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At least 307 records · Page 17Linked to original sources
PubMed2004

Challenges facing adjuvants for cancer immunotherapy.

An adjuvant is defined as a product that increases or modulates the immune response against an antigen (Ag). Based on this general definition many authors have postulated that the ideal adjuvant should increase the potency of the immune response, while being non-toxic and safe. Although dozens of different adjuvants have been shown to be effective in preclinical and clinical studies, only aluminium-based salts (Alum) and squalene-oil-water emulsion (MF59) have been approved for human use. However, for the development of therapeutic vaccines to treat cancer patients, the prerequisites for an ideal cancer adjuvant differ from conventional adjuvants for many reasons. First, the patients that will receive the vaccines are immuno-compromised because of, for example, impaired mechanisms of antigen presentation, non-responsiveness of activated T cells and enhanced inhibition of self-reactivity by regulatory T cells. Second, the tumour Ag are usually self-derived and are, therefore, poorly immunogenic. Third, tumours develop escape mechanisms to avoid the immune system, such as tumour editing, low or non-expression of MHC class I molecules or secretion of suppressive cytokines. Thus, adjuvants for cancer vaccines need to be more potent than for prophylactic vaccines and consequently may be more toxic and may even induce autoimmune reactions. In summary, the ideal cancer adjuvant should rescue and increase the immune response against tumours in immuno-compromised patients, with acceptable profiles of toxicity and safety. The present review discusses the role of cancer adjuvants at the different phases of the generation of antitumour immunity following vaccination.

Adjuvants, Immunologic↗
PubMed2000

Cancer immunotherapy targeting Wilms' tumor gene WT1 product.

The Wilms' tumor gene WT1 is expressed at high levels not only in acute myelocytic and lymphocytic leukemia and in chronic myelocytic leukemia but also in various types of solid tumors including lung cancers. To determine whether the WT1 protein can serve as a target Ag for tumor-specific immunity, three 9-mer WT1 peptides (Db126, Db221, and Db235), which contain H-2Db-binding anchor motifs and have a comparatively higher binding affinity for H-2Db molecules, were tested in mice (C57BL/6, H-2Db) for in vivo induction of CTLs directed against these WT1 peptides. Only one peptide, Db126, with the highest binding affinity for H-2Db molecules induced vigorous CTL responses. The CTLs specifically lysed not only Db126-pulsed target cells dependently upon Db126 concentrations but also WT1-expressing tumor cells in an H-2Db-restricted manner. The sensitizing activity to the Db126-specific CTLs was recovered from the cell extract of WT1-expressing tumor cells targeted by the CTLs in the same retention time as that needed for the synthetic Db126 peptide in RP-HPLC, indicating that the Db126-specific CTLs recognize the Db126 peptide to kill WT1-expressing target cells. Furthermore, mice immunized with the Db126 peptide rejected challenges by WT1-expressing tumor cells and survived for a long time with no signs of autoaggression by the CTLs. Thus, the WT1 protein was identified as a novel tumor Ag. Immunotherapy targeting the WT1 protein should find clinical application for various types of human cancers.

Animals↗
PubMed2002

WT1 as a novel target antigen for cancer immunotherapy.

