Abstract
To explore the potential for molecular immunotherapies in the treatment of malignant gliomas, we evaluated the efficacy of subcutaneous tumor cell vaccines in the treatment of intracranial 9L tumors, using 9L gliosarcoma cell lines stably transduced with the murine interleukin-4 cDNA (9L-IL4), the herpes simplex virus-thymidine kinase cDNA (9L-Tk) or both (9L-IL4-Tk). The expression of multiple genes from a single transcript was achieved by incorporating internal ribosomal entry site (IRES) cassettes in the retroviral constructs. Subcutaneous immunization of rats with nonirradiated 9L-IL4 cells or 9L-IL4-Tk cells followed by treatment with ganciclovir (GCV) completely protected the animals from a subsequent intracranial challenge with wild-type 9L cells. In contrast, only 50% of animals immunized with 9L-Tk cells and 0% of 9L-neo immunized animals rejected the same challenge with wild-type 9L. More importantly, treatment of established (day 3) intracranial 9L tumors with genetically engineered tumor cells resulted in long-term survival (>100 days) for 25–43% of 9L-IL4-Tk immunized animals and for 27% of nonirradiated 9L-IL4 immunized animals. In striking contrast, no 9L-Tk, 9L-neo or irradiated 9L-IL4 immunized animals survived for more than 33 days. As a marker of a cellular immune response, splenocytes from nonirradiated 9L-IL4, 9L-Tk or 9L-IL4-Tk immunized animals produced interferon-gamma (IFN-γ) in greater amounts than those from 9L-neo immunized or Hank’s balanced salts solution (HBSS) treated animals when stimulated with wild-type 9L in vitro. Our findings support the use of tumor cell vaccines expressing the IL-4 and HSVtk genes for the treatment of malignant gliomas.
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References
Murphy JB, Sturm E . Conditions determining the transplantability of tissues in the brain Rockefeller Inst Med Res 1926 21: 183–197
Gordon LB et al. Growth of P511 mastocytoma cells in BALB/c mouse brain elicits CTL response without tumor elimination J Immunol 1997 159: 2399–2408
Mitchell MS . Relapse in the central nervous system in melanoma patients successfully treated with biomodulators J Clin Oncol 1989 7: 1701–1709
DeMicco C . Immunology of central nervous system tumors (review) J Neuroimmunol 1989 25: 93–108
Kalman B, Lublin FD . Immunopathogenic mechanisms in experimental allergic encephalomyelitis (review) Curr Opin Neurol Neurosurg 1993 6: 182–188
Sampson JH et al. 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 1996 93: 10399–10404
Wakimoto H et al. Intensified antitumor immunity by a cancer vaccine that produces granulocyte–macrophage colony-stimulating factor plus interleukin 4 Cancer Res 1996 56: 1828–1833
Bozik ME, Chambers WH, Gilbert M, Lotze MT . Treatment of 9L gliosarcoma with IL-4 producing 9L vaccine. FASEB meeting 1996 (Abstr )
Noelle R et al. Increased expression of Ia antigens on resting B cells Proc Natl Acad Sci USA 1984 81: 6149–6153
Hu-Li J et al. B cell stimulatory factor I (interleukin 4) is a potent costimulant for normal resting T lymphocytes J Exp Med 1987 165: 157–161
Kawakami Y, Rosenberg SA, Lotze MT . Interleukin 4 promotes the growth of tumor-infiltrating lymphocytes cytotoxic for human autologous melanoma J Exp Med 1988 168: 2183–2191
Barks JL, McQuillan JJ, Iademarco MF . TNF-alpha and IL-4 synergistically increase vascular cell adhesion molecule-1 expression in cultured vascular smooth muscle cells J Immunol 1997 159: 4532–4538
Tepper RI, Pattengale PK, Leder P . Murine interleukin-4 displays potent anti-tumor activity in vivo Cell 1989 57: 503–512
Pericle F et al. An efficient Th2-type memory follows CD8+ lymphocyte-driven and eosinophil-mediated rejection of a spontaneous mouse mammary adenocarcinoma engineered to release IL-4 J Immunol 1994 153: 5659–5673
Golumbek PT et al. Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4 Science 1991 254: 713–716
Bozik ME et al. T-cell dependent intracerebral tumor regression of a 9L gliosarcoma expressing mIL-4 in a syngeneic host. Proc Annu Meet Am Assoc Cancer Res 1996; 36: A2800 (Abstr )
Mayordomo JI et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumor immunity Nature Med 1995 1: 1297–1302
Rosenzwajg M, Camus S, Guigon M, Gluckman JC . The influence of interleukin (IL)-4, IL-13, and Flt3 ligand on human dendritic cell differentiation from cord blood CD34+ progenitor cells Exp Hematol 1998 26: 63–72
Culver KW et al. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors Science 1992 256: 1550–1552
Ram Z et al. In situ retroviral gene transfer for the treatment of brain tumors in rats Cancer Res 1993 53: 83–88
Ram Z et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producer cells Nature Med 1997 3: 1354–1361
Moolten FL . Tumor chemosensitivity conferred by inserted Herpes thymidine kinase genes: paradigm for a prospective cancer control strategy Cancer Res 1986 46: 5276–5281
Barba D, Hardin J, Sadelain M, Gage FH . Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors Proc Natl Acad Sci USA 1994 91: 4348–4352
Chen SH et al. Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival Cancer Res 1996 56: 3758–3762
Benedetti S et al. Limited efficacy of the HSV-TK/GCV system for gene therapy of malignant gliomas and perspectives for the combined transduction of the interleukin-4 gene Hum Gene Ther 1997 8: 1345–1353
Townsend SE, Su FW, Atherton JM, Allison JP . Specificity and longevity of antitumor immune responses induced by B7-transfected tumors Cancer Res 1994 54: 6477–6483
Allione A et al. Immunizing and curative potential of replicating and nonreplicating murine mammary adenocarcinoma cells engineered with interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte–macrophage colony-stimulating factor, and gamma-interferon gene or admixed with conventional adjuvants Cancer Res 1994 54: 6022–6026
Santodonato L et al. Cure of mice with established metastatic Friend leukemia cell tumors by a combined therapy with tumor cells expressing both interferon-alpha 1 and herpes simplex thymidine kinase followed by ganciclovir Hum Gene Ther 1996 7: 1–10
Tahara H et al. Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector J Immunol 1995 154: 6466–6474
Okada H et al. Gene therapy against an experimental glioma using adeno-associated virus vectors Gene Therapy 1996 3: 957–964
Stoppacciaro A et al. Genetic modification of a carcinoma with the IL-4 gene increases the influx of dendritic cells relative to other cytokines Eur J Immunol 1997 27: 2375–2382
Dranoff G et al. 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 1993 90: 3539–3543
Danos O, Mulligan RC . Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges Proc Natl Acad Sci USA 1988 85: 6460–6464
Pear WS, Nolan GP, Scott ML, Baltimore D . Production of high-titer helper-free retroviruses by transient transfection Proc Natl Acad Sci USA 1993 90: 8392–8396
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Okada, H., Giezeman-Smits, K., Tahara, H. et al. Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine. Gene Ther 6, 219–226 (1999). https://doi.org/10.1038/sj.gt.3300798
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DOI: https://doi.org/10.1038/sj.gt.3300798
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