title: Increasing radiation dose improves immunotherapy outcome and prolongation of tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma.
abstract: Previously, we developed a clinically relevant therapy model for advanced intracerebral B16 melanomas in syngeneic mice combining radiation and immunotherapies. Here, 7 days after B16-F10-luc2 melanoma cells were implanted intracerebrally (D7), syngeneic mice with bioluminescent tumors that had formed (1E10(5) to 7E10(6) photons per minute (>1E10(6), large; <1E10(6), small) were segregated into large-/small-balanced subgroups. Then, mice received either radiation therapy alone (RT) or radiation therapy plus immunotherapy (RT plus IT) (single injection of mAbPC61 to deplete regulatory T cells followed by multiple injections of irradiated granulocyte macrophage colony stimulating factor transfected B16-F10 cells) (RT plus IT). Radiation dose was varied (15, 18.75 or 22.5 Gy, given on D8), while immunotherapy was provided similarly to all mice. The data support the hypothesis that increasing radiation dose improves the outcome of immunotherapy in a subgroup of mice. The tumors that were greatly delayed in beginning their progressive growth were bioluminescent in vivo-some for many months, indicating prolonged tumor "dormancy," in some cases presaging long-term cures. Mice bearing such tumors had far more likely received radiation plus immunotherapy, rather than RT alone. Radiotherapy is a very important adjunct to immunotherapy; the greater the tumor debulking by RT, the greater should be the benefit to tumor immunotherapy.
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. smilowitz@uchc.edu.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Smilowitz
authors.affiliation: Department of Biology, Brookhaven National Laboratory, Upton, NY, 11973, USA.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Micca
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sasso
authors.affiliation: Department of Anatomic Pathology and Laboratory Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Reconstructive Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA.
authors.forename: Nathanial
authors.initials: N
authors.lastname: Dyment
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Xue
authors.affiliation: Department of Statistics, University of Connecticut, 215 Glenbrook Road, Storrs, CT, 06269-4120, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D018450:Disease Progression; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007167:Immunotherapy; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009367:Neoplasm Staging; D011829:Radiation Dosage; D047368:Tumor Burden / Q000276:immunology / Q000528:radiation effects; D014964:X-Ray Therapy
keywords: Immunotherapy; Intracerebral melanoma; Radiation dose; Radiation therapy; Tumor dormancy