In situ adenoviral interleukin 12 gene transfer confers potent and long-lasting cytotoxic immunity in glioma

Liu, Yunhui; Ehtesham, Moneeb; Samoto, Ken; Wheeler, Christopher J.; Thompson, Reid C.; Villarreal, Luis P.; Black, Keith L.; Yu, John S.

doi:10.1038/sj/cgt/7700399

Cited by 11 publications

(14 citation statements)

References 9 publications

(13 reference statements)

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“…22 Use of a high-titer adenoviral vector encoding IL-12 is another strategy that was reported to induce antitumor responses in a glioma model. 23 Previous studies indicated that transfection of genomic DNA from the malignant cells into a fibroblast cell line resulted in stable integration and expression of the transferred DNA. 24,25 Both the genotype and the phenotype of the cells that took up the exogenous DNA were altered as portions of the transferred DNA were expressed.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Immunity to Intracerebral Breast Cancer in Mice Immunized With a cDNA-based Vaccine Enriched for Immunotherapeutic Cells

Lichtor

Glick

Feldman

et al. 2008

Journal of Immunotherapy

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Structural differences between malignant and nonmalignant cells of the same individual form the basis of clinical immunotherapeutic strategies. Previously, we reported the therapeutic properties of a vaccine prepared by transfer of a cDNA-expression library from breast cancer cells into a highly immunogenic allogeneic fibroblast cell line where genes specifying an array of breast cancer antigens were expressed. Here, we report the application of this cell-based vaccination strategy for breast cancer metastatic to the brain. As relatively few cells in the vaccine were expected to have incorporated cDNA fragments specifying breast cancer antigens (most specify normal cellular constituents), an enrichment strategy was employed to increase the proportion of immunotherapeutic cells. Enhanced immunity to the neoplasm mediated predominantly by CD4+, CD8+, and NK/LAK cells was generated in the spleens of mice injected intracerebrally into the tumor bed with cells from the enriched vaccine, which translated into prolonged survival. Regulatory T cells (CD4+CD25+Foxp3+-positive) were relatively deficient in the spleen cells from tumor-bearing mice injected intracerebrally with the enriched vaccine.

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Section: Discussionmentioning

confidence: 99%

Enhanced Immunity to Intracerebral Breast Cancer in Mice Immunized With a cDNA-based Vaccine Enriched for Immunotherapeutic Cells

Lichtor

Glick

Feldman

et al. 2008

Journal of Immunotherapy

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“…The use of IL-12 has generated significant interest in the field of tumor immunotherapy and on the basis of successful results obtained in preclinical models has been tested in Phase I and II clinical trials [13][14][15][16][17]. Several approaches have focused on the local release of IL-12 at the site of a tumor via methods including IL-12 transfected fibroblasts or DC [18] [19], in vivo transfection of tumor cells via viral vectors [20][21][22][23][24][25][26], or electroporation of plasmid DNA [4,[27][28][29][30]. Beyond the technical complexities and potential complications of these approaches, the clinical results have been disappointing and have dampened enthusiasm for intratumoral cytokine-based immunotherapies.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-α in a model of metastatic breast cancer

Sabel

Griffith

et al. 2009

Breast Cancer Res Treat

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Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy.

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“…One major immunotherapeutic approach involves the gene transfer of immune-stimulating cytokines including IL-4, IL-12 and Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Infiltrating immune cells were found in brain tumors but their function can be modified by tumor-derived immuno-suppressors such as TGF-β [97], IL-10 [98] and Fas ligands [99], and earlier studies have used immunestimulating cytokines IL-4 [100] or IL-12 [101,102] to overcome immunosuppression by these suppressive molecules produced by cancer cells.…”

Section: Immunotherapy For Brain Tumorsmentioning

confidence: 99%

Neural Stem Cell-based Gene Therapy for Brain Tumors

Kim

2010

Stem Cell Rev and Rep

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Advances in gene-based medicine since 1990s have ushered in new therapeutic strategy of gene therapy for inborn error genetic diseases and cancer. Malignant brain tumors such as glioblastoma multiforme and medulloblastoma remain virtually untreatable and lethal. Currently available treatment for brain tumors including radical surgical resection followed by radiation and chemotherapy, have substantially improved the survival rate in patients suffering from these brain tumors; however, it remains incurable in large proportion of patients. Therefore, there is substantial need for effective, low-toxicity therapies for patients with malignant brain tumors, and gene therapy targeting brain tumors should fulfill this requirement. Gene therapy for brain tumors includes many therapeutic strategies and these strategies can be grouped in two major categories: molecular and immunologic. The widely used molecular gene therapy approach is suicide gene therapy based on the conversion of non-toxic prodrugs into active anticancer agents via introduction of enzymes and genetic immunotherapy involves the gene transfer of immune-stimulating cytokines including IL-4, IL-12 and TRAIL. For both molecular and immune gene therapy, neural stem cells (NSCs) can be used as delivery vehicle of therapeutic genes. NSCs possess an inherent tumor tropism that supports their use as a reliable delivery vehicle to target therapeutic gene products to primary brain tumors and metastatic cancers throughout the brain. Significance of the NSC-based gene therapy for brain tumor is that it is possible to exploit the tumor-tropic property of NSCs to mediate effective, tumor-selective therapy for primary and metastatic cancers in the brain and outside, for which no tolerated curative treatments are currently available.

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In situ adenoviral interleukin 12 gene transfer confers potent and long-lasting cytotoxic immunity in glioma

Cited by 11 publications

References 9 publications

Enhanced Immunity to Intracerebral Breast Cancer in Mice Immunized With a cDNA-based Vaccine Enriched for Immunotherapeutic Cells

Enhanced Immunity to Intracerebral Breast Cancer in Mice Immunized With a cDNA-based Vaccine Enriched for Immunotherapeutic Cells

Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-α in a model of metastatic breast cancer

Neural Stem Cell-based Gene Therapy for Brain Tumors

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