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  • 1
    ISSN: 1432-0851
    Keywords: Active specific immunization ; NDV-modified tumour cells ; Microcultures ; Tumour vaccines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to understand further the effects of Newcastle-disease-virus(NDV)-modified tumour vaccines we investigated the feasibility of isolating lymphocytes from the site of injection of patients undergoing postoperative active specific immunization (ASI) with autologous NDV-modified tumour cells. Delayed-type-hypersensitivity(DTH)-like reactions from five cancer patients were surgically removed, minced and the tissue particles were digested with collagenase and DNase. Lymphoid cells recovered were expanded in a highly efficient limiting-dilution analysis system optimized for T cell growth [Moretta et al. (1983) J Exp Med 157: 743] and lymphocyte microcultures (clonal probability 〉0.8) could be grown for up to 1 year. Analysis of the microcultures for phenotype and function showed that the majority were positive for CD4 (92%) and TCRαβ (96%). Concanavalin-A-induced production of interleukin-2 (IL-2), IL-6, interferon γ and tumour necrosis factor α was detected in more than 70% of the microcultures. Lectin-dependent cytotoxicity was only very rarely observed. The general characteristics of the microcultures obtained support the notion of a DTH-like reaction taking place at the site of tumour cell challenge. The possibility of in vitro expansion and cultivation of T lymphocytes from ASI vaccination sites should help to elucidate further the role of these cells in active specific immunization against autologous tumour cells.
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  • 2
    ISSN: 1433-8726
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Thirty patients with advanced renal cell carcinoma (RCC), 23 of whom had distant metastases in at least one organ, were entered after nephrectomy into a protocol involving vaccination with Newcastle disease virus (NDV)-modified autologous tumour material, with a subsequent induction week and repetitive bi-weekly cycles of interleukin-2 (rIL-2) and interferon α2b/rIFN-α2b at a lower s. c. dose (1.5 million Cetus units m−2 day−1 every 12 h on 2 days and 3 million IU/m2 once a day on days 1, 3 and 5). The inpatient treatment was followed by a maintenance phase during which 0.3 million Cetus units/m2 rIL-2 was given s. c. every 12 h on days 1–5 and 3 million IU m−2 day−1 rIFN-α2b was administered on days 1, 3, and 5 on an outpatient basis. All but 3 patients completed the induction week and 6 weeks of outpatient therapy. No grade 3 or 4 toxicities occurred during the therapy. Therapy was discontinued for 3 patients because of rapid tumour progression. Of the 23 evaluable RCC patients, 3 exhibited a complete response and 4 displayed partial remission, 7 showed stable disease during 1–18 months (median = 5 months) of therapy, and progression was seen in 9. We conclude that vaccination with autologous tumour material combined with s. c. rIL-2 and rIFN-α2b administration can induce regressions in patients with advanced RCC and that even in non-responding patients a more favourable course of the disease can be achieved.
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  • 3
    ISSN: 1573-7276
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A variant of the highly metastatic mouse lymphoma ESb was isolated from ESb suspension culture by repeated selection for adhesiveness to plastic. The adhesion variant ESb-MP was shown to have greatly reduced malignant potential and a change in organotropism. ESb-MP cells metastasized into the kidney with a high frequency (80% of mice), whereas the ESb cells only rarely infiltrated the kidney (4% of mice). Two subclones of the adherent variant (ESb-M2 A8, ESb-M2 H6) showed a reduced malignant potentialin vivo very similar to the ESb-MP cell line, but only the clone ESb-M2 A8 infiltrated the kidney. Cell motility and chemotaxis of the various tumor lines was tested in a modified Boyden chamber assay. ESb-MP cells always migrated about 45 μm into a nitrocellulose filter of 8 μm pore size during 4 h incubation, whereas ESb cells and the two subclones migrated only to a distance of 12–25 μm. There was no apparent correlation betweenin vitro motility and malignancyin vivo. The addition of several factors known to be chemoattractant for granulocytes (C5a, FMLP) or for tumor cells (FMLP, laminin, fibronectin) did not affect the migration of ESb or ESb-MP cell lines. Enhanced migration of the ESb-MP cell line was, however, observed when kidney conditioned medium (KCM) was used as attractant in the lower chamber. This was not true for ESb cells. Additionally, within the subclones of the ESb-MP cell line, there was a remarkable correlation between kidney metastasisin vivo and responsiveness to KCMin vitro. The motility stimulating effect of KCM was due to a chemotactic activity. ESb cells, which did not respond to KCM, responded to other factor(s) derived from inflammatory exudate fluid. We conclude that the stimulation of tumor cell motility by an organotropic factor was highly selective for certain tumor lines. The correlation, between responsivenessin vitro and kidney metastasisin vivo, suggests that it is not so much the random migration of tumor cells which plays a role in metastasis but the motility following selective stimulation by tissue-derived factors and chemoattractants.