Wild-type Wilms' tumor gene WT1 is expressed at high levels not only in most of acute myelocytic, acute lymphocytic, and chronic myelocytic leukemia, but also in various types of solid tumors including lung cancer. We tested the ability of the gene product (WT1) to serve as a target antigen for tumor specific immunotherapy both in human in vitro system and mouse in vivo system. In the latter, we can evaluate the efficacy and the side effects of WT1 vaccination in vivo. In the human in vitro system, two WT1 peptides that contain HLA-A2.1 binding anchor motifs were determined to bind to HLA-A2.1 molecules. Peripheral blood mononuclear cells (PBMC) from an HLA-A2.1-psitive donor were repeatedly stimulated in vitro with TAP-deficient T2 cells pulsed with each of these two peptides, and CD8-positive cytotoxic T lymphocytes (CTLs) that specifically lyse WT1-expressing, HLA-A2.1-positive tumor cells were induced. Other groups also have succeeded in generating CTLs which specifically lyse WT1-expressing leukemia cells, and which do not inhibit colony-formation of normal hematopoietic cells that express WT1 at physiological levels. In the mouse in vivo system, immunization of C57BL/6 mice with one WT1 peptide with relatively high binding affinity for H-2D(b) molecules, which contain H-2D(b) binding anchor motifs, induced CTLs, which specifically lysed WT1-expressing tumor cells in an H-2D(b)-restricted manner. Furthermore, mice immunized with the WT1 peptide (peptide vaccination) or WT1 cDNA (DNA vaccination) rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to WT1-expressing normal organs by the induced CTLs. The WT1 protein has been identified as a novel tumor antigen and recent investigations provide a rationale for developing WT1-based adoptive T cell therapy and vaccination against various kinds of malignant neoplasms.

Animals↗
PubMedDate not supplied

Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone.

Our preliminary studies in humans have shown that the pineal neurohormone melatonin (MLT) may enhance the antitumor activity of IL-2, by confirming the existence of a neuroendocrine control on cytokine effects. On this basis, a study was started to evaluate the influence of a concomitant administration of MLT and low-dose IL-2 in cancer patients, who had progressed during a previous immunotherapy with IL-2 alone. The study included 14 patients with advanced solid tumors (lung 6; kidney 4; stomach 2; liver 1; melanoma 1). IL-2 was given at a daily dose of 3 million IU s.c. for 6 days/week for 4 weeks. MLT was given orally at a daily dose of 40 mg every day, starting 7 days prior to IL-2. Objective tumor regression, consisting of a partial remission (PR), was achieved in 3/14 (21%) patients (lung 1; kidney 1; liver 1). Six other patients had a stable disease (SD), while the remaining 5 cases progressed. PR and SD were associated either with a significantly longer survival at 1 year, or with a significantly higher increase in lymphocyte and eosinophil mean number with respect to the patients with disease progression. This preliminary study suggests that advanced solid neoplasms resistant to IL-2 may become responsive to IL-2 therapy by a concomitant administration of the pineal hormone MLT, which could act by enhancing IL-2 antitumor immune effect and/or by increasing the susceptibility of cancer cells to the cytolysis mediated by IL-2-induced cytotoxic lymphocytes.

Aged↗
PubMed2003

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy.

Intravesical bacillus Calmette-Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS- and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer.

Adjuvants, Immunologic↗
PubMed2004

Cancer immunotherapy with chemoattractant peptides.

The chemokine/chemokine receptor network is an essential part of an intricate system of immunosurveillance and homeostasis, it promotes or suppresses neovascularization, affects and regulates directly or indirectly growth and metastasis of malignant cells. Numerous studies have been conducted to harness this network as therapeutic agents for cancer to redress the chemokine balance and control angiogenesis and tumour growth and metastasis. Second generation of immunotherapeutics and chemoattractant-based vaccines use chemokines and chemoattractant peptides to elicit antitumor immunity by a specific targeting and modulating subsets of effector leukocytes, including professional antigen presenting cells.

Animals↗
PubMed2005

HER-2: a biomarker at the crossroads of breast cancer immunotherapy and molecular medicine.

The oncoprotein encoded by the HER-2 oncogene is a member of the HER family of receptor tyrosine kinases and is actually the first successfully exploited target molecule in new biomolecular therapies of solid tumors. The association of HER-2 overexpression with human tumors, its extracellular accessibility, as well as its involvement in tumor aggressiveness are all factors that make this receptor an appropriate target for tumor-specific therapy. In addition, HER-2 overexpression fosters its immunogenicity, as shown by the frequency of B and T cell-mediated responses against this oncoprotein in cancer patients, and it is being investigated as a promising molecule for either passive and active immunotherapy strategies. This review summarizes a number of immune intervention approaches that target HER-2 in breast cancer.

Animals↗
PubMed1987

Adjuvant specific active lung cancer immunotherapy trials. Tumor-associated antigens.

