Transcriber: Madhumithra Subramanian Karthikesh Reviewer: Zsófia Herczeg
So I remember the first time I learned about cancer.
I was about ten years old, and I was on a family trip,
visiting relatives in Vancouver, Canada.
One night after dinner, some of us went into the living room to play cards,
and we were all having a great time, laughing, shouting
when I thought I heard something in the background.
No one else seemed to notice.
So I turned to one of my aunts and asked, “Did you hear that?”
And then we all became quiet.
And then we all heard the unmistakable sound
of someone throwing up.
And that someone was my grandmother.
I later learned that my grandmother had colorectal cancer,
and she’s throwing up because of the chemotherapy
that she was taking.
Colorectal cancer would take my grandmother's life.
My story is in no way unique,
and most, if not everyone listening today
has been impacted by cancer.
Despite decreasing cancer death rates in the United States,
the reality is approximately 600,000 people will die of cancer
in the United States this year.
600,000!
That’s about the same number of people in the city of Portland,
gone every year because of cancer.
So what are we doing about this?
Well, I believe the key to eradicating cancer
is within each and every one of us.
It’s your immune system.
In fact, if there’s only one thing that you remember from my talk today,
I hope it’s this:
without doubt, the immune system is capable of curing advanced cancer.
(Applause)
The problem, however, is that the immune system
can’t cure some patients
because cancer can find ways to evade the immune response.
What if we could help the immune system,
engineer it in a way that makes it better attack cancer?
Well, we actually can.
And today I'm going to describe how we're doing it.
But first,
what is your immune system?
It’s simply parts of your body that are involved with keeping you safe
from things like bacteria and viruses.
You’ve probably heard of some of these components:
tonsils, spleen, lymph nodes, white blood cells.
And while there are many different types of white blood cells,
today I’d like to focus on one particular type of white blood cell
called the T-cell.
And so within each and every one of us,
we have billions upon billions of T-cells patrolling, keeping us safe.
And most of these T-cells are not the same because they express a unique receptor
protruding from the cell’s surface called a T-cell receptor.
Each T-cell receptor can recognize something different,
which allows the billions of T-cells in your body
to respond to virtually any microscopic invader
that enters your body.
For example, let’s say you’re infected with the flu.
Flu virus infects one of your cells.
There will be a small number of T-cells in your body,
the ones with the right T-cell receptor,
that will be able to recognize and eliminate the virus infected cells.
But what does this have to do with cancer?
Well, it turns out that in patients with cancer,
they too have T-cells, ones with a right T-cell receptor
that can actually recognize and target their own cancer.
But the fact that the cancers continue to grow
means that these T-cells are losing the battle.
So how might we help these T-cells out?
Well, one approach to help these T-cells
was developed by a pioneer in the cancer immunotherapy field,
Dr. Steve Rosenberg,
and it’s called adoptive cell therapy.
In the first generation of adoptive cell therapy,
a tumor is removed from a patient.
Then the T-cells within the tumor are amplified, expanded to large numbers,
typically in the billions.
And then these T-cells are reinfused back into the patient.
And so the premise behind this approach is actually quite simple
that some of the T-cells within the tumour are there
because they’re recognizing the cancer.
But again, they’re losing the battle.
But if you can somehow amplify,
generate a large army of these tumor reactive T-cells,
then perhaps this army can then overwhelm and destroy the cancer.
Did this therapy work?
This therapy was tested most extensively in patients with metastatic melanoma,
which is the deadliest form of skin cancer.
I'd like to show you one example of what this therapy can do.
So here’s a patient, young patient
with this bulky melanoma on the shoulder and neck area
that had spread to lymph nodes.
Dr. Rosenberg’s team grew out the T-cells within one of his tumors,
amplified them to the billions
and then infused them back into the patient.
As seen in this image here,
just 12 days later, you can see that the melanomas
have essentially melted away.
And so they tested -
(Applause)
And so after testing this therapy
in hundreds of patients with metastatic melanoma,
a few lessons were learned.
The first lesson was that adoptive cell therapy
could cure some patients with metastatic melanoma,
could lead to the complete destruction, eradication
of all traces of cancer in some patients.
This demonstrated that T-cells could be powerful weapons against cancer.
The second lesson learned was that T-cells targeting cancer mutations
likely mediated the curative responses.
Some of you may know this,
but a cancer cell is different than a normal cell
because it’s got changes or mistakes in the DNA and protein sequences.
These mistakes are called mutations.
And maybe you’re not surprised now but in patients with cancer,
there are T-cells, the ones with the right T-cell receptor,
that can actually target the unique mutations
So while melanoma is deadly, it’s actually relatively rare.
