Immunomodulation By Tasquinimod: Combination With Immunotherapy Results In Enhanced Cd8 T Cell Responses And Improved Antitumor Effects.

Purpose: The novel anti-tumor agent tasquinimod (ABR-215050) is being developed for treatment of metastatic castration-resistant prostate cancer. Proof of concept has been demonstrated in a Phase II trial by delaying disease progression and increasing overall survival, and enrollment of patients to a global pivotal Phase III trial (10TASQ10) is ongoing. Tasquinimod targets the tumor microenvironment resulting in anti-angiogenesis, inhibition of metastasis and immunomodulation. A target molecule of tasquinimod is the S100A9 protein which has been demonstrated to affect the accumulation and function of CD11b+Gr-1+ regulatory myeloid cell subsets. Given the major contribution of these cells to the immunosuppressive tumor environment, modulation of this cell population could contribute to the anti-tumor effects by tasquinimod and enhance the effects of cancer immunotherapy. In this study, we evaluated the immunomodulatory effects of tasquinimod when combined with tumor-targeted superantigens (TTS); an immunotherapeutic strategy which is highly dependent on activation of effector T cells directed against the tumor. Experimental design: The effect of tasquinimod treatment on CD11b+ myeloid cell populations was analyzed by flow cytometry in cell suspensions from spleens and from B16 tumors growing subcutaneously. In addition, B16-5T4 expressing tumors were treated with tasquinimod (30 mg/kg), the TTS fusion protein 5T4Fab-SEA (25 μg/kg), or the combination. Tumor growth and tumor-directed T cell responses were monitored. Results: The number of CD11b+ myeloid cells significantly increased in tumor bearing mice. Tasquinimod treatment inhibited tumor growth and reduced the CD11b+Ly6G-Ly6Chigh monocytic subpopulation of CD11b+Gr-1+ cells. In addition, less CD206-expressing tumor-associated macrophages were detected. Combining tasquinimod and TTS immunotherapy significantly enhanced the anti-tumor effects compared to the mono therapies. This was accompanied with increased numbers of TTS-activated CD8+ T cells in the tumors over a prolonged period of time. Conclusions: This study demonstrates that tasquinimod modulates the tumor infiltrating myeloid cell subsets and suppresses tumor growth. In line with an effect on the immunosuppressive tumor microenvironment, combining tasquinimod with the immunotherapy TTS gave rise to significantly improved anti-tumor effects. These data suggest that tasquinimod reduces tumor-induced immune suppression and that tasquinimod combined with immunotherapy could represent a novel and promising anti-cancer strategy. Citation Format: Anette Sundstedt, Anders Olsson, Martin Stenstrom, Mona Celander, Marie Torngren, Helena Eriksson, Gunnar Hedlund, David Liberg, Tomas Leanderson. Immunomodulation by tasquinimod: Combination with immunotherapy results in enhanced CD8 T cell responses and improved antitumor effects. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B17.