Abstract
The cytokine approach to gene therapy of cancer stems from early studies of direct, repeated injection of recombinant cytokines at the tumor site, and extension of the bystander effect that enables a few cytokine gene transduced cells in a tumor to bring about its total destruction. This effect can be extended through the immune system, since cytokine-activated regression of a small mass of tumor cells can afford systemic protection. Transduced cells used as a vaccine provide a local concentration of both cytokine and tumor antigens. Cytokines sustain antigen uptake and presentation by increasing the immunogenic potential of the environment through the recruitment of antigen presenting cells and leukocytes, and activation of a cascade of events which amplify and tone up the efficacy of a vaccine. The promises and difficulties of this approach are discussed by considering what is still missing from experimental studies and what can best be done as soon as possible in animals and humans to reach compelling conclusions.
Similar content being viewed by others
References
Forni G, Giovarelli M, Cavallo F, Consalvo M, Allione A, Modesti A, Musiani P, Colombo MP: Cytokine induced tumor immunogenicity: From exogenous cytokines to gene therapy. J Immunother 14: 253–257, 1993
Colombo MP, Modesti A, Parmiani G, Forni G: Perspectives in cancer research: Local cytokine availability elicits tumor rejection and systemic immunity through granulocyte-T-lymphocyte cross-talk. Cancer Res 52: 4853–4857, 1992
Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, White DE: Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210: 474–484, 1998
Bubenik J, Perlmann P, Indrova M, Simova J, Jandlova T, Neuwirt J: Growth inhibition of an MG-induced mouse sarcoma by TCGF (IL-2)-containing preparations. Cancer Immunol Immunother 14: 205–206, 1983
Bubenik J, Voitenok NN, Kieler J, Prasslov VS, Chumakov PM, Bubenikova D, Simova J, Jandlova T: Local administration of cells containing an inserted IL-2 gene and producing IL-2 inhibits growth of human tumours in nu/nu mice. Immunol Lett 19: 279–282, 1988.
Tepper RL, Pattengale K, Leder P: Murine interleukin-4 displays a potent antitumor activity in vivo. Cell 57: 503–512, 1989
Kim TS, Russel SJ, Collins MK: Immunization with interleukin-2-secreting allogeneic mouse fibroblasts expressing melanoma-associated antigens prolongs the survival of mice with melanoma. Int J Cancer 55: 865–872, 1993
Roth C, Delassus S, Even J: Inhibition of tumor growth by histoincompatible cells expressing IL-2. In: Forni G, Foà R, Santoni A, Frati L (eds) Cytokine-induced tumor immunogenicity. Academic Press, London, 1994, pp 163–181
Cavallo F, Giovarelli M, Gulino A, Vacca A, Stoppacciaro A, Modesti A, Forni G: Role of neutrophils and CD4+T lymphocytes in the primary and memory response to non-immunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene transfection. J Immunol 149: 3627–3635, 1992
Tahara H, Zeh HJ3rd, Storkus WJ: Fibroblasts genetically engineered to secrete interleukin 12 can suppress tumor growth and induce antitumor immunity to a murine melanoma in vivo. Cancer Res 54: 182–189, 1994
Lotze MT, Rubin JT: Gene therapy of cancer: a pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response. Human Gene Therapy 5: 41–55, 1994
Fearon ER, Pardoll DM, Itaya T, Golumbek P, Levitsky HI, Simons JW, Karasuyama H, Vogelstein B, Frost P: Interleukin 2 production by tumor cells by passes T helper function in the generation of an antitumor response. Cell 60: 397–403, 1990
Watanabe Y, Kuribayashi K, Miyatake S, Nishihara K, Nakayama E, Taniyama T, Sakata T: Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci USA 86: 9456–9460, 1989
Forni G, Cavallo F, Consalvo M, Allione A, Dellabona P, Casorati G, Giovarelli M: Molecular approaches to cancer immunotherapy. Cytokines Mol Ther 1: 225–248, 1995
Kawamura H, Rosenberg SA, Berzofsky JA: Immunization with antigen and interleukin 2 in vivo overcomes Ir gene low responsiveness. J Exp Med 162: 381–389, 1985
