dr. Coley,
he created Coley's toxin.
And he had this one patient who had
this awful tumor on his face.
And he created this toxin, which was really
mushed up bacterial components, and injected it in the site.
And this gentleman received at least [INAUDIBLE] or so
rounds of these injections.
And it did lead to regression, and this man
continued to live for several more years
than would have expected for this type of tumor.
And I think we now recognize that this was probably
the first adjuvant.
So with all the biological and molecular understanding
that we've gained, a very effective way
to jumpstart the immune system is
to remind the immune system of those external pathogens.
So these were microbial components
that were mushed up and injected onsite.
So perhaps he was able to awaken those T-cells that
happened to already be there and get them
to work, at least for this person, effectively
for a number of years.
Since that time, we've come up with a list
of so many different ways to think
about antigens or adjuvants and formulations and deliveries.
And it can be quite bewildering.
But I will say that, in between all of this mixing and matching
of complements, there have been some notable responses
that we've seen in patients.
So I will remind you that, for early stage bladder cancer,
we are using a microbial complement to treat that.
This has been in use for decades now.
There have been, in another virally-mediated early type
of carcinoma, there have been peptide vaccines
that have been able to generate clinical responses
in this setting.
And some of you will know about the first FDA-approved
immunotherapy, which is Provenge,
a vaccine for prostate cancer.
So there are a few examples of where vaccines have worked.
But what's especially exciting to me right now
is that we have an ever-growing toolkit that
seems quite clinically efficacious,
that makes the possibility of vaccines seem like a reality
So one is, in terms of adjuvants,
I'll just mention as an example.
This Poly ICLC is, again, a microbial component
that has been distilled down to its active ingredient
and has been already tested in clinical trials.
There's been a number of different studies
that have used long peptides.
So this is peptides that can be synthesized
and given in a syringe, and used as a way to deliver antigens.
And then Arlene already mentioned the antibodies
that we have to block immunosuppression.
So what we need is actually a good target.
So what are we going to go after?
And there, I would say that we are in a time where
we can identify neoantigens.
I already talked about how each tumor has its own specific set
Well, at least some of those mutations
will generate peptides that have altered amino acid.
So it can be translated.
It can generate these altered peptides.
Some of them have the potential to bind
to the patient's own HLA molecules.
And it is this coupling that allows these peptides to be
displayed on a tumor surface, where t-cells
can come and recognize them.
So neoantigens are those antigens
that are born out of mutation and are
present on the tumor specifically, but not
on normal cells.
And so this has always been conceptualized
to be a really ideal type of antigen.
But what was missing for so long was the ability
to systematically identify them.
What we have now is new technologies
that allow us to use DNA and RNA sequencing
so that we can readily identify these new antigens.
We can confirm that their expression
is present on the tumor cells.
We also have very well-vetted out prediction algorithms that
allow us to rapidly identify whether those peptides
that we're identifying from our DNA
and RNA analysis would bind to that person's own HLA
And these are what we call candidate neoantigens.
And really, conceptualized as hitting the sweet spot.
Because by virtue of arising from tumor mutations,
they have exquisite specificity in terms of expression
on tumor cells, and akin to pathogens,
they are highly immunogenic.
Because we do not automatically have
a way of deleting out T-cells that might react to them.
And this is really different than where we've historically
been, in terms of the type of antigens
that we have tried to use for vaccines or immunotherapy.
And these are what we call the shared
overexpressed self-antigens that are variable
in terms of their specificity for expression on the tumor,
and variable in the degree to which they're immunogenic.
Now, if you've been following this, what's
been very gratifying is that, aside from conception and idea
that these would be ideal antigens,
there is now lots of exciting data
that has cropped up in the last three
to four years that have really supported
the idea that neoantigens truly appear to be effective tumor
Some of that data comes from studies
that have looked at hundreds and thousands of tumors
and try to identify those antigens,
and look at clinical outcome and compare whether those tumor
samples that had higher numbers of neoantigen
seem to do better in terms of survival,
compared to those that had lower neoantigen load.
These types of studies have also tried
to look at specific diseases or specific treatment settings.
Other studies have asked, well, if neoantigens
are such great antigens, are they actually expanded?
Can I see whether or not they're expanded in those settings
where patients demonstrably have clinical responses?
And the answer is yes.
After stem cell transplant, after cellular therapy,
after checkpoint blockade therapy,
in fact, there have been a number of interesting studies
that have shown that these T-cells seem
to expand out and have specificity for neoantigens.
And finally, both in model systems and in patients,
it's been demonstrated that neoantigen-specific T-cells can
directly kill tumor cells.
So really, with all this data, it's
been very supportive of the idea that these are
in fact immunogenic antigens.
And then maybe the next logical step
is, well, if that's the case, can we
not generate individualized personalized vaccines?
If we know what the mutations are in the individual's tumors,
can we not actually generate a vaccine
that would be specific for that individual person?
And so the concept that we had already quite some time ago
was, could we not take a tumor, have normal cells sequence
the DNA from these in parallel?
And then use the HLA typing information
and predict what are those peptides that
are personal for that specific individual,
come up with a synthesis strategy
that we could make peptides, for example, that were reactive,
that would be predicted to be individualized
for that individual's tumor, and get it in a syringe
where we could give it as a vaccine?
