FUTURE OF MEDICINE

Artificially boosting the body's immune response against cancer is the most
exciting advance in the treatment of tumors in the past couple of years. But
as the jam-packed sessions at a recent scientific conference in New York
City made clear, a lot of questions remain to be answered before anyone can
declare victory in the war on cancer. Among them: What is the best way
to kick the immune system into action? Will immunotherapy work for all
sorts of people with all kinds of cancer or just for a lucky few? Is there a way
to make the treatments less dangerous or expensive?
It was standing room only for many of the presentations at the
first International Cancer Immunotherapy Conference, which took place
from September 16 to 19.* Speaker after speaker started their talks by
disclosing financial ties to a variety of companies ranging from
pharmaceutical giants to their own start-ups. The audience consisted
primarily of scientists and physicians. But sprinkled among the 1,400
attendees, in addition to the usual smattering of journalists, were a number
of industry scouts and finance people seeking to glean the next big
investment opportunity or joint project possibility.
Jill O'Donnell-Tormey, chief executive officer of the Cancer Research
Institute, proclaimed 2015 "a truly special year for cancer immunotherapy."
The U.S. Food and Drug Administration approved two new immunotherapy
drugs, she noted, "more than half of the current cancer clinical trials include
some form of immunotherapy," several groups are working on possible
combination therapies and oncologists around the world are recognizing "a
paradigm shift in cancer." But as exciting as these advances are, she
continued, "we know that we are only at the beginning" in terms of being
able to understand or broadly use them.
Reality check
The first thing you need to know about the researchers studying
immunotherapy for cancer is that every one of them seemingly has a few
patients who have responded extraordinarily well. Steven Rosenberg of the
National Cancer Institute no doubt takes the prize in this category. In 1984,
he treated a woman named Linda Taylor who had metastatic melanoma (an
aggressive type of skin cancer with a survival rate of less than 10 percent
after ten years). Taylor was the 81st patient to undergo the debilitating
therapy and the first to respond successfully. Within a few months her
tumors melted away and she remains alive and healthy today. Rosenberg
the keynote speaker at the conferencereports that his latest regimen is not
as hard on patients and results in 20 percent of them experiencing "a
complete and durable remission." That's about par for a lot of the immune
therapies now being studied.
The second thing you need to know is that there is a reason why the body
works so hard to suppress its immune reactions most of the time. The
immune system has such powerful weapons in its arsenal that it can kill you
faster than whatever ails you. And some of the things that doctors do to
prepare the body for immune treatment are just as toxic as chemotherapy
and radiation. (Indeed, for complex reasons, some immunotherapies
require a dose of chemotherapy or radiation as a first step.) As Rosenberg
says, "We have had some treatment-related deaths. That's been true in the
field as well as in our own experience."
With those sobering caveats in mind, however, there is no mistaking the
growing optimism among many cancer researchers. They are starting to
figure out when it's more important to take the brakes off the body's
immune responses, when to step on the accelerator to get a sluggish
reaction into high gearand when they can safely do both. As investigators
study different combinations of treatments and dosages, they can see
improvements in response rates and believe they are getting a better handle
on some of the most severe side effects.
Hot and cold tumors
Investigators have developed several different methods for tweaking a
patient's immune system so that it recognizes and attacks dangerous tumors
more effectively than it otherwise would. Some of these therapies feature
so-called monoclonal antibodies that interfere with cancer cells' ability to
fool the immune system into ignoring them. Known as checkpoint blockade,
these treatments so far appear to work best in melanoma and smoking-
induced lung cancer.
There are good biological reasons for that observation. Melanoma and
smoker's lung cancer both occur as a result of environmental exposurethe
former from the suns ultraviolet rays, the latter from carcinogens in
tobacco smoke. As a result, lots of mutations occur in the DNA of affected
cells. These mutations in turn lead to the production of many aberrant
proteins, which are usually recognized by the immune system as potentially
dangerous, and any cells that contain them are quickly marked for
destruction.
Researchers refer to these malignancies as "hot" tumors because they sport
a lot of deviant proteins that the immune system is likely to notice. They
need a long time to figure out how to shield themselves from the immune
systemwhich is part of the reason it typically takes decades for melanomas
and lung cancers to grow big enough to threaten someone's life.