Malkowsky M, Medawar PM, Thacher DR, Toy J, Hunt L, Rayfield S, Dorè C: Acquired immunological tolerance of foreign cells is impaired by recombinant interleukin 2 or vitamin A. Proc Natl Acad Sci USA 82: 536–540, 1985
Forni G, Giovarelli M, Santoni A, Modesti A, Forni M: Interleukin-2 activated tumor inhibition in vivo depends on the systemic involvement of host immunoreactivity. J Immunol 138: 4033–4041, 1987
Schmidt W, Schweighoffer, Herbst E, Maass G, Berger M, Schilcher F, Schaffner G, Bjrinstel ML: Cancer vaccines: The interleukin 2 dosage effect. Proc Natl Acad Sci USA 92: 4711–4714, 1995
Musiani P, Allione A, Modica A, Lollini PL, Giovarelli M, Cavallo F, Belardelli F, Forni G, Modesti A: Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha. Lab invest in press
Stoppacciaro A, Melani C, Parenza M, Mastracchio A, Bassi C, Baroni C, Parmiani G, colombo MP: Regression of an established tumour genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma. J Exp Med 178: 151–161, 1993
Stoppacciaro A, Forni G, Colombo MP: Different tumours transduced with different cytokine genes as G-CSF and IL-2 show inhibition of tumour take through neutrophil activation but differ in T cell functions. Folia Biol 40: 89–99, 1994
Bosco MC, Pericle F, Giovarelli M, Colombo MP, Ferrari G, Musiani P, Modesti A, Cavallo F, Novelli F, Forni G: An efficient Th-2-type memory follows CD8+lymphocyte driven and eosinophil mediated rejection of a spontaneous mouse mammary adenocarcinoma engineered to release IL-4. J Immunol 153: 5659–5672, 1994
Pericle F, Giovarelli M, Colombo MP, Ferrari G, Musiani P, Modesti A, Cavallo F, Novelli F, Forni G: An efficient Th-2-type memory follows CD8+lymphocyte driven and eosinophil mediated rejection of a spontaneous mouse mammary adenocarcinoma engineered to release IL-4. J Immunol 153: 5659–5672, 1994
Forni G, Pericle F, Giovarelli M: Effects of local cytokine therapy. In: Gearing A, Rossio J, Oppenheim JJ (eds) Clinical applications of cytokines: role in pathogenesis, diagnosis and therapy. Oxford Univ Press, New York, 1993, pp 187–194
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 antitumor immunity. Proc Natl Acad Sci USA 90: 3539–3543, 1993
Forni G, Foà R, Santoni A, Frati L (eds) Cytokine-induced tumor immunogenicity. Academic Press, London, 1994
Hock H, Dorsch M, Kunzendorf U, Uberla K, Diamantstein T, Blankenstein T: Vaccination with tumor cells genetically engineered to produce different cytokines: effectivity not superior to a classical adjuvant. Cancer Res 53: 714–716, 1993
Cavallo F, Di Pierro F, Giovarelli M, gulino A, Vacca A, Stoppacciaro A, Forni M, Modesti A, Forni G: Protective and curative potential of vaccination with IL-2 gene-transfected cells from a spontaneous mouse mammary adenocarcinoma. Cancer Res 21: 5067–5070, 1993
Allione A, Consalvo M, Nanni P, Lollini PL, Cavallo F, Giovarelli M, Forni M, Gulino A, Colombo MP, Dellabona P, Hock H, Blankenstein T, Rosenthal FM, Gansbacher B, colombo MC, Musso T, Gusella L, Forni G: Immunizing and curative potential of replicating and nonreplicating murine mammary adenocarcinoma cells engineered with IL-2, IL-4, IL-6, IL-7, IL-10, TNF-α, GM-CSF, and IFN-γ gene or admixed with conventional adjuvants. Cancer Res 54: 6022–6026, 1994
Consalvo M, Mullen C, Modesti A, Musiani P, Allione A, Cavallo F, Giovarelli M, forni G: 5-Fluorocytosine induced eradication of murine adenocarcinomas engineered to express the cytosine deaminase suicide gene requires host immune competence and leaves an efficient menory. J Immunol 154: 5302–5312, 1995
Giovarelli M, Musiani P, Modesti A, Dellabona P, Casorati G, Allione A, Consalvo M, Cavallo F, Di Pierro F, De Giovanni C, Musso T, Forni G: The local release of IL-10 by transfected muuse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic T lymphocyte and antibody dependent immune memory. J Immunol 155: 3112–3123, 1995
