Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy

Abstract

Our study investigated the immunomodulatory effects of sunitinib to rationally design combinational platforms with immunotherapies for the treatment of solid tumors. Using a mouse model, we studied the effects of sunitinib given for 4 weeks at concentrations comparable to 37.5–50 mg/day in humans, followed by 2 weeks off the drug (sunitinib 4/2). We assessed the effect of differently timed combinations of sunitinib and a poxvirus‐based vaccine encoding carcinoembryonic antigen (CEA) plus 3 costimulatory molecules on immune responses in CEA‐transgenic (CEA‐Tg) mice. Antitumor studies were performed in CEA‐Tg mice bearing CEA‐transfected MC38 murine colon carcinomas (MC38‐CEA), treated either concurrently or sequentially with sunitinib and vaccine. In vitro , sunitinib inhibited PDGFR phosphorylation on MC38‐CEA cells at concentrations similar to those biologically available during human treatment. In vivo, one cycle of sunitinib 4/2 caused bimodal immune effects: (a) decreased regulatory cells during the 4 weeks of treatment and (b) an immune‐suppression rebound during the 2 weeks of treatment interruption. In a model using CEA‐Tg mice bearing CEA⁺ tumors, continuous sunitinib followed by vaccine increased intratumoral infiltration of antigen‐specific T lymphocytes, decreased immunosuppressant T regulatory cells and myeloid‐derived suppressor cells, reduced tumor volumes and increased survival. The immunomodulatory activity of continuous sunitinib administration can create a more immune‐permissive environment. In combination with immunotherapies, sunitinib treatment should precede vaccine, to precondition the immune system, to maximize the response to vaccine‐mediated immune enhancement.