CLINICAL NEWS
Investigational Drug TEW-7197 Improves
Myeloma Outcomes Both as Single Agent
and in Combination With Ixazomib
TGF-β, a multifunctional cytokine, is produced in
multiple myeloma (MM) cells and cells in the bone
marrow (BM) tumor microenvironment (TME),
where it also stimulates MM progression through
the promotion of catabolic bone remodeling, IL-6
secretion, and Th17 T cell development.
In a preclinical mouse model presented at the
2017 AACR Annual Meeting, researchers evaluated
the anti-MM therapeutic potential of TEW-7197,
a small molecule TGF-β type I receptor kinase
inhibitor, as a single agent or in combination with
ixazomib. “Our data demonstrate that TEW-7197
effectively modulates the MM TME and is as-
sociated with a potent anti-myeloma effect in an
immunocompetent murine model of MM,” lead
author Byung-gyu Kim, DVM, of Case Western
Reserve University in Cleveland, Ohio, said during
his presentation of the results.
The preclinical immunocompetent 5T33MM
model was used to characterize the role of TGF-β
signaling in the BM TME. Mice with 5T33MM
cells expressing luciferase were treated with TEW-
7197, ixazomib, or combination TEW-7197 plus
ixazomib daily for 3 weeks.
On quantitative polymerase chain reaction
analysis, TEW-7197 attenuated the growth and vi-
ability of human and murine MM cells by inducing
apoptosis, and it inhibited TGF-β-induced activa-
tion of Smad2/3 in MM cells in vitro.
As a single agent, Dr. Kim and colleagues found
that TEW-7197 inhibited MM progression (per
peripheral blood monoclonal protein concentra-
tion and bioluminescence imaging before and after
treatment) and induced a decrease in mortality and
an increase in body weight.
TEW-7197 alone or in combination with ixazo-
mib also attenuated TGF-β activation of Smad2/3,
reduced the expansion of CD11b+Gr-1+ myeloid
derived suppressor cells in BM TME, and dimin-
ished the population of Foxp3+ regulatory T cells
in the spleen.
Combination therapy prolonged survival in
mice and had a synergistic anti-tumor effect by
significant reduction in both M-spike and BLI,
compared with either TEW-7197 or ixazomib
alone. “These data provide a rationale for clinical
evaluation of the combination therapy of ixazomib
and TEW-7197 as a potential therapeutic strategy
to improve outcomes in patients with MM,” the
authors concluded.
TEW-7197 is also being evaluated in phase I
clinical trials in patients with solid tumors and is
associated with an acceptable toxicity profile.
in a dose-dependent fashion.
Biophysical and functional experiments
indicated that BION-1301 recapitulated all charac-
teristics of the murine model. In vivo, BION-1301
suppressed T cell-independent B-cell responses to
the antigen NP-Ficoll. In addition, a humanized
SCID model confirmed APRIL blockade, supporting
the activity of BION-1301 in vivo. “[This] potentially
indicates that BION-1301 is active in targeting MM
cells in a tumor-protective bone marrow microenvi-
ronment,” Dr. Dulos and co-authors noted.
“These data suggest a rationale to develop BION-
1301 as a single agent and in combination with
lenalidomide, bortezomib, or possibly checkpoint
inhibitors, such as anti-PD-1,” Dr. Dulos and co-
authors concluded.
The study was sponsored by the agent’s manu-
facturer. The authors noted that BION-1301 is
expected to begin phase I trials this year. Patients with relapsed/refractory indolent B-cell lympho