Pedrizet GA, Ross SR, Staus HJ, Singh S, Koeppen H, Schreiber H: Animals bearing malignant grafts reject normal grafts that express through gene transfer the same antigen. J Exp Med 171: 1205–1220, 1990
Nathan C, Sporn MJ: Cytokines in the context. J Cell Biol 113: 981–985, 1991
Colombo MP, Lombardi L, Melani C, Paranza M, Baroni C, Ruco L, Stopacciaro A: Hypotoxic tumor death and modulation of endothelial adhesion molecules in the regression of G-CSF transduced tumors. Am J Pathol 148: 473–483, 1996
Piali L, Fichtel A, Terpe HJ, Imhof BA, Gisler RH: Endothelial vascular cell adhesion molecule 1 expression is suppressed by melanoma and carcinoma. J Exp Med 181: 811–816, 1995
Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, Mc Vicar DW, Ochoa A: Alteractions in signal transduction molecules in T lymphocytes from tumor bearing mice. Science 258: 1795–1798, 1992
Salvadori S, Gansbacher B, Pizzimenti AM, Zier KS: Abnormal signal transduction by T cells of mice with parental tumors is not seen in mice bearing IL-2-secreting tumors. J Immunol 153: 5176–5282, 1994
Singh S, Ross SR, Acena M, Rowley DA, Schreiber H: Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells. J Exp Med 175: 139–146 1992
Boon T, Cerottini JC, Van den Eynde B, Van der Bruggen P, Van Pel A: Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12: 337–365, 1994
Belldegrun A, Muul LM, Rosenberg SA: Interleukin 2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity. Cancer Res 48: 206–214, 1988
Alexander J, Rayman P, Edinger M, Connelly R, Tubbs R, Bukowski R, Pontes E, Finke J: TIL from renal-cell carcinoma: restimulation with tumor influences proliferation and cytolytic activity. Int J Cancer 45: 119–124, 1990
Kim TY, van Eschenbach AC, Filaccio MD, Hayakawa K, Parkinson DR, Balch CM, Itoh K: Clonal analysis of lymphocytes from tumor, peripheral blood, and nontumorous kidney in primary renal cell carcinoma. Cancer Res 50: 5263–5268, 1990
Schendel DJ, Gansbacher B, Oberneder R, Kriegmair M, Hofstetter A, Reithmuller G, Segurado OG: Tumor-specific lysis of human renal cell carcinomas by tumor-infiltrating lymphocytes. J Immunol 151: 4209–4220, 1993
Parmiani G, Colombo MP, Melani C, Arienti F: Cytokine gene transduction in the immunotherapy of cancer. Adv Pharmacol In press, 1996
Mandelboim O, Berke G, Fridkin M, Feldman M, Eisenstein M, Eisenbach L: CTL induction by a tumor-associated antigen octapeptide derived from a murine lung carcinoma. Nature 369: 67–71, 1994
De Plaen E, Lurquin C, Van Pel A, Mariam ÄB, Szikora J, Wolfel T, Sibille C, Chomez P, Boon T: Immunogenic (tum-) variants of mouse tumor P815: cloning of the gene of tumantigen P91A and identification of the tum-mutation. Proc Natl Acad Sci USA 85: 2274–2283, 1988
Noguchi Y, Chen Y, Old LJ: A mouse mutant p53 product recognized by CD4 and CD8 T cells. Proc Natl Acad Sci USA 91: 3171–3175, 1994
Bronte V, Tsung K, Rao JB, Chen PW, Wang M, Rosenberg SA, Restifo NL: IL-2 enhances the function of recombinant poxvirus-based vaccines in the treatment of established pulmonary metastases. J Immunol 154: 5282, 1995
Paglia P, Chiodoni C, Rodolfo M, Colombo MP: Murine dendritic cells loaded in vitro with soluble protein prime CTL against tumor antigen in vivo. J Exp Med 185: 317–322, 1996
Huang YC, Golumbeck P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H: Role of bone-marrow derived cells in presenting MHC class I-restricted tumor antigens. Science (Washington, DC) 264: 961–965, 1994
Parmiani G, Colombo MP: Somatic gene therapy of human melanoma: preclinical studies and early clinical trials. Melanoma Res 5: 295–301, 1995
Coulie PG, Somville M, Lehmann F, Hainault P, Brasseur F, Devos R, Boon T: Precursor frequency analysis of human cytolytic T lymphocytes directed against autologous melanoma cells. Int J Cancer 50: 289–297, 1992
Mazzocchi A, Belli F, Mascheroni L, Vegetti C, Parmiani G, Anichini A: Frequency of cytotoxic T lymphocyte precursors (CTLp) interacting with autologous tumor via the T-cell receptor: limiting dilution analysis of specific CTLp in peripheral blood and tumor-invaded lymph nodes of melanoma patients. Int J Cancer 58: 330–339, 1994
