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Health


RESEARCHERS LABEL EARLY CAR-T THERAPY PATIENT ‘CURED’ AFTER LIVING A DECADE
WITHOUT CANCER

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By Angus Chen Feb. 2, 2022

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A sample showing myeloid leukemia. The field of CAR-T cancer therapy has evolved
to include treatments for leukemia, lymphoma, and other cancers. Wellcome
Collection
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In 2010, Doug Olson became the second person in the world to receive CAR-T cell
therapy, an experimental tactic to engineer his own immune cells to fight
cancer. His doctors had tempered expectations for how well it would fight off
Olson’s chronic lymphocytic leukemia, an incurable blood cancer — it was a last
stab in the dark, one with no guarantees.

“It was, at the time, an idea way out there,” Carl June, an immunologist at the
University of Pennsylvania and the senior researcher on the experiment, said in
a call Tuesday with reporters. “In the informed consent document that Doug
signed, we thought [the CAR-T cells] would be gone in a month or two.”

But as the researchers tracked Olson and another patient, what they saw was
remarkable: Year after year, the CAR-T cells persisted, actively watching for
cancer cells. Olson has now been cancer-free for a decade, June and his
colleagues reported Wednesday in Nature. The results are so enduring that June
dared to use a word that oncologists are usually loath to say: cured.

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“We can say it was a cure for Doug, because these are the most mature and oldest
results available reported in scientific literature. Because they were the first
treated,” June said. “Ten years on, no leukemia cells, and we still have CAR-T
cells that are on patrol and surveillance from leukemia.” The first patient
treated with CAR-T, Bill Ludwig, also remained cancer-free until his death from
Covid-19 in January 2021.

Related:


A NEW BIOTECH STARTUP LOOKS TO SIDESTEP A KEY PROBLEM WITH CAR-T CANCER
THERAPIES

Such enduring results are a landmark scientific achievement for a field that has
seen a wave of advances since the first patients were treated a decade ago.
There are now approved CAR-T therapies for six different indications including
different types of leukemia, lymphoma, and myeloma. Many patients treated with
CAR-T therapy so far have eventually experienced a relapse of cancer, making the
enduring response from these first two patients extraordinary.

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“It’s a big milestone. It makes you think about everything that’s happened in
the last 10 years,” said Marcela Maus, an immunologist at Mass General Hospital
Cancer Center who was not involved with the work. “These first two patients were
both pretty remarkable in terms of long-term remission, and the subjects of a
publication that really catalyzed the whole field. It led to the flurry of
activity in the biotech space and clinical development of CAR-T as a therapy.”

The new research also provides a close look at how CAR-T cells behave in the
body over time, with detailed data from routine blood draws on Olson.

“The new paper really describes in great detail what happened to the first two
patients,” Maus said. “As an immunologist, it’s really interesting to see the
evolution of a very specific T cell response, when you know exactly the day they
went in and had an exposure, then carefully followed over 10 years.”

Related:


SCIENTISTS ARE MAKING CAR-T CELLS MORE CLEVER. HERE’S WHAT THE NEXT GENERATION
COULD LOOK LIKE

The therapy works by isolating immune cells known as T cells from the patient’s
body. Then, researchers use a virus to genetically engineer a synthetic receptor
— known as a CAR, or chimeric antigen receptor — onto the T cell’s surface. This
CAR can bind to a specific target, in this case a protein found on immune B
cells called CD19, and it can activate the T cell to kill any cell bearing this
target. Because chronic lymphocytic leukemia, the cancer that Olson and Ludwig
had, are malignancies of the B cell, the engineered cells could recognize
cancerous B cells and destroy them.

Olson didn’t notice any changes in the weeks after he received his first
infusion in December 2010. Then he started to feel seriously ill — as if he’d
been floored by a terrible flu – and he was hospitalized. At this time, the data
suggest that the CAR-T cells he’d just received were proliferating rapidly as a
type of T cell known as a killer T-cell. These are known as CD8 cells, and they
were assassinating every cancer cell they could find.

“You kill large numbers of cancer cells, and they spill their contents into the
blood. That can make people quite sick and cause damage to kidneys which Doug
did have,” explained David Porter, Olson’s oncologist at the University of
Pennsylvania.

Olson also experienced some symptoms often attributed to cytokine release
syndrome, which happens when CAR-T cells flood the body with cytokines, immune
compounds that white blood cells use to kill. It can cause flu-like symptoms in
some patients, but in some cases, these cytokine storms can lead to fluid
leaking into the lungs, extreme fevers, neurological damage, and even death.

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At the end of Olson’s three-day stay in the hospital, Porter told him that about
18% of his white blood cells were CAR-T cells. The next week, Olson went back
for a check-up. Both he and Porter were delighted and shocked by the result.

“Doug, we cannot find a single cancer cell in your body. Your bone marrow is
completely free of [the cancer],” Porter told him. It took roughly another six
months after treatment for certain markers of residual disease to go away.

Over the next several months, the data suggested that the patients’ CAR-T cells
were transforming from the killer CD8 T cells and into CD4 T cells, or “helper”
T cells. These tend to remain in the body and help form a long-term immune
memory, but typically are less involved in actively killing diseased cells.

In the years that followed, the CAR-T cell population did what our own natural T
cells normally do: shift back and forth between types. By the nine-year mark,
the researchers could only find CD4 cells, suggesting that the cells had
stabilized into a long-term population of helper T cells.

When the scientists isolated those CD4 cells nine years after treatment, they
bore markers that usually suggest immune cells are too exhausted to keep doing
their work. Despite that, these CD4 CAR-T cells could still recognize and
unexpectedly destroy cancer cells in the lab, which led June and his colleagues
to suspect that the cells were preventing the return of cancer in the patients
by killing off any B cells the body makes.

Immunologists are now speculating about what these observations might mean about
the evolution of CAR-T cells in the body and why they work so spectacularly for
some patients. Maybe there’s something special about a CAR in a CD4 cell that
makes the T cells still functional after so many years. Maybe having a flexible
population of CAR-T cells that can shift between different types —  including
CD4, CD8, and gamma-delta T cells — is important, MGH’s Maus mused. “Multiple
cells can have effects, and maybe more than one is better,” she said.

It’s exactly the kind of brainstorming the authors wanted to spark — questions
whose answers could ultimately help scientists “generate the next iteration of
therapies,” said Joseph Melenhorst, an immunologist at the University of
Pennsylvania and the lead author of the paper.

For Olson, the results point to a reason for optimism, at least for some
patients, when options are scarce.  “That day back in 2010 when I was infused
with my CAR-Ts, and my tumor cells disappeared – it meant there was a whole new
treatment paradigm,” he said. “ [For cancer patients], it’d make a big
difference in their hope. And if there’s no cure for [them] today, there’s a
possibility that around the corner, there will be.”

Correction: A previous version of this story misspelled Doug Olson’s name.

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ABOUT THE AUTHOR REPRINTS


ANGUS CHEN

Cancer Reporter

Angus Chen is a cancer reporter at STAT.


angus.chen@statnews.com

@angrchen


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