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

Int J Cancer. 2012 Apr 15;130(8):1948-59. doi: 10.1002/ijc.26219. Epub 2011 Aug 8.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / immunology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology*
  • Carcinoembryonic Antigen / genetics
  • Carcinoembryonic Antigen / immunology
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / therapy
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Flow Cytometry
  • Humans
  • Immune System / drug effects
  • Immune System / immunology*
  • Indoles / administration & dosage
  • Indoles / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology*
  • Pyrroles / administration & dosage
  • Pyrroles / immunology*
  • Receptors, Platelet-Derived Growth Factor / immunology
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sunitinib
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Treatment Outcome


  • Antineoplastic Agents
  • Cancer Vaccines
  • Carcinoembryonic Antigen
  • Indoles
  • Pyrroles
  • Receptors, Platelet-Derived Growth Factor
  • Sunitinib