So immunotherapy, basically, is a form of therapy that is highly effective for many
human malignancies and what is cool about it is it's designed to go after the heterogeneity
of cancer. So the more foreign the cancer looks, the more it piques the immune system's
curiosity. So, guys that develop drugs, they think the heterogeneity of cancer is a landmine.
Immunologists see the heterogeneity of cancer as a gold mine. Right, got that? Pretty tricky.
Anyway, so the way that immunotherapy works is you trigger an immune response, it swarms
all over the cancer, cytotoxic immune cells then inject venomous stuff into the cancer,
and the cancer goes away.
So that's all real cool; we have many different weapons now to treat cancer using immunotherapy,
most of them are referred to as "checkpoint blockade"—Nivolumab, Opdivo so forth and
so on. Why is checkpoint blockade so important? Before 1995 everyone knew how to trigger immune
response against cancer, but no one could drive them to therapeutic outcome. In 1995 Dr. Allison
identified something that keeps the immune system going and going, and that was called
checkpoint blockade which related to inhibitors of the immune system.
So what does that mean?
So, I was working with Jim Allison at the time when all this information was coming
up and that's kind of where these slides came from. Jim Allison shows that there were two
signals that were required [to] turn-on a T cell. Once you deliver two [signals] the
T cells get very excited. Subsequently, you get an army of these T cells that can recognize
an antigen, go after it, and kill something like a tumor.
Okay, but Jim Allison also found that shortly after T cells activated another low receptor
showed up on surface at that time. It was called CTLA-4. He didn't know it did, but
he worked it out, and what he found out was after a T cell gets activated CTLA-4 shows
up and it shuts down the immune response. Pretty cool. Based on that he hypothesized
that CTLA-4 functioned like the brakes on a car to stop the immune system.
So after he figured that out he came up with even a brighter idea. What happens if we jam
the brakes on the immune system using an antibody against CTLA-4. Could it let the immune system
keep going and going and going to fight cancer. And basically the idea was give monoclonal
antibody, the immune system would keep going, subsequently you'd wipe out cancer and guess
what?
In 2011 the first checkpoint inhibitor, Yervoy, was approved for the treatment of human malignancies.
It is the first time in the history of management of metastatic melanoma that they saw overall
survival advances or advantages, and that was Yervoy. So it was the first one that worked
for human malignancy.
I got to be the first author on the attempt to treat advanced prostate cancer with Yervoy
and my study failed, and still it failed by 0.[0]03%. So I missed by three one thousands
of a point, and unfortunately FDA didn't approve it and BMS abandoned attempts for treatment
of advanced prostate cancer with Yervoy.
Fear not. So, a lot of people also know have heard PD-1, anti-PD-1 therapy. So the whole
PD-1, anti PD-1 therapy story to some extent came out of my laboratory. We had found this
molecule B7-H1 on the surface of kidney cancers, and what was really weird is whenever a patient
had B7-H1 on the surface of their cancer they didn't do very well. On the other hand, if
you didn't have B7-H1 on the surface of your kidney cancer you lasted a long time. This
one molecule could predict independently who's going to live or die after kidney surgery.
So our hypthesis at that time became: Well, maybe B7-H1 gets deployed by cancer like barbed
wire to poke holes in the immune system. So that was the hypothesis, and from that there
was a great kind of excitement about developing anti PD-1, PD-L1 therapies. What's funny is
B7-H1 turned out to be PD-1 ligand. That's ligand that binds to PD-1. So the idea then
became if you block B7-H1 or PDL-1, or if you block the receptor PD-1, just like CTLA-4,
you get the immune system to keep going and going to fight the battle against cancer.
So, now what do we have? We have a ton of additional agents to treat human malignancy
with immunotherapy, and this includes Nivolumab (which is Opdivo), Keytruda, so forth and
so on. Virtually every phramalogic group out there is trying to develop an immunotherapy
for treatment of cancer. Nobody talks to me about this by the way. So now it's been approved
for lung cancer, bladder cancer, so forth, melanoma, renal cell carinoma.
This is an example of a patient I treated with Ipilimumab. Guy had a PSA of 88, gave
him "Ippy," his PSA dropped down to 1.3, all the disease in his chest went away. It was
amazing. Still bothered me he had a little PSA. I ran him through my C-11 Choline PET
scanner. I found two additional spots that didn't respond to immunotherapy. We cut those
out, we just cut them out. PSA went to zero; he's doing fine.
So the bottom line with immunotherapy is we're still trying to work it out. I think immunotherapy
has been a miracle for a lotof very serious malignancies. I think there are a couple kinks
that need to be worked out for prostate cancer. I hope one day someone has the energy and
the time to work it out. I do know that we're working on various avenues of increasing priming
responses and so forth, but can't get it all done.
So, I'll leave it at that. Thank you very much.