摘要:

NY-ESO-1 is an attractive candidate tumor antigen for the development of immunotherapies for a wide variety of cancers. It is expressed in multiple types of tumors, but its normal tissue distribution is predominantly limited to the testes and ovaries; furthermore, both humoral and cellular immune responses can be mounted against this protein. Three overlapping HLA-A2.1–restricted T-cell epitopes have been identified within NY-ESO-1. In this investigation, the authors evaluated the in vitro immunogenicity of these peptides. From 2 of 12 HLA-A2.1+patients with metastatic melanoma, peptide-reactive cytotoxic T-lymphocytes were generated using either NY-ESO-1:157–167 or NY-ESO-1:157–165 but not NY-ESO-1:155–163. Because NY-ESO-1:157–165 is a 9 amino acid peptide completely contained within NY-ESO-1:157–167, it seemed likely that this peptide was the minimal determinant, and thus it was selected for continued study. An amino acid substitution of C to V was introduced into NY-ESO-1:157–165 at P9 to attempt to improve its immunogenicity by enhancing its binding affinity to HLA-A2.1 and increasing its stability in solution, because the C residue is readily oxidized, leading to dimerization of the peptide. From 5 of 20 HLA-A2.1+patients with metastatic melanoma, NY-ESO-1:157–165(165V) stimulated cytotoxic T-lymphocytes in vitro, which recognized peptide-pulsed target cells and HLA-A2.1+NY-ESO-1+tumor cells, suggesting that this peptide may be clinically valuable for the treatment of patients with NY-ESO-1+tumors.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Mucin-1 (MUC-1), which is overexpressed in more than 90% of human breast cancers, is a potential target for immunotherapy. To develop a mouse model appropriate for the immunotherapy of human cancer, mouse mucin-1 (muc-1) fusion protein, containing ten tandem repeats, was made and used to immunize C3H/HeOuj mice, which supposedly have a high incidence of breast cancer. C3H/HeOuj mice were injected eight times with 5 &mgr;g oxidized mannan muc-1–glutathione-S-transferase (MMFP) with or without cyclophosphamide, which is used to increase cellular immunity. At 80 age weeks, only 12.1% (4 of 33) mice of the untreated C3H/HeOuj mice had mammary tumors. The reason for the low incidence of breast cancer in these mice is not known, but all the mammary tumors were MUC-1+breast adenocarcinomas and were transplantable to C3H/HeOuj mice. The incidence was 11.4% (4 of 35) in mice injected with MMFP; 38.2% (13 of 34) in mice given cyclophosphamide; and 14.3% (2 of 14) in mice treated with glutathione-S-transferase. That is, cyclophosphamide increased the incidence of mammary tumors, and metastases were found in only these mice. Fewer tumors (6 of 34 or 17.6% compared with 13 of 34 or 38.2% with cyclophosphamide only) occurred in the group immunized with MMFP and cyclophosphamide. Mice immunized with MMFP had high levels of muc-1 antibodies and cellular immune responses (the frequency of the precursor of the cytotoxic T-lymphocyte cell was 1 of 40,000 to 1 of 100,000), which were not found in control groups. The occurrence of muc-1 immunity, particularly the presence of large amounts of anti–mucin-1 antibodies, had no effect on tumor incidence. Thus, the immunization with murine muc-1 reduced the tumor incidence in only cyclophosphamide-treated mice and led to strong muc-1 antibody production and to cellular responses. These findings have implications for human tumor immunotherapy in which strong antibody and weak cellular responses are to be expected and, indeed, have been found.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors report the results of a phase I clinical study using semiallogeneic cancer vaccines formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat patients with metastatic adenocarcinomas of the gastrointestinal tract. A specially engineered cell line, FO1-12, was used to generate semiallogeneic hybrids by fusion with patient-derived tumor cells; the hybrids express HLA class I and II haplotypes derived from both parental cells. For treatment, the vaccine was mixed with GM-CSF, irradiated, and injected intradermally into patients at weekly or biweekly intervals. Vaccinations were associated with minimal or no toxicity and showed that semiallogeneic hybrids formulated with GM-CSF can induce a specific antitumor immune response in some patients, as measured by a delayed-type hypersensitivity response to autologous tumor cells. Because of the simplicity, feasibility, and flexibility of this immunotherapeutic approach, semiallogeneic hybrid vaccines have the potential to be used in the treatment of virtually any type of cancer.