The majority of cancer related deaths
are due to cancer that we’ve all heard of,
difficult to treat cancers: colon cancer breast cancer, lung cancer,
liver cancer, pancreatic cancer, bile duct cancer,
head and neck cancers, and others.
So could we harness mutation reactive T-cells
to treat these difficult to treat cancers?
I’d like to highlight one patient
during my training with Dr. Rosenberg at the NIH
that begins to answer this question.
The patient’s name is Melinda Bachini.
She is 41, a mother of six,
when she is diagnosed with widely metastatic cholangiocarcinoma,
which is also known as bile duct cancer.
She had surgery, multiple lines of chemotherapy,
but as you can see from these scans,
the bile duct cancer had spread and invaded into her lungs.
You can see these bulky masses of bile duct cancer in her lungs.
So we took one of Melinda’s tumors into the lab, we grew out the T-cells,
and in Melinda’s case, we’re actually able to find T-cells
that targeted a specific mutation expressed by her cancer.
We amplified these T-cells,
and then we infused over 100 billion of these mutation T-cells
reactive T-cells back into her.
And then we waited.
And I remember being very anxious because this was the first time ever
that mutation reactive T-cells were being harnessed
to treat this sort of cancer.
And then her one month scans came in,
and it showed that the tumors were shrinking.
And I was relieved but only for a split second
because the scientist in me was wondering how long would this response last for?
Fortunately for Melinda, this response was long lasting,
as you can see in these scans two years later.
(Applause)
You can see that the tumors have substantially shrank,
and some have actually disappeared.
And in fact, here’s Melinda with me just a few years ago
outside my lab here in Portland, Oregon.
(Applause)
And as of today, she remains alive, healthy and well
almost nine years after the infusion of those mutation reactive T-cells.
(Applause)
And while we are excited by these results and happy for Melinda,
the harsh reality was that this therapy did not help other patients
with these difficult to treat cancers.
So we went back to the drawing board.
Why was this therapy failing these other patients?
Well, it turns out that T-cells, like humans, can age.
They can become all exhausted.
And it turns out that many of the T-cells within the tumor
are just that, they’re old and tired.
Remember, these T-cells have been likely in the tumor for a long time,
maybe months, maybe even years,
fighting the battle in a hostile tumor environment.
And they’re losing the battle, and they’re getting old and exhausted.
If that’s the case,
how would we get around an old, exhausted T-cell?
Well, what if we could first find a mutation reactive T-cell -
it could be old and exhausted,
and then isolate that T-cell receptor that I was telling you about,
and then genetically insert that
into younger T-cells within peripheral blood of these patients?
In essence, performing a T-cell receptor transplant.
This might sound like science fiction.
But this strategy is known as T-cell receptor or TCR gene therapy,
and it's being tested in clinical trials.
And my lab at Providence Cancer Institute right here in Portland, Oregon
was the first in the world
to use this therapy to treat patients with pancreatic cancer.
(Applause)
And I’d like to highlight one patient, Kathy Wilkes, 71-year-old woman
that we treated with TCR gene therapy.
So Kathy had metastatic pancreatic cancer.
She had surgery, chemotherapy,
chemotherapy plus radiation therapy and another experimental immunotherapy.
But as you can see in these scans of her lung,
the pancreas tumors had actually spread to her lungs and were growing.
So for Cathy, we took her blood cells
and then into her blood T-cells, we genetically inserted a T-cell receptor
that specifically targeted a mutation expressed by her cancer.
And then we amplified these cells in the lab,
and then we infused about 15 billion of these gene engineered T-cells
back into her.
And then we waited - anxiously as usual.
And then her one month scans came in,
showed that the tumors were shrinking.
But again, I was relieved for only a short while
because the scientist in me was wondering
how long this response would last for.
As seen in these scans just six months later.
It shows that the tumors were shrinking, and they actually shrank by about 70%.
And only while time will tell how long this response will last for,
this was actually the first proof of principle
that this TCR gene therapy targeting a mutation
could cause metastatic pancreatic cancer to shrink.
(Applause)
Despite promise,
TCR gene therapy has not worked for other patients with pancreatic cancer.
And it’s a tough pill to swallow to have patients die
despite your best efforts.
But I’m optimistic.
And I’m optimistic because the ability
to insert a T-cell receptor into another T-cell
to redirect it to target cancer
is only the beginning of T-cell gene engineering.
In addition to this, we can insert genes into T-cells
that protect them from the suppressive effects of tumors.
We can insert genes into T-cells
that greatly enhance their ability to kill cancer cells.
In essence, gene engineering can be used to armor and supercharge T-cells
so that they have a better chance of eradicating cancer in more patients.
(Applause)
So while cancer is formidable, so are we.
I believe with innovations in gene engineered cell therapies.
It is only a matter of time before we finish cancer.
(Applause)