摘要:

The immunotherapy of cancer is predicated on the belief that it is possible to generate a clinically meaningful antitumor response that provides patient benefit, such as improvement in the time to progression or survival. Indeed, immunotherapeutics with dendritic cells (DC) as antigen-presenting delivery vehicles for cell-based vaccines have already improved patient outcome against a wide range of tumor types (1–9). This approach stimulates the patient's own antitumor immunity through the induction or enhancement of T-cell immunity. It is generally believed that the activity of cytotoxic T lymphocytes (CTL), the cells directly responsible for killing the tumor cells in vivo, are directed by DC. Therefore, the goal of many current designs for DC-based vaccines is to induce strong tumor-specific CTL responses in patients with cancer. In practice, most studies for DC-based cancer vaccine development have focused on the development of methods that can effectively deliver exogenous tumor antigens to DC for cross-priming of CD8+T cells through the endogenous MHC class I processing and presentation pathway (10). To date, many methods have been developed or evaluated for the delivery of defined and undefined tumor antigens to DC. This review provides a brief summary on these methods, the techniques used in these methods, as well as the advantages and disadvantages of each method.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

T-cell activation involves multiple signaling pathways. In this report, we conducted in vitro and in vivo immune function analysis of tumor-draining lymph node (TDLN) cells after anti-CD3/anti-CD28 activation versus anti-CD3 activation alone in a murine tumor model. In cytokine release assays, the doubly activated TDLN cells secreted significantly greater amounts of IFN-&ggr; and GM-CSF in response to specific tumor antigen compared with anti-CD3 activated cells. In adoptive immunotherapy, the doubly activated TDLN cells were more effective in mediating regression of 3-day pulmonary metastases compared with anti-CD3 activated cells. Although there was predominant proliferation of CD8+cells after either activation procedure, the mean-fold expansion of CD4+cells was significantly greater after anti-CD3/anti-CD28 activation than anti-CD3 activation alone. Using magnetic bead-enriched T-cell subsets, we found that either CD4+or CD8+doubly activated TDLN cells could independently mediate tumor regression. Furthermore, the doubly activated CD4+cells were more effective than CD8+cells in adoptive immunotherapy on a per-cell basis. The antitumor activity mediated by CD4+or CD8+cells could be significantly enhanced with the exogenous administration of IL-2. CD28 co-stimulation of tumor-primed lymphoid cells promotes the generation of potent tumor reactive effector cells, particularly CD4+T cells, with antitumor activity in adoptive immunotherapy.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Human rhabdomyosarcoma cells express HER/erbB growth factors receptors. Receptors belonging to this family are overexpressed and play a role in many types of epithelial and neural cancer and have been selected as targets for cancer therapy. In this paper EGF-R, HER-2 and HER-3 receptors were tested as therapeutic targets of immunotoxins in human rhabdomyosarcoma. Rhabdomyosarcoma cells were treated with indirect immunotoxins consisting in primary specific murine monoclonal antibodies recognizing EGF-R, HER-2 and HER-3 followed by secondary F(ab´)2antimouse immunoglobulin linked to saporin-S6, a type 1 ribosome-inactivating protein (RIP) from the seeds ofSaponaria officinalis. The indirect immunotoxin targeting EGF-R caused a significant inhibition in cell growth and protein synthesis and a strong increase in apoptosis in rhabdomyosarcoma cells, whereas indirect immunotoxins against HER-2 and HER-3 were ineffective. The toxic activity of anti-EGF-R immunotoxin was also observed on rhabdomyosarcoma cells expressing low level of EGF-R. EGF-R could be a novel therapeutic target of immunotoxins in human rhabdomyosarcoma.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Successful immunization requires that mature dendritic cells (mDCs) prime T cells in secondary lymphoid tissue (LT). Previously, the authors have shown that LT T cell activation has an increased costimulatory threshold for a proliferative response as compared with peripheral blood (PB) T cells. Therefore, to optimize mDC immunogenicity, DC maturation was studied using LT T cells as responders. While mDCs obtained with soluble CD40Ligand (sCD40L) or a sCD40L/IFN&ggr; combination similarly expressed the CD83 and CCR7 molecules on their membrane, only the latter secreted IL-12. sCD40L/IFN&ggr; mDCs, as compared with sCD40L mDCs, enhanced allogeneic LT T cell proliferation, LT CD4+ cell IFN&ggr; production and LT CD8+ cell cytotoxicity. Enhancement could be predominantly ascribed to IL-12 secreted by sCD40L/IFN&ggr; mDCs and to additional costimulatory signals as shown remarkably in the IFN&ggr; response when IL-12 was neutralized. Therefore, in addition to their membrane phenotype, mDCs to be used in immunization protocols should be assessed for IL-12 secretion as a surrogate marker for an optimum costimulatory potential.