Cancer immunotherapy using cells modified with cytokine genes (original) (raw)
Related papers
Cytokine gene transfer in tumor cells as an approach to antitumor therapy
International Journal of Clinical & Laboratory Research, 1992
The transfer of cytokine genes into cancer cells, resulting in cytokine release directly at the site of tumor growth, has proven effective in inhibiting tumor growth in the absence of any toxic effect. Some cytokines induce tumor suppression even in T-cell-deficient mice, suggesting their potential therapeutic effect in poorly immunogenic tumors; other cytokines induce memory T cells that protect mice from subsequent tumor injection. The effects of cytokine genes transferred into tumor cells are summarized and implications discussed.
Immunotherapy. I: Cytokine gene transfer strategies
Cancer metastasis reviews
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 huma...
Gene Modification Strategies to Induce Tumor Immunity
2005
strategies to correct deficiencies in the response against cancer. The following provides a review of ge-Cancer Immunology Program Peter MacCallum Cancer Center netic intervention strategies to overcome existing limitations of immune defenses at five crucial stages of East Melbourne, Victoria 3002 Australia the adaptive immune response ) and discusses how these might be integrated to develop improved therapies for cancer.
Cancer Immunology, Immunotherapy, 2002
Cytotoxic T cells can recognize and kill tumor cells that present peptides derived from tumor-associated antigens (TAA) on their surface when associated with major histocompatibility complex (MHC) class I molecules. However, immune responses to tumor-associated antigens are often suppressed by a tumor-induced state of immune anergy. Previous work has attempted to overcome tumor-induced T cell anergy by the direct injection of vectors carrying genes encoding one of a variety of cytokines. Polyclonal stimulation of T cells, preferably via the TCR complex, results in a cascade of cytokines associated with T cell activation and thus may be better able to overcome T cell anergy. We have previously reported the use of the highly attenuated MVA poxvirus to express on tumor cells, in vitro and in vivo, antibodies specific for the CD3epsilon chain (KT3). When injected into growing tumors, these constructs induce the activation of immune effector cells and result in rejection of the tumor. A variety of recombinant adenovirus (Ad) vectors expressing immunostimulatory and/or immunoattractant molecules have now been produced. With this collection of viruses, we have carried out in vivo analyses of combinations of vectors in tumor therapy experiments. For example, we have tested, in murine tumor models, the combination of MVA-KT3 with Ad expressing recently identified cytokines [for example interleukin-12 (IL-12), IL-18] as well as chemokines (e.g. RANTES, MIP1beta). One combination, MVA-KT3/Ad-IL-12/Ad-MIP1beta causes rejection of 100% of growing RENCA tumors. Much attention has been focused on cancer gene therapy using gene transfer of single agents. These data show that antigenic stimulation via the MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising approach to cancer gene therapy which is more likely to bypass tumor immunosuppression mechanisms.
Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells
Cancer Immunology, Immunotherapy, 2006
We have developed immuno-gene therapy for malignant melanoma and prostate cancer. The therapy is based on monocyte-derived dendritic cells (DCs) that are transfected with autologous melanoma-mRNA or mRNA from three prostate cancer cell lines (DU-145, LN-CaP and PC-3). A broad spectrum of tumourassociated antigens will be included in both DCvaccines. The use of autologous melanoma-mRNA moreover allows targeting of individual tumour antigens that are specific to each patient. Effective protocols have been established for mRNA-transfection by square wave electroporation and for the generation of clinical grade DCs. A full scale preclinical evaluation demonstrated in vitro T cell responses in 6/6 advanced melanoma patients. The responses were specific to antigens encoded by the transfected tumour-mRNA. Recently, we have conducted two phase I/II trials, in advanced malignant melanoma and androgen-resistant prostate cancer. Successful vaccine preparations were obtained for all 41 patients elected. No serious adverse effects were observed. Specific T cell responses (T cell proliferation and/ or IFNc ELISPOT) were demonstrated in 9/19 evaluable melanoma patients and in 12/19 prostate cancer patients. The response rates were higher for patients receiving intradermal vaccination, compared to intranodal injection. Thirteen prostate cancer patients developed a decrease in log-slope PSA. The PSA-response was significantly related to the T cell response (P=0.002). We conclude that the DC-vaccine is feasible and safe, and that T cell responses are elicited in about 50% of patients.
In vivo cytokine gene transfer by gene gun reduces tumor growth in mice
Proceedings of the National Academy of Sciences of the United States of America, 1995
Implantation of tumor cells modified by in vitro cytokine gene transfer has been shown by many investigators to result in potent in vivo antitumor activities in mice. Here we describe an approach to tumor immunotherapy utilizing direct transfection of cytokine genes into tumorbearing animals by particle-mediated gene transfer. In vivo transfection of the human interleukin 6 gene into the tumor site reduced methylcholanthrene-induced fibrosarcoma growth, and a combination of murine tumor necrosis factor alpha and interferon gamma genes inhibited growth of a renal carcinoma tumor model (Renca). In addition, treatment with murine interleukin 2 and interferon gamma genes prolonged the survival of Renca tumor-bearing mice and resulted in tumor eradication in 25% of the test animals. Transgene expression was demonstrated in treated tissues by ELISA and immunohistochemical analysis. Significant serum levels of interleukin 6 and interferon gamma were detected, demonstrating effective secretion of transgenic proteins from treated skin into the bloodstream. This in vivo cytokine gene therapy approach provides a system for evaluating the antitumor properties of various cytokines in different tumor models and has potential utility for human cancer gene therapy.