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Biomedical subjects

R A Stahel

Publications and source records attributed to R A Stahel.

At least 109 records · Page 6Linked to original sources
PubMed1991

Polyclonal anti-idiotypic antibodies mimicking the small cell lung carcinoma antigen cluster-5A interact with a panel of antibodies and induce specific immune response in animals.

Polyclonal anti-idiotypic antibodies (ab2) were generated by immunising goats with the murine IgG2a monoclonal antibody SWA20 which recognises the SCLC antigen cluster-5A, a tumour-associated sialoglycoprotein. Ab2 was shown to bind specifically to antibody SWA20, but not to isotype matched control antibodies. Pre-incubation with ab2 completely inhibited target cell binding of antibody SWA20 and of four other antibodies to cluster-5A antigen, while no effect was seen with antibodies to cluster-1 and cluster-w4 antigen. By these criteria the ab2 population consists of antibodies resembling in their reactivity pattern the cluster-5A antigen. Ab2 was used for immunisation of rabbits and two strains of mice; control animals received PBS or nonspecific goat IgG. Anti-anti-idiotype sera (ab3) were analysed in a series of radioimmunoassays for reactivity with goat IgG and reactivity with ab2. After blocking the nonspecific anti-goat response, ab3 could be shown to bind specifically to ab2 idiotype. As examined by an indirect cell ELISA with fixed cells, two out of six ab3 sera showed significantly higher binding ratios to antigen-positive SW2 cells as compared to antigen negative control cells. These findings indicate that the goat anti-SWA20 idiotype antibodies functionally represent the SCLC antigen cluster-5A and therefore may have potential for modulating the anti-tumour response through idiotypic network interactions.

Animals↗
PubMed1991

Cytotoxic activity of ricin A chain immunotoxins recognising cluster 1, w4 and 5A antigens associated with human small cell lung cancer.

The potential of mouse monoclonal antibodies raised against the human small cell lung cancer (SCLC) cell line SW2 to form active immunotoxins was evaluated using an indirect assay of immunotoxin cytotoxicity. Monoclonal antibodies recognising different SCLC-associated antigens, designated as cluster w4 and cluster 5A antibodies by the First International Workshop on SCLC Antigens, mediated the cytotoxic action of a screening agent made by linking ricin A chain to sheep anti-mouse IgG Fab' fragment. In contrast, monoclonal antibodies belonging to cluster 1 gave no significant cytotoxic effects in conjunction with the screening agent. Immunotoxins made by the direct chemical conjugation of ricin A chain to SWA11 (cluster w4) and SWA20 (cluster 5A) both exhibited selective toxic effects upon the SW2 cell line in tissue culture, inhibiting the incorporation of 3H-leucine by 50% at a concentration (IC50) of approximately 3 x 10(-10) M. An immunotoxin made with SEN36 (cluster 1) was much less potent with an IC50 greater than 1 x 10(-8) M.

Antibodies, Monoclonal↗
PubMed1990

Imaging and therapy of small cell carcinoma xenografts using 131I-labeled monoclonal antibody SWA11.

The IgG2a monoclonal antibody SWA11 has been evaluated as a radioimmunotherapeutic agent for use in the treatment of small cell cancer of the lung. This antibody was initially selected for in vivo localization studies in a nude mouse model system because of its high affinity for the SW2 small cell cancer cell line in vitro. Following i.v. injection of 125I labeled antibody into nude mice bearing SW2 xenografts good selective accumulation was observed with 10.5% of injected material/g of tumor. The level remained constant from day 2 to day 4 following injection. At day 4 the tumor:blood ratio was 7:1 and tumor:liver, tumor:kidney, and tumor:lung ratios were 17:1, 24:1, and 12:1, respectively. Initial radioimmunotherapeutic studies performed on established small cell cancer of the lung xenografts have shown reduction in tumor burden following a single injection of 300 microCi of 131I labeled SWA11 with no evidence of regrowth up to day 34 postinjection. Histological evaluation of treated tumors revealed large areas of necrosis and extensive fibrosis. A few residual cells of tumor origin could be observed and these displayed atypical morphology. The clonogenic potential of such cells remains to be determined by long term observation.

