CANCER
BUILDING A
BETTER CAR
More than anything else in cancer therapy in half a century,
the chimeric antigen receptor stands poised to alter the entire
treatment paradigm. But it’s not there yet.
From a treatment perspective, the
chemotherapy regimen for acute lymphoblastic
leukemia, or ALL, is impressively effective.
“It’s got a cure rate of 85 percent,” says pediatric
hematologist and immunologist Terry Fry, MD,
one of the world’s preeminent investigators
of cancer immunotherapy. “To be clear, that’s
not remission. That’s five years out. It is by
all standards probably the most effective
chemotherapy regimen out there.
In trials, it achieved an astonishing 89 percent
remission rate. That’s in just 4 months of
treatment, compared to the nearly 3 years of
traditional chemotherapy ALL patients typically
undergo — with none of the harsh, painful effects.
“Traditional chemotherapy is effective but toxic,”
says pediatric oncologist Michael Verneris, MD,
another primary investigator of the CD19 CAR.
“And in many cases, it’s not effective.”
We want to change the practice of medicine.”
MICHAEL VERNERIS, MD
Director, Bone Marrow Transplant and Cellular Therapy,
The Barton Family Endowed Chair for Bone Marrow Transplant
“There are certainly unmet needs, but really
we’re doing pretty well,” he continues. “So
it’s interesting that this field is where we’ve
developed this new therapy.”
That new therapy would be the CD19-targeted
chimeric antigen receptor, or CAR, the world’s
first commercially available cancer gene and
immunotherapy, approved by the FDA in 2017.
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As Director of Bone Marrow Transplant
and Cellular Therapy at Children’s Colorado,
Dr. Verneris sees that firsthand — not just in
the 15 percent of ALL patients chemotherapy
fails, but in patients with worse prognoses:
neuroblastomas, sarcomas, metastatic and
secondary cancers. Even for kids cured, he’s
seen the scars chemo leaves in its wake.
“We want to change the practice of medicine,”
says Dr. Verneris. not be T cells. They may not even come from
the patient.
Bigger applications Starting with induced pluripotent stem cells,
Dr. Verneris’s lab is working to grow and
engineer natural killer cells in the
same way patient cells are modified
now. Leveraging the human
leukocyte antigen matching
techniques of blood and marrow
transplant, his lab could
potentially grow CAR cell lines
that could treat a wide variety
of patients.
Still, CAR therapy is not without problems. By a
year out, the 89 percent remission rate drops in
half. The modified T cells die off. Leukemia cells
mutate to resist them. The cancer returns.
“We’re working on the guts of how the CAR
activates the T cell,” says Dr. Fry. “We’re using
the patient’s own cells as the material to make
the CAR, and sometimes you get a bad cell. With
CD19 you can overcome that in many patients.
But once we start applying it to other cancers,
the quality of the cell is going to be a real issue.”
Dr. Fry is already working to apply it to other
cancers. Acute myeloid leukemia, or AML, is
a logical next step — and his lab is developing
a CAR to target CD33, a protein myeloid cells
express. He’ll be kicking off a multisite clinical
trial starting at the National Cancer Institute
and expanding to five other sites, including
Children’s Colorado, this year.
His lab also continues to expand its arsenal
for ALL, aiming to improve durability. For that,
they’re rolling out novel CARs targeting both
CD19 and CD22, as well as a cytokine receptor
expressed on a high-risk subset of ALL known as
TSLPR. Those trials, too, will kick off this year.
Meanwhile, Dr. Verneris’s lab is on a mission to
adapt CARs for solid tumors. They don’t work
for that currently, he says, because they can’t
penetrate tumors.
“You get a cut on your finger, there’s 10 thousand
things that happen,” Dr. Verneris observes.
Cascades of signals draw cells and agents to the
area to destroy bacteria, stop the bleeding and
close up the wound.
With manipulation, CAR cells could feasibly be
programmed to co-opt those normal immune
mechanisms to migrate toward and into tumor
tissue. Those future CARs, says Dr. Verneris, may
“You could take them right off
the shelf,” he says.
Bigger access
Those next-generation CARs, Dr. Fry
says, will grow not from a single lab or even
one institution, but out of collaborations that
span the globe.
As part of the “Pediatric Cancer Dream
Team,” funded by Stand Up to Cancer and St.
Baldrick’s Foundation, Dr. Fry’s lab works
directly with the cancer genomics
and immunology players pushing
the front lines of treatment. And
as a Cancer Immunotherapy
Trials Network site, Children’s
Colorado will bring those new
developments to the clinic.
Pediatric cancer immunologist
Terry Fry, MD, works with pediatric
bone marrow transplant expert Mark
Kohler, MD, under the hood. They’re
working to develop new targets for CAR-T
cells to improve durability and expand the
scope of treatment. Dr. Fry holds the Robert
J. and Kathleen A. Clark Endowed Chair for
Pediatric Cancer Therapeutics.
NEW CONSTELLATIONS
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