CAR T-Cell Therapies
blastic plasmacytoid dendritic cell neoplasm and
acute myeloid leukemia following a patient death
after the development of cytokine release syndrome
(CRS) and lung infection. 11 A potential explanation
for the severity of CRS in that patient is that T cells
from healthy donors may be more potent than those
from sick patients. The company is working with the
investigators and the FDA to resume the trials with
an amended protocol.
When the Cure Creates a Disease
Sending a patient’s own T cells to boot camp may
seem relatively innocuous, but safety issues have
plagued the development of this revolutionary
approach. Several other trials have been delayed
or halted due to patient deaths, and numerous
investigational CAR T-cell products have been
abandoned because of toxicities.
The adverse events (AEs) commonly associated
with CAR T-cell therapy – tumor lysis syndrome,
neurotoxicity, and CRS – are not well understood. 12
CRS, an inflammatory response indicative
of high immune activity, is the most frequently
observed toxicity. Most patients who develop CRS
experience mild or moderate flu-like symptoms
that subside over time, but some experience severe
CRS that can lead to life-threatening multi-organ
dysfunction. Symptoms of CRS can appear weeks
after infusion and require intensive care unit (ICU)–
level care through the acute phase.
“We know ... that you
can use engineered
cells to do specific
things in vivo for
therapy. ... Now we
just need to know
more about for how
long and in which
patients.”
—ADRIAN P. GEE, PhD
Neurotoxicity, also known by the technical term
“CAR-T-cell-related encephalopathy syndrome,”
is the second most common AE, and it can occur
concurrent with or after CRS.
Tisagenlecleucel was approved with a boxed
warning for CRS and neurologic events and, because
of the observed risks, a Risk Evaluation and Mitiga-
tion Strategy.
Since the early days of CAR T-cell development,
when the first cases of CRS threw physicians for
a loop, investigators have developed algorithms
and protocols to identify patients at greatest risk of
AEs and to manage their occurrence. Research has
shown, for instance, that if a patient has the cytokine
marker interleukin (IL)-6, he or she is more likely to
progress to severe CRS; in clinical trials of tisagenle-
cleucel, administration of the IL-6 receptor-blocking
antibody tocilizumab led to complete resolution of
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ASH Clinical News
CRS in 69 percent of patients. On the same day as
tisagenlecleucel’s approval, the FDA expanded the
indication for tocilizumab to include treatment of
CAR T cell–induced, severe or life-threatening CRS
in patients ≥2 years of age. 1
Cerebral edema also remains poorly understood
and difficult to manage. Recently, investigators from
multiple institutions and medical disciplines formed
the CAR-T-cell-therapy-associated TOXicity (CAR-
TOX) Working Group to develop a monitoring,
grading, and management system for acute toxicities
associated with these new therapies. 12
Although the side effects are not trivial, experi-
enced transplant centers are familiar with managing
most of them, Dr. Majhail noted. His hope is that
future generations of CAR T-cell products will offer
better safety profiles, with clinical trials clarifying
the optimal timing of CAR T-cell administration
and the therapies to manage toxicities.
“We know the concept – that you can use engi-
neered cells to do specific things in vivo for therapy – is
correct,” Dr. Gee affirmed. “Now we just need to know
more about for how long and in which patients.”
The Health Economics of
CAR T-Cell Therapy
The unprecedented response rates with tisagenle-
cleucel come at unprecedentedly high costs: Novar-
tis priced tisagenlecleucel at $475,000 for a single
infusion. Despite the sticker shock experienced by
most, some analysts consider it a reasonable list
price for this new line of therapies.
“The price does make your eyes water at first
glance, but this product is potentially transforma-
tive in the management of this patient population. I
think it’s in the right ballpark,” said Stephen Palmer,
PhD, professor and deputy director of the Team
for Economic Evaluation and Health Technology
Assessment at the Centre for Health Economics
at the University of York in the United Kingdom.
“However, inevitably, there is significant uncertainty
regarding whether the modeled long-term value will
be realized in clinical practice.”
CAR T-cell products are truly personalized,
likely costing more to manufacture per individual
patient than any other therapy, Dr. Palmer offered in
defense of the price tag. Also, they address an unmet
need and offer treatment that is potentially curative.
In support of their pricing, Novartis cited a
health technology assessment (HTA) published in
February 2017 by the U.K.’s National Institute for
Health and Care Excellence (NICE), of w