摘要:

Summary:Recent advances in the understanding of the mechanisms leading to tumor recognition by the immune system have shown that, at least in the case of human melanoma, the majority of cytotoxic T lymphocytes (CTL) identified in association with in vivo tumor regression after interleukin-2 therapy recognize nonmutated molecules expressed by most melanoma cells. For this reason, peptide-based or whole protein vaccination protocols against melanoma-associated antigens (MAA) are ongoing in several institutions, with the goal of inducing tumor regression by enhancing in vivo specific antitumor CTL reactivity. The rationale for the use of such vaccines is supported by: (a) preclinical evidence that vaccination with major histocompatibility complex class I restricted epitopes can enhance effectively cellular immunity, (b) evidence that potent antimelanoma CTL reactivity can be generated by repetitive in vitro stimulation of peripheral blood monocytes with MAA, and (c) evidence that the systemic administration of the same MAA can elicit antitumor CTL reactivity in vivo. As strategies are being developed for the development of sound vaccines, two basic approaches are investigated: one vaccination strategy is based on the administration of the specific amino acid sequence recognized by the CTL in association with a particular human leukocyte antigen (HLA) restriction element, and the other is based on the administration of the whole antigenic molecule, which relies on the organism's antigen-processing capabilities to render suitable the antigen for induction of HLA class I restricted CTL reactivity in vivo. Among the various factors complicating T-cell-based vaccination approaches stands the polymorphism of the HLA molecules. HLA are the most polymorphic of human genes, and because such polymorphism is clustered in the functional peptide-binding region, the binding of antigenic peptides is necessarily restricted to specific HLA alleles. This limits the interactions between CTL and antigen to specific sequences for each HLA allele. For this reason, the ability of an individual antigen to function as a T-cell immunogen in the context of different HLA allele restriction elements is an open question. It seems logical that whole- molecule vaccines have the potential advantage of broader use across patient populations. In particular, large antigenic molecules may contain multiple peptide sequences with putative binding properties for different HLA alleles, which in turn may elicit T-cell reactivity across the polymorphism of HLA. Such a concept, however, relies on the assumption that the same antigen may function with similar efficiency as an immunogen in association with different HLA alleles, independently from the epitopic sequence recognized in the various situations. This concept has been challenged recently by several practical observations and remains, in our opinion, an open question. This review will address the practical question of immunogenicity of molecules across the HLA polymorphism. We postulate that the complexity and success of the development of peptide-based vaccination strategies depend on the severity of this restriction, which is currently only incompletely studied and understood. Although no solutions are offered to the problem, emphasis is placed on the importance of this question, hopefully to stimulate the interest of other researchers, particularly in clinical settings, toward the investigation of this type of problem.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:The human carcinoembryonic antigen (CEA), which is expressed in several cancer types is a potential target for antigen-specific immunotherapy. In this study, we show that dendritic cells (DC) pulsed with an HLA class I restricted CEA cytotoxic T lymphocyte (CTL) peptide epitope can stimulate T cells to kill CEA peptide loaded T2 target cells as well as CEA expressing tumor lines in the presence of interleukin-7(IL-7) in an HLA-restricted manner. This has been demonstrated for carcinoma patients as well as healthy donors. The DC-CEA + IL7 stimulated cultures contained predominantly CD3+CD8+CD56−cells indicative of MHC class I resticted CTL. In addition, DC-CEA + IL-7 stimulated cells showed higher levels of CD69 expression compared with cells stimulated with IL-7 alone, implying an activated phenotype. When the T-cell receptor (TCR) from CTL cultures stimulated with DC-CEA + IL-7 was analyzed, an oligoclonal pattern of expression was found for certain Vβ subfamilies compared with the polyclonal patterns shown by IL-7 or phytohemagglutinin stimulated T cells from the same donors. This TCR restriction appeared to be maintained and enhanced after additional rounds of restimulation with DC-CEA + IL-7. The association between cytotoxicity and TCR restriction suggests that TCR analysis may be useful as an in vitro indicator to monitor alterations in the T-cell population in response to antigen-specific immunotherapies.