And already, at the Dana-Farber, we've
conducted and recently completed two proof of concept studies.
One in high-risk melanoma, as well as
previously untreated glioblastoma, that have in fact
demonstrated safety, feasibility,
and immunologic activity.
And so I think we're really here now at a time of a paradigm
shift in terms of, at least in the field of vaccinology,
where we have the ability to find these neoantigens
and conceive of ways of targeting not one,
but multiple antigens that are specific for a person's
individual tumor in a tumor-specific
in immunogenic fashion.
And so I had to put this up, because I often think about,
well, I like Star Wars.
But also, I think one of the opportunities
that we've been afforded by checkpoint blocking antibodies
is that we do have a Obi-Wan Kenobi that
has been able to bring down the shields from the Death Star.
And so I think part of our challenge
is how to use that opportunity and put this opportunity
together, so that we can actually get in there
and actually ultimately destroy the enemy.
And so I would say that, again, coming together
with what Arlene said, combinations.
I think that's really where our future is.
She's talked about overcoming the immunosuppression.
But can we also add another step,
which is potent/specific, anti-tumor,
That is certainly where vaccines come in.
But also, cellular therapy also has a really important role.
So I'm going to pass the podium to my colleague, Dr. Jerome
Ritz, who will tell us more about that.
Thank you, Cathy.
So I'm here to talk about cellular therapy.
So we've heard a lot about the immune system.
And the immune system works, in large part,
through the generation of cells that
are part of this immune system, that can then actually
do the work.
They either make the antibodies that fight infections,
or they actually attack these invaders themselves.
And the question is, can we use cells as the treatment itself?
And this gets us to the idea of thinking
about cells as a living drug.
Now, that's not a totally new concept
because we've been involved in stem cell transplantation
for 40 or 50 years.
So if we think about a stem cell transplant,
this is for a patient, often with leukemia or lymphoma,
or for a patient who has an abnormal immune system that
is not able to make their own immune system,
not make their own blood cells.
Well, we know that if we can find an HLA-matched brother,
sister, or an unrelated donor, and if we transfer
those stem cells into the individual,
that we can actually get rid of the leukemia.
And that can last for a long time.
There's a single transplant, and that single transplant
of a relatively small number of stem cells
actually lasts for the lifetime of the recipient
and continues to make blood for the rest of their time.
Well, it turns out that we can do that with immune cells,
and with T-cells, too.
T-cells are long-lived cells.
We can generate those T-cells.
It's been done primarily here in the past
for virus-specific T-cells.
Or it's been done from taking T-cells from actual tumors,
growing them up, activating them, and giving them back
as a T-cell therapy.
So these are actually long-lived, if you will,
Unlike an antibody or a chemical that
is going to be great degraded over time,
these cells can live.
They can multiply in the recipient.
And I'm not going to talk about it today,
but I'll mention it at the very end,
there's actually a new way of generating cells,
long-lived cells, through reprogramming.
And that's the ability to start with a mature cell
and reprogram that cell so that it may become an immature stem
And then once you have that immature stem cell,
that cell can then be programmed to make other mature cells
in the body, often the same individual.
So that's an exciting, very, very new technology
for cell therapy that is yet in the future.
But I think it's going to be coming.
So another way of thinking about this
is, if you think about the evolution of cell therapies,
what I mentioned to you initially about stem cell
Well, we've been doing stem cell transplants for over 40 years.
It's a common procedure.
There are over 20,000 done in the United States,
over 50,000 worldwide, in each year.
But what we're doing is we're taking
a mixed cellular product, we're taking where we can get,
and infusing that into the recipient.
And that's where the whole field started.
We're now at a point where we can
begin to identify specific cells within a larger context.
We can purify those cells.
We can activate them.
We can expand them.
And we can then give them some more defined therapy.
What's coming now in the future, and I'm
going to talk a lot about chimeric antigen receptor, CAR,
T-cells, we can now actually start with a cell,
and we can genetically engineer it
to do what we want it to do for that individual.
So all of this is really the evolution of cells,
starting with a mixed cellular product 30, 40 years ago,
then being able to identify the cells that we really want.
And now actually being able to engineer the cells that we
want for individual patients.
So how is that done?
So here's an example that has had
an awful lot of interest and excitement
over the last few years.
It's called-- can we go back a step?
It's the ability to generate chimeric antigen receptor
So you heard from Arlene and from Cathy
that T-cells have specific receptors that can be
used to identify cancer cells.
Well, in this approach, we start with a patient.
This would be a patient with leukemia or lymphoma.
We do a leukapheresis procedure that
allows us to get out large numbers of the patient's
Those T-cells are then activated in the laboratory.
And then they're genetically engineered
through various viral vectors to now express
a new receptor, a receptor that is now
going to be able to allow those T-cells to actually recognize
the patient's own cancer cells.
Those cells are generated in the laboratory,
and they're expanded for a week or two weeks or three weeks
until we get enough of those cells.
And then they're infused back into the patient, where
they now become a living drug.
Those cells, now our immune cells,
derive from that patient.
They now can go because they now have a new receptor.
