Abstract
These studies sought to determine the gene expression and short-term effects of intralesional lipid-complexed immunogene therapy with constructs encoding Staphylococcus aureus enterotoxin A and canine interleukin-2 (L-SEA/cIL-2) in dogs with tumors of various histotypes, and then to assess the safety and efficacy of repeated L-SEA/cIL-2 injections in dogs with spontaneous soft tissue sarcomas (STS). In the first study, pet dogs with a variety of tumors received a single intralesional injection of L-SEA/cIL-2, and surgical excision was performed 48 h later. In the second study, dogs with histologically confirmed STS were treated weekly for a maximum of 12 weeks with escalating doses of L-SEA/cIL-2. Tumors were then surgically excised and assessed histologically and immunohistochemically. Overall, treatments were well tolerated, with no dose-limiting toxicities encountered. At 48 h, in the single injection study, plasmid DNA was detected in 14 of 16 tumor samples, and plasmid-specific mRNA was detected in 3 of 14. In the multiple injection study, the overall response rate in dogs with STS was 25%, consisting of 3 complete responses (CR) and 1 partial response (PR). Diffuse lymphoplasmacytic inflammation was observed in all tumors from patients experiencing CR or PR, whereas these changes were not evident in tumors from nonresponders. The infiltrate was composed primarily of CD3+ cells at 48 h from the single-injection study, and was composed of both CD3+ and CD79a+ cells at 12 weeks in responding dogs from the multiple-injection study. In conclusion, these studies suggests that intralesional L-SEA/cIL-2 immunotherapy is well tolerated, results in detectable transgene expression in canine tumors, and has antitumor activity in dogs with spontaneous STS.
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Silagi S, Dutkowski R, Schaefer A (1988) Eradication of mouse melanoma by combined treatment with recombinant human interleukin-2 and recombinant murine interferon-gamma. Int J Cancer 41:315
Yeung RS, Vollmer C, Taylor DD, Palazzo J, Weese JL (1992) Intratumoral rIL-2 based immunotherapy in B16 melanoma. J Surg Res 53:203
Den Otter W, Hill FWG, Klein WR, Koten JW, Sterenberg PA, De Mulder PHM, Rhode C, Stewart R, Faber JAJ, Ruitenberg EJ, Rutten VPMG (1995) Therapy of bovine ocular squamous-cell carcinoma with local doses of interleukin-2: 67% complete regressions after 20 months of follow-up. Cancer Immunol Immunother 41:10
DeStefani A, Valente G, Forni G, Lerda W, Ragona R, Cortesina G (1996) Treatment of oral cavity and oropharynx squamous cell carcinoma with perilymphatic interleukin-2: clinical and pathologic correlations. J Immunother 19:125
Farkkila M, Jaaskelainen J, Kallio M, Blomstedt G, Raininko R, Virkkunen P, Pateau A, Sarelin H, Mantyla M (1994) Randomised, controlled study of intratumoral recombinant gamma-interferon treatment in newly diagnosed glioblastoma. Br J Cancer 70:138
Mattijssen V, De Mulder PH, De Graeff A, Hupperets PS, Joosten F, Ruiter DJ, Bier H, Palmer PA, Van den Broek P (1994) Intratumoral PEG-interleukin-2 therapy in patients with locoregionally recurrent head and neck squamous-cell carcinoma. Ann Oncol 5:957
Forni G, Giovarelli M, Cavallo E, Consalvo M, Allione A, Modesti A, Muisani P, Colombo MP (1993) Cytokine-induced tumor immunogenicity: from exogenous cytokines to gene therapy. J Immunother 14:253
Dow SW, Fradkin LG, Liggitt DH, Willson AP, Heath TD, Potter TA (1999) Lipid-DNA complexes induce potent activation of innate immune responses and antitumor activity when administered intravenously. J Immunol 163:1552
Fox BA, Drury M, Hu HM, Cao Z, Huntzicker EG, Qie W, Urba WJ (1998) Lipofection indirectly increases expression of endogenous major histocompatibility complex class I molecules on tumor cells. Cancer Gene Ther 5:307
Hofland H, Huang L (1995) Inhibition of human ovarian carcinoma cell proliferation by liposome-plasmid DNA complex. Biochem Biophys Res Commun 207:492
Galanis E, Hersh EM, Stopeck AT, Gonzalez R, Burch P, Spier C, Akporiaye ET, Rinehart JJ, Edmonson J, Sobol RE, Forscher C, Sondak VK, Lewis BD, Unger EC, O'Driscoll M, Selk L, Rubin J (1999) Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience. J Clin Oncol 17:3313