In these cases the immune system has already dispatched lots of immune
cells to the tumor; it's just that the cancer manages to turn the defenders off
whenever they arrive. Checkpoint blockade reawakens the immune cells
that have already found their way inside the tumor to start killing the
malignant cells in the immediate vicinity and anywhere else they may be
found in the body.
Intriguingly, combining checkpoint blockade drugs results in fewer extreme
side effects for patients with melanoma than for those with lung cancer.
"This is something that is very recently being recognizedmaybe in the past
two years," says Jedd Wolchok, an oncologist at Memorial Sloan Kettering
Cancer Center in New York City. "The same doses of the same medicine may
not be tolerated equally in patients who have different cancers. We may
have to use less medicine in patients with lung cancer. [Immunotherapy] is
not one size fits all."
In any event, many kinds of cancer (such as prostate, ovarian and
pancreatic) are caused by just a handful of genetic mutations. They do not
create the wide range of malfunctioning proteins that would usually attract
the immune system's attention. As a result, these tumors are not typically
filled with lots of slumbering immune cells waiting to be reawakened;
checkpoint blockade, therefore, usually doesn't work on them. They are, in
the parlance of cancer immunologists, "cold" tumors.
And yet, several investigators reported on efforts to turn such cold tumors
hot so they could then be targeted with immunotherapy. Padmanee Sharma,
an immunologist at The University of Texas M. D. Anderson Cancer Center,
for example, described a study in which men with apparently aggressive
prostate cancer were given hormone treatment prior to surgery in order to
first kill a few of their cancer cells before their tumor is removed. Once these
cells die, the various proteins and other compounds that are usually found
inside them spill into the body. Somehow, this makes it easier for the
immune system to pay attention and it starts sending immune cells to tackle
whatever microscopic bits of tumor might be left elsewhere in the body after
the operation. Unfortunately, as Sharma told the audience, their subsequent
response to immune-boosting drugs was short-lived. She and her colleagues
are pursuing several different ideas, however, to make it last longer.
Finding the right balance
Indeed, the idea that you don't have to kill all the cancer cells in a tumor to
get the immune system going sparked a lot of interest at the conference. Ira
Mellman, Genentechs vice president of cancer immunology, wondered
aloud whether "chemotherapy may in fact be, to some extent,
immunotherapy." By killing a few cells, it may prime the immune system to
respond better to later treatments. In some cases the release of cancer
proteins jump-starts the immune response. In others a chemotherapy drug
such as gemcitabine actually releases the brakes by temporarily eliminating
the cells whose normal job is to tamp down the immune system.
Stanford University oncologist Ron Levy has taken this concept one step
further by using low-dose radiation treatment to kill a few malignant cells
in 15 patients with non-Hodgkin's lymphoma who had several visible
tumors. Then he injected an experimental immunostimulatory compound
directly into a single lesion in each of these patients. By doing so, he found
he could lower the amount of drug he needed to trigger a reaction. Acting on
a single tumorwhich doesn't require as much medicine as trying to reach
all the tumors in the bodywas sufficient to trigger a general immune
response.
Most of the patients in Levy's study exhibited some kind of response; even
tumors that had not been treated started to shrink in a few people.
Generally speaking, it took six months to two years to see the changes. One
38-year-old man experienced a complete response, meaning all observable
signs of the cancer disappeared throughout the bodyan outcome that
lasted more than a year. (A "complete response" is not necessarily the same
thing as a cure because undetectable amounts of cancer might still be
lurking somewhere in the body.) "We're trying to make this response more
common and more durable," Levy said. His next step is to try to combine
this method for stimulating the immune system with monoclonal antibodies
that prevent tumors from shutting the immune system down (given at
1/20th of the usual dose). "We hope to eliminate toxicity by going local and
lowering the effective dose," he told meeting participants. Although Levy
has started treating at least one person with this newer combo approach, he
was not yet ready to share results.
Investigators presented several other promising immunotherapies at the
conference but no roundup would be complete without mentioning the so-
called CAR T cells, many of which have received orphan drug or
"breakthrough status" by the FDA in the past 18 months.
CAR T cells are immune cells that have been genetically engineered to target
tumors in a much more powerful way than normal immune cells can. To
date, clinical trials conducted at Memorial Sloan Kettering, the Fred
Hutchinson Cancer Research Center and the University of Pennsylvania
Perelman School of Medicine have demonstrated remission rates of about
90 percent in several advanced cancers of the blood and lymph systems
(again, not necessarily the same as a cure but still astounding).