They can now go target and find the patient's own tumor cells.
This has been done most successfully
using CD19 as a tumor antigen. And this
is an antigen that is expressed by normal B-cells,
but also all of the cancers that come from the B-cell lineage.
So that would include acute lymphocytic leukemia,
chronic lymphocytic leukemia, and B-cell lymphoma.
So these are actually a relatively large,
different kinds of cancers that now can be
treated using CD19 CAR T-cells.
That's just the first target.
There have now recently been several papers that
have shown that another antigen called BCMA, stands
for B-cell maturation antigen, it's
another antigen and that is expressed by myeloma tumor
And that also can be generated into a CAR T cell,
again, specifically for patients with myeloma.
So just to show you how this field has evolved,
the whole genetic engineering field,
starting over 20 years ago, people
tried to generate these chimeric receptors,
that they could put them into cells.
And they started out by taking a signaling domain.
This is a receptor that is now synthetically put
into a cell that has one binding domain.
It has one signaling domain.
People use different kinds of binding domains,
actually, to take an antibody.
The binding domain, the specificity of an antibody,
hook it up to a signaling domain.
And these actually worked in some animal models,
but actually were not very effective in patients.
The trick was to enhance the signaling capacity
of these receptors.
And when you begin to add signaling domains
and costimulatory domains, that Arlene Sharpe talked about,
you can begin to add those together into a receptor.
You get a much more powerful signal that is transmitted.
And these are now the receptors, the CAR receptors, that
are now being very effective.
Of course, you can go even further.
You can add multiple different signaling domains.
These are called second-generation CARs.
We now have third-generation CARs.
We have armored CARs.
We have all kinds of different CARs
that people are beginning to use in clinical trials.
This actually is a diagram, that I borrowed from a paper
from Michel Sadelain, that actually shows the CD19 CAR
T-cells, the vectors, that are actually
being used in clinical trials.
And they all have many features in common.
They're all a little bit different.
But the ones that are effective have two signaling domains.
These have CD28 as a signaling domain, in addition to
These have 4-1BB, in addition to CD3 zeta.
They all have very similar receptors,
all against the specific CD19 antigen.
And these are the ones that are currently
being tested in clinical trials that are showing really
very dramatic efficacy.
Now, Cathy, in her talk, talked about having specific T-cells,
with T-cell receptors to generate
those cells expressing receptors for specific tumor antigens.
Well, those can also be genetically engineered
and put into cells that may not express them already.
So you can generate both an antibody
CAR that's called a surface antigen CAR,
or a transgenic TCR CAR.
So both of these are now being developed for patients
for different treatments.
The advantage to this is that it really
attacks a target, an engine that is
expressed on the surface of the tumor cell, of the cancer cell.
The advantage of this approach is, as Cathy identified,
these are actually specific for internal proteins,
internal mutation, so that you can
see different kinds of tumor targets
using these two different approaches.
So CD19 CAR T-cells have really hit the hype, as it were.
And the reason is because they've
been very effective in patients with
relapsed B-cell malignancies that have actually
failed all other treatments.
And in that setting, anywhere from 50% to 90%
of patients with these various diseases,
pre-B-cell ALL, CLL, B-cell lymphoma, Hodgkins disease,
actually can now respond to these chimeric antigen receptor
And as I said, these are effective in patients,
both pediatric and adult patients, that
have failed other treatments.
And everyone is expecting that the FDA will actually
approve these as living drug therapies sometime later
this year or next year.
However, there is a price to pay,
in that there are some significant toxicities
with these treatments.
First of all, these antigens may not be expressed only
on the tumor cells.
Certainly the ones that are expressed
on the surface of the tumor cell,
but also some normal cells.
So those cells can also be eliminated.
When these T-cells get activated,
and actually, they can expand 1,000 fold within a week,
you get the release of various growth factors and cytokines
that can be very toxic in itself.
And then there's also very poorly-explained neurotoxicity.
And then, even though these patients
have very dramatic responses, some of those patients
actually do relapse, even after they've had this treatment.
This is data from the University of Pennsylvania.
Really, one of the leaders in developing
this type of treatment.
This is for patients with relapsed ALL.
Their response rate is very high.
And about a year afterwards, still, 50% of the patients
are doing very well.
And these are patients where you would expect very few, if any,
of these patients to survive this long after treatment.
So it's really very dramatic therapy
in patients who have failed other treatments.
So this is now an area of intensive investigation.
This, again, from another review paper
that came out earlier this year, just looking
at the various types of trials that have either
been completed or ongoing.
And there are 20 different CAR T-cell
targets that are being evaluated in clinical trials.
And for each one of these targets,
there may be five or six different clinical trials.
These are the trials that are actually looking at the TCR
targets that I mentioned.
There's a little bit less activity for these.
But these also are, I think, going to be very promising.
So this is an area of very, very active investigation.
So as I said, I think the challenges in this treatment
is that there are some toxicities.
And so people are really looking at how
to manage these toxicities.
And as more people get treated, as people more become better
at understanding what's working and what's not working,
these toxicities are being managed.
There is a relapse.
And sometimes, these patients relapse because the cells
actually stop persisting.
And so sometimes, you may need to actually give
a second dose of those cells.
