Immunotherapy with bovine aortic endothelial cells in subcutaneous and intracerebral glioma models in rats: effects on survival time, tumor growth, and tumor neovascularization
ABSTRACT High-grade gliomas are aggressive tumors of the central nervous system characterized by endothelial cell proliferation and a high degree of vascularity. Conventional antitumoral treatments (i.e., surgery, radiotherapy, and chemotherapy) do not achieve satisfactory results (median survival in glioblastoma 12-18 months). It has been suggested that immunotherapy with xenogenic endothelial cells could slow tumor growth rate in a number of tumors in a murine model, but the study did not include gliomas. In experiments performed in our laboratory, vaccination with proliferating bovine aortic endothelium increased survival time in Fischer rats inoculated intracerebrally with 9L. Immunotherapy was also able to reduce the growth of subcutaneously injected 9L gliosarcoma cells in Fischer rats and to decrease microvessel density within the tumors, in the absence of major organ toxicity. Immunoglobulins (Ig) in the sera from vaccinated rats stained bovine aortic endothelium as well as human umbilical vein endothelium in active proliferation. Moreover, immune sera from immunized rats stained microvessels of human malignant glioma specimens and vessels of intracerebrally implanted tumors. Two proteins of MW of 11 and 19 kDa were identified by Western blot as targets of Ig elicited by vaccination. A possible future development is to select peptides/proteins suitable for vaccination in humans, avoiding the biohazards connected with xenogenic whole-cell vaccination.
- SourceAvailable from: Petr G Lokhov
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- "Previously this approach has been shown to inhibit the growth of experimental tumors in mouse models (Chen et al., 2006; Corsini et al., 2004; Okaji et al., 2004; Okaji et al., 2006; Scappaticci and Nolan, 2003; Wei et al., 2000). However, there are additional considerations to this approach. "
ABSTRACT: Endothelial antigens that stimulate immune-mediated damage of tumor vessels represent possible targets forthe development of antiangiogenic vaccines aimed at preventing the progression of solid tumors. Since antigensexpressed on the cell surface are accessible targets for both humoral and cell-mediated immune responses, the abilityto isolate extracellular protein fragments from endothelial cells by proteolytic digest is a proposed strategy for thecreation of antiangiogenic vaccines. Human microvascular endothelial cells (HMEC) were isolated from an abdominalsubcutaneous adipose tissue biopsy. Both non-activated endothelial cells (nHMEC) and tumor-activated endothelialcells (aHMEC) were obtained. HMEC lysate and cleaved fragments of cell surface proteins (FCSP) of HMEC had totalprotein concentrations of 135 μg/mL and 2 μg/mL, respectively. Despite this difference in concentration, FCSP wereable to stimulate immune cells in cytotoxicity assays better than the HMEC lysate. Moreover, FCSP obtained fromtumor-activated endothelial cells were able to stimulate an immune response toward tumor-activated endothelial cells.Based on these results, FCSP of endothelial cells appear to provide a comprehensive set of surface antigens that areable to induce targeted, immune-mediated cytotoxic effects against tumor endothelial cells. These fi ndings represent asuccessful strategy to produce safe and pure antigens for the production of antiangiogenic vaccines.Journal of Cancer Science and Therapy 01/2010; DOI:10.4172/1948-5956.1000037
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ABSTRACT: Angiogenesis is critical for tumor growth and metastasis. Tumor tissues induce the expression of angiogenesis-associated proteins on endothelial surface that can be targeted for tumor immunotherapy. In our study, the rat tumor endothelial proteins (EP) were isolated in situ via biotinylation of tumor vascular endothelial luminal surface followed by streptavidin affinity chromatography. The isolated tumor EP contained numerous up-regulated angiogenesis-associated endothelial proteins. The administration of these tumor EP as a vaccine to mice reduced the microvessel density in subcutaneous primary LLC tumors, delayed spontaneous LLC tumor metastasis and prolonged post-surgery life span. T lymphocytes from tumor EP-vaccinated mice lysed human umbilical vascular endothelial cells, but not tumor cells in vitro, in a dose-dependent manner. Furthermore, adoptive transfer of antitumor EP antibodies in vivo targeted to tumor endothelium and inhibited spontaneous LLC tumor metastasis. This study provides a successful preclinical exploration of the active immunotherapy for tumor by targeting tumor angiogenesis.International Journal of Cancer 07/2009; 125(1):124-32. DOI:10.1002/ijc.24362 · 5.01 Impact Factor
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ABSTRACT: A recent advance in anti-cancer therapies has been the use of cancer cells to develop vaccines. However, immunization with cancer cell-based vaccines has not resulted in significant long-term therapeutic benefits. A possible reason for this is that while cancer cells provide surface antigens that are targets for a desired immune response, they also contain a high abundance of housekeeping proteins, carbohydrates, nucleic acids, lipids, and other intracellular contents that are ubiquitous in all mammalian cells. These ubiquitous molecules are not the intended targets of this therapy approach, and thus, the immune response generated is not sufficient to eliminate the cancer cells present. In this review, a discussion of the cell surface of cancer cells is presented in relation to the goals of improving antigen composition of cancer cell-based vaccines. Strategies to enrich vaccines for cancer-specific antigens are also discussed.Journal of Cancer 11/2010; 1:230-41. DOI:10.7150/jca.1.230 · 2.64 Impact Factor