Animals↗
PubMed1990

Thyroiditis after treatment with interleukin-2 and interferon alpha-2a.

Serial thyroid functions studies were carried out in patients with melanoma and renal cell carcinoma treated with interleukin-2 (3 MU m-2 by continuous infusion days 1-4) and interferon alpha-2a (6 MU m-2 subcutaneously on days 1 and 4), both given on alternate weeks. The results on eight patients who completed at least three cycles of treatment are described. Four patients developed thyroid dysfunction with a hyperthyroid phase of 2 weeks followed by a hypothyroid phase ranging from 12 to 24 weeks. Two patients became clinically symptomatic and required treatment. Fine-needle aspirates of the thyroid were obtained in three patients with thyroid dysfunction. The cytology revealed a mixed cellular infiltrate with lymphocytes and histiocytes, and immunocytochemical staining showed strong HLA-DR expression of all thyrocytes, both suggestive of an autoimmune thyroiditis. One patient with thyroiditis developed anti-thyroglobulin antibodies, the serology of all other patients was normal. Patients with thyroid dysfunction tended to have higher in vivo stimulated lytic activity of peripheral mononuclear blood cells and had significantly higher levels of CD16 positive blood cells as compared to euthyroid patients. The possibility of autoimmune thyroiditis should be anticipated in future trails combining interleukin-2 and interferon alpha-2a.

Adult↗
PubMed1990

Selective cytotoxic effects of a ricin A chain immunotoxin made with the monoclonal antibody SWA11 recognising a human small cell lung cancer antigen.

The potential of mouse monoclonal antibodies for recognising different antigens associated with human small cell lung cancer (SCLC) to form active immunotoxins was assessed by an indirect in vitro screening assay. The screening agent used was a conjugate made by linking ricin A chain to a sheep anti-mouse IgG Fab' fragment via a disulphide bond. The monoclonal antibodies SWA11 and SWA20 both mediated the toxic effects of ricin A chain against the HC12 classic SCLC cell line in dose-dependent fashion. The SWA11 antibody was the more effective; in combination with the screening agent at a concentration of 1 x 10(-7) M, it inhibited the incorporation of [3H] leucine into HC12 cells by 94% compared with only 44% inhibition in the case of SWA20. An immunotoxin made by the direct chemical conjugation of ricin A chain to SWA11 exhibited selective toxic effects upon HC12 cells in tissue culture inhibiting the incorporation of [3H] leucine by 50% at a concentration (IC50) of 6.2 x 10(-10) M and by 98% at 1 x 10(-7) M. SWA11-ricin A chain had an IC50 of 4.4 x 10(-10) M against the NCI-H69 classic SCLC cell line but showed no cytotoxic activity against the human lung adenocarcinoma cell line NCI-H23 at a concentration of 1 x 10(-8) M.

Antibodies, Monoclonal↗
PubMed1990

Placebo controlled phase I/II study of subcutaneous GM-CSF in patients with germ cell tumors undergoing chemotherapy.

Patients with metastatic germ cell tumors undergoing five-day chemotherapy with etoposide, vinblastin, bleomycin and cisplatinum were given recombinant GM-CSF (mammalian glycosylated, Sandoz/Schering-Plough) at increasing dose levels of 75, 150, 300 or 600 micrograms protein/day in a double blind placebo controlled study. The drug was administered SC twice a day for 5 days starting 24 hours after completion of chemotherapy. Fourteen treatment courses, 10 with GM-CSF and 4 with placebo in 11 patients were evaluable for assessment of toxicity and hematological recovery, and 2 were not evaluable due to complications of progressive germ cell tumor. One patient receiving the highest dose level developed a delayed skin reaction at the site of injection. Fever under 38.5 degrees C and a flu-like syndrome were observed in 4/5 patients receiving the higher two dose levels, but not with lower dose levels or placebo. Two patients experienced mild bone pain. The neutrophil nadir was similar in the two groups, but the duration of neutropenia was significantly shorter in the GM-CSF group. At day 21 of chemotherapy the neutrophil count was 2.57 +/- 1.37 10(9)/l with GM-CSF, and 1.01 +/- 0.56 10(9)/l with placebo (p less than 0.05). Patients receiving GM-CSF could be retreated on day 21, whereas in patients given placebo, retreatment was delayed for an average of 7 days (p less than 0.05). Thus, a 5-day treatment with GM-CSF given subcutaneously resulted in a significant shortening of neutropenia and allowed for the timely administration of the subsequent cycle of chemotherapy.

