CLINICAL NEWS
CD22: A New Target for CAR T-Cell Therapy
in Patients With B-ALL?
The revolutionary chimeric antigen receptor
(CAR) T-cell therapies that gained approval from
the U.S. Food and Drug Administration in 2017
both target CD19; the success in targeting that
antigen has prompted investigators to look for
new targets.
Results from a small, phase I, dose-
escalation trial published in Nature
Medicine suggest that targeting CD22 led
to clinical activity against B-cell acute
lymphocytic leukemia (B-ALL), including
leukemia that was resistant to anti-CD19
immunotherapy. Though the relapse rate
with this therapy was high, “this study gives
hope to the idea that there may be another
similar, very potent treatment,” commented
Crystal Mackall, MD, director of the Park-
er Institute for Cancer Immunotherapy
at Stanford University and corresponding
author of the study. “This is the first time
that we’ve seen response rates anything like
we achieved when we were first testing the
CD19 CAR T-cell therapy.”
Terry J. Fry, MD, of the Pediatric
Oncology Branch at the Center for Cancer
Research at the National Institutes of
Health’s National Cancer Institute, and co-
authors evaluated the safety and potential
efficacy of anti-CD22 CAR T-cell therapy
in 21 pediatric and adult patients (median
age = 19 years; range = 7-30 years) with
relapsed or refractory B-ALL. All patients
had undergone at least one prior hema-
topoietic cell transplantation (HCT), and
two had received two prior HCTs. Most pa-
tients (n=17) had previously been treated
with CD19-directed immunotherapy,
including 15 patients who had received
CD19-targeted CAR T-cell therapy.
Patients received one of three anti-CD22
CAR T-cell doses: 3×10 5 cells/kg (n=6),
1×10 6 cells/kg (n=7), and 3×10 6 cells/kg (n=8).
Sixteen patients experienced cyto-
kine release syndrome (CRS; grade 1 in
9 patients and grade 2 in 7 patients), a
common adverse event (AE) associated
with CAR T-cell therapy. CRS coincided
with CAR T-cell expansion and occurred
after day five of treatment, the researchers
noted. A dose-limiting toxicity (DLT; grade
3, self-limited, non-infectious diarrhea
during CRS) occurred in one patient at the
first dose level (3×10 5 ), which required a
protocol-specific expansion of the first dose
level to six patients. No other DLTs were
observed in patients at the first or second
dose level (1×10 6 ).
Two patients receiving dose level three
(3×10 6 ) developed dose-limiting grade 4
hypoxia that was associated with rapid dis-
ease progression. Therefore, the researchers
selected 1×10 6 anti-CD22 CAR T cells/kg
as the recommended phase II dose; this
dosing cohort was expanded to include 13
total patients.
In the first 16 patients with available, complete
assessments, transient visual hallucinations (n=2),
mild unresponsiveness (n=1), mild disorientation
(n=1), and mild to moderate pain (n=2) were
observed but returned to baseline levels by day 28
post-infusion. All patients who achieved remis-
sion reported B-cell aplasia, including those who
were not previously B-cell aplastic.
Twelve of 21 patients (57%) achieved com-
plete remission (CR), mostly patients at the
MCL-1, a BCL-2 family member, is an
in MCL-1–dependent AML 1-3
MCL-1 dependence may drive progression
of AML 1,2
Acute myeloid leukemia (AML) is associated with high
mortality and is challenging to treat, with an overall 5-year
survival rate of 27%. 4,5 Standard therapies often fail to
achieve the goal of inducing complete remission in
25%–50% of patients, and relapse is common even in patients
who have an initial response to treatment. 1,5
Disease progression and treatment resistance in a subset *
of AML have been associated with a key anti-apoptotic
protein, myeloid cell leukemia 1 (MCL-1). 1,2 This is referred to
as MCL-1 dependence. 6 Understanding the role of MCL-1 can
inform therapeutic targeting strategies in AML. 7
Downregulation of MCL-1 to enable apoptosis
of leukemic blasts may be a rational
therapeutic strategy in MCL-1–dependent AML 7
The activity of cyclin-dependent kinase 9 (CDK9)
is essential for the transcription of MCL-1 mRNA in
leukemic blasts. 9,10
CDK9
Recruitment
of CDK9
CDK9
RNA
polymerase II
MCL-1 may have multiple roles in sustaining
AML blasts 1,3
MCL-1 is a member of the apoptosis-regulating BCL-2 family
of proteins. 8 In normal function, MCL-1 is essential for early
embryonic development and for the survival of multiple
cell lineages, including lymphocytes and hematopoietic
stem cells. 3
However, in MCL-1–dependent AML, MCL-1 has been
shown to sustain the survival of AML cells, which may lead
to relapse. 1 MCL-1 dependence is also associated with
resistance to agents that otherwise have activity against
leukemic blasts. 8
MCL-1
expression
Because of the short half-life of MCL-1 (2-4 hours),
the effects of targeting upstream pathways
are expected to reduce MCL-1 levels rapidly. 11
CDK9 inhibition has been shown to block MCL-1
transcription, resulting in the rapid downregulati