Abstract
The rapid advances that have taken place in tumor immunology within the past decade have fostered renewed interest in the use of immune-based therapies for the treatment of cancer (1,2). Numerous strategies, which aim to provoke and augment anti-tumor immunity in cancer patients, have been developed and are being tested in clinical trials (2–4). One strategy that has worked well in preclinical mouse models involves the use of immune stimulatory molecules, i.e., cytokines, to augment the anti-tumor activity of the immune system (5–7). The early studies focused on the systemic administration of selected cytokines to promote a nonspecific augmentation of an already existing anti-tumor immunity (5,7). While successful in murine models, particularly with interleukin (IL)-2 and -12, the systemic delivery of cytokines has not been efficacious in the clinics due to severe systemic toxicity. Systemic administration of immunotherapeutic agents ignores the paracrine nature of their activity. With the advent of molecular techniques that allowed efficient genetic modification of tumor cells in vitro, cytokine gene-modified tumor cell vaccines became the preferred alternative to systemic therapy. This approach results in the local and sustained release of cytokines by the tumor cells at the vaccine site, which induces the development of a tumor-specific, systemic anti-tumor immunity while circumventing the toxicity associated with systemic delivery (4–7).
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Sogn, J. A. (1998) Tumor Immunology: The Glass is Half Full. Immunity 9, 757–763.
Davis, I. D. (2000) An overview of cancer immunotherapy. Immunol. Cell Biol. 78, 179–195.
Minev, B. R., Chavez, F. L., and Mitchell, M. S. (1999) Cancer Vaccines: Novel approaches and new promise. Pharmacol. Ther. 81(2), 121–139.
Dranoff, G. (1998) Cancer gene therapy: connecting basic research with clinical inquiry. J. Clin. Oncol. 16, 2548–2556.
Colombo, M. P. and Forni, G. (1997) Immunotherapy I: cytokine gene transfer strategies. Cancer Met. Rev. 16, 421–432.
Gilboa, E. (1996) Immunotherapy of cancer with genetically modified tumor vaccines. Semin. Oncol. 23(1), 101–107.
Tuting, T., Storkus, W. J., and Lotze, M. T. (1997) Gene-based strategies for the immunotherapy of cancer. J. Mol. Med. 75, 478–491.
Cavallo, F., Signorelli, P., Giovarelli, M., Musiani, P., Modesti, A., Brunda, M. J., et al. (1997) Anti-tumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12. J. Natl. Cancer Inst. 89(14), 1049–1058.
Dranoff, G., Jaffee, E., Lazenby, A., Golumbek, P., Levitsky, H., Brose, K., et al. (1993) 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 90, 3539–3543.
Cavallo, F., Di PIerro, F., Giovarelli, M., Gulino, A., Vacca, A., Stoppacciaro, A., et al. (1993) Protective and curative potential of vaccination with interleukin-2-gene-transfected cells from a spontaneous mouse mammary adenocarcinoma. Cancer Res. 53, 5067–5070.
Allione, A., Consalvo, M., Nanni, P., Lollini, P. L., Cavallo, F., Giovarelli, M., et al. (1994) 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-α, granulocyte-macrophage colony stimulating factor and γ-interferon gene or admixed with conventional adjuvants. Cancer Res. 54, 6022–6026.
Gansbacher, B., Zier, K., Daniels, B. Cronin, K., Bannerji, R., and Gilboa, E. (1990) Interleukin-2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J. Exp. Med. 172, 1217–1224.
Gansbacher, B., Bannerji, R., Daniels, B. Zier, K., Cronin, K., and Gilboa, E. (1990) Retroviral vector-mediated gamma-interferon gene transfer into tumor cells generates potent and long-lasting anti-tumor immunity. Cancer Res. 50, 7820–7825.
Golumbek, P. T., Lazenby, A. J., Levitsky, H. I., Jaffee, L. M., Karasuyama, H., Baker, M., and Pardoll, D. M. (1991) Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science 254, 713–716.
Zitvogel, L., Tahara, H., Robbins, P. D., Storkus, W. J., Clarke, M. R., Nalesnik, M. A., and Lotze, M. T. (1995) Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts. J. Immunol. 155, 1393–1403.
Tahara, H., Zitvogel, L., Storkus, W. J., Zeh, H. J. 3rd, McKinney, T. G., Schreiber, R. D., et al. (1995) Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector. J. Immunol. 154, 6466–6474.
Lotze, M. T. and Rubin, J. T. (1994) Gene therapy of cancer: a Pilot study of IL-4-gene-modified fibroblasts admixed with autologous tumor to elicit an immune response. Human Gene Ther. 5, 41–55.
Bramson, J. L., Hitt, M., Addison, C. L., Muller, W. J., Gauldie, J., and Graham, F. L. (1996) Direct intratumoral injection of an adeno-virus expressing interleukin-12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12. Hum. Gene Ther. 7, 1995–2002.
Zhang, J. F., Hu, C., Geng, Y., Selm, J., Klein, S. B., Orazi, A., and Taylor, M. W. (1996) Treatment of a human breast cancer xenograft with an adenovirus vector containing an interferon gene therapy. Proc. Natl. Acad. Sci. USA 93, 4513–4518.
Toloza, E. M., Hunt, K., Swisher, S., McBride, W., Lau, R., Pang, S., et al. (1996) In vivo cancer gene therapy with a recombinant interleukin-2 adenovirus vector. Cancer Gene Ther. 3, 11–17.
Hartikka, J., Sawdey, M., Cornefert-Jensen, F., Margalith, M., Barnhart, K., Nolasco, M., et al. (1996) An improved plasmid DNA expression vector for direct injection into skeletal muscle. Hum. Gene Ther. 7, 1205–1217.
