ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Interleukin (IL)-12 is a cytokine originally identified from medium conditioned by an Epstein-Barr virus transformed cell line. IL-12 has been shown to increase IFN-&ggr; secretion from NK and T cells, significantly enhance cytolytic activity in both of these cell types, and promote the development of Th1/Tc1 immune responses. These properties make IL-12 an attractive candidate for the development of various clinical protocols ranging from the treatment of viral diseases to tumor immunotherapy. The initial attempts to use IL-12 in the treatment of tumors demonstrated toxicity at potentially therapeutic doses. To circumvent the toxicity associated with IL-12 administration, the authors have developed an adoptive immunotherapy protocol that uses IL-12 for a brief period during ex vivo T cell activation. They show that IL-12 conditioning may be achieved without altering the growth characteristics of the in vitro expanding T cells. T cells generated in the presence of IL-12 show a shift to a Th1/Tc1 dominant phenotype. The resultant cells are more potent killers in vitro and in vivo as assessed by CTL assays and tumor regression. The ability to harness the potent Th1/Tc1 generating potential of IL-12 while avoiding its associated in vivo toxicity has the potential to benefit a large number of clinical trial protocols using adoptive transfer of T cells specific for tumors, viruses, or intracellular pathogens.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Dendritic cells (DC) are attractive candidates for innovative cancer immunotherapy by virtue of their ability to function as powerful antigen presenting cells and elicit potent antitumor cytotoxic immune responses. With the aim of generating antitumor immunity, the authors sought to enhance in vivo tumor antigen presentation by using an intratumoral DC vaccination strategy in the setting of partially irradiated intracranial brain tumors. Fisher rats, implanted with 9L gliomas in the right corpus striatum, were treated with freshly cultured, unpulsed syngeneic DC inoculated directly into the tumor bed. Intracranially inoculated DCs were found to drain to ipsilateral deep cervical lymph nodes. This was associated with increased local and systemic antitumor cytoxicity, as evidenced by robust infiltration of treated tumors with CD4+and CD8+T cells as well as by increased IFN-&ggr; protein and message levels in in vitro restimulated splenic lymphocytes. DC therapy resulted in prolonged survival and immunity to subsequent intracranial tumor re-challenge. These results demonstrate the viability of intratumoral DC vaccination as an effective therapeutic strategy for intracranial glioma.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Macrophage-derived chemokine is chemotactic for a variety of leukocytes, and has been shown to be involved in TH2-mediated cellular immunity. To evaluate the role of this chemokine in tumor immunity in vivo, an adenovirus vector encoding the human macrophage-derived chemokine cDNA (AdMDC) was administered to established murine tumors. Gene transfer with AdMDC significantly inhibited tumor growth and prolonged animal survival. AdMDC was not directly cytotoxic to tumor cells, but splenocytes from animals that received intratumoral AdMDC were able to lyse syngeneic tumor cells, and purified splenic CD8+cells secreted interferon-&ggr; in a tumor-specific manner. The antitumor activity of AdMDC was lost in mice lacking CD8+T lymphocytes, but surprisingly, it was preserved in animals lacking CD4+cells, as was the systemic cytotoxic T lymphocyte response. Systemic NK cells did not play a role in the antitumor immune response induced by AdMDC. Experiments using knockout mice demonstrated that host expression of MHC Class I, but not Class II, IL-4, or IL-12, was necessary for AdMDC to exert its antitumor effect, and immunohistochemistry demonstrated infiltrates of CD8+and CD86+cells, but not CD4+cells in treated tumors. These studies highlight a new function for macrophage-derived chemokine by demonstrating that it possesses in vivo antitumor activity with CD8+T cells as the effector cells, and interestingly, that the CD4+cell/MHC II pathway of CD8+cell activation is not required for the antitumor effects of this chemokine.