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:A variety of human melanoma-associated antigens (MAA) have been identified that can be recognized by T lymphocytes in a major histocompatibility complex-restricted fashion. Among them, tyrosinase, MART-1/Melan- A, and gp100 are derived from nonmutated melanocyte lineage-specific antigens (Ag). These Ag can be recognized by CD8+and, in the case of tyrosinase, CD4+T cells. The in situ expression of MAA may be a significant cofactor in determining the recognition of melanoma targets by Ag-specific T cells. In this study, we examined the patterns of expression of these MAA using immunohistochemical methods on 30 metastatic tumor deposits derived from 25 patients. MAA expression was heterogeneous among the 30 specimens and also within individual lesions. Of note, 23% of the samples examined failed to express the gp100 protein, and 17% of samples had no detectable expression of MART-1. In contrast, all lesions demonstrated some degree of tyrosinase expression even in cases where both gp1OO and MART-1 were not detectable. In addition, 60% of samples (18 of 30) showed strong positivity for tyrosinase (>75% of cells staining) compared with 40% for gp100 and 36% for MART-1. Currently, a number of experimental immunotherapies for melanoma are directed against the MAA tyrosinase, MART-1, and gp100.Although threshold levels of Ag required for T-cell recognition have not yet been defined, tumor-associated Ag expressed in high density,such as tyrosinase,may be better targets for future immunotherapy trials.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:Using a murine metastasis model,we have previously shown that antigenpresenting cells (APC) loaded with un fractionated peptides derived from poorly immunogenic, highly metastatic tumor cells represent a potent form of tumor vaccine. The antimetastatic effect of peptide pulsed APC could be further enhanced by pretreating the cells with antisense oligonucleotides directed against the TAP-2 gene to increase the density of specific peptide-major histocompatibility complex (MHC) class I complexes and thereby improve the APC function of the treated cells (Nair SK et al.,J Immunol1996;156:1772). In this study, we investigated whether similar strategies can be used to enhance the potency of human dendritic cells (DC) to present antigen. We show that human DC pulsed with peptides encoding known cytotoxic T-lymphocyte (CTL) epitopes stimulate both memory and primary CTL responses in vitro after two cycles of stimulation with the peptide-pulsed DC. Two approaches were used to increase the density of specific peptide-MHC complexes on the surface of DC. One approach was to inhibit transporter associated with antigen presentation (TAP) function using TAP antisense oligonucleotides. The second approach was to inhibit the endogenous generation of the peptide epitopes by pretreating the DC with a proteasome inhibitor. Treatment of DC with either TAP antisense oligonucleotides or with a protea some inhibitor resulted in a dramatic enhancement of primary CTL induction.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:The context in which an antigen is presented shapes the nature of the immune response to that antigen and can result in B cell activation, T cell activation, or immune tolerance. To elicit anti-tumor immune responses, various cell types have been employed as cellular adjuvants with tumor antigens, and recently several groups have shown that dendritic cells (DCs), cultured with tumor lysates, tumor antigens, or peptides eluted from tumor cells, induced significant anti-tumor immunity in vivo. In all of these approaches, the DCs were pulsed with an exogenous source of antigen. An alternative method is to engineer DCs to express tumor antigens. We genetically modified DCs to express β-galactosidase (β-gal) as a surrogate tumor antigen and then tested the anti-tumor activity of the β-gal+DCs in mice against a β-gal+murine melanoma cell line. A single vaccination with the gene-modified DCs protected mice against a lethal dose of (β-gal-B16 melanoma cells and induced β-gal-specific cytotoxic T lymphocytes. These results demonstrate that expression of tumor antigens by DCs is a potent method of inducing tumor antigen-specific responses in vivo.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:Interferon-γ-inducing factor (IGIF) is a novel cytokine that stimulates T-cell proliferation, augments natural killer (NK) cell lytic activity, and induces interferon- γ (IFN-γ) production in established type 1 T-helper (Thl) cells in the presence of anti-CD3 antibody. The in vitro induction of IFN-γ by recombinant murine IGIF in these cells was more potent than that induced by murine interleukin-12 (IL-12) and occurred apparently independent of murine IL-12. Here we report that subcutaneous injection into mice of tumor cells transfected with murine IGIF complementary DNA (cDNA) resulted in ≥ 10-fold increase of mitogen-stimulated IFN-γ production in cultured splenocytes. In addition, IGIF-transfected Renca and K1735 tumor cells can be rejected in vivo. The IGIF antitumor effect was abrogated in mice that were sublethally irradiated or depleted of both CD4+and CD8+T cells but not in mice depleted of either subpopulation alone. The antitumor effect mediated by IGIF appears to be dependent on IFN-γ production, because in vivo neutralization of IFN-γ was accompanied by growth of IGIF-transfected tumors in 100% of the animals. Taken together, our results show that murine IGIF can elicit T-cell-dependent antitumor immunity associated with IFN-γ induction.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

