摘要:

Activation of apoptosis via death receptors is a tightly regulated event, and the death pathway itself is open to interference on the part of soluble or membrane-bound decoy receptors. The aggregation state of the death-inducing ligand is a crucial factor, particularly when these molecules are used as recombinant drugs against tumors. Whether tumors are sensitive to such ligands is determined by both the net abundance of death receptors versus decoy receptors and the balance between intracellular apoptotic and antiapoptotic mechanisms. This means that in vivo elimination of tumor cells by effector arms such as T lymphocytes, natural killer cells, macrophages, and dendritic cells is dependent on both the function of activated lymphoid cells and the genetic properties of tumor cells. Death receptor ligands, however, may be a double-edged sword. When expressed on cytotoxic T lymphocytes, natural killer cells, monocytes, and dendritic cells, they induce the apoptosis of many tumor cells, whereas their expression on tumor cells induces the apoptosis of killer cells. The in vivo result is influenced by the number of infiltrating cells, their state of activation, the cytokine repertoire in the tumor microenvironment, and the ability of the tumor to produce soluble factors inhibiting their cytolytic functions.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Cancer-testis antigens expressed by different-histotype transformed cells are suitable targets for tumor immunotherapy. However, their heterogeneous expression in neoplastic lesions limits the eligibility of patients for cancer-testis antigen–directed vaccination, and low levels of cancer-testis antigens' expression may impair immune recognition of malignant cells. Because of the primary clinical relevance of cancer-testis antigens' expression in neoplastic tissues, 68 unrelated or sequential metastatic lesions from 56 patients were used to characterize the molecular mechanisms regulating the presence and levels of expression of different cancer-testis antigens of theMAGEfamily (i.e.,MAGE2,3and4) in cutaneous melanoma. Polymerase chain reaction-based methylation analyses showed that methylation status of specific cytosine-guanine dinucleotides in the promoters of investigated cancer-testis antigens correlated with their heterogeneous expression within unrelated metastatic melanoma lesions, and with their homogeneous expression among sequential metastases from three patients with melanoma. Unlike methylated promoters, unmethylated promoters ofMAGE2,3and4genes drove the expression of reporter gene-enhanced green fluorescent protein after transient transfection of cancer-testis antigen–positive Mel 142 melanoma cells. Furthermore, de novo expression ofMAGE3gene induced by the treatment of Mel 195 melanoma cells with the DNA hypomethylating agent 5-aza-2´-deoxycytidine was associated with a 6%–12% demethylation of selected cytosine-guanine dinucleotides in its promoter. Finally, 5-aza-2´-deoxycytidine induced a 16-fold increase ofMAGE3expression in Mel 313 melanoma cells expressing constitutively low levels of the antigen, but did not affect that of Mel 275 melanoma cells expressing high baseline levels ofMAGE3.Overall, these findings identify promoter methylation as a shared mechanism directly regulating the expression of therapeutic cancer-testis antigens in metastatic melanomas, and foresee the clinical use of 5-aza-2´-deoxycytidine to design new chemoimmunotherapeutic strategies in patients with melanoma.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Administration of Flt3 ligand (FL) to mice causes dendritic and natural killer cells to increase but certain solid tumors to regress. Depending on the particular tumor model used, T cells and natural killer cells have been implicated in the protective immune response induced by FL. The current study examined the effects of FL administration on tumor establishment and progression in metastatic and primary tumor models to correlate anatomic location with immunotherapeutic efficacy. FL mediated significant (p ≤ 0.05) therapeutic activity against pulmonary metastases of the murine MC-38 colon adenocarcinoma, particularly when cytokine administration was initiated before tumor inoculation. However, progressive intraabdominal tumors sometimes were observed even in the relative absence of pulmonary metastases. Significant, although less dramatic, antimetastatic effects were observed with MCA-205 and MCA-102 sarcomas and D5 (B16BL6) melanoma. In contrast, FL was ineffective against subcutaneous MC-38 tumors or against several intracranial tumors. This suggests that besides the administration dose, the efficacy of this cytokine depends on the tumor type and possibly the location of the inoculated tumor. Antitumor activities of FL were abolished by whole-body irradiation (500 cGy) and partially abolished by systemic depletion of CD8, CD4, or natural killer cells. The results indicate that optimization of FL immunotherapy of tumors will require a firmer understanding of the relative contributions of tumor burden, location, immune system requirements, and other factors.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Lymphohematopoietic malignancies are common spontaneous diseases of dogs whose clinical presentation and biologic behavior closely resemble their human counterparts. The goal of this study was to define the potential to use canine lymphoma and leukemia as suitable models to refine therapeutic approaches targeting the interleukin-2 receptor (IL-2R). The authors evaluated the patterns of IL-2R expression in 13 dogs with multicentric non-Hodgkin's lymphoma (NHL) and in six dogs with leukemia (acute lymphocytic leukemia, n = 3; chronic lymphocytic leukemia in blast crisis, n = 1; acute monoblastic leukemia, n = 2). The authors first cloned and sequenced the complete coding domains of the wild-type canine IL-2R &agr;-chain gene. They next used qualitative reverse transcription polymerase chain reaction (RT-PCR) analysis to examine IL-2R &agr;, &bgr;, and &ggr;csubunit expression in the tumors. Messenger RNA (mRNA) for the interleukin-2 receptor &agr;, &bgr;, and &ggr;csubunits that comprise the high-affinity receptor was present in samples from all dogs with NHL. Expression of functional surface IL-2R also was observed flow cytometrically in NHL cells from all four dogs tested. Leukemic cells from one dog with B cell acute lymphocytic leukemia and two dogs with acute monoblastic leukemia expressed mRNA for all three subunits, whereas cells from another dog with B cell leukemia and both dogs with T cell leukemia expressed only mRNA for the &bgr; and &ggr;csubunits that comprise the intermediate-affinity receptor. These results indicate that the IL-2R is commonly expressed in canine lymphohematopoietic malignancies, and support the suitability of this large-animal model to evaluate targeted IL-2R cancer therapy using approaches of interest in the treatment of humans with hemolymphatic cancers.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The tumor-associated autoantigenMUC1is intensively studied as a potential target for antigen-specific immunotherapy of cancer. Previous reports concerning experiments in preclinical murine tumor models have provided evidence supporting the feasibility of this approach. However, such studies have not been performed with clonal cytotoxic T lymphocyte populations displaying a highly definedMUC1specificity. The authors demonstrate that the immunodominantMUC1-specific cytotoxic T lymphocyte response in C57BL/6 mice is directed against an H-2Kb–restricted epitope,MUC119–27, which is derived from the N-terminal signal sequence of theMUC1protein. Processing of this epitope was independent of transporter of antigen presentation and proteasome function. Importantly, successful immunotherapy ofMUC1-overexpressing tumors inMUC1-transgenic mice was not accompanied by damage to normal somaticMUC1-positive tissues, even when this involved the infusion of large numbers of clonal cytotoxic T lymphocyte that recognized the immunodominantMUC1epitope. Although the risk for autoimmune pathology is limited, data indicate that immune tolerance inMUC1-positive subjects restricts the breadth of theMUC1-specific cytotoxic T lymphocyte repertoire that is available for recruitment to immunotherapeutic antitumor responses.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The data presented here describe a novel approach to enhance the use of antibodies in diagnostic and therapeutic applications. Using a peptide copied from a rare self-binding (autophilic) antibody structure, the authors were able to convert by chemical cross-linking an anti-CD20 antibody to a self-binding (autophilic) structure. The autophilic antibody exhibited better binding to target tumor cells than the naked antibody. By the mechanism of hyper-cross-linking a B-cell receptor (CD20) on tumor cells, the rate of apoptosis is significantly increased, leading to strong inhibition of tumor growth in culture. The demonstration of enhanced binding and apoptosis targeting the CD20 B-cell marker serves as an example for developing second-generation therapeutic antibodies against non-Hodgkin lymphoma.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

This study was conducted to determine whether reactivity to melanoma cells of pretreatment peripheral blood mononuclear cells (PBMCs) from patients with metastatic melanoma correlated with subsequent response to treatment with interleukin-2 (IL-2). The sensitivity of the quantitative real-time polymerase chain reaction (PCR) assay was optimized, including the total number of cells used (3 × 106in 1 mL), the responder-to-stimulator cell ratio (5:1), the optimal time to incubate PBMCs with tumor (2 h), the appropriate tumor stimulators (melanoma cell lines differing only in the expression of histocompatibility leukocyte antigen [HLA-A2]), the duration of recovery in the culture of PBMCs after cryopreservation (18–24 h), and the medium used (Iscove, 10% human AB serum). Using this optimized assay to detect HLA-A2–restricted antitumor reactivity in the pretreatment PBMCs from patients with melanoma, positive reactive responses were detected in 7 of 28 patients with an objective clinical response to IL-2 therapy compared with 6 of 21 positive reactive responses in nonresponding patients. None of 12 healthy donors were positive in this study. Thus, there was no significant difference in the reactivity of pretreatment PBMCs when responders were compared with nonresponders, although the melanoma patients had an increased incidence of response compared with healthy donors (p = 0.05). The PBMCs from 11 of the 13 melanoma patients with pretreatment HLA-A2–restricted antimelanoma reactivity were tested against a panel of transfectants expressing known shared melanoma antigens. Anti–MART-1 reactivity was detected in the pretreatment PBMCs of three patients. It thus appears that some melanoma patients are immunologically primed to antigens expressed on the tumor surface, although the HLA-A2–restricted antimelanoma activity detected in this real-time PCR assay was not predictive of patients' responses to IL-2 therapy.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Clonotypic B cells circulating in patients with multiple myeloma (MM) express CD20, and it has been suggested that these cells may be clonogenic. Furthermore, 20% of patients with MM express CD20 on their bone marrow plasma cells (BMPCs). Therefore, the authors began a phase II clinical study to determine the activity of the anti-CD20 monoclonal antibody rituximab in MM patients. Nineteen previously treated MM patients received 375 mg/m2rituximab per week for 4 weeks. Three months after initiation of treatment, patients were assessed for response and received a second course of therapy if their disease was stable (SD) or they achieved a partial response (PR). Six of 19 (32%) patients had either a PR (n = 1) or SD (n = 5), with a median time to treatment failure of 5.5 months (mean, 10.3 months; range, 3–27+ months). All six patients who had a PR or SD had CD20+BMPC. Overall, rituximab therapy was well tolerated. Because most patients with MM poorly express CD20 on their BMPCs, the authors evaluated agents for their ability to induce CD20 expression and thereby facilitate rituximab binding on MM cells. These studies show that interferon-gamma (IFN-&ggr;) induced CD20 expression on MM BMPCs, MM B cells, and healthy donor BMPCs. In contrast, CD20 expression on chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma, healthy donor B cells, and progenitor cells was unaffected by IFN-&ggr;. Rituximab binding to the BMPCs of MM patients was also increased after culture with pharmacologically attainable levels of IFN-&ggr; (1–100 U/mL). In conclusion, these studies suggest that MM patients with CD20+BMPCs may benefit from rituximab therapy. Furthermore, IFN-&ggr; induces CD20 expression on MM BMPCs and B cells and facilitates rituximab binding to MM BMPCs, providing the rationale for clinical trials to examine its use with CD20-directed serotherapies in MM.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The authors determined the safety and efficacy of recombinant high-dose interleukin-2 administration in patients with brain metastases. This retrospective review included 1,069 patients with metastatic melanoma or renal cell carcinoma who received high-dose interleukin-2 alone or in combination with other immunotherapy or chemotherapy from July 1985–July 2000. All patients were evaluated for both toxicity and response. Only the first exposure to interleukin-2 was considered. Parameters evaluated among the groups included toxicity profiles, reasons for stopping treatment, number of interleukin-2 doses per cycle, and response to therapy. Three patient groups were compared. Group 1 (n = 27) comprised patients with previously treated brain metastases (surgery or radiation), group 2 (n = 37) comprised patients with untreated brain metastases, and group 3 (n = 1,005) comprised patients without brain metastases. For most comparisons between patients with brain metastases and those without, no significant differences were noted in toxicity profiles or reasons for stopping interleukin-2 therapy. Patients with previously treated brain metastases received fewer interleukin-2 doses per cycle (median, 6.5) than patients with previously untreated brain metastases (median, 7.5) or patients without brain metastases (median, 7.5). Patients with previously treated brain metastases demonstrated an 18.5% overall clinical response to interleukin-2 treatment. However, patients with evaluable (previously untreated) brain metastases had an overall 5.6% response rate, which was less than the 19.8% response rate of patients without brain metastases. Two of thirty-six patients with evaluable brain metastases demonstrated objective regression of intracranial and extracranial disease after receiving interleukin-2. Carefully selected patients with brain metastases can safely receive high-dose interleukin-2, and some can experience a response to treatment at intracranial and extracranial disease sites.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Dendritic cells (DC) are essential for the generation of primary adaptive immune responses, but their full immunostimulatory capacities are only reached upon maturation. The authors compared several clinical-grade adjuvants of bacterial origin to determine their ability to induce phenotypic and functional maturation of monocyte-derived DC (Dendritophages, D&phis;; IDM, Paris, France) differentiated with granulocyte-macrophage colony-stimulating factor and interleukin-13 in single-use cell processors (VacCell; IDM, Paris, France). Monophosphoryl lipid A,Mycobacterium bovisbacillus Calmette-Guérin, and Ribomunyl (Pierre Fabre Medicament, Boulogne, France) all appeared able to provide the signal necessary to initiate D&phis; maturation. However, only Ribomunyl (Pierre Fabre Medicament) (containing membrane and ribosomal fractions from four bacterial strains) allowed the authors to obtain a significant enhancement of allostimulatory abilities and cytokine production by D&phis; in the absence of active cellular infection. Addition of interferon-gamma (IFN-&ggr;) to Ribomunyl resulted in more pronounced upregulation of CD83, major histocompatibility complex class I, and B7 molecules by D&phis;. Moreover, the IFN-&ggr; addition modulated their cytokine secretion, allowing higher levels of bioactive interleukin-12 concomitant with lower levels of interleukin-10. In kinetic studies, D&phis; contact with Ribomunyl and IFN-&ggr; for 6 hours was sufficient to trigger a maturation process that completed spontaneously. Thus, Ribomunyl in association with IFN-&ggr; represents a suitable agent for the ex vivo production of mature monocyte-derived DC that can be used as cellular vaccines to promote a potent type 1 immune response.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID