                        
   
Immunomodulatory drugs (IMiDs) are potent thalidomide
derivatives, which markedly stimulate T-cell proliferation, as well as IL-2 and
IFN-a production, but do not inhibit
phosphodiesterase 4 (PDE-4)[1].
CC-5013 (Revimid™) is 50 to 2000 times more potent than thalidomide in
stimulating T-cell proliferation triggered via the T-cell receptor (TCR), and 50
to 100 times more potent than thalidomide in augmenting IL-2 and IFN-a
production. In addition, CC-5013 triggers dose-dependent decreased secretion of
TNF-a, IL-1b,
and IL-6; and triggers increased secretion of IL-10. The IC50 of CC-5013 for
inhibiting LPS induced TNF-a secretion
by PBMC is ~100 nM (25.9 ng/mL), whereas thalidomide has an IC50 of ~194 µM
(50.2 µg/mL)[2].
Based upon these more potent effects of IMiDs than thalidomide on normal cells,
their relative anti-MM activities have also been compared. In vitro
studies show an IC 50 of 0.4 µM (103.6 ng/ml) for CC-5013 against MM cell lines
and patient cells[3]
which are resistant to conventional therapy; in contrast, even at concentrations
up to 100 µM (25.8 µg/mL), thalidomide decreases MM cell proliferation by only
15 or 20%[4].
These studies further demonstrate that CC-5013 decreases binding of MM cells to
bone marrow stromal cells (BMSCs); inhibits the production in the BM milieu of
cytokines (IL-6, VEGF, TNF-a) mediating
growth and survival of MM cells; blocks angiogenesis; and stimulates host
anti-MM NK cell immunity[5],
[6].
In addition, CC-5013 inhibits tumor growth, decreases angiogenesis, and
prolongs host survival in a human plasmacytoma mouse model[7].
These preclinical studies suggest that CC-5013 may overcome drug resistance,
even to thalidomide, in MM cells. The remarkable in vitro and in vivo activity
of CC-5013 against resistant MM cells in pre-clinical studies provided the
framework for a Phase I dose-escalation trial of CC- 5013 in patients with
relapsed/refractory MM. Importantly, CC-5013 achieved either response or
stabilization of disease in 19 of 24 (79%) evaluable patients (90%CI: 61%, 91%)
and demonstrated a favorable toxicity profile. The dose-limiting toxicity was
neutropenia after the first 28 days at the 50 mg a day dose. Dose reduction and
the addition of growth factors allowed for continuation of therapy in all
patients. In addition, myeloma responses were observed in all dose groups,
including the 5 mg daily dose group.
References:
[1]
Corral LG, Haslett PAJ, Muller GW, et al. Differential cytokine
modulation and T cell activation by two distinct classes of thalidomide
analogues that are potent inhibitors of TNF-_.
J Immunol. 1999; 163:380-386
[2]
Muller G, Chen R, Huang SY, et al. Amino-substituted thalidomide
analogs: potent inhibitors of TNF-a production. Bioorg. Med. Chem. Lett.
1999; 9:1625-1630.
[3]
Teoh G, Urashima M, Greenfield EA, et al. The 86 kD subunit of Ku
autoantigen mediates homotypic and heterotypic adhesion of multiple
myeloma cells. J Clin Invest. 1997;101:1379-1388
[4]
Hideshima T, Chauhan D, Shima Y, et al.
Thalidomide and its analogs overcome drug resistance of human multiple
myeloma cells to conventional therapy. Blood 2000; 96:2943-2950.
[5]
Gupta D, Treon SP, Shima Y, et al. Adherence of multiple myeloma
cells to bone marrow stromal cells upregulates vascular endothelial
growth factor secretion: therapeutic applications. Leukemia.
2001;15:1950-1961
[6]
Davies FE, Raje N, Hideshima T, et al. Thalidomide and
immunomodulatory derivatives augment natural killer cell cytotoxicity in
multiple myeloma. Blood. 2001; 98:210-216.
[7]
Lentzsch S, LeBlanc R, Podar K, et al.
Thalidomide and its immunomodulatory analogs inhibit human multiple
myeloma cell growth and angiogenesis in vivo. 2001;submitted
|
Questions,
Suggestions or to Enquire about a trial
Maps & Directions