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Interest in semi-allogeneic vaccines has been increasing, as demonstrated by the publication of successful preclinical and clinical studies by others and us that validate this immunotherapeutic approach to cancer and HIV-infection. We now report that lymphocytes from an HLA-A2+melanoma patient, stimulated with a GP100-derived epitope and semi-allogeneic hybrids, lysed target cells presenting this peptide more efficiently than lymphocytes stimulated with GP100 peptide alone. Phenotypic analysis with GP100/HLA-A2 tetramer complexes also demonstrated a significant increase in the size of the GP100-specific CD8+lymphocyte pool when PBMC were stimulated with both peptide and semi-allogeneic hybrids. Analyses of PBMC from other donors further suggest that this stimulatory effect of semi-allogeneic hybrids results from an increase in the HLA-restricted recall response of CD8+cytotoxic T lymphocytes against melanoma-derived antigens. Likewise, lymphocytes from an HIV-infected patient that had been stimulated with a mixture of HIV-derived peptides and semi-allogeneic hybrids also demonstrated significantly greater antigen-specific cytotoxicity and tetramer reactivity compared with those lymphocytes that had been stimulated with peptides alone.Our approach should provide useful information for the design of future clinical studies treating patients with melanoma or HIV with therapeutic vaccines consisting of a combination of semi-allogeneic hybrids and immunodominant antigenic peptides.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The identification of HLA restricted immune dominant cytotoxic T cell (CTL) epitopes limits immune therapy. Cytomegalovirus (CMV) disease remains a significant cause of morbidity after allogeneic stem cell transplantation. Adoptive immune therapy using CTLs stimulated with immune dominant CMV pp65 peptides may be effective in preventing CMV disease, but immune dominant CMV peptides have been identified for only a few HLA class I molecules. The purpose of this study was to use a novel molecular system to establish a rapid and precise method to identify new HLA-restricted CMV epitopes. Cytomegalovirus pp65 peptides expected to bind to the HLA-24 molecule were identified with a computer algorithm. Five candidate peptides were screened by direct ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) from CMV-seropositive HLA-A*2402 individuals, and quantitative real time PCR (qRT-PCR) was used to evaluate CTL responses by measuring interferon-&ggr; (IFN-&ggr;) transcripts. One of the five candidate peptides, pp65341–350(QYDPVAALFF), induced significant quantities of IFN-&ggr; mRNA production after 3 hours. PBMCs from CMV-seropositive HLA-A*2402 individuals sensitized in vitro with pp65341–350also recognized CMV-infected targets. In conclusion, the measurement of IFN-&ggr; mRNA by qRT-PCR can be used to detect CTL responses 3 hours after peptide stimulation of a small quantity of PBMCs. This method has an advantage over other methods used to identify immune dominant epitopes in that it does not require in vitro expansion of CTLs with cytokines or virally infected targets. As a result, this method measures naturally induced immune reactions.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Advanced renal cell carcinoma is a chemoresistant disease. Immunotherapy with alpha interferon or interleukin (IL)-2 has produced response rates of approximately 15%, but better treatments are needed. IL-4 is a cytokine produced by activated CD4+ lymphocytes and has pluripotent activities including inhibiting the in vitro proliferation of human renal cell carcinoma cell lines. In this trial, patients were required to have a histologic diagnosis of renal cell adenocarcinoma with measurable disease and performance status (SWOG) of 0–1. Patients had to have adequate bone marrow, renal, and hepatic function as well as no clinically significant pulmonary or cardiac dysfunction. IL-4 was given by subcutaneous injection at a dose of 5 &mgr;g/kg/d, daily for 28 days followed by a 7-day rest period. Fifty-eight patients were registered with seven patients ineligible and two patients not analyzable because they did not receive treatment. In the 49 eligible and analyzable patients, there were no confirmed complete or partial responses. There was one unconfirmed partial response in retro-caval lymph