Ten-year follow-up of a phase 2 study of dose-intense paclitaxel with cisplatin and cyclophosphamide as initial therapy for poor-prognosis, advanced-stage epithelial ovarian cancer.

BACKGROUND: The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced-stage epithelial ovarian cancer (EOC) who were receiving dose-intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule. METHODS: Patients with stage III/IV EOC received cyclophosphamide 750 mg/m(2), followed by a 24-hour infusion of paclitaxel 250 mg/m(2) and cisplatin 75 mg/m(2) on Day 2. Filgrastim began on Day 3 at 10 microg/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel. RESULTS: Sixty-two patients were enrolled. Thirty-two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent-to-treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow-up of 11.4 years, the median progression-free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel. CONCLUSIONS: The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Oncology Group suggest that further study is warranted of dose-dense or dose-intense paclitaxel regimens in women with newly diagnosed, advanced-stage EOC.

Assessment of fusion cells from patient-derived ovarian carcinoma cells and dendritic cells as a vaccine for clinical use.

PURPOSE: To evaluate a protocol that allowed the successful generation of DC and OVCA cells, fusion of these two cell types and assessment of stimulatory ability of the fusion cells for clinical use. PATIENTS AND METHODS: Ovarian cancer (OVCA) cells and dendritic cells (DC) were isolated or generated from 22 patients with OVCA and subsequently fused with PEG. The stimulatory ability of fusion cells including T cell proliferation and induction of cytotocic T lymphocytes (CTL) was assessed. In addition, the impact of radiation, freezing and thawing of the fusion cells was evaluated. RESULTS: OVCA cells derived from 22 patients were successfully fused with autologous DC. The created heterokaryons expressed tumor-associated antigens, such as MUC1 and CA-125, and DC-derived MHC class II and costimulatory molecules. The fusion cells were functional in stimulating the proliferation of autologous T cells. In addition, CD4 and CD8 T cells derived from patients with ovarian cancer were stimulated by fusion cells and produced IFN-gamma as demonstrated with intracellular staining. Significantly, T cells primed by fusion cells produced MHC class I-dependent lysis of autologous ovarian tumor cells. One cycle of fusion-cell stimulation can maintain the CTL activity up to 25 days. CONCLUSIONS: The fusion of human OVCA cells and DC created immunogenic cells capable of stimulating CD4 and CD8 T cells. The effects of the processes required for preparing a vaccine for clinical use, including freezing and thawing and irradiation, do not interfere with the immunogenic properties of the fusion cells.

Dendritic cells fused with human cancer cells: morphology, antigen expression, and T cell stimulation.

Fusion of human dendritic cells (DC) with tumor cells is an effective approach for delivering tumor antigens to DC, and DC/tumor fusion cells are potent stimulators of autologous T cells. However, the integration and morphology of DC/tumor fusion cells has not been examined. In the present study, we fused patient-derived DC to autologous breast or ovarian carcinoma cells. The fusion cells possessed the properties of both parent cells. After fusion, the cytoplasm of the two cells was integrated, whereas their nuclei remained separate entities. Colocalization of MUC1 peptide and HLA-DR molecules was observed on fusion cells under the immunoelectron microscope. Coculture of patient-derived peripheral blood mononuclear cells (PBMC) with DC/tumor fusion cells resulted in activation of CD4 and CD8 T cells as assessed by IFN-gamma secretion, HLA-A*0201-MUC1 tetramer, and standard cytotoxic T lymphocyte (CTL) assays. The present study provides first evidence of integration of human DC and tumor cells and links their properties to T cell activation.

Immunologic quantitation of the carcinoma specific human carcinoma antigen in clinical samples.

BACKGROUND: Based on the cross-reactivity of the human carcinoma antigen, HCA, with epiglycanin, a mouse mammary carcinoma cell surface glycoprotein, HCA has been detected in the tissue and blood of patients with every type of epithelium-derived cancer tested. METHODS: Competitive binding assays utilized the following antiepiglycanin antibodies: a polyclonal rabbit antiserum (immunoglobulin [Ig] G and IgM) in a radioimmunoassay; mouse monoclonal antibodies (Ab-1, IgM) on immunoplates; anti-idiotypic (Ab-2) and anti-anti-idiotypic (Ab-3) monoclonal antibodies (both IgG) from spleen cells of C57BL mice immunized, respectively, with Ab-1 and Ab-2, and utilized on immunoplates. IgG and IgM antibodies were evaluated for their ability to detect HCA and to distinguish between the blood of patients with, or without, carcinomas. RESULTS: Assays with the rabbit antiserum distinguished plasmas of metastatic breast carcinoma patients from those of patients with benign breast disease with a sensitivity of approximately 93% (specificity 90%). Antiepiglycanin IgM monoclonal antibodies (i.e., AE3) showed high specificity and sensitivity (> 90%) with sera from advanced carcinoma patients when compared with normal sera. The IgG anti-anti-idiotypic (Ab-3) monoclonal antibodies (i.e., AF2), which bind the same epitope as Ab-1, appear to possess less nonspecific binding capacity, however, than the Ab-1 (IgM) antibodies. Anti-Ab-1 (i.e., C8F2) anti-idiotypic monoclonal antibodies, which bear an idiotope equivalent to the epitope present in epiglycanin and the HCA, demonstrated greater consistency as a standard calibrator and for coating wells than epiglycanin. CONCLUSIONS: The concentration of the HCA in the body fluids of patients with carcinomas may be accurately determined by competitive binding assays. It is suggested that the use of anti-idiotypic antibodies (IgG), rather than epiglycanin/HCA, and Ab-3 anti-anti-idiotypic antibodies (IgG), rather than Ab-1 (IgM), will improve the consistency, as well as the sensitivity and specificity, of the assay.