Reduction of immune inhibitory myeloid derived suppressor cells by low dose sunitinib combined with a cancer vaccine to provide therapeutic benefit to tumor-bearing mice.

Abstract

e23084 Background: Sunitinib is a receptor tyrosine kinase inhibitor (RTK) approved as a monotherapy for the treatment of advanced RCC, gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. At the approved doses, it inhibits angiogenesis in tumors and targets RTKs (PDGF receptor, VEGF receptor, KIT, FLT-3, and RET) involved in tumor cell growth. Sunitinib also has been shown in murine studies and patients, to exhibit immunomodulatory properties that reduce a heterogeneous population of cells termed myeloid derived suppressor cells (MDSCs) and restore the immune stimulatory Th1 cytokine profile of T cells. The approved anti-angiogenic sunitinib dosing regimens in RCC have a safety profile that is overall manageable with the most commonly reported sunitinib-related grade 3 adverse events including hypertension, fatigue, diarrhea and hand-foot syndrome. Although the tolerability of sunitinib as monotherapy was acceptable in advanced stage diseases, the drug’s side effect profile could potentially pose challenges for use in combination with other oncology therapies. Thus, if the dose of sunitinib could be lowered to improve the side effect profile without impacting its immune modulatory properties, it could be combined with cancer vaccine regimens, offering a better tolerated and highly potent immunotherapy for patients with cancer of all stages. Methods: To evaluate the relationship of dose of sunitinib on its immunomodulatory properties, the pharmacokinetic profile, the frequency of MDSCs, cytokine profile, vaccine induced immune responses and anti-tumor efficacy were monitored in a subcutaneous tumor bearing BALB-neuT mice in the presence or absence of a cancer vaccine. Results: The data suggested that sunitinib doses below the approved daily dose of 50 mg may maintain the drug’s immune modulatory properties and improve overall survival when given concurrently with a cancer vaccine. Conclusions: The data suggested that low dose sunitinib can be administered as an immunomodulator to reduce MDSCs safely in combination with potent, multi-component cancer vaccine regimens.