Anti-IL-23 Monoclonal Antibody Synergizes in Combination with Targeted Therapies or IL-2 to Suppress Tumor Growth and Metastases

Abstract

Immunosuppressive barricades erected by tumors during the evolution of immune escape represent a major obstacle to many potentially effective cancer therapies and vaccines. We have shown that host interleukin (IL)-23 suppresses the innate immune response during carcinogenesis and metastasis, independently of effects on the proinflammatory cytokine IL-17A. Based on these findings, we envisioned that IL-23 neutralization might offer a promising strategy to modulate immunosuppression, particularly in combination with immunostimulatory agents. Here we show that by itself a neutralizing monoclonal antibody (mAb) to IL-23 suppressed early experimental lung metastases in the B16F10 mouse model of melanoma and also modestly inhibited the subcutaneous growth of primary tumors. These antitumor effects were respectively mediated by natural killer cells or CD8 þ T cells. More notably, combinatorial treatments of anti-IL-23 mAb with IL-2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers. Cancer Res; 71(6); 2077-86. Ó2011 AACR.

Combined Anti-CD40 and Anti–IL-23 Monoclonal Antibody Therapy Effectively Suppresses Tumor Growth and Metastases

“…Recently, we reported that a neutralizing monoclonal antibody (mAb) to mouse IL-23p19 alone suppressed early experimental B16F10 melanoma lung metastases and modestly inhibited subcutaneous tumor growth. More importantly, the use of anti-IL23p19 mAb in combination with IL-2 or anti-erbB2 mAb treatment significantly inhibited subcutaneous growth of established mammary carcinoma and suppressed established experimental and spontaneous lung metastases (5). Overall, these data suggest that IL-23 is an important immunosuppressive cytokine in developing tumors and metastases and that targeting IL-23 in combination with other promising immune targets is a rational and effective means to treat cancer.…”

“…1 Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne; 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria; 3 Immunology in Cancer and Infection Laboratory; 4 Cancer Immunoregulation and Immunotherapy Laboratory, Queensland Institute of Medical Research; 5 School of Medicine, University of Queensland, Herston, Queensland, Australia; and 6 AMGEN Incorporated, Seattle, Washington mAb combination is superior to either therapy alone and the effect is NK/T-and IL-12p35 dependent.…”

New insights into IL-12-mediated tumor suppression

“…[43][44][45][46] Whereas in B16 melanoma this effect was mediated by a subset of innate lymphoid cells (ILCs), the By using mice lacking IL-23, IL-23 receptor or anti-IL23p19 blocking antibodies, endogenous IL-23 was shown to promote tumor growth in different tumor models. 142,143 In colorectal carcinoma, the effects of IL-23 were mimicked after blocking IL-17A. 144 In DMBA/ TPA-induced skin papillomas and MCA-induced fibrosarcomas, the protumorigenic effects of IL-23 were independent of the main Th17 cytokine.…”

Anti-metastatic Effect of Garlic Hexane Extract on Lung Metastasis Induced by Melanoma B16F10 Cells in Mice

“…The B16F10 mouse melanoma cell line was chosen on the basis of its high metastatic potential in this study. Specifically, the B16F10 line has been shown to metastasize to the lungs when injected into the lateral tail vein and the majority of cells find themselves in the pulmonary tissue, but some are also localized in other organs [2] and is accepted as useful model for the study of lung metastasis [23]. We showed that the mice received B16F10 cells only implanted, the melanoma cells quite well and the lungs of these hosts were visibly riddled with metastatic tumor nodules within 21 days (Fig.…”