nodes, but no verifying measurement was done. There were seven patients with stable disease, no response, 25 with increasing disease/progression, and 16 patients whose assessment was inadequate to determine response. The median time to progression was 3 months, and the median survival was 13 months. Toxicity was significant with the most common side effects nausea, vomiting, or diarrhea, followed by headache/pain and malaise/fatigue/lethargy. There were 13 instances of grade 4 toxicity that occurred in nine different patients. Unique toxicities included Bell's palsy in three patients and hypoglycemia in a previously well-controlled diabetic. Despite promising growth inhibitory and immunologic effects, IL-4 in this dose and schedule is not useful for the treatment of patients with disseminated renal cell carcinoma.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Adoptive immunotherapy with anti-CD3-expanded lymphocytes from lymph nodes draining alloantigen gene-modified autologous tumor vaccines is an effective treatment of poorly immunogenic murine tumors. This phase I/II study was performed to determine the feasibility and toxicity of combining ex vivo gene transfer of autologous tumor cells and adoptive immunotherapy with anti-CD3-expanded tumor vaccine draining lymph node lymphocytes (TVDLN) in patients with metastatic melanoma and renal cell cancer (RCC). To facilitate the generation of tumor-specific lymphocytes in the TVDLN, autologous tumor cells were modified by gene transfer ex vivo to express the alloantigen HLA-B7, a modification that has the potential to enhance the immunogenicity of the tumor cells. After vaccination with gene-modified tumor cells, patients' lymph nodes were harvested; TVDLN lymphocytes were activated and expanded ex vivo with anti-CD3 and interleukin-2 (IL-2), and adoptively transferred to patients in combination with systemic IL-2. Twenty patients, nine with melanoma and 11 with RCC were treated. Tumor was harvested successfully in all 20 patients. Ex vivo gene transfer was performed using lipofection with a lipid: DNA plasmid complex containing the genes for HLA-B7 and &bgr;2-microglobulin. The mean expression of HLA-B7 by autologous tumor cells after gene transfer was 4.53% (range 0.3%–12.1%). Lymph nodes were harvested from all 20 patients with a mean of 53 × 107and 60 × 107cells obtained from the gene-modified and unmodified tumor vaccine sites, respectively. Successful expansion of adequate TVDLN was accomplished in 19 of 20 harvests of unmodified vaccines and in 18 of 20 gene-modified vaccines. No major toxicities were noted after vaccination with autologous tumor cells or adoptive transfer of ex vivo activated TVDLN lymphocytes. Typical IL-2-related toxicities were observed in all patients. No objective tumor regressions were observed. MHC class I restricted, tumor-specific cytokine secretion was observed in lymphocytes from TVDLN and the peripheral blood of vaccinated patients.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Interleukin-2 is an effective agent against renal cell carcinoma and melanoma, but it has been associated with autoimmune sequelae such as hypothyroidism and vitiligo. A 64-year-old man with non-insulin-dependent diabetes and metastatic renal cell carcinoma developed insulin-dependent diabetes after his first cycle of therapy with high-dose (HD) interleukin-2. After additional therapy with interleukin-2, the patient developed generalized myasthenia gravis (MG) and polymyositis, both of which responded to treatment with corticosteroids and plasmapheresis. To investigate the role of IL-2 in the development of these autoimmune complications, autoantibody titers were assayed from serum obtained before and after IL-2 treatment and after treatment with corticosteroids plus plasmapheresis. Before IL-2 treatment, the patient had antibodies directed against insulin, islet cell antigens, and striated muscle. Acetylcholine receptor antibody levels were normal before starting IL-2. After treatment with IL-2, the patient developed acetylcholine receptor binding antibodies and exhibited an increase in the striated muscle antibody titer from 1:40 to 1:160. Recovery from the MG and polymyositis was associated with substantial decreases in the acetylcholine receptor and striated muscle antibody titers. These findings suggest that HD IL-2 accelerated the progression of latent autoimmune diabetes and myositis in this patient whose tolerance to islet cell antigens and striated muscle had already been broken and precipitated a break in tolerance to the acetylcholine receptor resulting in the development of MG. This case demonstrates the importance of prompt recognition of IL-2-induced MG and shows how this complication can be successfully managed with aggressive therapy.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID