In this pilot study, we investigated the ability of autologous dendritic cells pulsed ex vivo with tumor–specific idiotype protein to stimulate host antitumor immunity when infused as a vaccine. Four patients with follicular B–cell lymphoma received a series of three or four infusions of antigen–pulsed dendritic cells followed, in each instance, by subcutaneous injections of soluble antigen two weeks later. All patients developed measurable antitumor cellular immune responses. In addition, clinical responses have been measured with one patient experiencing complete tumor regression, a second patient having partial tumor regression, and a third patient resolving all evidence of disease as detected by a sensitive tumor–specific molecular analysis.
Lynch, R.G. et al. Immunoregulation of murine myeloma cell growth and differentiation: A monoclonal model of B cell differentiation. Immunol. Rev. 48, 45–80 (1979).
Levy, R., Hatzubia, A., Brown, S., Maloney, D. & Dilley, J. Immunoglobulin idiotype: A tumor-specific antigen for human B-cell lymphomas. in Malignant Lymphomas, ch. 5 (Academic Press, New York, 1982).
Maloney, D.G., Kaminski, M.S., Burowski, D., Haimovich, J. & Levy, R. Monoclonal anti-idiotype antibodies against the murine B cell lymphoma 38C13: Characterization and use as probes for the biology of the tumor in vivo and in vitro. Hybridoma 4, 191–209 (1985).
Miller, R.A., Maloney, D.G., Warnke, R. & Levy, R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N. Engl. J. Med. 306, 517–522 (1982).
Maloney, D.G. et al. Monoclonal anti-idiotype antibody therapy of B-cell lymphoma: The addition of a short course of chemotherapy does not interfere with the antitumor effect nor prevent the emergence of idiotype-negative variant cells. Blood 80, 1502–1510 (1992).
Campbell, M.J., Esserman, L., Byars, N.E., Allison, A.C. & Levy, R. Idiotype vaccination against murine B cell lymphoma. Humoral and cellular requirements for the full expression of antitumor immunity. J. Immunol. 145, 1029–1036 (1990).
Tao, M.H. & Levy, R. Idiotype/granulocyte-macrophage colony-stimulating factor fusion protein as a vaccine for B-cell lymphoma. Nature 362, 755758 (1993).
Chen, T.T., Tao, M.H. & Levy, R. Idiotype-cytokine fusion proteins as cancer vaccines. Relative efficacy of IL-2, IL-4, and granulocyte-macrophage colony-stimulating factor. J. Immunol. 153, 4775–4787 (1994).
George, A.J., Folkard, S.G., Hamblin, T.J. & Stevenson, F.K. Idiotypic vaccination as a treatment for a B cell lymphoma. J. Immunol. 141, 2168–2174 (1988).
Campbell, M.J., Esserman, L. & Levy, R. Immunotherapy of established murine B cell lymphoma: Combination of idiotype immunization and cyclophos-phamide. J. Immunol. 141, 3227–3233 (1988).
Hsu, F.J. et al. Clinical trials of idiotype-specific vaccine in B-cell lymphomas. Ann. NY Acad. Sci. 690, 385–387 (1993).
Kwak, L.W. et al. Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors. N. Engl. J. Med. 327, 1209–1215 (1992).
McCabe, B.J. et al. Minimal determinant expressed by a recombinant vaccinia virus elicits therapeutic antitumor cytolytic T lymphocyte responses. Cancer Res. 55, 1741–1747 (1995).
Kantor, J. et al. Immunogenicity and safety of a recombinant vaccinia virus vaccine expressing the carcinoembryonic antigen gene in a nonhuman primate. Cancer Res. 52, 6917–6925 (1992).
Steinman, R.M. The dendritic cell system and its role in irnmunogenicity. Annu Rev. Immunol. 9, 271–296 (1991).
Larsen, C.P. et al. Regulation of immunostimulatory function and costimula-tory molecule (B7-1 and B7-2) expression on murine dendritic cells. J. Immunol. 152, 5208–5219 (1994).
Hathcock, K.S., Laszlo, G., Pucillo, C., Linsley, P. & Hodes, R.J. Comparative analysis of B7-1 and B7-2 costimulatory ligands: Expression and function. J. Exp. Med. 180, 631–640 (1994).
Hart, D.N.J. & McKenzie, J.L. Isolation and characterization of human tonsil dendritic cells. J. Exp. Med. 168, 157–170 (1988).