The 10-year cumulative experiences of five year survivals of patients entered into a successful phase II specific active tumor-associated antigen (TAA) immunotherapy trial, a successful phase III specific active immunotherapy trial A and of patients from centers with acceptable protocol violation levels of an unsuccessful specific active immunotherapy trial B are evaluated. Here the authors report the efficacy of specific active TAA immunotherapy when the protocol is adhered to strictly, where the induction of cell-mediated immunity to TAA indicated a successful adherence to the protocol rather than the strategic result when centers from the third trial with major violations are included. The authors repeat here a summary of each of the three separate trials, each of the three trials having been reported elsewhere in their entirety, so that these total results may be compared to the present analysis. The survival experiences of a total of 234 lung cancer Stage I and Stage II patients, including all violations, from centers in northern New York, northern New Jersey, western Pennsylvania and eastern Canada show a statistically valid (P = 0.0002) 5-year survival difference between the control groups (receiving adjuvant alone or no treatment) at 49% survival and the specific active immunotherapy groups at 69% survival. The best promise of specific active immunotherapy alone in an adjunctive treatment setting is with early stage lung cancer. In addition to tests which monitor the effect of TAA immunotherapy induction of long-lasting cell-mediated immunity, tests (monoclonal antibody-derived epitope enzyme immunoassays) were developed to monitor specific, early antibody rises in the bloodstream (circulating humoral immunity).

Adjuvants, Immunologic↗
PubMed2000

Antigen-specific cancer immunotherapy using a GM-CSF secreting allogeneic tumor cell-based vaccine.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cell-based vaccines are currently one of the major forms of cancer vaccines. However, the preparation of GM-CSF-transduced autologous tumor vaccines is time-consuming and technically challenging. In addition, the host antigen presenting cells, rather than the tumor vaccine cells themselves, present tumor-specific antigens and prime the host T cells. Therefore, we tested the efficacy of antigen-specific allogeneic tumor vaccines. We used human papillomavirus 16 (HPV-16) E7 protein as a model tumor antigen, which is associated with the development of most cervical carcinoma. B16, a C57BL/6 (H-2(b)) derived melanoma cell line, was genetically engineered to produce GM-CSF alone (B16GM), HPV-16 E7 alone (B16E7), or both (B16GME7). These vaccine cells were injected into BALB/c (H-2(d)) mice (10(6) cells/mouse). Two weeks later, mice were challenged with 10(5) live HPV-16 E7(+) BL-1 (H-2(d)) tumor cells and monitored for tumor progression twice weekly. To determine the effective cell population in the antitumor immunity elicited by B16GME7, we carried out in vivo antibody depletion experiments using CD4 and CD8 specific antibodies. In addition, as a measure of the immune responses produced by B16GME7, we performed an in vitro cytotoxic T lymphocyte assay using a standard chromium release method. We found that all of the mice vaccinated with B16GME7 remained tumor free 49 days post-BL-1 challenge. In contrast, mice vaccinated with B16GM and B16E7 did not show any tumor protection against a similar dose of BL-1 cells. Furthermore, the antitumor immunity produced by B16GME7 was dependent on both CD4 and CD8 T cells. In addition, E7-specific cytotoxic T lymphocyte activity could be readily demonstrated in mice immunized with B16GME7. These results suggest that allogeneic tumor cells transduced with GM-CSF and the tumor antigen, HPV-16 E7, cannot only generate an E7-specific cytotoxic T lymphocytes response in vitro, but can also elicit a potent antitumor immune response against an E7 expressing tumor in vivo.

Animals↗
PubMed2003

Combination of monocyte-derived dendritic cells and activated T cells which express CD40 ligand: a new approach to cancer immunotherapy.

