title: A rationally designed combined treatment with an alphavirus-based cancer vaccine, sunitinib and low-dose tumor irradiation completely blocks tumor development.
abstract: The clinical efficacy of therapeutic cancer vaccines remains limited. For effective immunotherapeutic responses in cancer patients, multimodal approaches capable of both inducing antitumor immune responses and bypassing tumor-mediated immune escape seem essential. Here, we report on a combination therapy comprising sunitinib (40 mg/kg), single low-dose (14 Gy) tumor irradiation and immunization with a therapeutic cancer vaccine based on a Semliki Forest virus vector encoding the oncoproteins E6 and E7 of human papillomavirus (SFVeE6,7). We previously demonstrated that either low-dose irradiation or sunitinib in single combination with SFVeE6,7 immunizations enhanced the intratumoral ratio of antitumor effector cells to myeloid-derived suppressor cells (MDSCs). On the basis of these results we designed a triple treatment combinatorial regimen. The trimodal sunitinib, low-dose irradiation and SFVeE6,7 immunization therapy resulted in stronger intratumoral MDSC depletion than sunitinib alone. Concomitantly, the highest levels of intratumoral E7-specific CD8+T cells were attained after triple treatment. Approximately 75% of these cells were positive for the early activation marker CD69. The combination of sunitinib, low-dose tumor irradiation and SFVeE6,7 immunization dramatically changed the intratumoral immune compartment. Whereas control tumors contained 0.02 E7-specific CD8+T cells per MDSC, triple treatment tumors contained more than 200 E7-specific CD8+T cells per MDSC, a 10,000-fold increased ratio. As a result, the triple treatment strongly enhanced the immunotherapeutic antitumor effect, blocking tumor development altogether and leading to 100% tumor-free survival of tumor-bearing mice. This study demonstrates that this multimodal approach elicits superior antitumor effects and should be considered for clinical applications.
authors.affiliation: Department of Medical Microbiology; Tumor Virology and Cancer Immunotherapy; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands.
authors.forename: Oana
authors.initials: O
authors.lastname: Draghiciu
authors.affiliation: Department of Medical Microbiology; Tumor Virology and Cancer Immunotherapy; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Boerma
authors.affiliation: Department of Medical Microbiology; Tumor Virology and Cancer Immunotherapy; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands.
authors.forename: Baukje Nynke
authors.initials: BN
authors.lastname: Hoogeboom
authors.affiliation: Department of Gynecology; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Medical Microbiology; Tumor Virology and Cancer Immunotherapy; University of Groningen; University Medical Center Groningen ; Groningen, The Netherlands.
authors.forename: Toos
authors.initials: T
authors.lastname: Daemen
keywords: Semliki Forest virus; cancer vaccine; low-dose local tumor irradiation; sunitinib; suppressive factors