Stopeck AT, Hersh EM, Akporiaye ET, Harris DT, Grogan T, Unger E, Warneke J, Schluter SF, Stahl S (1997) Phase I study of direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7, in patients with metastatic melanoma. J Clin Oncol 15:341
Stopeck, A.T, Jones A, Hersh EM, Thompson JA, Finucane DM, Gutheil JC, Gonzalez R (2001) Phase II study of direct intralesional gene transfer of Allovectin-7, an HLA-B7/Beta-2-microglobulin DNA-liposome complex, in patients with metastatic melanoma. Clin Cancer Res 7:2285
Daniels GA, Galanis E (2001) Immunotherapy of renal cell carcinoma by intratumoral administration of an IL-2 cDNA/DMRIE/DOPE lipid complex. Curr Opin Mol Ther 3:70
Gleich LL, Gluckman JL, Nemunaitis J, Suen JY, Hanna E, Wolf GT, Coltrera MD, Villaret DB, Wagman L, Castro D, Gapany M, Carroll W, Gillespie D, Selk LM (2001) Clinical experience with HLA-B7 plasmid DNA/lipid complex in advanced squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 127:775
Belldegrun A, Tso CL, Zisman A, Naitoh J, Said J, Pantuck AJ, Hinkel A, deKernion J, Figlin R (2001) Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology. Hum Gene Ther 12:883
Lando PA, Hedlund G, Dohlsten M, Kalland T (1991) Bacterial superantigens as anti-tumour agents: induction of tumour cytotoxicity in human lymphocytes by Staphylococcal enterotoxin A. Cancer Immunol Immunother 33:231
Micusan VV, Thibodeau J (1993) Superantigens of microbial origin. Sem Immunol 5:3
Sriskandan S, Evans TJ, Cohen J (1996) Bacterial superantigen-induced human lymphocyte responses are nitric oxide dependent and mediated by IL-12 and IFN-gamma. J Immunol 156:2430
McCormack JE, Callahan JE, Kappler J, Marrack PC (1993) Profound deletion of mature T cells in vivo by chronic exposure to exogenous superantigen. J Immunol 150:3785
Dow SW, Potter TA (1997) Expression of bacterial superantigen genes in mice induces localized mononuclear cell inflammatory responses. J Clin Invest 99:2616
Shrayer DP, Kouttab N, Hearing VJ, Wanebo HJ (1998) Immunization of mice with melanoma cells transfected to secrete the superantigen, staphylococcal enterotoxin A. Cancer immunol Immunother 46:7
Tordsson JM, Ohlsson LG, Abrahmsen LB, Karlstrom PJ, Lando PA, Brodin TN (2000) Phage-selected primate antibodies fused to superantigens for immunotherapy of malignant melanoma. Cancer Immunol Immunother 48:691
Dow SW, Elmslie RE, Wilson AP, L R, Gorman C, Potter TA (1998) In vivo tumor transfection with superantigen plus cytokine genes induces tumor regression and prolongs survival in dogs with malignant melanoma. J Clin Invest 101:2406
Vail DM, MacEwen EG (2000) Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest 18:781
Kuntz C, Dernell W, Powers BE, Devitt C, Straw RC, Withrow SJ (1997) Prognostic factors for surgical treatment of soft-tissue sarcomas in dogs: 75 cases (1986-1996). J Am Vet Med Assoc 211:1147
Nomura T, Nakajima S, Kawabata K, Yamashita F, Takakura Y, Hashida M (1997) Intratumoral pharmacokinetics and in vivo gene expression of naked plasmid DNA and its cationic liposome complexes after direct gene transfer. Cancer Res 57:2681
Brehm D, Steinberg HM, Haviland J, Van Winkle T (1995) A retrospective evaluation of 51 cases of peripheral nerve sheath tumors in the dog. J Am An Hosp Assoc 31:349
Graves G, Bjorling D, Mahaffey E (1988) Canine hemangiopericytoma: 23 cases (1967–1984). J Am Vet Med Assoc 192:99
Postorino N, Berg R, Powers BE, McChesney A, Taylor R, Withrow SJ (1988) Prognostic factors for canine hemangiopericytoma: 50 cases (1979–1984). J Am An Hosp Assoc 24:501
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The authors would like to dedicate this manuscript to their esteemed colleague and coauthor, the late Dr. E. Gregory MacEwen. They would also like to acknowledge the expert technical assistance of Lynda Beaver, Jean Tullis, and Robin Serino.
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Thamm, D.H., Kurzman, I.D., Macewen, E.G. et al. Intralesional lipid-complexed cytokine/superantigen immunogene therapy for spontaneous canine tumors. Cancer Immunol Immunother 52, 473–480 (2003). https://doi.org/10.1007/s00262-003-0387-6
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DOI: https://doi.org/10.1007/s00262-003-0387-6