Another high-grade malignancy that shares some features with
AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN), is
both rare and unusually aggressive. It mostly affects men (75-90%
of patients) and often presents initially as skin lesions. BPDCN is
likely under-recognized and can be misdiagnosed as cutaneous
lymphoma. It accounts for less than 1 percent of all hematologic
malignancies.
“There is an urgent unmet need for relapsed/refractory AML
and BPDCN,” explained Elizabeth Budde, MD, PhD, from the
City of Hope National Medical Center in Duarte, California. “For
patients with AML who have a recurrence after allogeneic he-
matopoietic cell transplantation (alloHCT), the prognosis is very
poor. For those with BPDCN, there are no approved therapies and
really no accepted standard of care.” Median overall survival (OS)
for these patients is only 12 to 14 months without HCT, she noted.
Dr. Budde’s group is testing CAR T-cell therapy candidates in both
AML and BPDCN. Hope for CAR T-cell therapy,” said Dr. Budde.
“We have yet to see any severe graft-versus-host disease,
neurologic toxicity, or dose-limiting toxicity [associated with the
CD123-targeting approach], but we started with a very conserva-
tive dose so as we escalate, we have to be careful,” she said.
Researchers at City of Hope have also observed CRS in their
trial patients – four with grade 1 CRS, and one with grade 2 CRS.
But Dr. Budde feels confident that her dedicated CAR T-cell team
can identify and manage CRS successfully.
Among the dozens of ongoing CAR T-cell trials worldwide,
only a handful are for AML, MDS, or other myeloid malignancies.
CD33 is considered the most promising myeloid-associated target,
but there are CAR T-cell products in development targeting other
antigens or antigen combinations that have shown promising
preclinical results, including CD123. The possibility of combin-
ing CAR T cells with immune checkpoint inhibitors to enhance
anti-leukemic effects also is under investigation. 3
CAR Ts Go Target Hunting Assembly Line CARs
CAR T-cell therapies use harvested T cells expanded and
re-engineered to express a recombinant receptor that targets a
tumor-specific protein. The retrained T-cells are infused back
into the patient’s body to proliferate and eradicate cancer cells.
In August 2017, tisagenlecleucel became the first CAR T-cell
therapy approved by the U.S. Food and Drug Administration
(FDA) and is indicated for the treatment of children and young
adults with B-cell precursor ALL that is refractory or in second
or later relapse. The second CAR T-cell product to market was
axicabtagene ciloleucel. In October 2017, axicabtagene ciloleucel
was approved for the treatment of adult patients with relapsed or
refractory large B-cell lymphoma. Both revolutionary therapies
target CD19-expressing cells.
“We are still in the early days of CAR T-cell therapies for
myeloid leukemia, in part because we just don’t have a target
that is as pristine as CD19,” Dr. Budde said. “Any of the antigens
we target might also be found on normal stem cells, making
myeloablation or prolonged neutropenia a major concern. We
also need the correct antigen to make the CAR T cells persist in
the hostile microenvironment inside the bone marrow.”
Dr. Budde’s group is testing an experimental CAR T-cell prod-
uct targeting CD123, which is often overexpressed on AML blasts
and LSC–enriched cell subpopulations compared with expression
in normal HSCs and myeloid progenitors. 2 The trial has a built-in
rescue strategy requiring all patients to have an identified donor
or stem cell source for alloHCT. The CAR T-cell treatment is
expected to serve as a bridge to potentially curative alloHCT.
“So far, we have treated six patients who had refractory AML
following alloHCT,” Dr. Budde reported. “They have all tolerated
the treatment well, and we have not seen any treatment-related
myeloablation.” The researchers also noted that this CAR T-cell
therapy produced “promising anti-leukemic activity.”
In the BPDCN cohort, they’ve treated two patients. The first
is in complete remission more than 60 days post-infusion. “There
are only about 60 patients diagnosed each year with BPDCN, so
we are hoping to have more of those patients referred to City of
Just as the Ford Model T is generally regarded as the first efficiently
produced, affordable, and reliable automobile that opened travel
to the masses, an off-the-shelf, allogeneic CAR T-cell product
could open immunotherapy to much larger populations.
“The biggest roadblock today is related to the production of the
‘one-off ’ CAR T-cell products,” Dr. Daver explained. “If we can get
an off-the-shelf product that works and has a similar safety profile
to the custom-designed cells, we could stockpile 15 or 20 doses – or
even more in large institutions. When a suitable patient comes in,
we could just admit him or her and administer the therapy, like we
do with antibody drug conjugates or immune checkpoints.”
It remains to be seen whether the “universal” products being
tested now are as safe and effective as autologous CAR products,
he noted. Cellectis, a French biotechnology company, is devel-
oping allogeneic CAR T-cell products, including UCART123
for AML and BPDCN and UCART19 for ALL, and was th e first
sponsor to open a clinical trial of allogeneic T-cells in late 2017.
However, while the UCART19 ALL product is showing clinical
activity, the UCART123 product ran into some early trouble.
In September 2017, the FDA placed a clinical hold on phase
I studies of UCART123 in patients with BPDCN and AML
following a patient death related to CRS and lung infection. In
November, protocol adjustments allowed the trials to be restarted
with a lower dose. Since then, additional patients have been
safely dosed and updates are awaited. 3
How to Harness T Cells
Beyond CAR products, there are a few other immunotherapies that
direct the body’s endogenous T cells against tumors. According to
Dr. Daver, two promising approaches being heavily pursued are
bispecific antibodies and immune checkpoint inhibitors.
Bispecific antibodies are monoclonal antibodies engineered to
have dual receptors: one binds to a T-cell’s CD3 receptor and the
other targets the malignant cells. A number of AML-associated
antigens are under investigation, Dr. Daver noted, including CD33,
CD123, and CLL1.
May 2018
19