But sometimes, the tumors actually figure out a way
of deleting that target antigen. So even though it's
something that is expressed very commonly, and at high level,
cancers are very smart and they figure out
how to protect themselves.
And then, I think solid tumors, so we've
talked about leukemias and lymphomas and myelomas.
The big challenge is, how do you get these CAR T-cells to really
infiltrate a solid tumor where you
have problems of what is the right antigen, what
is the right target?
How do you get the T-cells to target into the tumor
And once the T-cells get there, even though they're genetically
engineered to get there, how are they going to protect
themselves from the immunosuppressive environment
that the cancer has generated?
And so again, combination therapies,
trying to figure out how to pull all this together,
they're going to be very important.
And then, in the last few minutes
that I have, I want to spend a few minutes talking
about what's actually also needed in this type of therapy,
is you actually need a place to make these cells.
And that's what we call the cell manufacturing
for the early phase trials.
And because these are very complex therapies,
require a lot of work to generate one dose of cells,
the cost of these is, I think, going to be very high.
So one of my hats at the Dana-Farber
is as the head of what we call the Cell Manipulation Core
So this is a laboratory that we've
developed to actually do this under controlled situations.
And the mission of our laboratory
is to provide safe and effective cellular products for use
in clinical trials.
These are for patients who are getting stem cell transplant,
but also for patients with cancer
who are getting these innovative cell therapies.
Unlike a drug or an antibody that you
can get from a pharmaceutical company,
or you can actually have made for a lot
of different patients, these individual therapies,
we're talking about making one cell
product that's actually going to go for only one patient.
That's the ultimate personalized therapy.
So this is the people that work in our laboratory,
just to show that these are all clean room environments.
To actually get into the facility, you have to gown up.
There's constant monitoring of the environment
and the procedures that are ongoing to make sure
that there is no contamination, that these products are
safe and sterile.
Because of the increased interest in this,
we're actually building a new facility.
It's going to be located on the 12th floor of the Smith
Building at the Dana-Farber Cancer Institute.
It's going to be completed in about a year from now.
And this is just a design, looking at this facility.
All of these light blue rooms here,
that are shown in magnification here,
are all clean room suites designed
to make products for individual patients.
But you need to have the place to do it.
You also need to have the well-trained people that can
they can manufacture the cells.
But then, you need to have quality control systems.
You need to have quality assurance.
You have to deal with all the regulatory issues.
You have to keep track of everything
in the data that's generated in the facility.
And then you have to have an inventory system for all
the different bits and pieces that go into actually
making these things.
So it's a complex environment, and we already
have about 50 people who are working full time
in this facility.
So just to end here, I think the points I've tried to make
is that I think it is actually feasible to make these living
drugs not just for a stem cell transplant,
but for patients as a cancer therapy.
It's likely that the CD19 CAR T-cells are actually going
to be FDA-approved sometime later this year or early
But they have toxicities.
And so it's important to think about that,
and to develop even better generations of these CAR
T-cells that have the same efficacy,
but avoid some of the toxicities.
Now we know this is effective for some blood cancers.
Leukemias and lymphomas, solid tumors, I think,
will also be an important target for these.
And so there's an awful lot that's
going on to be able to engineer these cells and how to do this.
There's a lot of work going on, so stay tuned.
I think there'll be a lot of progress
to be made in this area.
There you are.
Thanks to the organizers for inviting me here.
It's really an honor to speak in front of you today.
It's also an honor to follow Jerry Ritz, who's
been a pioneer in the field that I started in 20 years ago,
focusing on bone marrow transplant
and cellular therapies.
I didn't really last very long in that field.
I wasn't very successful.
About five years in, someone pulled me aside
and said something about not earning all of my salary.
And I was given the opportunity to move
from hematologic malignancies, like leukemia and lymphoma,
over to what Jerry was describing.
What we call solid tumors.
Tumors that start in major organs, like the kidney.
Melanoma, lung cancer.
And that's what I've been focusing on
for the last 20 years.
But in the first 15 of those years,
it wasn't exactly a great career move.
And I'll describe a little of my history, the history
of solid tumor immunotherapy, and how
some of the basic science that's been done by some of the folks
here at Harvard has changed not just my career,
but the outcomes for our patients with solid tumors.
So you've heard a lot about different approaches
I'm going to focus on a few of these.
The first one I'm going to talk about
is one that was actually developed over 30 years ago,
the so-called cytokine therapy.
You can think of cytokines as protein messengers
of the immune system.
They communicate between different cell types
and tell them to turn on or turn off.
And some of the most important cytokines,
when it comes to fighting cancer,
are agents like interleukin-2, or interferon.
And they're actually natural substances,
meaning we all have them in our bodies at all times.
We think they're there to help us fight off infections,
like viral infections.
But they can be synthesized in the lab
and made into large volumes, and given back to patients
to essentially act like an accelerator
on the immune system.
To put it into overdrive.
And what impact did that have?
Well, 30 years ago, this is looking at an x-ray.
This is before the advent of CT technology.
You can look at the scan on the right
as a young patient with metastatic melanoma.
You see all those blotches in the lung.
That's all disease.
Those are all individual melanoma metastases,
Stage IV solid tumors.