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Previous studies in cancer patients demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulated the interleukin (IL)-2 receptor on T lymphocytes and monocytes suggesting that subsequently administered IL-2 would produce greater immune effects. The authors treated 21 patients with metastatic renal cell carcinoma and melanoma on a randomized phase I study to test this hypothesis. All 21 patients received a fixed dose of IL-2 (72,000 IU/kg every 8 hours for 5 days) administered intravenously as an inpatient. Patients were randomized to receive IL-2 alone or in combination with GM-CSF at a dose of 125 or 250 mcg/m2/d (Sargramostim; Immunex Corporation, WA, U.S.A.) daily for 7 days by subcutaneous injection starting on day 1, the day before IL-2 treatment. The results from this study demonstrated that GM-CSF did not worsen the toxicities produced by IL-2 alone. Grade 3 confusion occurred in four patients, three who received IL-2 alone. No partial or complete tumor responses were seen. Assays of serum soluble IL-2 receptor (sIL2R) and neopterin, measures of T cell and monocyte activation, respectively, demonstrated a significant increase in sIL2R but not neopterin, 24 hours after the first dose of GM-CSF. In combination with IL-2, the higher dose of GM-CSF (250 mcg/m2) produced higher sIL2R levels on days 3 and 7 than the 125-mcg/m2dose of GM-CSF or IL-2 alone. Although neopterin levels did not increase after 1 day of GM-CSF, the addition of IL-2 resulted in a significantly increased neopterin level on day 3 at the higher dose of GM-CSF. On day 7, neopterin levels in all three groups were similarly increased over baseline. Ten days after treatment, neopterin levels had returned to normal, but sIL2R levels remained markedly increased (12 fold) over baseline in the higher GM-CSF dose group. The authors conclude that 1) monocyte activation was not significantly enhanced by 1 day of GM-CSF treatment; 2) the 250-mcg/m2GM-CSF dose plus IL-2 produced superior T cell activation compared with a lower dose of GM-CSF plus IL-2 or to IL-2 alone; and 3) the combination of GM-CSF and IL-2 was safe and tolerable but was not associated with any clinical responses.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Epidermal growth factor receptor (EGFR) overexpression has been detected in many tumors of epithelial origin, and it is often associated with tumor growth advantages and poor prognosis. h-R3 is a genetically engineered humanized antibody (mAb) that recognizes an epitope located in the extracellular domain of human EGFR. The antibody exhibited potent in vitro and in vivo antitumor effect on EGFR overexpressing cell lines. To study safety, pharmacokinetics, and biodistribution, 12 patients with advanced epithelial-derived tumors received single intravenous infusion of h-R3 at four dose levels. Safety evaluation was made according to World Health Organization toxicity criteria. For biodistribution, 3 mg of the total dose were labeled with99m-Technetium and then pooled with the rest of the dose. Anterior and posterior whole-body images were acquired using a gamma camera. Blood samples were taken for pharmacokinetics, antiidiotypic response, and for soluble EGFR detection. After hR3 administration, no evidence of severe toxicity was observed. Secondary reactions were mild and moderate and mainly consisted of tremors, fever, and vomiting. No anaphylactic or skin reactions were detected. Qualitative analysis of whole-body images showed that the liver had the highest mAb uptake. Pharmacokinetic analysis revealed that elimination half-lives and the AUC increased linearly with dose, while total body clearance decreased when increasing doses of h-R3. No relation between shed EGFR and mAb clearance was found. No antiidiotypic response against h-R3 was detected. Several phase II trials are now underway to evaluate the efficacy of h-R3 in the treatment of advanced cancer patients.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The authors retrospectively reviewed the medical records of 129 patients with stage IB and II cervical cancer (93 squamous cell carcinomas, 30 adenocarcinomas, and 6 adenosquamous carcinomas) who underwent primary surgery between 1989 and 2000. Vascular invasion is the predictor of recurrence, and lymphocytic infiltrates within the tumor is associated with favorable outcome in cervical cancer. Hence, 129 patients were divided into three groups according to the presence or absence of vascular invasion (VI) and perivascular lymphocytic infiltrates (PLI); VI− (n = 77), VI+PLI− (n = 26), and VI+PLI+ (n = 26), to evaluate the significance of PLI. Age, clinical stage, histology, tumor grade, depth of stromal invasion, VI and PLI, tumor size, ovarian metastasis, pelvic lymph node metastasis, postoperative irradiation, and chemotherapy were assessed statistically for recurrence of the disease by Cox regression analysis. Disease-free survival was analyzed using Kaplan-Meier survival analysis. Recurrence was observed in 32 (25%) of all 129 cases. In a multivariate analysis, VI (P= 0.003) and histology (P= 0.006) remained significantly associated with recurrence. When divided into three groups, the hazard ratio for recurrence was higher in the absence of PLI (2.95 in VI+PLI− group versus 2.07 in VI+PLI+ group), andPvalue became significant in the absence of PLI (0.008 in VI+PLI− group versus 0.106 in VI+PLI+ group). In Kaplan-Meier survival analysis, only the VI+PLI− group (P= 0.006) was significantly associated with worse survival compared with the VI− group. These results suggest that the coexistence of perivascular lymphocytic infiltrates is associated with a better prognosis in cases with vascular invasion.