Use of Spontaneous Epstein-Barr Virus-Lymphoblastoid Cell Lines Genetically Modified to Express Tumor Antigen as Cancer Vaccines: Mutated p21rasOncogene in Pancreatic Carcinoma as a Model
Boris KubuschokRudolf SchmitsFrank HartmannChristiane CochloviusRainer BreitJ. KönigG. PistoriusMartin SchillingChristoph RennerMichael Pfreundschuh
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Abstract:
Spontaneous Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (SP-LCLs) can be easily obtained from latently EBV-infected cancer patients and used as a source of antigen-presenting cells (APCs) for immunotherapy. Using point-mutated (codon 12) p21(ras) (muRas) as a model tumor antigen, we evaluated the practicability of using genetically modified SP-LCLs as cancer vaccines for patients with pancreatic cancer expressing mutated Ras (muRas). The repeated stimulation of peripheral blood mononuclear cells (PBMCs) from patients with muRas-LCLs elicited a strong, muRas-specific T cell response. A significant cytotoxic activity against EBV virus proteins or components of the expression vector was not observed. The T cells were able to recognize naturally presented muRas, as shown by their cytotoxicity against muRas (Gly-12 to Val-12 or Asp-12)-expressing tumor cells. The T cell response was mainly MHC class I restricted, and peptides containing amino acids 5 to 14 of muRas-Val-12 and muRas-Asp-12 were identified as immunogenic peptides for HLA-A2. In contrast to the situation in patients with putatively muRas-primed T cells, muRas-LCLs were not able to prime naive T lymphocytes from healthy controls. Vaccination of a pancreatic cancer patient with muRas-LCL induced muRas-specific T cells in PBMCs after 4 weeks. We conclude that genetically modified muRas-LCLs can efficiently present tumor antigens to the immune system and induce antigen-specific cytotoxic T cell responses in vitro and in vivo.Keywords:
Cancer Immunotherapy
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The critical role of antigen-specific T-cells in the eradication of cancer has been demonstrated in numerous animal models, while significant challenges need to be conquered before antigen-specific T-cell immunotherapy can achieve true success in clinical practice. These challenges include: (1) weak or nonimmunogenicity of spontaneous tumors, (2) negative immune regulation mechanisms of the host immune system, (3) immune inhibition exerted by tumor cells, (4) physical barrier in solid tumor, and (5) escape or resistance to immune attack by tumor cells. Nonetheless, significant success has been achieved in several clinical trials recently, highlighting the possibility of successful manipulation of the immune system for control and elimination of tumor. We focused our study on summarizing the current knowledge and corresponding strategies for improving autologous cytotoxic T-cell (CTL)-based cancer immunotherapy, which include the following aspects: (1) the selection of tumor antigens for stimulation of CTL, (2) strategies of enhancing maturation and antigen presentation activity of dendritic cells (DC), (3) strategies of activation and maintenance of CTL response, and (4) recruitment of suitable immune effector cells to tumor sites. The successful manipulation of the immune system, based on the more and more detailed knowledge of tumor immunology, may finally reach the goal of "immune surveillance of malignancy."
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Immunotherapy is a type of cancer treatment that works by harnessing the power of the immunesystem to recognize and attack cancer cells. Unlike traditional cancer treatments likechemotherapy and radiation therapy, which directly target cancer cells, immunotherapy aims toboost the body's natural defenses against cancer. The immune system is a complex network ofcells, tissues, and organs that work together to protect the body against harmful invaders likeviruses, bacteria, and cancer cells. Normally, the immune system is able to recognize and destroycancer cells as they develop, but sometimes cancer cells can evade detection and continue togrow and spread. Immunotherapy works by stimulating the immune system to recognize andattack cancer cells more effectively.
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The influenza A virus nucleoprotein (NP) and matrix protein are major targets for human virus-specific cytotoxic T-lymphocyte (CTL) responses. Most of the CTL epitopes that have been identified so far are conserved. However, sequence variation in CTL epitopes of the NP has recently been demonstrated to be associated with escape from virus-specific CTLs. To assess the extent of variation in CTL epitopes during influenza A virus evolution, 304 CTL clones derived from six study subjects were obtained with specificity for an influenza A/H3N2 virus isolated in 1981. Subsequently, the frequency of the CTL clones that failed to recognize a more recent influenza virus strain isolated in 2003 was determined. In four of six study subjects, CTLs were found to be specific for variable epitopes, accounting for 2.6 % of all CTL clones. For some of these CTL clones, the minimal epitope and the residues responsible for abrogation of T-cell recognition were identified.
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BACKGROUND AND METHODS The ability of peripheral blood mononuclear cells (PBMC) to generate cytotoxic T lymphocytes (CTL) that react against alloantigens was evaluated in hemophilic patients (He) with or without human immunodeficiency virus (HIV) infection. RESULTS AND CONCLUSIONS We demonstrated that PBMC from HIV seronegative and seropositive He had a decreased response when compared to normal controls. The decreased CTL response to alloantigens may be due to the immunosuppressive effects of factor VIII or IX concentrates, as well as to the different pathway of HIV infection when compared to other acquired immunodeficiency syndrome risk groups.
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Abstract Considerable controversy has arisen regarding the Ly phenotypes of cytotoxic T lymphocytes (CTL) and their precursors (CLP) to alloantigens and modified-self antigens. Although there is general agreement that all CTL and their pregenitors express the Ly2 alloantigen, the presence of the LY1 alloantigen on either CTL or CLP is debated. Clonal assays for CLP, capable of detecting single CLP in the absence of accessory cells, have recently been developed. This assay system provides a sensitive means of determining the Ly phenotypes of CLP to alloantigens or trinitrophenyl- (TNP) modified self antigens. Lymph node cells from C57BL/6 (Ly-1.2, 2.2, 3.2) or CBA (Ly-1.1, 2.1, 3.2) mice were treated with anti-Ly serum and complement (C), and the frequencies of CLP of the treated populations to alloantigens or TNP-modified self antigens were determined. We found that the number of CLP reactive to alloantigens or TNP-modified self antigens were greatly reduced after treatment with either anti-Ly-1 or anti-Ly-2 serum and C in both C57BL/6 and CBA mice. In other words, the CLP to alloantigens or TNP-modified self antigens in these 2 strains of mice are Ly 1+2+. We also found that the CTL derived from the Ly1+2+ CLP were also Ly1+2+. The significance of this finding with respect to the cytotoxic repertoire for alloantigens and modified self antigens is discussed.
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Vaccine-induced cytotoxic T lymphocytes (CTLs) play a critical role in adaptive immunity against cancers. An important goal of current vaccine research is to induce durable and long-lasting functional CTLs that can mediate cytotoxic effects on tumor cells. To attain this goal, there are four distinct steps that must be achieved. To initiate a vaccine-induced CTL antitumor immune response, dendritic cells (DCs) must capture antigens derived from exogenous tumor vaccines in vivo or autologous DCs directly loaded in vitro with tumor antigens must be injected. Next, tumor-antigen-loaded DCs must activate CTLs in lymphoid organs. Subsequently, activated CTLs must enter the tumor microenvironment to perform their functions, at which point a variety of negative regulatory signals suppress the immune response. Finally, CTL-mediated cytotoxic effects must overcome the tolerance induced by tumor cells. Each step is a complex process that may be impeded in many ways. However, if these steps happen under appropriate regulation, the vaccine-induced CTL antitumor immune response will be more successful. For this reason, we should gain a better understanding of the basic mechanisms that govern the immune response. This paper, based on the steps necessary to induce an immune response, discusses current strategies for enhancing vaccine-induced CTL antitumor immune responses.
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