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The provision of the T-cell costimulatory molecule B7 to tumor cells can be an effective way to trigger a tumor-specific cytolytic T-cell response. One way to provide B7 to tumor cells would be to couple an antitumor antibody directly to B7. Such a molecule should target tumors displaying antigen and provide the costimulatory signal to T cells, resulting in the initiation of an antitumor T-cell response. To this end, a fusion protein was designed that incorporates a single-chain antibody fragment (scFv) to erbB-2 (Her2/neu), an oncogene product overexpressed by 30% to 50% of breast carcinomas, and the ECD of B7–2 (CD86). This fusion protein, expressed and purified fromPichia pastoris, was shown to retain binding activity to both counter receptors, erbB-2 and CD28. The fusion protein was also shown to target erbB-2–positive tumor cells and to deliver a CD28-specific T-cell costimulatory signal. These results suggest that a fusion protein engineered to target tumor cells and signal T cells for activation may be an effective means of cancer immunotherapy. Further studies should be performed to characterize the fusion protein in erbB-2 tumor-bearing mice for in vivo tumor targeting, biodistribution, and efficacy.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The human tumor microenvironment includes a mixture of tumor cells, inflammatory cells, fibroblasts, and endothelial cells, all of which are tethered to an extracellular matrix. It has been difficult to study the dynamic interactions of these cells in human tumors in situ for obvious ethical and logistical considerations that prohibit experimental manipulations of tumors while still in patients. Fresh tissue from human lung tumor biopsy implanted into SCID mice was shown to remain viable, and the histologic appearance of the tumor microenvironment was maintained in the tumor xenografts for at least 3 months. In this study, the authors established that the inflammatory cells within human tumor xenografts can suppress tumor growth, and that this suppression is a result, in part, of endogenously produced interleukin-12 (IL-12) because IL-12 neutralizing antibodies enhance the growth of the tumor xenografts. The tumor-inhibitory activity of the inflammatory leukocytes is also enhanced by the local and sustained release of human recombinant IL-12 into the tumor microenvironment from cytokine-loaded biodegradable microspheres. Neither the anti–IL-12 neutralizing antibody nor the delivery of exogenous IL-12 from microspheres had any effect on tumor xenografts in the absence of the inflammatory leukocytes. In conclusion, the inflammatory cells within the tumor microenvironment of human lung tumor xenografts are functional and can suppress tumor growth, and the dynamic effects of the inflammatory cells can be modulated by exogenous cytokines.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Recombinant viruses can produce cytokines in tumors mobilizing an immune response to tumor cells. In this study, the authors investigated gene expression, in vivo antitumor efficacy, and safety of attenuated recombinant vaccinia virus (rVV) carrying murine cytokine genes interleukin (IL)-2 (rVV–mIL-2), IL-12 (rVV–mIL-12), and both IL-2 and IL-12 (rVV-2–12) in an athymic nude mice model. Significant tumor inhibition (p < 0.05) was observed in a preestablished subcutaneously implanted C6 glioma model using rVVs at doses ranging from 102to 107plaque forming units (PFU). An antitumor effect did not depend on the dose of the rVV–mIL-2 and rVV–mIL-12 viruses. All constructed rVVs induced a high level of cytokine expression in vitro and in vivo. Most groups injected with high doses of recombinant viruses encoding cytokine genes (105to 107PFU) showed signs of cytokine toxicity, whereas in the low-dose treatment groups (102to 103PFU) toxicity was greatly reduced. The antitumor activity of rVV–mIL-12 was associated with increases in both the percentage and number of natural killer T cells in the spleen. Local detection of interferon-&ggr; and tumor necrosis factor-&agr; was also correlated with tumor growth arrest induced by the treatment. High-dose VV control vector per se induced tumor inhibition by activating Mac-1+cells in blood, but the antitumor effect was less pronounced compared with rVV-carrying cytokine genes (p < 0.05). These results suggest that attenuated recombinant strains of VV at low doses may potentially be efficient vectors for cancer immunotherapy.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors wanted to determine whether adding interferon-&agr; (IFN-&agr;) to chemotherapy regimens, in either induction or maintenance settings, provides additional survival benefits in follicular non-Hodgkin's lymphoma (NHL). A meta-analysis was performed based on published data from randomized controlled clinical trials involving nine separate study populations. Patients receiving IFN-&agr; (in either induction or maintenance therapy) had significantly increased 5-year and progression-free survival rates at 3 and 5 years compared with concurrent controls. The advantages of IFN-&agr; therapy were most marked in studies using anthracycline-containing induction chemotherapy; in these studies, patients who received IFN-&agr; had approximately 20% increased progression-free survival rates compared with controls and a lesser survival advantage. The available literature did not allow a determination of the relative benefit of IFN-&agr; in induction or maintenance treatments for NHL or a determination of the optimum duration of IFN-&agr; treatment. Although questions remain about its optimal use, IFN-&agr; appears to prolong survival time in patients with follicular NHL.