Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor B (TGFB). We investigated the efficacy of a novel small-molecule TGFB type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGFB signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC 50 , f200 nmol/L). SM16 penetrated tumor cells in vivo, suppressing tumor phosphorylated Smad2/3 levels for at least 3 h following treatment of tumor-bearing mice with a single i.p. bolus of 20 mg/kg SM16. The growth of established AB12 tumors was significantly inhibited by 5 mg/kg/d SM16 (P < 0.001) delivered via s.c. miniosmotic pumps over 28 days. The efficacy of SM16 was a result of a CD8 + antitumor response because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice and (b) CD8 + T cells isolated from spleens of mice treated with SM16 showed strong antitumor cytolytic effects whereas CD8 + T cells isolated from spleens of tumor-bearing mice treated with control vehicle showed minimal activity. Treatment of mice bearing large tumors with 5 mg/kg/d SM16 after debulking surgery reduced the extent of tumor recurrence from 80% to <20% (P < 0.05). SM16 was also highly effective in blocking and regressing tumors when given p.o. at doses of 0.45 or 0.65 g/kg in mouse chow. Thus, SM16 shows potent activity against established AB12 malignant mesothelioma tumors using an immune-mediated mechanism and can significantly prevent tumor recurrence after resection of bulky AB12 malignant mesothelioma tumors. These data suggest that ALK5 inhibitors, such as SM16, offer significant potential for the treatment of malignant mesothelioma and possibly other cancers.
Locally produced transforming growth factor-B (TGF-B) promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This article explores the potential for increased efficacy when combining immunotherapies with TGF-B suppression using the TGF-B type I receptor kinase inhibitor SM16. Adenovirus expressing IFN-B (Ad.IFN-B) was injected intratumorally once in established s.c. AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a Kras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing human papillomavirus-E7 (HPV-E7; Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine expression and cell populations were measured in tumors and spleens by real-time PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.IFN-B increased the number of intratumoral leukocytes (including macrophages, natural killer cells, and CD8 + cells) and increased the percentage of T cells expressing the activation marker CD25. SM16 also augmented the antitumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8 + T cells in the spleens but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-B signaling pathway augments the antitumor effects of Ad.IFN-B immune-activating or Ad.E7 vaccination therapy. The addition of TGF-B blocking agents in clinical trials of immunotherapies may increase efficacy.
Purpose: Transforming growth factor (TGF)- blockade has been proposed as an anticancer therapy; however, understanding which tumor patients might benefit most from such therapy is crucial. An ideal target of such inhibitory therapy might be malignant mesothelioma (MM), a highly lethal, treatment-resistant malignancy of mesothelial cells of the pleura and peritoneum that produces large amounts of TGF-. The purpose of this study was to explore the possible therapeutic utility of TGF- blockade on MM.Experimental Design: To evaluate this hypothesis, we tested the effects of a soluble TGF- type II receptor (sTGF-R) that specifically inhibits TGF-1 and TGF-3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-) and AB1 (which does not produce TGF-).Results: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-R. In contrast, AB1 tumors showed little response to sTGF-R. The mechanism of these antitumor effects was evaluated and determined to be primarily dependent on immune-mediated responses because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice or mice depleted of CD8 ؉ T cells and (b) CD8 ؉ T cells isolated from spleens of mice treated with sTGF-R showed strong antitumor cytolytic effects, whereas CD8 ؉ T cells isolated from spleens of tumor-bearing mice treated with of control IgG2a showed no antitumor cytolytic effects.Conclusions: Our data suggest that TGF- blockade of established TGF--secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-.
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