summarize this "As elegant as they are, however, CAR-T treatments have proven successful
only against one specific type of cancer called B-cell lymphoma. All B-cells,
normal and cancerous alike, express a protein called CD19, which is the
target used by the CAR-T cell to zero in and kill them. Since we can live
without B-cells, CAR-T works by obliterating all CD19-bearing cells.
Unfortunately, we have not yet identified a similar marker for other cancers.
If we are going to bring down overall cancer death rates, we need a more
broadly successful class of treatments. Luckily, the immunotherapy approach
continued to evolve. Now, a bit more than a decade later, a handful of
immunotherapy-based cancer drugs have been approved. In addition to CART, there is a class of drugs called “checkpoint inhibitors,” which take an
opposite approach to the T cell–based therapies. Instead of activating T cells
to go kill the cancer, the checkpoint inhibitors help make the cancer visible to
the immune system.
To simplify a very long and fascinating story,
[*3] a researcher from Texas
named James Allison, who has been working on immunotherapy for almost
as long as Steve Rosenberg, figured out how cancer cells hide from the
immune system by exploiting so-called checkpoints that are normally
supposed to regulate our T cells and keep them from going overboard and
attacking our normal cells, which would lead to autoimmune disease.
Essentially, the checkpoints ask the T cells, one last time, “Are you sure you
want to kill this cell?”
Allison found that if you blocked specific checkpoints, particularly one
called CTLA-4, you effectively outed or unmasked the cancer cells, and the
T cells would then destroy them. He tried the technique on cancer-prone
mice, and in one early experiment he arrived at his lab one morning to find
that all the mice who had received checkpoint-inhibiting therapy were still
alive, while the ones without it were all dead. It’s nice when your results are
so clear that you don’t even really need statistical analysis.
In 2018, Allison shared the Nobel Prize with a Japanese scientist named
Tasuku Honjo, who had been working on a slightly different
checkpoint called PD-1. The work of these two scientists has led to two
approved checkpoint-inhibiting drugs, ipilimumab (Yervoy) and
pembrolizumab (Keytruda), targeting CTLA-4 and PD-1, respectively.
All Nobel Prizes are impressive, but I’m pretty biased toward this one.
Checkpoint inhibitors not only saved the life of a third Nobel laureate, former
US president Jimmy Carter, who was treated with Keytruda for his metastatic
melanoma in 2015, but they also came to the rescue of a very good friend of
mine, a former colleague whom I’ll call Michael. When he was only in his
early forties, Michael was diagnosed with a very large colon tumor that
required immediate surgery. I still remember the cover of the magazine that I
flipped through anxiously while I was sitting in the waiting room during his
procedure. Michael is the kindest soul I think I’ve ever known, and his
brilliance and wit could make the worst day seem enjoyable during the years
we worked together. I could not imagine losing him.
His family and friends were elated when his surgery proved successful and
the pathology report found no sign of cancer in his nearby lymph nodes,
despite the advanced size of the primary tumor. A few months later, our joy
was turned back to despair as we learned that Michael’s cancer had been the
result of a genetic condition called Lynch syndrome. People with Lynch
syndrome usually know they have it, because it is inherited in a dominant
fashion. But Michael had been adopted, so he had no idea he was at risk. The
mutations that define Lynch syndrome all but guarantee that its carriers
develop early-onset colon cancer, as Michael had, but they are also at very
high risk for other cancers. Sure enough, five years after he dodged that first
bullet with colon cancer, Michael called to say that he now had pancreatic
adenocarcinoma. This was even more distressing, because as we both well
knew, this cancer is almost uniformly fatal.
Michael went to see the top pancreatic surgeon in his area, who confirmed
the worst: surgery was not possible. The cancer was too advanced. Michael
would have, at most, nine to twelve months to live. Making this all the more
heart-wrenching was the fact that Michael and his wife had just welcomed
their first children, twin girls, into the world that year. But The New England
Journal of Medicine had recently reported that some patients with mismatchrepair deficiency (common in Lynch syndrome) had been successfully treated
with Keytruda, the anti-PD-1 drug. It was a long shot, but it seemed at least
plausible that Michael might benefit from this drug. Michael’s doctors agreed
to test him, and the tests confirmed that Michael was indeed a candidate for
Keytruda. He was immediately enrolled in a clinical trial. While it is not
guaranteed to work on all such patients, it worked on Michael, turning his
immune system against his tumor and eventually eradicating all signs of
pancreatic cancer in his body.
So now he is cancer-free for a second time, and beyond grateful to have
survived a disease that should have killed him when his twin girls were still in
diapers. Now he gets to see them grow up. The price he paid is that while his
immune system was attacking his cancer, it went a bit overboard and also
destroyed his pancreas in the process. As a result, he now has type 1 diabetes,
since he can’t produce insulin anymore. He lost his pancreas, but his life was
saved. Seems like a fair trade, on balance.
