Retrovirus-Mediated Gene Transfer of the Human ?-IFN Gene: A Therapy for Cancer (original) (raw)
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Immunotherapy of malignancy by in vivo gene transfer into tumors
Proceedings of the …, 1993
The immune system confers protection against a variety of pathogens and contributes to the surveillance and destruction of neoplastic cells. Several cell types participate in the recognition and Iysis of tumors, and appropriate immune stimulation provides therapeutic effects in malignancy. Foreign major histocompatibility complex (MHC)
Gene Therapy, 1997
Stable transfection of tumor cells with IFN-␣ genes has delivery using retrovirally transduced syngeneic fibroblasts been shown to result in abrogation of tumor establishment was capable of suppressing the establishment of the poorly and induction of antitumor immunity. However, strategies immunogenic TS/A mouse mammary adenocarcinoma and suitable for the clinical application of IFN-␣ gene therapy induced antitumor immunity. Particle-mediated transient for cancer have not been reported. In this study, we investi-transfection of tumor cells using the gene gun led to the gated two gene delivery systems capable of mediating the production of up to 20 000 U IFN-␣/10 6 cells during the first local paracrine production of high levels of biologically 24 h and proved to be equally effective in suppressing active IFN-␣ in murine tumor models: retroviral transduc-establishment of TS/A adenocarcinoma and inducing antition of fibroblasts and particle-mediated transfection of tumor immunity. These results suggest that retroviral transtumor cells. In spite of the antiproliferative effects of IFN-duction of autologous fibroblasts can serve as an effective ␣, it was possible to obtain stable retroviral producer cell gene delivery method for IFN-␣ gene therapy of cancer. lines and transduce a variety of murine tumor cells includ-Particle-mediated transfection of freshly isolated tumor ing syngeneic fibroblasts to stably secrete 2000-5000 U cells may represent a clinically attractive alternative (40-100 ng) murine IFN-␣/10 6 cells/24 h. IFN-␣ transduc-approach for nonviral gene delivery. Both strategies cirtion of tumor cells abrogated tumorigenicity in establish-cumvent the difficulties in routinely establishing primary ment models and induced antitumor immunity in several tumor cell lines from the vast majority of human cancers. murine tumor model systems. Importantly, IFN-␣ gene
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...
T-Cell Receptor Gene Therapy of Established Tumors in a Murine Melanoma Model
Journal of Immunotherapy, 2008
Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-g secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies.
Cancer Immunology Immunotherapy, 2006
Many patients with various types of cancers have already by the time of presentation, micrometastases in their tissues and are left after treatment in a minimal residual disease state [Am J Gastroenterol 95(12), 2000]. To prevent tumour recurrence these patients require a systemic based therapy, but current modalities are limited by toxicity or lack of efficacy. We have previously reported that immune reactivity to the primary tumour is an important regulator of micrometastases and determinant of prognosis. This suggests that recruitment of specific anti-tumour mechanisms within the primary tumour could be used advantageously for tumour control as either primary or neo-adjuvant treatments. Recently, we have focused on methods of stimulating immune eradication of solid tumours and minimal residual disease using gene therapy approaches. Gene therapy is now a realistic prospect and a number of delivery approaches have been explored, including the use of viral and non-viral vectors. Non-viral vectors have received significant attention since, in spite of their relative delivery inefficiency, they may be safer and have greater potential for delivery of larger genetic units. By in vivo electroporation of the primary tumour with plasmid expressing GM-CSF and B7-1, we aim to stimulate immune eradication of the treated tumour and associated metastases. In this symposium report, we describe an effective gene based approach for cancer immunotherapy by inducing cytokine and immune co-stimulatory molecule expression by the growing cells of the primary tumour using a plasmid electroporation gene delivery strategy. We discuss the potential for enhancement of this therapy by its application as a neoadjuvant to surgical excision and by its use in combination with suppressor T cell depletion.
Interleukin 12 Gene Therapy of MHC-negative Murine Melanoma Métastases1
Immunological gene therapy of cancer relies heavily on the activation of T cells, but tumors with defects in MHC gene expression are not recog nized by MHC-restricted T cells. To investigate the potential of cytokine genes for the therapy of MHC-negative tumors, we transduced B78H1, a class I-negative murine melanoma clone, with a polycistronic vector car rying murine interleukin (II.I-I2 genes. The clones studied produced 400â€"25,000 pg/ml 11-12 their in vitro growth properties were similar to those of parental cells. A complete inhibition of growth was observed in vivo both after s.c. and i.v. administration of all II.-12 clones. II ,-12-