Interactions between dendritic cells (DCs) and activated T cells are critically important for the establishment of an effective immune response. To develop the basis for a new DC-based cancer vaccine, we investigated cell-to-cell interactions between human monocyte-derived DCs and autologous T cells that are activated to express the CD40 ligand (CD40L). Peripheral blood monocytes were cultured in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) to induce differentiation of DCs. Activated T cells (ATs) consisted of autologous peripheral blood lymphocytes that had been activated with phytohemagglutinin (PHA) and then stimulated with calcium ionophore to up-regulate expression of CD40L. Coculture of these DCs and ATs induced significant production of interleukin 12 (IL-12) and also enhanced the production of interferon gamma (IFN-gamma). The production of IL-12 was blocked by an anti-CD40L antibody or by separation of the DC and AT fractions by a permeable membrane. Furthermore, coculture of DCs and ATs induced DCs to upregulate CD83 expression and stimulated migration of DCs toward the macrophage inflammatory protein 3-beta (MIP-3beta). ATs also migrated toward the MIP-3beta. These results suggest a combination of DCs and ATs as a potentially effective therapeutic strategy.

Angiogenesis Inhibitors↗
PubMed2005

Insights into peptide-based vaccine design for cancer immunotherapy.

The presentation of peptides derived from tumor associated proteins (TAAs) by the major histocompatibility complex (MHC) to T cell receptor (TcR) initiates a cascade of events that constitute the immune response. Eliciting an effective immune response, however, requires the coordinated regulation of both the cellular and humoral arms of the immune system. The design of effective peptide-based vaccines for cancer immunotherapeutic applications, therefore, requires intimate knowledge and understanding of peptide-MHC (pMHC) as well as TcR-pMHC interactions. Despite the wealth of information available to date from X-ray crystallographic and biological studies, the task of rationally designing peptide-based vaccines that can effectively prevent and/or treat cancer cell proliferation remains challenging. The complexity of interactions involved are not readily predictable and are further complicated by the involvement of surrounding molecules in vivo, which can lead to reduced biological activity and/or unwanted side effects. Furthermore, the delivery of peptide-based vaccines into the cell, for further processing and presentation to effector cell, represents an additional challenge which needs to be addressed. The incorporation of appropriate chemical entities into peptide-based vaccines can improve cellular uptake thereby enhancing biological activity. Finally, the susceptibility of peptide-based vaccines to enzymatic degradation warrants the need for the incorporation of non-natural amino acids, retro-inversion and/or cyclization to improve bioavailability essentially reducing the required dosage with minimum side effects.

Antigens, Neoplasm↗
PubMed2003

Immunobiology of HER-2/neu oncoprotein and its potential application in cancer immunotherapy.

HER-2/neu (also known as HER2 or c-erb-B2) is a 185-kDa protein receptor with tyrosine kinase activity and extensive homology to the epidermal growth factor (EGF) receptor. HER-2/neu is expressed in many epithelial tumors and known to be overexpressed in approximately 20-25% of all ovarian and breast cancers, 35-45% of all pancreatic adenocarcinomas, and up to 90% of colorectal carcinomas. HER-2/neu overexpression represents a marker of poor prognosis. HER-2/neu-positive tumor cells are potentially good targets for tumor-reactive cytotoxic T lymphocytes which have been utilized in immunotherapeutic trials. In addition, the "humanized" monoclonal antibody Herceptin has been tested in several clinical trials and proved to be an effective adjuvant therapy for HER-2/neu-positive breast and ovarian cancers. Vaccinations aiming at generating T-cell responses are being examined in both experimental and clinical trials. Natural immunity at the level of T and B cells has been observed in patients with HER-2/neu-positive tumors confirming the immunogenicity of HER-2/neu and encouraging vaccination trials with HER-2 protein-derived subunits or synthetic peptides. This review summarizes recent data from patients with various types of HER-2/neu-overexpressing cancers carrying different HLA alleles and exhibiting preexistent immunity to HER-2/neu-derived synthetic peptides. It also discusses potential advantages of the various vaccination approaches to immunotherapy targeting the HER-2/neu molecule.

Antibodies, Monoclonal↗
PubMed2001

Development of a clinical-scale method for generation of dendritic cells from PBMC for use in cancer immunotherapy.