High-dose therapy with interleukin-2 (IL-2) can produce significant responses in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Several studies have shown the benefit of low-dose IL-2 in patients with RCC, but few studies have evaluated low-dose IL-2 in MM. We have used the following regimen: Interferon-a 10 million units subcutaneously on days 1, 3, 5, 8, 10, 12, 22, 24, and 26; and IL-2 60,000 IU/kg i.v. every 8 h on days 8-12 and 22-26. Patients had measurable MM or RCC and were excluded for ECOG status 3, brain metastases, or significant cardiopulmonary or renal dysfunction. Between January 1993 and April 1996, 38 patients with MM and 14 with RCC were treated. In MM, there were six responses (15.7%; 95% confidence interval 4.1-27.3%) (i.e., one complete response and five partial responses). Responses were seen in visceral and nodal disease. Responses were of good duration: 40+, 26+, 13, 6, 4, and 3 months. One response was seen in the 14 RCC patients. Treatment was considerably less toxic than with high-dose IL-2. All treatment was given in a medical or surgical ward with intensive care necessary in only two patients. More than 80% of patients received 80% of the predicted dose of IL-2. Dose-limiting toxicity consisted mainly of mild confusion or fatigue. In summary, this regimen is better tolerated and produces response rates within the range reported for high-dose IL-2 for patients with MM.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:Interferon-α is an accepted treatment for renal cell carcinoma, with a response rate -14%. Retinoic acid has been claimed to improve such a response rate when combined with interferon. We present the results of a phase II study combining interferona and all-trans retinoic acid (ATRA) in patients with metastatic renal cell carcinoma. Thirty-one patients who were not eligible for a trial of high-dose interleukin- 2 treatment (because of low performance status: 7 patients; prior immunotherapy: 11 patients; age 70: 8 patients, cardiac or respiratory failure: 4 patients; refusal for randomization: 1 patient) were enrolled in this study. Only one partial response was observed (3%). Despite the good tolerance observed with this association, ATRA does not improve the efficacy of interferon in this selected patient population (with poor prognosis). Such a treatment combination should not be further recommended in patients with metastatic renal cell carcinoma.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:Patients treated with high doses of interleukin-2 (IL-2) develop profound anorexia, malaise, loss of energy, mucositis, nausea, and vomiting, which may contribute to poor nutrition. We hypothesized that total parenteral nutrition (TPN) administration would ameliorate these changes and could improve fluid and electrolyte balance. A retrospective analysis of protein and energy intake was performed in 21 sequential patients who received a normal diet (controls) and 16 subsequent patients who received TPN during IL-2 treatment. The effect of TPN on laboratory abnormalities induced by IL-2 was also evaluated. Within 24 h of starting IL-2, mean energy intake declined to 2.5-2.8 kcat/kg in controls in contrast to the energy intake of 25-29 kcat/kg in patients receiving TPN. Protein nutrition was affected in a similar fashion, with a markedly lower protein intake in controls (0.08-0.12 g/kg) than in the TPN group (1.02-1.10 g/kg). TPN improved serum calcium and potassium concentrations, particularly during spontaneous diuresis after completion of IL-2 treatment. Unexpectedly, TPN decreased the frequency and severity of cholestatic jaundice caused by IL-2. Patients receiving TPN had an increased propensity for hyperglycemia and hypophosphatemia. High-dose intravenous bolus IL-2 therapy resulted in a markedly negative nutritional balance in control patients. A brief period of TPN during IL-2 treatment was well tolerated and corrected calorie and protein malnutrition. TPN administration also improved control of serum electrolytes. TPN did not adversely affect tumor progression or patient survival.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Summary:The anti-idiotype (Id) monoclonal antibody (mAb) 1A7 immunoglobulin Gl (IgGl, K), raised in syngeneic mice against the murine anti-ganglioside GD2 mAb 14G2a mimics a carbohydrate epitope on GD2 and serves as a surrogate protein antigen for this disialoganglioside. Immunization of allogeneic C57BL/6 mice and rabbits with 1A7 induced anti-GD2 antibodies of IgG isotype that recognize purified GD2 by enzyme-linked immunosorbent assay (ELISA) and GD2-positive human melanoma cells (M21/P6) by fluorescence-activated cell sorter (FACS) analysis. The specificity of the antisera for GD2 was further confirmed by dot-blot analysis. These antisera also specifically lyse GD2-positive M2l/P6 target cells in an antibodydependent cellular cytotoxicity assay. Taken together, these results suggest that the anti-Id 1A7 can induce GD2-specific IgG antibodies that can recognize cell surfaceassociated as well as soluble disialoganglioside GD2.

ISSN:1524-9557    

出版商:OVID    

年代:1998

数据来源: OVID