Adult↗
PubMed1990

ME1. A monoclonal antibody that distinguishes epithelial-type malignant mesothelioma from pulmonary adenocarcinoma and extrapulmonary malignancies.

ME1 is a monoclonal antibody reactive in frozen tissue sections with normal mesothelial cells and malignant mesotheliomas. In this immunoperoxidase study, ME1 reacted with all 40 epithelial type malignant mesotheliomas. Fifty percent or more of the mesothelioma cells were stained in all cases and the staining intensity was strong in 32 and moderate in eight. In contrast, all 19 well- and moderately differentiated pulmonary adenocarcinomas were completely negative, and of the total 88 non-mesotheliomatous malignancies studied, staining comparable to the mesotheliomas was seen in only 6 tumors (2 pulmonary adenocarcinomas, 2 adenocarcinomas of the breast, 1 adenocarcinoma of the pancreas, and 1 melanoma), although limited, weaker staining was seen in additional cases. Five of the six strongly to moderately positive nonmesotheliomatous tumors had immunoreactivity for complementary immunoreactants (CEA, Leu-M1, S-100 protein, HMB-45). Our results with ME1, the first monoclonal antibody that recognizes malignant mesothelial cells, provides a basis for using this reagent in the differential diagnosis of tumors of the pleura and peritoneum.

Adenocarcinoma↗
PubMed1989

[High-dosage chemo-radiotherapy with autologous bone marrow transfusion in malignant lymphoma: indications and personal experience].

We report the results of a pilot study of dose intensification with autologous bone marrow support in patients with malignant lymphoma. Since January 1988 11 patients with malignant lymphoma have been treated by intensive chemoradiotherapy or combination chemotherapy followed by autologous bone marrow support. 6 of the patients had non-Hodgkin's lymphoma in first remission with unfavorable histology and/or unfavorable clinical prognostic factors, and 5 patients were in second or subsequent remission (2 non-Hodgkin's lymphoma, 3 Hodgkin's disease). Bone marrow harvest and cryopreservation of marrow cells were uneventful. 10 patients showed full hematologic recovery, while one patient with Hodgkin's disease died early of pneumocystis pneumonia. With the exception of one interstitial pneumonitis of unknown etiology, the clinical course during hospitalization was otherwise uncomplicated. The mean duration of hospital stay was 33 days. 2 patients relapsed after dose intensification, while the others are in continued remission (median 7 months, range 2-14 months).

Adolescent↗
PubMed1989

Monoclonal anti-idiotypic antibody mimicking a tumor-associated sialoglycoprotein antigen induces humoral immune response against human small-cell lung carcinoma.

We have previously described the tumor-associated sialoglycoprotein antigen sGP90-135 defined by the murine LAM8 MAb. The antigen is characterized by strong membrane expression in a proportion of small-cell carcinomas of the lung, but little or no expression on normal tissues of epithelial or neural origin or on blood cells. With the aim of obtaining anti-idiotypic antibodies which might be useful as surrogates for sGP90-135 in vaccination studies, LOU rats were immunized with LAM8 MAb and their spleen cells fused with Y3 rat myeloma cells. The LY8-229 hybrid was selected by an anti-idiotype competition radioimmunoassay on antigen-positive target cells. LY8-229 was shown to be a rat IgG1 with high specificity for LAM8 combining site. Solubilized small-cell carcinoma extract, as well as antibody SEN16, which recognizes the same tumor-associated antigen sGP90-135, selectively inhibited 125I-LY8-229 binding to LAM8. Serum from BALB/c mice and DA rats immunized with anti-idiotypic antibody LY8-229 showed reactivity with antigen-positive target cell lines, but not with antigen-negative control cell lines. The induction of a specific immune response in 2 different species by the anti-idiotypic antibody LY8-229 suggests that LY8-229 bears the internal image of the antigen sGP90-135 and that it might be a candidate for immunotherapy trials in cancer patients.