And after a short course of immune therapy,
you can see the x-ray two years later.
That patient is still in remission.
That patient outlived their cancer.
And that was a truly exciting development
in the field of immunotherapy.
But we can talk a little bit about why
this had a limited application.
One of the reasons why is IL-2 when given in large amounts,
creates significant side effects.
But that wasn't the only reason why
IL-2 had a limited application.
But needless to say, this is one of the pioneers
in the field of IL-2.
This is Dr. Steven Rosenberg, who's still
at the NCI surgery branch.
I remember reading this article that was in Newsweek.
I don't even know if Newsweek still exists.
But at the time, I was in college reading this article.
And after reading it, I decided I
wanted to go to medical school.
It sounded like a really great idea.
And this is some of the early outcomes data
from some of those original trials.
This is a trial that my mentor, Mike Atkins,
presented about 10 years after some of Dr. Rosenberg's
And what this essentially shows is, in the patients
who had a major shrinkage of their disease
after getting interleukin-2, if you had a response,
if your cancer got smaller, the benefit could last for years.
You see 120 months here, these patients staying in response.
So what did the IL-2 experience teach us?
It taught us that remission was possible.
That we could take a person with normally a lethal disease,
and put them into remission that could last decades.
And some of these patients are still
coming to see us in clinic.
But what else did we learn during this process?
Well, it turns out your immune system, as you've heard,
is not very well-designed to fight cancer.
It's actually designed to fight infection.
And it's designed to turn on when you're
dealing with a viral infection.
If you've ever had a bad virus, you felt fever, chills, sweats,
those kind of things, that's your body revving up
to try to fight the infection.
Once it's contained, though, the immune system
is designed to shut off.
And it turns out that the brakes on the immune system,
as Dr. Sharpe was talking about, are actually more
potent than the accelerator.
But now, we understand some of these breaks.
And we can actually, while the immune system
is designed to shut it off, it can be reactivated.
And this is just a cartoon of just releasing the brakes
on the immune system.
And one of the most important breaks
on the immune cell, the T-cell, is a substance called CTLA-4.
Now, what happens when you release the brakes,
or you release the pressure on CTLA-4?
Well, this is from one of our first large studies,
Phase III randomized studies in 2010,
that was published in the New England Journal.
These are patients, again, with metastatic melanoma,
who had advanced cancer, Stage IV disease.
They were given a blocking antibody
intravenously that treated their disease
and improved their overall survival.
But more important is this was the first drug
to show an improvement in survival.
But more important, this is what's called a survival curve.
You can see these patients still alive two, three, four years
And their treatment is stopping here.
So once again, this is the ability of your immune system,
you're releasing the brakes on the immune system.
You're not treating the cancer directly.
You're treating the immune cells.
You're creating a benefit in some patients
that's lasting years after the treatment stops.
And this was the first time this was ever
shown in a solid tumor.
And it was outpatient treatment.
So unlike interleukin-2, which has so many side
effects it has to be given in the hospital,
CTLA-4 blockade could be given outpatient.
And patients could come in for treatment, get a benefit,
stop the treatment.
And the benefit, in some patients,
could last for a long time.
But the benefit doesn't come without some cost.
When you rev up the body's immune system,
sometimes the T-cells will actually
go after healthy cells.
And that's what you're seeing here on these slides.
So for example, you hope that when you activate the T-cells,
it's going to fight the cancer.
But sometimes, it can attack the skin.
You can see this patient here with red dermatitis, skin rash.
This is a brain MRI.
This is before CTLA-4 for blockade is given.
And after, you can see, what we're
looking at here in the circle is the pituitary gland.
This is the pituitary gland essentially being
attacked by the immune cells, which
can cause the pituitary gland to not function, which
is not good.
But it can be treated with supplements,
with hormones given.
This is also one of the more serious side effects.
This is looking at a CAT scan.
This white area here is an enlarged colon.
I'll show you a better picture here.
This is a picture of inside a patient's colon, who's
received CTLA-4 blockade.
If you've ever seen one of these before,
if you've ever seen your own colonoscopy,
this is a pretty swollen colon.
And that's because of the effects
of the immune activation.
Now, if detected early, these side effects
can be treated with immune suppression medications.
But they can be serious.
So this story is not just positive.
There are some side effects that we have
to manage on a regular basis.
One of the other concepts, and Arlene
didn't really go into this.
But she is so important in this part of the story, which we'll
talk about in a little bit, which is not only are there
breaks on your immune cells.
The cancer can actually create a braking system of its own.
It can actually create, I like to think of it as barbed wire.
Cathy described it as almost like a force field
in Star Wars.
The tumors can actually create a resistance
to T-cells that have detected them
as a threat, found their way into the tumor,
are about to kill the tumor.
And the tumor puts up this barbed wire,
or this so-called PD-L1, on the surface
of the tumor that takes active t-cell and says,
you're not going to kill me.
I'm going to stop you in your tracks.
Now it turns out, once this once these discoveries were made,
you can actually create antibodies
to block the activity of either PD-1 T-cells,
as Arlene was describing, or this PD-L1 defense that's
often on many tumor cells.
