title: Glioma immunotherapy by IL-21 gene-modified cells or by recombinant IL-21 involves antibody responses.
abstract: Most tumors of the central nervous system, especially glioblastoma, are refractory to treatment and invariably lethal. The aim of this study was to assess the ability of different interleukins (IL), IL-2, IL-12 and IL-21, produced by transduced glioma cells to activate an immune response and trigger intracranial tumor rejection. Such experiments were performed by the use of a slow-growing clone of GL261 (GL D2-60) that was used as orthotopic glioma model. Using GL D2-60-transduced cells, all cytokines elicited an immune response against the tumor. Most notably 100% of the animals receiving a primary implant of IL-21-transduced cells rejected the implant, and 76% of these animals survived to a subsequent rechallenge with GL261 parental cells, while the other transduced cytokine genes were not as effective. Rejection responses were also obtained by admixing wild-type tumor cells with IL-21-producing GL D2-60 cells, indicating a local bystander effect of IL-21. More importantly, IL-21-secreting GL D2-60 cells or 1 microg of rIL-21 protein stereotactically injected into established GL D2-60 tumors were able to trigger glioblastoma rejection in 90 and 77% of mice, respectively. Again most of these mice survived to GL261 rechallenge. Immune mice showed antibody responses to glioma antigens, predominantly involving IgG2a and IgG2b isotypes, which mediated complement- or cell-dependent glioma cell lysis. Antibody responses were crucial for glioma immunotherapy by IL-21-secreting GL D2-60 cells, as immunotherapy was uneffective in syngeneic microMT B-cell-deficient mice. These results suggest that IL-21 should be considered as a suitable candidate for glioma immunotherapy by local delivery.
authors.affiliation: Department of Translational Oncology, IST-National Institute for Cancer Research, Genova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.forename: Rosaria Maria Rita
authors.initials: RM
authors.lastname: Gangemi
authors.forename: Daniela
authors.initials: D
authors.lastname: Marubbi
authors.forename: Marzia
authors.initials: M
authors.lastname: Perera
authors.forename: Alberto
authors.initials: A
authors.lastname: Comes
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Corte
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy*; D024201:Bystander Effect; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005856:Germ-Free Life; D005910:Glioma / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic; D000098546:Interleukin-21
chemical_list: D000912:Antibodies, Neoplasm; D007376:Interleukin-2; D007378:Interleukins; D018664:Interleukin-12; D000098546:Interleukin-21