title: 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.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MA 20892, USA.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Farsaci
authors.forename: Jack P
authors.initials: JP
authors.lastname: Higgins
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000276:immunology*; D007211:Indoles / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D011758:Pyrroles / Q000008:administration & dosage / Q000276:immunology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D007211:Indoles; D011758:Pyrroles; D017479:Receptors, Platelet-Derived Growth Factor; D000077210:Sunitinib