This was the first large trial from just five years
ago in the New England Journal of Medicine,
which looked at one of the first PD-1
blocking antibodies in humans.
The reason this study was so important is
the patients on this study could have had one of five cancers.
They could have had melanoma or kidney cancer, the two cancers
that I treat.
But they also could have had colon cancer, prostate cancer,
or lung cancer.
And one of the exciting parts of this story
is, for the first time, we started
seeing activity outside of kidney cancer and melanoma
with these drugs.
We started seeing activity in lung cancer.
And when we saw that, we knew this was going to be big.
Because if you could get lung cancer to respond,
if you get the immune system to wake up and kill a lung cancer,
there was going to be a large list of cancers that would also
be sensitive to the treatment.
And that story has played out.
What did we see early on?
Well, this is a patient here with metastatic melanoma.
You can see a very large mass here
that I'm circling in the neck.
After treatment, with this outpatient immune therapy,
the mass gets much smaller.
You're seeing a picture of the side
of the neck of this patient.
And what you notice here, I don't
know if you can notice it, it's a little hard,
the woman is actually losing pigment in her skin.
And why is she doing that?
Well, because the T-cells are detecting
the malignant melanocytes, the malignant melanoma,
but also the healthy melanocytes.
So she's losing skin pigment.
So this is an immune reaction, which is dramatic.
You can see it on the microscope as well.
But for the first time, we're seeing this in other diseases,
similarly to this one case.
What else did we see in that initial trial?
Well, this is one of our patients with advanced kidney
You see this very large mass here in the left upper quadrant
of the abdomen.
The mass is so big, it's actually
growing through the abdominal wall here.
With treatment, once again, outpatient [INAUDIBLE]
treatment, you can see the mass getting much, much smaller.
And most importantly, this response
lasted, meaning this patient is still
having benefit from treatment several years
after finishing the therapy.
This is a little bit dramatic.
And I apologize to those people who
may be a little bit squeamish.
But I wanted to show this, because this drives home
the power of PD-1 blockade.
This is a woman who is 78 years old,
who actually had a cancer of the tongue that spread,
unfortunately, to her breast.
You can see the mass here.
This big, bright, angry-looking red thing here.
This person got an outpatient PD-L1 blockade.
You can see, just after two weeks,
you can already see it less angry, less red.
Within three weeks, you can see it's
almost like it's drying up here, and essentially dying.
And almost back to normal within six weeks of treatment.
Why am I showing this sort of graphic story?
Well, it points to several important parts of this story.
The reason why this tumor is so angry
is the immune system is already there.
The immune system is creating an inflammatory reaction
at the tumor that's causing, probably, the redness,
and probably pain and discomfort.
So the T-cells are there.
And what do you do when you give the antibody?
Essentially, those T-cells can now kill the tumor.
And that's why the killing of the tumor is so quick.
Because the T-cells have already detected it as a threat.
And now, the barbed wire around the tumor is blocked,
and they can kill.
And that's one of the reasons why this class of drugs
is not just more active, but is also less toxic.
Because the T-cells you're activating are
sitting, for the most part, at the tumor.
They're already there.
They're ready to do some damage.
But they can't.
You're not activating every T-cell in the body.
With some of these older treatments, like I mentioned
IL-2, for example, you're activating a much larger number
So you're creating much more side effects.
And the other interesting part of this story,
which I also wanted to mention, is this woman's 78.
These drugs are not more toxic as you give them
to older patients.
In fact, older patients tend to tolerate these treatments
very well and have often dramatic improvements.
This woman had failed multiple rounds of chemotherapy, which
is something we also see, is these treatments can work,
even after chemotherapy fails.
So Arlene showed something similar early on.
This is just a list of cancers where we're seeing activity.
And the list is long and growing all the time, which is good.
And in red are the places where we've
seen FDA approvals, where these treatments are now available.
So far, we've had 18 randomized trials.
And 16 have been positive.
So we're on a roll, although that's probably not
going to continue.
One important question I get a lot is,
do these work in some other cancers?
Well, so far, we're not seeing a lot of activity
in some very common cancers.
Like the most common form of breast cancer,
for example, and a lot of prostate cancer.
And you might ask why that is.
And we're still trying to figure that out.
But it may be because the typical breast cancer does not
generate as dramatic and immune response.
So we don't have the potential of activating those T-cells
at the tumor, like in the last case I showed.
But we're still trying to figure that out.
But I don't want to leave the impression that these
treatments work for most cancers, because they don't.
And they don't work for most patients
with cancers on this list.
So just following up, I was asked
to talk a little bit about combinations.
Oncologists are notorious for thinking,
if one drug is good, well, two drugs has got to be better.
And that's not always the case, because it can sometimes
lead to more side effects.
But there is a long list.
Because PD-1 blockade is relatively tolerable,
you can combine it with Dr. Wu's vaccines or Dr. Ritz's
cellular therapy, or chemotherapy and radiation,
without making those approaches too much more difficult.
And those are being done right now.
There are literally hundreds of clinical trials
ongoing around the world.
I just wanted to focus on one in the last few seconds
that I have.
This is combining the two approaches
that I mentioned, once again in melanoma.
This is combining CTLA-4 blockade,
releasing the brakes on the immune system,
and also adding PD-1 blockade on top.
So covering the barbed wire on melanoma.
And what does that produce?
Well, if you just release the breaks, about 16%
of patients with CTLA-4 blockade will
have a lasting benefit, a lasting
remission of their disease.
But if you do both at the same time
and you look two years later, at least in this trial
that we did, half of the patients hadn't progressed.
Meaning, essentially, their cancer
hadn't grown in over two years.
And some of these patients are in remission of their disease.
So whether we can do better than this, we'll have to see.
But it's truly exciting that, potentially, combinations
might take us a step beyond what we get with just PD-1 alone.
So we're in the era of immunotherapy.
And it certainly made a big splash
in our scientific journals.
Because of the impact across a variety of cancers,
it's also made an impact in the lay press.
But I just wanted to say two important things.
One, this would not have been possible,
this story, without the taxes that you folks pay,
that fund places like the NIH.
A lot of the money early on they'd
funded that led to these discoveries
was actually money that went not to study cancer,
but went to study things like autoimmunity and allergies
and all that sort of stuff.
A lot of that money went to people
like Arlene Sharpe, who is one of the three or four most
important people in this story.
She won't tell you that, because she's very humble.
But a lot of this wouldn't have been possible
without her work and her husband's work, Gordon Freeman.
So keep the support for research.
And hopefully, we can do better work in the next decade.
Thank you very much.
I'd like to invite all of our speakers to sit.
And we have a number of questions from the audience
and from Facebook that have been shared with me.
And so we'll have time to discuss a few of them.
The first question, several people
have asked how will the cost to patients of immune therapy
or vaccines compare with chemotherapy?
And will this be covered by insurance?
Do you want to take that?
So, go ahead.
Well, so I think--
well, David can speak to this as well.
I think the immune therapies that have been approved,
the anti-PD-1 antibodies and CTLA-4.
So these are now FDA-approved drugs.
And they are new treatments for lung cancer, for bladder
cancer, for [INAUDIBLE] cancer.
Those are being covered by insurance.
I'm sorry, so those are being covered by insurers.
They are expensive.
But I think almost any new therapy,
whether it's for autoimmune disease or for asthma
or for cancer, these are now very expensive agents.
The cellular therapies that I've talked about
have not yet been approved.
We do expect that they will be approved sometime this year.
We don't yet know how much they're going to cost.
We think they're going to be very expensive.
And we really don't know how expensive.
We don't know how insurers are going to deal with this.
It is a big challenge for the field.
Because just the cost of one of these drugs
can be tens of thousands of dollars.
Because it can be given month after month.
The good news is it can be given chronically.
The side effects don't build up.
But if you can stay on the drug, the costs continue to rise.
When you talk about adding expensive drugs together,
that will be a major issue.
And as a field, it's up to us to make
sure we're only giving these drugs to the patients most
likely to benefit, as opposed to giving them
to everyone, which is a pharmaceutical approach
to these things.
We also shouldn't be giving them longer than need be,
which is part of the reason why I focus a lot on creating
remissions of the disease.
If you can create a remission of a cancer,
well, then you can stop the treatment.
And also, that means the side effects stop.
That means the cost stops.
So as a field, I think we need to be pushing for treatments
that move us in that direction.
We generate that occasionally with patients.
But not enough yet.
And I think when you go think about that
in terms of the cellular therapies,
they're expensive because you're making a drug, a cell for one
And it's a lot of work.
It could be three weeks or three months
to actually do that work to generate
for that individual patient.
That builds up the expense.
But on the other hand, it is a one-time treatment.
It's a living drug that you really
expect to last for a long time.
And so that is going to be one of the mitigating factors.
I also think it's hard to know, I
think Jerry talked about saying that it's hard to know.
And I think when treatments are in their infancy, when they're
being tested, when they're in clinical trials,
they are expensive.
In the beginning, it is expensive
because there's a lot to test and a lot to optimize
and a lot to figure out.
If they do hit the mainstream, it's
hard to know how those costs will come down over time.
OK, maybe we should move on.
Another question that several people
have asked, how are people looking at genetic differences
in the treatment of cancer?
Very much worth thinking about how
to use the genetic information, on one hand to individualize.
I talked about the new antigen vaccines.
So that is one way to individualize our care.
Another way, another aspect that has been really
touted, and there's a lot of thought going into this,
is there a way that we can genetically test and figure
out, out of all the different menu of options
that we presented, what is the most efficacious way
So for one individual with one type of cancer,
it may be a vaccine.
For another person, it may be cellular therapy.
For another person, it may be a combination, together
with checkpoint blockade.
So I think we're at a time where we're all
thinking about all of that.
So we have, on one hand, lots of genetic data.
On the other hand, we have lots of developments
And I think a major thrust is how to bring that all together.
You hear a lot about generically what are termed biomarkers.
And a lot of the thrust of biomarker research
is to identify a marker of an individual patient that
will tell you what the best treatment would be.
Should it be this drug because the cancer has
this specific genetic mutation?
Should it be an immune therapy because there
are T-cell infiltrates that are already there,
like David talked about?
So I think being able to predict in a better way who
will respond to which treatment will also
help with the cost issue.
Because it is very expensive to give drugs.