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Sixteen patients with metastatic stage IV melanoma were treated with use of intravenous infusions of dendritic cells (DC) derived by incubation of plastic-adherent peripheral blood mononuclear cells (PBMC) with IL-4 and GM-CSF for 8 days in serumless AIM-V medium, followed by overnight pulsing with peptides. The tyrosinase368–376 (370D)and gp100209–217 (210M)peptides restricted to HLA class I A*0201 each differed from wild type by one amino acid modified to increase HLA binding. Median age was 49, with nine men and seven women. All patients, except one, had visceral disease. Patients received escalating doses of peptide-pulsed DCs at 10e7, 3 × 10e7, and 10e8cells/dose twice at 2 weeks apart, with toxicity and clinical and immune responses as the principal endpoints. The first infusion of DCs was fresh, and frozen DCs were given for the second infusion of each cycle. Mean DC purity by flow cytometry was 49%, with a mean HLA-DR level of 57%, CD86 of 41%, CD58 of 46%, and mean CD14 cells of 0.9%. Toxicity was minimal, with two patients having transient grade III DC-related toxicity. Ten patients received one cycle of treatment and six patients received two cycles of treatment. One patient had a complete remission (CR) of lung and pleural disease after two cycles of DC therapy. Two additional patients had stable disease and two patients had mixed responses. Overall immunity was assessed by recall skin testing with peptides, gamma interferon ELISA assays of peptide specific cytolytic T cell (CTL) stimulated twice with peptide, IL-2, and IL-7 over 24 days, and peptide-specific tetramer assays performed before and after vaccination. Five of 16 patients had an immune response to gp100 or tyrosinase by gamma interferon ELISA assay; four of five were clinically stable or had tumor regression. These data suggest that melanoma antigen peptide-pulsed DC given intravenously are not toxic, and regression or stability of tumor appeared to correlate with the detection of a peptide-specific immune response in the peripheral blood.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The goal of this study was to evaluate, in patients with prostate cancer, the toxicity profile and biologic activity of the bispecific antibody MDXH210, which has specificity for the non–ligand-binding site of the high-affinity immunoglobulin G receptor (Fc&ggr;RI) and the extracellular domain of the HER-2/neu proto-oncogene product. Patients with prostate cancer that expressed HER-2/neu were entered into a phase I dose-escalation trial of MDXH210. Patients received an intravenous infusion MDXH210 during a period of 2 h three times per week for 2 weeks and were monitored for toxicity. Pharmacokinetic and pharmacodynamic parameters were measured and included the biologic end points of monocyte-bound MDXH210, cytokine production, and clinical response. Seven patients were treated with MDXH210 doses ranging from 1 to 8 mg/m2. In general, MDXH210 was well tolerated, with only mild infusion-related malaise, fever, chills, and myalgias. No dose-limiting toxic effects were observed. Biologic effects included induction of low plasma concentrations of tumor necrosis factor-&agr; and interleukin-6 observed immediately after MDXH210 infusion and 70% saturation of circulating monocyte-associated Fc&ggr;RI with MDXH210 at a dose level of 4 to 8 mg/m2. Five of six patients had stable prostate-specific antigen levels during the course of 40 days or more. Circulating plasma HER-2/neu levels decreased by 80% at days 12 and 29 (p = 0.03 and 0.06, respectively, by the Wilcoxon signed rank test). MDXH210 can be given safely to patients with HER-2/neu–positive prostate cancer in doses of at least 8 mg/m2. At the doses studied, biologic activity was demonstrated and characterized by binding of MDXH210 to circulating monocytes, release of monocyte-derived cytokines, a decrease in circulating HER-2/neu, and short-term stabilization of prostate-specific antigen levels.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors evaluated the records of 371 patients with metastatic melanoma who received treatment with high-dose bolus interleukin-2. Patients with metastases only at cutaneous or subcutaneous sites had a higher objective response rate (50%) than did patients with metastases at these sites plus visceral sites (14%) or patients with metastases at visceral sites only (13%) (p<0.0001). Five patients with disease at cutaneous or subcutaneous sites plus visceral sites experienced regression only at the cutaneous or subcutaneous sites with progression at the visceral sites. Therefore, in the presence of visceral disease, the response rate at cutaneous or subcutaneous sites was only 17% compared with 50% when disease was at the latter sites only (p<0.001). These data suggest that melanoma lesions at cutaneous or subcutaneous sites are highly susceptible targets to interleukin-2–based therapies, but the presence of visceral disease is associated with a significant inhibition of response at cutaneous or subcutaneous sites.

ISSN:1524-9557    

出版商:OVID    

年代:2001

数据来源: OVID