Arienti, F., Sulé-Suso, J., Belli, F., Mascheroni, L., Rivoltini, L., Melani, C., et al. (1996) Limited anti-tumor T cell response in melanoma patients vaccinated with interleukin-2 gene-transduced allogeneic melanoma cells. Human Gene Ther. 7, 1955–1963.
Pardoll, D. M. (1995) Paracrine cytokine adjuvants in cancer immunotherapy. Annu. Rev. Immunol. 13, 399–415.
Cavallo, F., Giovarelli, M., Gulino, A., Vacca, A., Stoppacciaro, A., Modesti, A., and Forni, G. (1992) 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.
Brunda, M. J., Luistro, L., Warrier, R. R., Wright, R. B., Hubbard, B. R., Murphy, M., et al. (1993) Anti-tumor and antimetastatic activity of interleukin 12 against murine tumors. J. Exp. Med. 178, 1223–1230.
Nastala, C. L., Edington, H. D., McKinney, T. G., Tahara, H., Nalesnik, M. A., Brunda, M. J., et al. Recombinant IL-12 administration induces tumor regression in association with IFN-g production.
Morikawa, K., Okada, F., Hosokawa, M., and Koybayashi, H. (1987) Enhancement of therapeutic effects of recombinant interleukin-2 on a transplantable rat fibrosarcomaby the use of a sustained release vehicle, pluronic gel. Cancer Res. 54, 182–189.
Golumbek, P. T., Azhari, R., Jaffee, E. M., Levitsky, H. I., Lazenby, A., Leong, K., and Pardoll, D. M. (1993) Controlled release, biodegradable cytokine depots: a new approach in cancer vaccine design. Cancer Res. 53, 5841–5844.
Langer, R. (1998) Drug delivery and targeting. Nature 392 (Suppl.), 5–10.
Menei, P., Venier, M.-C., Gamelin, E., Saint-André, J.-P., Hayek, G., Jadaud, E., et al. (1999) Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma. Cancer 86, 325–330.
O’Hagan, D. T., Singh, M., and Gupta, R. K. (1998) Poly(lactide-co-glycolide) microparticles for the development of single-dose controlled-release vaccines. Adv. Drug Del. Rev. 32, 225–246.
Liu, L.-S., Liu, S.-Q., Ng, S. Y., Froix, M., Ohno, T., and Heller, J. (1997) Controlled release of interleukin-2 for tumour immunotherapy using alginate/chitosan porous microspheres. (1997) J. Controlled Rel. 43, 65–74.
Chen, L., Apre, R. N., and Cohen, S. (1997) Characterization of PLGA microspheres for the controlled delivery of IL-1a for tumor immunotherapy. J. Controlled Rel. 43, 261–272.
Putney, S. D. and Burke, P. A. (1998) Improving protein therapeutics with sustained-release formulations. Nature Biotechnol. 16, 153–157.
Mathiowitz, E., Jacob, J. S., Jong, Y. S., Carino, G. P., Chickering, D. E., Chaturvedl, P., et al. (1997) Biologically erodable microspheres as potential oral drug delivery systems. Lett. Nature 386, 410–414.
Hora, M. S., Rana, R. K., Nunberg, J. H., Tice, T. R., Gilley, R. M., and Hudson, M. E. (1990) Controlled release of interleukin-2 from biodegradable microspheres. Biotechnology 8, 755–758.
Egilmez, N. K., Jong, Y. S., Iwanuma, Y., Jacob, J. S., Santos, C. A., Chen, F.-A., et al. (1998) Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model. Cancer Immunol. Immunother. 46, 21–24.
Jong, Y. S., Egilmez, N. K., Jacob, J. S., Smith, L. P., Mottl, T. S., Chen, F.-A., et al. (1999) Evaluation of cytokine delivery systems for cancer immunotherapy. Proc. Mater. Res. Soc. Implants Tissue Engin. 550, 71–75.
Kuriakose, M. A., Chen, F.-A., Egilmez, N. K., Jong, Y. S., Mathiowitz, E., DeLacure, M. D., et al. (2000) Interleukin-12 delivered by biodegradable microspheres promotes the anti-tumor activity of human peripheral blood lymphocytes in a human head and neck tumor xenograft/SCID mouse model. Head Neck Surg. 22, 57–63.
Egilmez, N. K., Jong, Y. S., Hess, S. D., Jacob, J. S., Mathiowitz, E., and Bankert, R. B. (2000) Cytokines delivered by biodegradable microspheres promote effective suppression of human tumors by human peripheral blood lymphocytes in the SCID/Winn model. J. Immunother. 23, 190–195.
Egilmez, N. K., Jong, Y. S., Sabel, M. S., Jacob, J. S., Mathiowitz, E., and Bankert, R. B. (2000) In situ tumor vaccination with Interleukin-12 encapsulated biodegradable microspheres: induction of tumor regression and potent anti-tumor immunity. Cancer Res. 60, 3832–3837.
Sabel, M. S., Hill, H., Jong, Y. S., Mathiowitz, E., Bankert, R. B., and Egilmez, N. K. (2001) Neoadjuvant therapy with IL-12-loaded PLA microspheres reduces local recurrence and distant metastases. Surgery 130(3), 470–478.
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Egilmez, N.K., Jong, Y.S., Mathiowitz, E., Bankert, R.B. (2003). Tumor Vaccination with Cytokine-Encapsulated Microspheres. In: Driscoll, B. (eds) Lung Cancer. Methods in Molecular Medicine™, vol 75. Humana Press, Totowa, NJ. https://doi.org/10.1385/1-59259-324-0:687
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DOI: https://doi.org/10.1385/1-59259-324-0:687
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