It's even more expensive to give drugs that don't work.
Another question that we had is, do you
see CRISPR playing a role in future treatment of cancer
in immune approaches, or other approaches?
So CRISPR gene editing, I think, will play a role
in being able to genetically engineer the cells that we're
going to use for treatment.
So I think that's already being used and being applied.
Gene editing is going to be effective.
But you need to have a cell in which to edit genes,
and to work through.
And you need to have a laboratory,
like the one I showed you that we're building,
that will allow you to do that in a safe way.
So I think gene editing will really
facilitate the engineering of cells
that you really want to target to a specific cancer.
Do patients have to fail other therapies before receiving
CAR T-cell therapy?
Right now, yes.
I think right now, it's still an experimental treatment.
And it's really, before you know that something's working,
you really need to know the patient
that you have has exhausted other known treatments that you
So it's really only in patients who
have failed other treatments that these cells have
In the future, I think if they get approved
and if they're shown effective for patients
who fail treatment, then it makes sense to say,
well, is it is it possible to use it earlier
on in the course of disease?
We do a lot of stem cell transplants.
And initially, stem cell transplant was exclusively
for patients with leukemia or lymphoma,
who had failed all other treatments, as a last resort.
It turns out the results are much better if you actually
treat patients before they failed
all the various treatments.
So I think it may well move into an earlier phase of treatment
in the future.
So another question.
Vaccines are used often before illness occurs.
Do you think we can have personalized cancer vaccines
when an individual is a 100% healthy?
I mean, I agree.
In infectious disease, we always think about vaccines
to prevent illness.
In cancer, that's not where we've been.
But along the same lines as what Jerry mentioned,
which is vaccines are going to work the best when
your immune system is more competent and ready to do
One thing in the near-term that we can think about
is how to bring vaccines earlier in the course of disease,
not way toward the end when it's so hard to mount
any sort of immune response.
In terms of prevention, I think we're still
really far from that time.
But I do know that there's a lot of interest
out there about thinking and conceptualizing
how we can find those premalignant lesions,
for example, and trying to find specific genetic determinants
of the premalignant lesion.
And maybe we could vaccinate against that.
All concepts and things to test.
But certainly, it would be a promising approach.
Cathy did have this on one of her slides,
but HPV vaccine is actually a cancer vaccine.
And probably, it's really not used enough.
Cervical cancer can really be prevented over 90% of the time
by immunizing young people to the virus that
causes that cancer.
Have there been extensive studies of healthy people
with no cancer to identify immune system
differences between them and those with a cancer diagnosis?
And how can those findings help develop immune therapies
for those who need them?
You're pointing at me?
I don't know that anyone has done that.
I don't think so.
So I think there's been a lot of work, on the genomic side,
to look at variation in cancer responses
and degree of immune infiltrate over hundreds and thousands
of samples across many, many different cancers
that have been sampled.
In terms of comparison to normals,
I do know that, with respect for example to neoantigens,
it is true that if you take [INAUDIBLE] neoantigens
and you test them in normal donors,
there will be very, very robust responses.
There will also be responses in cancer patients.
But they are less strong and less broad.
But with something like a vaccine,
our hope is that we can put a little fuel into it
and generate those broad responses
that we see in normal donors.
I mean, it is known that patients
who are very immune deficient are more susceptible to cancer.
But it's not necessarily just one type cancer.
And their immune system has a lot of redundancies in it
and overlapping functions.
And so often, someone who might be
immune deficient in one area, other cells can compensate.
So you don't actually notice it very much.
It's really only in patients who have
very profound immune deficiency that you see
this very high risk of cancer.
So we'll have one last question.
How is the polio virus being used to combat cancer?
So I think that there are--
I'm not sure how much of it is polio virus, or only
But there are what are called oncolytic viruses that
are now being used.
So these are genetically-modified polio
virus, or other herpes viruses, that are genetically engineered
to allow them to infect the cancer cells
and kill cancer cells, but not allow them to spread.
And what that does at the cancer itself
is it releases all the other antigens.
And so there's an immune response that's
generated against the virus.
And then also, the immune response
against the dead cancer cells, that
is now one form of a vaccine, if you will.
We're using that approach in melanoma.
There's an actual FDA-approved drug
that's actually a herpes virus that's injected into a tumor
on the skin, or under the skin, to create
that local immune response that hopefully will generate a more
systemic response throughout the body.
Most of the patients who benefit from that injection
have relatively localized disease.
And one of the things folks are trying to do
is to take that modified virus, and combine it
with the checkpoint blockade, in hopes
of expanding the benefit that we see beyond to more
critical organs in the body.
As far as the polio story goes, I
know it's been looked at at Duke with patients
with brain tumors.
And there, they've seen mixed results.
And they made it all the way to 60 Minutes,
helping a couple of people.
But also, several people didn't do so well on that trial.
I don't know whether it's been expanded beyond that.
But the concept is the same idea,
which is to take a tumor that's not being recognized
by the immune system, create a localized immune response that
will then lead to more recognition,
more killing of the tumor by the immune system.
Well, I think, unfortunately, we've run out of time.
So I'd like to thank the audience for their attention
and thoughtful questions, and the speakers once again.