Abstract
Subcutaneous vaccination using granulocyte–macrophage colony-stimulating factor (GM-CSF)-transduced glioma cells substantially prolongs survival in the mouse GL261 glioma model. To potentiate the efficacy of GM-CSF-based vaccination, syngeneic C57BL/6 mice bearing pre-implanted intracerebral GL261 gliomas were vaccinated twice subcutaneously with various combinations of glioma cells retrovirally engineered to release GM-CSF, interleukin (IL)-4 or macrophage inflammatory protein (MIP)-1α. More than 80% of the animals vaccinated with GM-CSF-secreting or GM-CSF- and IL-4-secreting cells were long-term survivors (>120 days). Their survival was significantly prolonged compared with animals vaccinated with wild-type cells, which died after a median survival time of 30 days. The combination of IL-4 with GM-CSF did not provide a survival advantage over GM-CSF alone, regardless of whether the animals carried a small or large intracranial tumor load. Further, when the animals were vaccinated with a mixture of GM-CSF-, IL-4- and MIP-1α-secreting cells, the median survival was 37 days, and only 22% of the animals in this group were long-term survivors, similar to the vaccination effect of non-modified glioma cells. Thus, unexpectedly, the co-expression of MIP-1α, which was meant to attract T cells for stimulation by GM-CSF- and IL-4-stimulated dendritic cells, nullified the induction of an immune response against the GL261 glioma by a GM-CSF- and IL-4-expressing subcutaneous vaccine.
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References
Sampson JH, Bigner DD, Dranoff G: Cytokine-based gene therapy for brain tumors. In: Chiocca EA, Breakefield XO (eds) Gene Therapy for Neurological Disorders and Brain Tumors. Humana Press, Totowa, NJ, 1998, pp 231-294
Herrlinger U, Kramm CM, Johnston KM, Louis DN, Finkelstein D, Reznikoff G, Dranoff G, Breakefield XO, Yu JS: Vaccination for experimental gliomas using GM-CSF-transduced glioma cells. Cancer Gene Ther 4: 345-352, 1997
Visse E, Siesjo P, Widegren B, Sjogren HO: Regression of intracerebral rat glioma isografts by therapeutic subcutaneous immunization with interferon-γ, interleukin-7, or B7-1-transfected tumor cells. Cancer Gene Ther 6: 37-44, 1999
Wakimoto H, Abe J, Tsunoda R, Aoyagi M, Hirakawa K, Hamada H: Intensified antitumor immunity by a cancer vaccine that produces granulocyte-macrophage colony-stimulating factor plus interleukin 4. Cancer Res 56: 1828-1833, 1996
Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392: 245-252, 1998
Sallusto F, Lanzavecchia A, Mackay CR: Chemokine and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today 19: 568-574, 1999
Schall TJ, Bacon K, Camp RD, Kaspari JW, Goeddel DV: Human macrophage inflammatory protein α (MIP-1α) and MIP-1β chemokines attract distinct populations of lymphocytes. J Exp Med 177: 1821-1826, 1993
Taub DD, Turcovski-Corrales SM, Key ML, Longo DL, Murphy WJ: Chemokines and T-lymphocyte activation. I. β-chemokines costimulate human T lymphocyte activation in vitro. J Immunol 156: 2095-2103, 1996
Flesch IEA, Stober D, Schirmbeck R, Reimann J: Monocyte inflammatory protein-1α facilitates priming of CD8(+) T cell responses to exogenous viral antigen. Int Immunol 12: 1365-1370, 2000
Nakashima E, Oya A, Kubota Y, Kanada N, Matsushita R, Takeda K, Ichimura F, Kuno K, Mukaida N, Hirose K, Nakanishi I, Ujiie T, Matsushima K: A candidate for cancer gene therapy: MIP-1 alpha gene transfer to an adenocarcinoma cell line reduced tumorigenicity and induced protective immunity in immunocompetent mice. Pharm Res 13: 1896-1901, 1996
Baggiolini M, Dewald B, Moser B: Human chemokines: an update. Annu Rev Immunol 15: 675-705, 1997
Mule JJ, Custer M, Averbook B, Yang JC, Weber JS, Goeddel DV, Rosenberg SA, Schall TJ: RANTES secretion by gene-modified tumor cells results in loss of tumorigenicity in vivo: role of immune cell subpopulations. Hum Gene Ther 7: 1545-1553, 1996
Akbasak A, Oldfield EH, Saris SC: Expression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro. J Neurosurg 75: 922-929, 1991
Ausman JI, Shapiro WR, Rall DP: Studies on the chemotherapy of experimental brain tumors: development of an experimental model. Cancer Res 30: 2394-2400, 1970
Danos O, Mulligan RC: Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci USA 85: 6460-6464, 1988
Strik HM, Weller M, Frank B, Hermisson M, Deininger MH, Dichgans J, Meyermann R: Heat shock protein expression in human gliomas. Anticancer Res 20: 4457-4462, 2000
Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsatti A, Sozzoni S, Allavena P, Gray PA, Mantovani A, Sinigaglia F: Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187: 129-134, 1998
Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC: Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90: 3539-3543, 1993
Sampson JH, Archer GE, Ashley DM, Fuchs HE, Hale LP, Dranoff G, Bigner DD: Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the ‘immunologically privileged’ central nervous system. Proc Natl Acad Sci USA. 93: 10399-10404, 1996
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Herrlinger, U., Aulwurm, S., Strik, H. et al. MIP-1α Antagonizes the Effect of a GM-CSF-Enhanced Subcutaneous Vaccine in a Mouse Glioma Model. J Neurooncol 66, 147–154 (2004). https://doi.org/10.1023/B:NEON.0000013497.04322.fc
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DOI: https://doi.org/10.1023/B:NEON.0000013497.04322.fc