Lollini PL, De Giovanni C, Landuzzi L, Nicoletti G, Frabetti F, Cavallo F, Giovarelli M, Forni G, Modica A, Modesti A, Musiani P, Nanni P: Transduction of genes coding for a histocompatibility (MHC) antigen and for its physiological inducer γ-interferon in the same cell. Efficient MHC expression and inhibition of tumor and metastasis growth. Hum Gene Ther 6: 743–752, 1995
Cascinelli N, Foà R, Parmiani G: Active immunization of metastatic melanoma patients with interleukin-4 transduced, allogeneic melanoma cells. A phase I-II study. Hum Gene Ther 5: 1059–1064, 1994
Gansbacher B, Houghton A, Livingston P: A pilot study of immunization with HLA-A2 matched allogeneic melanoma cells that secrete interleukin-2 in patients with metastatic melanoma. Hum Gene Ther 3: 677–690, 1992
Lotze MT, Rubin JT: 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 5: 41–55, 1994
De la Salle H, Hanau D, Fricker D, Urlacher A, Kelly A, Salamero J, Powis SH, Donato L, Bausinger H, Laforet M, Jeras M, Spenher D, Bieber T, Falkenrodt A, Cazenave JP, Trowsdale J, Tongio MM: Homozygous human TAP peptide transporter mutation in HLA class I deficiency. Science 265: 237–241, 1994
Salter RD, Cresswell P: Impaired assembly and transport of HLA-A and-B antigens in a mutant T × B cell hybrid. EMBO J 5: 943–949, 1986
Carbone FR, Moore MW, sheil JM, Bevan MJ: Induction of cytotoxic T lymphocytes by primary in vitro stimulation with peptides. J Exp Med 167: 1767–1779, 1988
Celis E, Tsai V, Crimi C, DeMars R, Wentworth PA, Chesnut RW, Grey HM, Sette A, Serra HM: Induction of antitumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. Proc Natl Acad Sci USA 91: 2105–2109, 1994
Rivoltini L, Kawakami Y, Sakaguchi K, Southwood S, Sette A, Robbins PF, Marincola FM, Salgaller ML, Yannelli JR, Appella E, Rosenberg SA: Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1. J Immunol 154: 2257–2265, 1995
Salgaller ML, Afshar A, Marincola FM, Rivoltini L, Kawakami Y, Rosenberg SA: Recognition of multiple epitopes in the human antigen gp100 by peripheral blood lymphocytes stimulated in vitro with synthetic peptides. Cancer Res 55: 4972–4979, 1995
Anichini A, Mortaccini R, Maccalli C, Squarcina P, Fleischhauer K, Mascheroni L, Parmiani G: Cytotoxic T cells directed to tumor antigens not expressed on normal melanocytes dominate HLA-A2.1-restricted immune repertoire to melanoma. J Immunol 156: 208–217, 1996
Morton DL, Foshag LJ, Hoon DSB, Nizze A, Wanek LA, Chang C, Davtyan DG, Gupta RK, Elashoff R, Irie RF: Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg 216: 463–482, 1992
Mukherji B, Chakraborty NG, Yamasaki S, Okino T, Yamase H, Sporn JR, Kurtzman SK, Ergin MT, Ozols J, Meehan J, Mauri F: Induction of antigen-specific cytolytic T-cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci USA 92: 8078–8082, 1995
Marchand M, Weynants P, Rankin E: Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer 63: 883–885, 1995
Hara T, Takechi Y, Houghton AN: Implicating a role for immune recognition of self in tumor rejection: passive immunization against the brown locus protein. J Exp Med 182: 1609–1614, 1995
Forni G, Giovarelli M: Strategies for cell-mediated immunotherapy of cancer: killing or help? Immunol Today 7: 202–203, 1986
Colombo MP, Forni G: Cytokine gene transfer in tumor inhibition and tentative tumor therapy: Where are we now? Immunol Today 15: 48–51, 1994
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern cooperative oncology group trial EST 1684. J Clin Oncol 14: 7–17, 1996
Balch C, Buzaid A: Finally, a successful adjuvant therapy for high-risk melanoma. J Clin Oncol 14: 1–3, 1996
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Colombo, M.P., Forni, G. Immunotherapy I: Cyclosine gene transfer strategies. Cancer Metast Rev 15, 317–328 (1996). https://doi.org/10.1007/BF00046345
Issue Date:
DOI: https://doi.org/10.1007/BF00046345