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)