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  • 4
    ISSN: 1573-7276
    Keywords: cell adhesion molecule ; cytolysis ; L1 ; monolayer invasion assay ; tumor necrosis factor-α
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: The cell adhesion molecule (CAM) Ll is involved in homotypic and heterotypic adhesion between neural cells. It has recently also been identified on leucocytes. We have investigated the expression of L1 on hematopoietic tumor cell lines and found that several tumors including the ESb-MP lymphoma are positive for L1. A potential role for L1 in spontaneous metastasis formation was examined using these cells. From wild-type (wt) L1high lymphoma cells we selected by a fluorescence-activated cell sorter (FACS) stable L1low expression variants. Syngeneic DBA/2 mice injected subcutaneously with L1low clones showed faster primary tumor growth, developed visceral metastases significantly faster and died earlier than animals carrying L1high wt cells. L1high revertants from the L1low variants showed again a reduced metastatic capacity and a malignancy similar to the wt cells. Expression of L1 on the tumor variants and revertants correlated directly with their homotypic aggregation behaviour in vitro. L1 expression correlated negatively with metastatic capacity. These results suggest that L1 molecules may contribute to the overall malignant potential of the lymphoma cells, presumably by interfering with cell-cell interactions critical for tumor growth and dissemination.
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  • 5
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Active specific immunotherapy was performed in a phase I study in 20 colorectal cancer patients after surgical resection of the tumor. An autologous tumor cell vaccine surface modified by Newcastle disease virus (NDV) was used, which showed the following characteristics. After mechanical and enzymatic dissociation of the tumor tissue an average of 5 × 107 cells/g tissue was obtained. According to trypan blue dye exclusion assay the average viability was 72%. Following irradiation (200 Gy) the inactivation of proliferative activity of the cells could be demonstrated by the absence of incorporation of3H-labelled thymidine. The cells were, however, still metabolically active as shown by the incorporation of [3H]-uridine and a mixture of3H-labelled amino acids. Epithelium-specific antigens (detected by mAb HEA125) were expressed on more than 75% cells of the cell suspension indicating a high amount of (epithelium-derived) tumor cells. In order to increase the immunogenicity of the tumor cells the suspended cells were infected by the nonlytic, apathogenic Ulster strain of NDV. The successful modification of tumor cells with NDV could be shown by electron microscopy. Three weeks postoperatively cells were thawed, virus-modified, and inoculated intradermally in the upper thigh. Several cell and virus concentrations were tested in each patient. As control, tumor cells without NDV, NDV alone and normal colon mucosa were used. The number of tumor cells ranged from 2 × 106 up to 2 × 107 cells and NDV concentrations from 4 to 64 hemagglutination units (HU) were tested. Sixteen patients responded with a delayed-type hypersensitivity (DTH) skin reaction to the vaccine. The best DTH reaction, measured 24 h following vaccination, was obtained using a vaccine consisting of 1 × 107 tumor cells and 32 HU NDV (median induration of 8 mm). Response to NDV alone was seen in 2 patients only (median induration of 3 mm); 12 patients responded to tumor cells (1 × 107) alone (median induration of 4 mm). Of 10 patients tested with normal colorectal mucosa, 4 responded with a median induration of 3.5 mm. DTH responses to the vaccine of 1 × 107 tumor cells and 32 HU NDV increased throughout the repeated vaccinations to a median induration of 9.5 mm at the end of the therapy. No severe side-effects in the course of the immunotherapy, except for mild fever in 4/20 patients, were observed. The results of our phase I study show that this type of autologous colorectal tumor cell vaccine is ready for a large clinical trial to prove its efficacy.
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  • 6
    ISSN: 1432-1335
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
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