—
Michael was one of the lucky ones. As of yet, the various immunotherapy
treatments that have been approved still benefit only a fairly small percentage
of patients. About a third of cancers can be treated with immunotherapy, and
of those patients, just one-quarter will actually benefit (i.e., survive). That
means that only 8 percent of potential cancer deaths could be prevented by
immunotherapy, according to an analysis by oncologists Nathan Gay and
Vinay Prasad. They work when they work, but only in a small number of
patients and at great cost. Nevertheless, just two decades ago—when I was
feeling frustration as a cancer surgeon in training—patients like former
president Carter or my friend Michael, and countless others, would have all
died.
But I (and others who know much more than I do) believe that we have
had only a small taste of what can be accomplished via immunotherapy.
One idea that is currently being explored is the notion of combining
immunotherapies with other treatments. One recent paper describes a clinical
trial where a platinum-based chemotherapy was used in combination with a
checkpoint inhibitor, resulting in improved overall survival in patients with
lung cancer. These patients were not sensitive to the checkpoint inhibitor
alone, but something about the chemo made the cancer more sensitive, or
more “visible” if you will, to the immunotherapy. It’s an extension of the idea
of “stacking” therapies that we mentioned earlier.
To make immunotherapy more widely effective, we need to devise ways
to help our immune cells detect and kill a broader array of cancers, not just a
few specific types. Genetic analysis reveals that some 80 percent of epithelial
cancers (that is, solid organ tumors) possess mutations that the immune
system can recognize—thus making them potentially vulnerable to immunebased treatments.
—
One very promising technique is called adoptive cell therapy (or adoptive cell
transfer, ACT). ACT is a class of immunotherapy whereby supplemental
T cells are transferred into a patient, like adding reinforcements to an army,
to bolster their ability to fight their own tumor. These T cells have been
genetically programmed with antigens specifically targeted at the patient’s
individual tumor type. It is similar to CAR-T cell therapy, which we
discussed earlier, but much broader in scope. As cancer grows, it quickly
outruns the immune system’s ability to detect and kill it; there simply aren’t
enough T cells to do the job, particularly when the cancer reaches the point of
clinical detection. This is why spontaneous remission, as happened with
James DeAngelo, is so rare. The idea behind ACT is basically to overwhelm
the cancer with a huge number of targeted T cells, like supplementing an
army with a brigade of trained assassins.
There are two ways to do ACT. First, we can take a sample of a patient’s
tumor and isolate those T cells that do recognize the tumor as a threat. These
are called tumor-infiltrating lymphocytes (TILs), but there may only be a few
million of them, not enough to mount a complete response against the tumor.
By removing the TILs from the body and multiplying them by a factor of
1,000 or so, and then reinfusing them into the patient, we can expect to see a
much better response. Alternatively, T cells can be harvested from the
patient’s blood and genetically modified to recognize his or her specific
tumor. Each of these approaches has advantages and disadvantages,
[*4] but
the interesting part is that ACT effectively means designing a new,
customized anticancer drug for each individual patient.
This is obviously a costly proposition, and a very labor-intensive process,
but it has a lot of promise. The proof of principle is here, but much more
work is needed, not only to improve the efficacy of this approach but also to
enable us to deliver this treatment more widely and more easily. And while
the cost may seem prohibitive at first, I would point out that conventional
chemotherapy is also very expensive—and its remissions are almost never
permanent.
One striking feature of immune-based cancer treatment is that when it
works, it really works. It is not uncommon for a patient with metastatic
cancer to enter remission after chemotherapy. The problem is that it virtually
never lasts. The cancer almost always comes back in some form. But when
patients do respond to immunotherapy, and go into complete remission, they
often stay in remission. Between 80 and 90 percent of so-called
complete responders to immunotherapy remain disease-free fifteen years out.
This is extraordinary—far better than the short-term, five-year time horizon
at which we typically declare victory in conventional cancer treatment. One
hesitates to use the word cured, but in patients who do respond to
immunotherapy, it’s safe to assume that the cancer is pretty much gone.
The important message here is that there is hope. For the first time in my
lifetime, we are making progress in the War on Cancer, if we can even still
call it that. There are now treatments that can, and do, save the lives of
thousands of people who would have inevitably died just a decade ago.
Twenty years ago, someone with metastatic melanoma could expect to live
about six more months, on average. Now that number is twenty-four months,
with about 20 percent of such patients being completely cured. This
represents measurable progress—almost entirely thanks to immunotherapy.
Improved early detection of cancer, which we will discuss in the final section
of this chapter, will likely make our immunotherapy treatments still more
effective.
Immunotherapy traveled a rocky road, and it could have been abandoned
completely at many points along the way. In the end, it survived because its
chimerical successes turned out to be not so chimerical, but mostly thanks to
the determination and persistence of visionary scientists such as James
Allison, Tasuku Honjo, Steve Rosenberg, and others, who kept going even
when their work seemed pointless and possibly crazy.
"