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Adoptive immunotherapy with tumor infiltrating lymphocytes (TIL) and interleukin (IL)-2 is reasonably effective in the treatment of patients with advanced melanoma. However, theoretically it should be of greater benefit as adjuvant therapy, especially in high-risk stages (resected stages III and IV). In a preliminary study, 25 patients (aged 23–72 years) with stage III–IV melanoma who underwent resection of metachronous metastases were reinfused with TIL cultivated and expanded in vitro with IL-2 from surgically removed metastases. IL-2 (starting dose 12 × 106IU/m2) was co-administered as a continuous infusion according to West's scheme. A total of 8/22 (36.3%) evaluable patients were disease-free (DF) at a median follow-up of 5 years. DF survival (DFS) and overall survival (OS) rates were 44% and 37%, respectively, at 2 years, and 52% and 45% at 3 years. The CNS was the only site of disease recurrence in 57% of patients who relapsed. DF patients received a higher median dose of IL-2 than those who progressed (total dose 110 × 106versus 86 × 106IU/m2, respectively). The progressive reduction in IL-2 dosage allowed all patients to complete treatment without permanent grade 4 toxicity. Analysis of tumor immunosuppression factors in lymphocytes inside the tumor (TCR ζ and ε chains, p56lck, FAS, and FAS-ligand) confirmed that the immunologic potential of TIL, depressed at the time of metastasectomy, was significantly restored after in vitro culture with IL-2. Adoptive immunotherapy with TIL and IL-2 could improve DFS and OS, although further work is required to determine its role in the treatment of patients with high-risk melanoma.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Thirty HLA-A2+women with metastatic breast cancer received up to 14 vaccinations with MDA-MB-231-CD80, an HLA-A2+allogeneic breast cancer cell line, which had been lipofected with the cDNA for the CD80 costimulatory molecule. Tumor cells were administered with BCG or GM-CSF as an adjuvant. Sera obtained before and after vaccination were analyzed for antibodies to tumor cell lysate, MUC1, HER2/neu and p53. Since the cell line was grown in fetal bovine serum (FBS), sera were also analyzed for antibodies to FBS. Eighteen of 24 patients for whom sera were available exhibited anti-FBS activity at baseline. Eleven of these 18 patients and all six patients without baseline anti-FBS activity showed an increased titer after vaccination. The anti-FBS activity required that serum samples be absorbed in excess FBS to detect specific antibodies to tumor cell lysate. A two-fold increase in the titer of IgG specific to tumor cell lysate was observed in 6 patients. Eight of 24 patients made an antibody response to HER-2/neu, four of 24 to MUC1 and one of 24 to p53. Although antibody production to a variety of tumor cell-associated antigens was detected our results suggest that a whole cell vaccine comprising a CD80-transfected allogeneic breast cancer cell line with adjuvant BCG or GM-CSF was not a reliable method to induce significant antibody responses in women with advanced breast cancer.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Antigen-presenting cells (APC), such as dendritic cells (DC), are the key component of many cancer immunotherapy strategies. However, DCs comprise a rare population of clinically obtainable cells and are compromised in function in cancer-bearing hosts. Clinical trials therefore rely upon DC generated ex vivo. The authors hypothesized that systemic administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin (IL)-4 might lead to the differentiation of DC from their precursors and enhance their number and function in vivo, as it does in vitro. Subjects with advanced malignancies were treated in this phase I, multiple cohort, dose-escalation trial combining GM-CSF (2.5 &mgr;g/kg/d) plus IL-4 (0–6.0 &mgr;g/kg/d). A cycle consisted of 14 days of cytokine therapy and 14 days of observation (cohorts A–D), or alternating 7-day treatment and observation periods (cohort E). Subjects were followed clinically to determine a maximally tolerated dose (MTD), and complimentary in vitro studies were performed to determine a biologically active dose (BAD). Twenty-one subjects received treatment on this outpatient-based protocol. Treatment was well tolerated and generally characterized by Grade 1 and 2 cytokine related toxicities. The MTD was determined to be GM-CSF 2.5 &mgr;g/kg/d plus IL-4 6.0 &mgr;g/kg/d (cohort E). Treatment in cohort D (GM-CSF 2.5 &mgr;g/kg/d plus IL-4 4.0 &mgr;g/kg/d) was well tolerated and resulted in a BAD. Systemic GM-CSF plus IL-4 provides a mechanism for increasing the number and function of APC in cancer patients. Future clinical applications of this strategy are numerous and include the potential as a strong vaccine adjuvant.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID