Use Of Cancer Vaccines Research Articles

Effect of Piceatannol in Human Monocyte-Derived Dendritic Cells In Vitro

Piceatannol is an anti-inflammatory, immunomodulatory, and antiproliferative stilbene that has been shown to interfere with the cytokine signaling pathway. Dendritic cells (DCs) play a pivotal in the initiation of T-cell–mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. This study investigated the effect of piceatannol on the phenotypic and functional maturation of human monocyte-derived DCs in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6days, followed by another 2days in the presence of piceatannol or LPS. DCs harvested on day 8 were examined using functional assays. The expression levels of CD1a, CD80, CD83, and CD86 as expressed by mean fluorescence intensity (MFI) on DCs differentiated from immature DCs after culture with 1 μM of piceatannol for 2days were enhanced and decreased endocytic activity. Piceatannol-treated DCs also displayed enhanced T-cell stimulatory capacity in a MLR, as measured by T-cell proliferation. Similar results were obtained with DCs differentiated with LPS from immature DCs. However, piceatannol did not inhibit phenotypic and functional maturation induced by LPS from immature DCs. Piceatannol-treated DCs induced the differentiation of naive T cells towards a helper T-cell type 1 (Th1) response at DCs/T (1:5) cells ratio depending on IL-12 secretion. These results demonstrate that piceatannol may be used on DC-based vaccine for cancer immunotherapy. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

The Emergence of Modern Cancer Immunotherapy

The Emergence of Modern Cancer Immunotherapy

Recent developments in therapeutic cancer vaccines

Therapeutic cancer vaccines are being developed with the intention of treating existing tumors or preventing tumor recurrence. While the results of clinical trials, predominantly in the metastatic setting have been sobering, the central hypothesis of active immunotherapy i.e. that the human immune system can be activated to recognize and destroy tumor cells, remains a viable one. We believe that a fundamental shift in how clinical trials are performed, and what concepts they test is required to make meaningful strides towards future clinical use of cancer vaccines. First, we must reappraise whether the metastatic setting is the appropriate arena to test these agents. Second, we must arrive at a consensus on the most important biologic endpoints and rapidly test vaccines for their ability to achieve these endpoints. Third, we need to expend more effort on understanding how to manipulate the immune system beyond the initial stimulation provided by a vaccine. Fourth, in order to permit comparison of results across different studies, it would be helpful to narrow down the large number of vaccine platforms. We will discuss the current state of development of cancer vaccines and the relevance for future clinical use of these agents to treat and prevent cancers.

Sublethal Irradiation of Human Tumor Cells Modulates Phenotype Resulting in Enhanced Killing by Cytotoxic T Lymphocytes

Local radiation of tumor masses is an established modality for the therapy of a range of human tumors. It has recently been recognized that doses of radiation, lower than or equal to those that cause direct cytolysis, may alter the phenotype of target tissue by up-regulating gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. Previously, we demonstrated that radiation increased Fas (CD95) gene expression in carcinoembryonic antigen (CEA)-expressing murine tumor cells, which consequently enhanced their susceptibility to CEA-specific CTL-mediated killing. The present study was designed to determine whether these phenomena also occur with human tumor cells. Here, 23 human carcinoma cell lines (12 colon, 7 lung, and 4 prostate) were examined for their response to nonlytic doses of radiation (10 or 20 Gy). Seventy-two hours postirradiation, changes in surface expression of Fas (CD95), as well as expression of other surface molecules involved in T-cell-mediated immune attack such as intercellular adhesion molecule 1, mucin-1, CEA, and MHC class I, were examined. Twenty-one of the 23 (91%) cell lines up-regulated one or more of these surface molecules postirradiation. Furthermore, five of five irradiated CEA(+)/A2(+) colon tumor cells lines demonstrated significantly enhanced killing by CEA-specific HLA-A2-restricted CD8(+) CTLs compared with nonirradiated counterparts. We then used microarray analysis to broaden the scope of observed changes in gene expression after radiation and found that many additional genes had been modulated. These up-regulated gene products may additionally enhance the tumor cells' susceptibility to T-cell-mediated immune attack or serve as additional targets for immunotherapy. Overall, the results of this study suggest that nonlethal doses of radiation can be used to make human tumors more amenable to immune system recognition and attack and form the rational basis for the combinatorial use of cancer vaccines and local tumor irradiation.

Dendritic cell-tumor fusion vaccines for renal cell carcinoma.

Renal cell carcinoma is a malignant disease that demonstrates resistance to standard chemotherapeutic agents. A promising area of investigation is the use of cancer vaccines to educate host immunity to specifically target and eliminate malignant cells. Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely effective in generating primary immune responses. DCs that are manipulated to present tumor antigens induce antitumor immunity in animal models and preclinical human studies. A myriad of strategies have been developed to effectively load tumor antigen onto DCs, including the introduction of individual peptides, proteins, or tumor-specific genes, as well as the use of whole tumor cells as a source of antigen. A promising approach for the design of cancer vaccines involves the fusion of whole tumor cells with DCs. The DC-tumor fusion presents a spectrum of tumor-associated antigens to helper and cytotoxic T-cell populations in the context of DC-mediated costimulatory signals. In animal models, vaccination with DC-tumor fusions resulted in protection from tumor challenge and regression of established metastatic disease. We have conducted phase 1 dose escalation studies in which patients with metastatic breast and renal cancer underwent vaccination with DC-tumor fusions. Twenty-three patients underwent vaccination with autologous DC-tumor fusions. Vaccination was well tolerated without substantial treatment-related toxic effects. Immunologic responses and disease regression were observed in a subset of patients. Future studies will explore the effect of DC maturation and cytokine adjuvants on vaccine potency.

Dendritic cells maturation promoted by M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, drive a potent Th1 polarization

Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Dendritic cells (DCs) play a pivotal in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. In this study, we investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, can drive DCs maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days, followed by another 2 days in the presence of M1, M4 or TNF-α as a maturation stimulus. Stimulation with 20 μM of M1 or M4 increased expression level of CD80, CD83 and CD86 as expressed by mean fluorescence intensity (MFI) and decreased endocytic activity. M4-primed mature DCs also displayed enhanced T cells stimulatory capacity in a MLR, as measured by T cell proliferation. Mature DCs differentiated with M1 or M4 induced the differentiation of naı̈ve T cells towards a helper T cell type 1 (Th1) response at DC/T (1:5) cells ratio depending on IL-12 secretion. In CTL assay, the production of IFN-γ and 51 Cr release on M4-primed mature DCs was more augmented than of immature DCs or TNF-α-primed mature DCs. These results suggest that M4 may be used on DC-based vaccines for cancer immunotherapy.

352. Intentional Killing of Normal Melanocytes by Gene Transfer Generates Curative Anti Melanoma Immunity without Obligate Autoimmunity

Most tumor vaccination strategies depend upon the molecular identification of specific tumor rejection antigens and/or the use of patient derived tumor materials. In addition, there is a strong correlation between the use of cancer vaccines and the induction of autoimmune reactivity. We hypothesised that in situ, inflammatory killing of a normal tissue from which a tumor derives may generate autoimmune reactivity to self antigens expressed in that tissue as well as in the tumor cells. Here we report that simple intradermal injection of 2 plasmids promoted tissue specific, inflammatory killing of melanocytes and induced an immune response that eradicated systemically established B16 tumors. The therapeutic response was CD8+T cell dependent but, significantly, was rapidly suppressed in vivo and did not induce autoimmune disease in animals in which tumors had been cured. The T cell response was characterized by selection of B16 tumor variants which grow extremely aggressively in vivo, are amelanotic and which have lost expression of the tyrosinase and TRP-2 antigens. The mechanism of antigen loss was, at least in part, through epigenetic mechanisms. These could be reversed by long term growth in culture or, more rapidly, by treatment with the de-methylating agent 5-azacytidine. Depletion of putative regulatory T cells within the CD25+ T cell population improved therapeutic efficacy. Finally, vaccination could be further improved using adoptive transfer of activated T cells with specificity for an antigen that was not a target of the initial T cell response raised by melanocyte killing. These data demonstrate that inflammatory killing of a normal tissue can lead to the immunoselection of tumor cell growth variants. They also raise the prospect that such vaccinations could be effectively used in combination with other conventional anti tumor treatment modalities.

Dendritic cell KLH loading requirements for efficient CD4 + T-cell priming and help to peptide-specific cytotoxic T-cell response, in view of potential use in cancer vaccines

This study focuses on a Keyhole Limpet Hemocyanin (KLH) adjuvant strategy to augment efficacy of dendritic cell-based vaccines that use class I-restricted peptides. Requirements for loading dendritic cells (DC) with KLH were first determined in order to optimally prime CD4 + T cells. These KLH-loaded cells were pulsed with antigenic peptide and cultured with T cells to induce a cytotoxic T lymphocyte (CTL) response against the peptide. Such a concomitant presentation of KLH and peptide by the same DC strongly augmented the peptide-specific CTL response, as compared to the response induced by DC pulsed with the peptide alone. This adjuvant effect was more pronounced for poorly immunogenic antigens. The use of optimised peptide and KLH-loaded DC may improve the efficacy of therapeutic anti-tumour peptide vaccination.

Efficient Synthesis of Ganglioside GM2 for Use in Cancer Vaccines

A target antigen for cancer immunotherapy, ganglioside GM2, is expressed on the cell surface of several human cancer types. An efficient chemical synthesis can now make available ample amounts of a structurally well-defined synthetic GM2, free of biological contaminants. This greatly facilitates the systematic construction of safe and efficient GM2 cancer vaccines.

Considerations for the Use of Cytokine-Secreting Tumor Cell Preparations for Cancer Treatment

Limited efficacy of chemotherapy in most solid tumors has revived interest in immunotherapeutic approaches for cancer. One novel form of immunotherapy is the use of cancer vaccines consisting of tumor cells genetically engineered to secrete cytokines. The rationale for this immunization strategy is based on the existence of tumor-specific antigens, on the importance of the cellular arm of the immune system in mediating an effective antitumor response, and on the role of cytokines in regulating the cellular immune response. Such tumor vaccines showed considerable promise in various animal models and induced potent antitumor immunity in the host, which led to regression of established tumors and, moreover, produced immunological memory protecting animals from a subsequent tumor challenge at a distant site. Translated to the human patient, this implies that genetically modified tumor vaccines may be able to eradicate or reduce existing tumor deposits to subclinical levels as well as provide long-term protection from regrowth of tumor cells. This report will review and discuss the concept and rationale for the use of cytokine-secreting tumor vaccines for the treatment of human malignancies.

Active Specific Immunotherapy – A New Modality of Cancer Treatment Involving the Patient’s Own Immune System

This review deals with active specific immunotherapy (ASI) – a type of cancer immunotherapy which involves the use of cancer vaccines for active immunization of cancer patients. It starts with theoretical foundations, then summarizes preclinical data from animal models and then presents and discusses clinical observations from respective immunotherapy trials. Based on new insights into T-cell stimulation (two-signal activation) and on own experience in immunological cancer rejection in metastasizing animal tumor models, we propose for ASI studies the use of a two-component cancer vaccine for postoperative active immunization. As a specific component, we use intact, viable, radiation-inactivated autologous tumor cells, which should represent the closest match to a patient’s own cancer. If this is not possible, cells from allogeneic corresponding tumors or from homologous tumor cell lines could be used. As a second nonspecific component, we have good experience with a virus, the Newcastle Disease Virus (NDV), which can easily attach to the cells of the vaccine to facilitate the delivery of costimulatory signals to tumor-reactive T cells. Clinical experience with ASI and variables of potential importance for the design of cancer vaccines are also reviewed.