Enhancing the potency of a whole-cell breast cancer vaccine in mice with an antibody-IL-2 immunocytokine that targets exposed phosphatidylserine
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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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: The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra- tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies.Human Vaccines & Immunotherapeutics 09/2013; 10(1). DOI:10.4161/hv.26568 · 3.64 Impact Factor
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ABSTRACT: The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as Interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2–treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.Cytokine & Growth Factor Reviews 08/2014; 25(4). DOI:10.1016/j.cytogfr.2014.07.018 · 6.54 Impact Factor