The aim of this study was to examine the hypothesis that a combination of
proteasome inhibition by
bortezomib and immune
therapy with
interleukin-12 (IL-12) can produce enhanced antitumor efficacy relative to the effects of either of these agents alone. A mouse xenograft model of myeloma was developed. The mice were randomly divided into saline control (NS),
IL-12 (0.4 µg/animal; intraperitoneal),
bortezomib (0.75 mg/kg; intravenous), and bortezomib+IL-12 groups. Effects of treatments on
tumor growth were assessed by before and
after treatment comparisons and group comparisons. The effects of various treatments on the number of peripheral blood lymphocytes and natural killer (NK) cells were assessed by complete blood count and flow cytometry analysis. The cell-killing function of NK cells in splenocytes was evaluated using the
lactate dehydrogenase release assay.
IL-12 treatment alone produced a mild decrease in
tumor volume compared with control (P>0.05).
Bortezomib alone resulted in substantial inhibition of
tumor growth at varying time points, reaching ~65 and ~60% reduction in
tumor volume after 15 and 21 days of
therapy, respectively. At the same time points, the combination
therapy produced ~75 and ~84% decreases in
tumor growth, respectively, which were significantly greater than the reduction produced by
bortezomib monotherapy.
Tumors resumed growth upon termination of
bortezomib treatment at 2 weeks, although the
tumor volume was still significantly smaller than that in the time-matched NS and
IL-12 animals. This rebound of
tumor growth was completely prevented with the combination
therapy, and
tumor volume continued to decrease throughout the time course. The percentage and total number of NK cells were significantly decreased after
bortezomib monotherapy and combination
therapy; however, they remained unaltered after
IL-12 treatment compared with no treatment. Further, combination
therapy significantly restored the
bortezomib-induced functional impairment of the cell-killing capability of NK cells, relative to
bortezomib alone. We conclude that the bortezomib-IL-12 combination
therapy offers superior antitumor efficacy over monotherapy with either
bortezomib or
IL-12 in a mouse model of myeloma. Restoration of
bortezomib-induced functional impairment of NK cells by
IL-12 may be a mechanism for the synergetic effects of the two agents. Therefore, a combination of the two agents may represent a more rational therapeutic approach for myeloma.