Freudenthal, P.S. & Steinman, R.M. The distinct surface of human blood dendritic cells, as observed after an improved isolation method. Proc. Natl. Acad. Sci. USA 87, 7698–7702 (1990).
Macatonia, S.E. et al. Dendritic cells produce IL-12 and direct the development of Thl cells from naive CD4+ T cells. J. Immunol. 154, 5071–5079 (1995).
Pure, E. et al. Antigen processing by epidermal Langerhans cells correlates with the level of biosynthesis of major histocompatibility complex class II molecules and expression of invariant chain. J. Exp. Med. 172, 1459–1469 (1990).
Inaba, K., Metlay, J.P., Crowley, M.T. & Steinman, R.M. Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J. Exp. Med. 172, 631–640 (1990).
Mehta, D.A., Markowicz, S. & Engleman, E.G. Generation of antigen-specific CD8+ CTLs from naive precursors. J. Immunol. 153, 996–1003 (1994).
Mehta, D.A., Markowicz, S. & Engleman, E.G. Generation of antigen-specific CD4+ T cell lines from naive precursors. Ear. J. Immunol. 25, 1206–1211 (1995).
Fagnoni, F.F. et al. Role of B70/B7-2 in CD4+ T cell immune responses induced by dendritic cells. Immunology 85, 467–474 (1995).
Flamand, V. et al. Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo. Eur. J. Immunol. 24, 605–610 (1994).
Boog, C.J. et al. Abolition of specific immune response defect by immunization with dendritic cells. Nature 318, 59–62 (1985).
Takamizawa, M., Fagnoni, F., Mehta, D.A., Rivas, A. & Engleman, E.G. Cellular and molecular basis of human gamma delta T cell activation: Role of accessory molecules in alloactivation. J. Clin. Invest. 95 296–303 (1995).
Carroll, W.L., Thielemans, K., Dilley, J. & Levy, R. Mouse × human heterohy-bridomas as fusion partners with human B cell tumors. J. Immunol. Methods 89, 61–72 (1986).
Koch, F. et al. Antigen processing in populations of mature murine dendritic cells is caused by subsets of incompletely matured cells. J. Immunol. 155, 93–100 (1995).
Nijman, H.W. et al. Antigen capture and major histocompatibility class II compartments of freshly isolated and cultured human blood dendritic cells. J. Exp. Med. 182, 163–174 (1995).
Boel, P. et al. BAGE: A new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 2, 167–175 (1995).
Marchand, M., Brasseur, F., van der Bruggen, P., Coulie, P., & Boon, T., Perspectives for immunization of HLA-A1 patients carrying a malignant melanoma expressing gene MAGE-1. Dermatology 186, 278–280 (1993).
Marland, G., Bakker, A.B.H., Huijbens, R.J.F., Adema, G.J. & Figdor, C.G. Primary immune response induction by dendritic cells. J. Cell. Biol. suppl 21A, 21 (1995).
Kotera, Y., Fontenot, J.D., Pecher, G., Metzgar, R.S. & Finn, O.J. Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res. 54, 2856–2860 (1994).
Caux, C., Dezutter, D.C., Schmitt, D. & Banchereau, J. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360, 258–261 (1992).
Romani, N. et al. Proliferating dendritic cell progenitors in human blood. J. Exp. Med. 180, 83–93 (1994).
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 alpha. J. Exp. Med. 179 1109–1118 (1994).
Hsu, F.J. & Levy, R. Preferential use of the VH4 immunoglobulin gene family by diffuse large cell lymphoma. Blood 86, 3072–3082 (1995).
Grabstein, K. . in Selected Methods in Cellular Immunology (eds. Mishell, B.B. & Shiigi, S.M.) 124–137 (Freeman, San Francisco, 1980).
About this article
Cite this article
Hsu, F., Benike, C., Fagnoni, F. et al. Vaccination of patients with B–cell lymphoma using autologous antigen–pulsed dendritic cells. Nat Med 2, 52–58 (1996). https://doi.org/10.1038/nm0196-52
Scientific Reports (2021)
Journal of Experimental & Clinical Cancer Research (2020)
Reversal of the immunosuppressive tumor microenvironment by nanoparticle-based activation of immune-associated cells
Acta Pharmacologica Sinica (2020)
Scientific Reports (2020)
NIR-II probe modified by poly(L-lysine) with efficient ovalbumin delivery for dendritic cell tracking
Science China Chemistry (2020)