BACKGROUND: There is growing interest in the use of dendritic cells (DCs) for treatment of malignancy and infectious disease. Our goal was to develop a clinical scale method to prepare autologous DCs for cancer clinical trials. METHODS: PBMC were collected from normal donors or cancer patients by automated leukapheresis, purified by counterflow centrifugal elutriation and placed into culture in polystyrene flasks at 1 x 10(6) cells/mL for 5-7 days at 37 degrees C, with 5% CO(2), with IL-4 and GM-CSF. Conditions investigated included media formulation, supplementation with heat in activated allogeneic AB serum or autologous plasma and time to harvest (Day 5 or Day 7). DCs were evaluated for morphology, quantitative yield, viability, phenotype and function, including mixed leukocyte response and recall response to tetanus toxoid and influenza virus. RESULTS: DCs with a typical immature phenotype (CD14-negative, CD1a-positive, mannose receptor-positive, CD80-positive, CD83-negative) were generated most consistently in RPMI 1640 supplemented with 10% allogeneic AB serum or 10% autologous plasma. Cell yield was higher at Day 5 than Day 7, without detectable differences in phenotype or function. In pediatric sarcoma patients, autologous DCs had enhanced function compared with monocytes from which they were generated. In this patient group, starting with 8.0 +/- 3.7 x 10(8) fresh or cryopreserved autologous monocytes, DC yield was 2.1 +/- 1.0 x 10(8) cells, or 29% of the starting monocyte number. DISCUSSION: In the optimized clinical-scale method, purified peripheral monocytes are cultured for 5 days in flasks at 1 x 10(6) cells/mL in RPMI 1640, 10% allogeneic AB serum or autologous plasma, IL-4 and GM-CSF. This method avoids the use of FBS and results in immature DCs suitable for clinical trials.

Cell Culture Techniques↗
PubMed1999

Cancer immunotherapy by antisense suppression of Ii protein in MHC-class-II-positive tumor cells.

This study was aimed at creating a more effective tumor cell vaccine by suppressing Ii protein in the presence of MHC class II molecules within a cancer cell. Absence of the Ii protein, which normally blocks the antigenic-peptide-binding site of MHC class II molecules at synthesis in the endoplasmic reticulum, presumably increases the range of cancer-related epitopes presented to CD4+ helper T cells. Effective suppression of Ii protein was achieved with an antisense, phosphorothioate oligonucleotide, which was selected on the basis of (1) the RNase H activation assay, (2) an assay for Ii protein suppression, and (3) a test for potency with respect to the extent of base sequence ("sequence walking"). The SaI murine sarcoma, which is MHC-class-I+ and MHC-class-II-, Ii-protein-, upon transfection with genes for either interferon gamma or the MHC class II transactivator, came to express MHC class II molecules and Ii protein. In each line of transfected tumor cells, the antisense oligonucleotide profoundly suppressed Ii protein in 35%-55% cells, without affecting expression of MHC class II molecules. Inoculation of mice with such Ii-protein-suppressed tumor vaccine cells, after either formaldehyde fixation or X-irradiation, led to much greater protection against challenge with the parental SaI sarcoma than did inoculation with untreated cells. This approach to cancer cell vaccination can be applied in a wide range of human tumors.

Animals↗
PubMed2005

Renewed interest in cancer immunotherapy with the tumor necrosis factor superfamily molecules.

Molecules belonging to the Tumor Necrosis Factor (TNF) and TNF receptor superfamilies have explosively expanded through the era of genomics and bioinformatics. Biological investigations of these molecules have explored their potency as attractive targets for cancer therapy. Anti-tumor mechanisms mediated by TNF superfamily molecules (TNFSF) could be classified into direct actions onto tumor cells and indirect effects through immune or non-immune components of tumor-bearing host. In this review, we focus on TRAIL, CD40, 4-1BB (CD137), and LIGHT as promising molecules to mediate powerful and selective anti-tumor responses, and summarize their unique effector mechanisms. In addition, optimal approaches to manipulate these molecules for cancer therapy are also discussed. We try to provide an insight into a role of TNFSF in cancer therapeutics and highlight each of their potency to be an important player in anti-cancer strategies.

Antigens, CD↗