Abstract
Background: We examined alternative methods of delivering cytokines as an adjunct for priming lymph node (LN) cells draining sites of vaccine inoculation for the purpose of generating immune cells for adoptive immunotherapy.
Methods: Using syngeneic murine tumors we examined the ability of IL-2, IL-4, or GM-CSF delivered locally to a site of tumor inoculum to induce antitumor reactive draining LN cells. Mice were inoculated subcutaneously with tumor cells transduced to secrete cytokine; tumor cells admixed with fibroblasts transduced to secrete cytokine; or intralesional inoculation of cytokine in established tumor to induce sensitized LN cells capable of mediating tumor regression in adoptive transfer.
Results: Both IL-4 and GM-CSF cytokines were effective in enhancing the antitumor reactivity of vaccine-primed LN cells compared to IL-2, which was ineffective. The local delivery of GM-CSF by autocrine or paracrine secretion of genetically engineered cells, as well as direct intratumoral delivery was capable of upregulating LN sensitization compared to systemic administration, which did not.
Conclusions: The local delivery of GM-CSF as an adjuvant for tumor vaccination can be accomplished by various methods, including direct injection, which avoids the need for gene transfer.
Similar content being viewed by others
References
Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG, Levy R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells.Nature Medicine 1996; 2(1):52–8.
Mayordomo JI, Zorina T, Storkus WJ, et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity.Nature Medicine 1995;1(12):1–6.
Reeves ME, Royal RE, Lam JS, Rosenberg SA, Hwu P. Retroviral transduction of human dendritic cells with a tumor-associated antigen gene.Cancer Res 1996;56:5672–7.
Huang AYC, Bruce AT, Pardoll DM, Levitsky HI. Does B7-1 expression confer antigen-presenting cell capacity to tumors in vivo?J Exp Med 1996;183:769–76.
Baskar S, Clements VK, Glimcher LH, Nabavi N, Ostrand-Rosenberg S. Rejection of MHC class II-transfected tumor cells requires induction of tumor-encoded B7-1 and/or B7-2 costimulatory molecules.J Immunol 1996;156:3821–7.
Yang G, Mizuno MT, Hellström KE, Chen L. B7-negative versus B7-positive P815 tumor.J Immunol 1997;158:851–8.
Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more.Immunol Today 1996;17:138–46.
Cheever MA, Disis ML, Bernhard H, et al. Immunity to oncogenic proteins.Immunol Rev 1995;145:33–59.
Miller AR, McBride WH, Hunt K, Economou JS. Cytokine-mediated gene therapy for cancer.Ann Surg Oncol 1994;1:436–50.
Roth JA, Cristiano RJ. Gene therapy for cancer: what have we done and where are we going?J Natl Cancer Inst 1997;89:21–39.
Barth RJ, Bock SN, Mulé JJ, Rosenberg SA. Unique murine tumor-associated antigens identified by tumor infiltrating lymphocytes.J Immunol 1990;144:1531–7.
Yoshizawa H, Chang AE, Shu S. Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2.J Immunol 1991;147:729–37.
Aruga A, Aruga E, Cameron MJ, Chang AE. Different cytokine profiles released by CD4+ and CD8+ tumor-draining lymph node cells involved in mediating tumor regression.J Leukoc Biol 1997;61:1–10.
Arca MJ, Krauss JC, Aruga A, Cameron MJ, Shu S, Chang AE. Therapeutic efficacy of T cells derived from lymph nodes draining a poorly immunogenic tumor transduced to secrete granulocyte-macrophage colony-stimulating factor.Cancer Gene Ther 1996;3:39–47.
Geiger JD, Wagner PD, Cameron MJ, Shu S, Chang AE. Generation of T-cells reactive to the poorly immunogenic B16-BL6 melanoma with efficacy in the treatment of spontaneous metastases.J Immunother 1993;13:153–65.
Wexler H. Accurate identification of experimental pulmonary metastases.J Natl Cancer Inst 1966;36:641–5.
Arca MJ, Krauss JC, Strome SE, Cameron MJ, Chang AE. Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes.Cancer Immunol Immunother 1996;42:237–45.
Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor a.J Exp Med 1994;179:1109–18.
Chang AE, Sondak VK, Bishop DK, Nickoloff BJ, Mulligan RC, Mulé JJ. Adoptive immunotherapy of cancer with activated lymph node cells primed in vivo with autologous tumor cells transduced with the GM-CSF gene.Hum Gene Ther 1996;7:773–92.
Shawler DL, Dorigo O, Gjerset RA, Royston I, Sobo RE, Fakhrai H. Comparison of gene therapy with interleukin-2 gene modified fibroblasts and tumor cells in the murine CT-26 model of colorectal carcinoma.J Immunother 1995;17:201–8.
Tahara H, Zeh HJ, Storkus WJ, et al. Fibroblasts genetically engineered to secrete interleukin 12 can suppress tumor growth and induce antitumor immunity to a murine melanoma in vivo.Cancer Res 1994;54:182–9.
Lotze MT, Rubin JT, Carty S, et al. Gene therapy of cancer: a pilot study of IL-4 gene-modified fibroblasts admixed with autologous tumor to elicit an immune response.Hum Gene Ther 1994;5:41–55.
Disis ML, Bernhard H, Shiota FM, Hand SL, Gralow JR, Huseby ES, Gillis S, Cheever MA. Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines.Blood 1996;88:202–10.
Leong SPL, Enders-Zohr P, Zhou YM, Allen RE, Sagebiel RW, Glassberg AB, Hayes FA. Active specific immunotherapy with GM-CSF as an adjuvant to autologous melanoma (AM) vaccine in metastatic melanoma.Proc ASCO 1996;15:437.
Meko JB, Yin JH, Tsung K, Norton JA. High cytokine production and effective antitumor activity of a recombinant vaccinia virus encoding murine interleukin 12.Cancer Res 1995;55:4765–70.
Lee SS, Eisenlohr LC, McCue PA, Mastrangelo MJ, Lattime EC. Intravesical gene therapy: in vivo gene transfer using recombinant vaccinia virus vectors.Cancer Res 1994;54:3325–8.
Lattime EC, Lee SS, Eisenlohr LC, Mastrangelo MJ. In situ cytokine gene transfection using vaccinia virus vectors.Semin Oncol 1996;23:88–100.
Nabel GJ, Nabel EG, Yang Z-Y, et al. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans.Proc Natl Acad Sci USA 1993;90:11307–11.
Nabel GJ, Gordon D, Bishop DK, et al. Immune response in human melanoma after transfer of an allogeneic class I major histocompatibility complex gene with DNA-liposome complexes.Proc Natl Acad Sci USA 1996;93:15388–93.
Rakhmilevich AL, Turner J, Ford MJ, McCabe D, Sun WH, Sondel PM, Grota K, Yang N-S. Gene gun-mediated skin transfection with interleukin 12 gene results in regression of established primary and metastatic murine tumors.Proc Natl Acad Sci USA 1996;93:6291–6.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kurane, S., Arca, M.T., Aruga, A. et al. Cytokines as an adjuvant to tumor vaccines: Efficacy of local methods of delivery. Annals of Surgical Oncology 4, 579–585 (1997). https://doi.org/10.1007/BF02305540
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02305540