Enhancing the potency of a whole-cell breast cancer vaccine in mice with an antibody-IL-2 immunocytokine that targets exposed phosphatidylserine. Vaccine
ABSTRACT Phosphatidylserine (PS), an anionic phospholipid normally restricted to the inner leaflet of the plasma membrane, is immunosuppressive when externalized on the outside of cell membranes. Exposed PS inhibits the maturation and function of dendritic cells (DCs), and induces the production of multiple immunosuppressive mediators. In the present study, we determined whether blocking these effects of PS while simultaneously introducing interleukin-2 (IL-2) could improve the immunogenicity of a whole-cell cancer vaccine. An immunocytokine (2aG4-IL2) was made by genetically linking IL-2 with a PS targeting antibody, 2aG4, that can block the immunosuppressive effects of PS. The 2aG4-IL2/4T1 vaccine was generated by coating the PS exposed on irradiated 4T1 cells with 2aG4-IL2. Tumor growth, spontaneous metastasis, and survival of vaccinated mice challenged with live 4T1 tumor cells were assessed. Eighty percent of mice inoculated with 2aG4-IL2/4T1 vaccine survived free of tumor, as compared with 20% in the 2aG4/4T1 group, 20% in the C44-IL2/4T1 group, and none in the C44/4T1 control group (P=0.001 for 2aG4-IL2/4T1 versus all others groups). The incidence, number of spontaneous lung metastases was significantly lower in the 2aG4-IL2/4T1 vaccinated group than in the other groups. Splenocytes from 2aG4-IL2/4T1 vaccinated mice had significantly higher 4T1 specific cytotoxicity and ability to secrete interferon-gamma (IFNγ) than did splenocytes from mice in the other groups. These results demonstrate that a potent whole-cell vaccine can be created by coating irradiated tumor cells with 2aG4-IL2. Such vaccine could potentially be an effective treatment modality for patients with residual disease or at "high-risk" for recurrence.
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- "Interestingly, another study has shown that anti-PS antibodies can elicit immune antitumor responses by converting myeloid-derived suppressive cells into tumoricidal M1 macrophages or dendritic cells capable of engaging cytotoxic T cell– dependent cytotoxicity . Preclinical studies showed good targeting efficacy of PS-directed antibodies in several tumor models     . In orthotopic mouse models of pancreatic cancer, Beck et al. showed that gemcitabine plus the PS-targeting antibody 3G4 had additive antitumor activity and significantly reduced metastases . "
ABSTRACT: Pancreatic cancer remains one of the most intractable cancers, with a dismal prognosis reflected by a 5-year survival of ~6%. Since early disease symptoms are undefined and specific biomarkers are lacking, about 80% of patients present with advanced, inoperable tumors that represent a daunting challenge. Despite many clinical trials, no single chemotherapy agent has been reliably associated with objective response rates above 10% or median survival longer than 5 to 7 months. Although combination chemotherapy regimens have in recent years provided some improvement, overall survival (8-11 months) remains very poor. There is therefore a critical need for novel therapies that can improve outcomes for pancreatic cancer patients. Here, we present a summary of the current therapies used in the management of advanced pancreatic cancer and review novel therapeutic strategies that target tumor biomarkers. We also describe our recent research using phosphatidylserine-targeted saposin C-coupled dioleoylphosphatidylserine nanovesicles for imaging and therapy of pancreatic cancer. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Translational oncology 06/2015; 10(3). DOI:10.1016/j.tranon.2015.03.011 · 3.40 Impact Factor
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ABSTRACT: Classical swine fever (CSF) is a highly infectious hemorrhagic disease that affects domestic and wild swine. Live attenuated vaccines for classical swine fever viruses (CSFV) can provide rapid onset protection against CSF. However, because of serious safety concerns regarding the use of modified-live virus vaccines, the development of novel CSFV vaccines is urgently required. The E2 protein plays a vital role in viral replication and is essential in CSF development; thus represents an ideal vaccine target. Transgenic plants provide cost-effective and scalable systems for the production and delivery of viral protein, and might have potential use as oral vaccines. In this study, we generated a transgenic lettuce expressing the CSFV E2 gene, under the control of the CaMV 35S promoter, using Agrobacterium-mediated transformation. We confirmed the stable integration and transcriptional expression of the E2 gene using genomic DNA PCR amplification and quantitative real-time PCR analysis, respectively. We then confirmed E2 expression using Western blot analysis. Based on ELISA analysis, levels of E2 protein in leaf tissues of different transgenic lines ranged between 0.21 and 0.53 μg mg−1 of the total soluble protein. We detected E2-specific antibodies in mice following their subcutaneous and oral immunization with protein extracts from transgenic lettuce. Following the vaccination of mice with the recombinant E2 protein, we identified upregulated IFN-γ and IL-10 in their splenocytes.Plant Cell Tissue and Organ Culture 06/2013; 113(3). DOI:10.1007/s11240-013-0290-6 · 2.61 Impact Factor
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ABSTRACT: Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.Current Medicinal Chemistry 03/2012; 19(12):1751-64. DOI:10.2174/092986712800099811 · 3.85 Impact Factor