Animals↗
PubMed1989

[Decrease in systemic fungal infections in hematological neoplasms with empirical use of amphotericin B therapy].

An incidence of up to 30% of systemic fungal infections at autopsy, and difficulties in diagnosing systemic mycosis antemortem, have led to the empiric use of amphotericin B in patients with hematological malignancies. Routine empiric anti-fungal treatment was initiated at our institution in 1982. Amphotericin B and initially for 3 days flucytosine was given to granulocytopenic patients with unremitting (after 48-72 h) or recurrent fever during antibiotic treatment, or with newly detected pulmonary infiltrates, sinusitis, and skin and retinal lesions suggestive of fungal infection. With this approach the rate of systemic fungal infections decreased from 10% to 4% (p less than 0.02). The reduction was most prominent in patients with acute myelogenous leukemia, where fungal infections decreased from 16% to 4% (p less than 0.025).

Amphotericin B↗
PubMed1989

Tolerance and effectiveness of recombinant interleukin-2 (r-met Hu IL-2 [ala-125]) and lymphokine-activated killer cells in patients with metastatic solid tumors.

The tolerance of a recombinant human interleukin-2 (rIL-2, r-met Hu IL-2 [ala-125], Ortho Pharmaceutical) and its antitumor effectiveness in combination with lymphokineactivated killer (LAK) cells was examined in 26 patients with metastatic solid tumors, including 14 renal cell carcinomas, seven melanomas, three extragonadal germ cell tumors refractory to chemotherapy and two colon carcinomas. rIL-2 was administered as a bolus at 30,000 U/kg every 8 h on days 1-5 and days 12-19. Leukapheresis was done on days 8-12, lymphocytes were incubated with rIL-2 for 3 or 4 days in vitro and reinfused on days 12, 13 and 15. The mean number of reinfused cells was 5.1 x 10(10) per patient. IL-2 dose and schedule were adjusted according to toxicity. Patients received a median of 100% (range 87-100%) of planned rIL-2 on days 1-5 and a median of 71% (range 13-100%) on days 12-19. Capillary leak syndrome with hypotension and impaired renal function and CNS toxicity were the major reasons for dose modification. Patients with renal cell carcinoma, most of whom underwent a prior nephrectomy, had a reduced tolerance to rIL-2. Partial responses were documented in three renal cell carcinomas and one melanoma. The median response duration was 5.5 (range 1-6) months.

Adult↗
PubMed1989

Expression of the small cell carcinoma antigens of cluster-5 and cluster-5A in primary lung tumours.

The expression of the small cell carcinoma (SCLC) antigens cluster-5 (antibody LAM8) and cluster-5A (antibody SWA20) was examined on a panel of routinely processed biopsy or surgical specimens of 290 lung tumours by immunoperoxidase staining. Antigen expression was largely restricted to SCLC. Of over 150 tissue samples evaluated, moderate or strong antigen expression was found in 49% (cluster-5) and 45% (cluster-5A). Concordance in expression of the two antigens was seen in 71% of SCLC samples, with 35% expressing both antigens strongly, 8% moderately and 28% being negative for both antigens. Antigen expression was independent of the morphological subtype of SCLC. Primary lung tumours of other histology, including squamous cell carcinoma, large cell carcinoma, adenocarcinoma, mesothelioma or carcinoid had no significant antigen expression. Of 135 tumours, strong or moderate expression of both antigens was seen only in two cases. 20%, mostly carcinoids, were weakly positive for cluster 5 and 4% for cluster 5A antigen. The remainder were antigen negative. No significant antigen expression was seen in 25 normal lung tissues. The membrane antigens of SCLC cluster 5 and 5A are markers for SCLC and their expression in tissues is tumour-associated.

Antigens, Neoplasm↗
PubMed1989

Immunolocalisation and imaging of small cell cancer xenografts by the IgG2a monoclonal antibody SWA11.

We describe here a murine monoclonal antibody of the IgG2a isotype which was generated against the SW2 human small cell carcinoma cell line. The antibody, SWA11, was shown to bind to a partially defined antigen preferentially expressed on cell lines of small cell carcinoma origin. In vitro binding studies revealed 6.1 x 10(5) antigenic sites on the SW2 cell line and the Ka to be 1.2 x 10(9)M-1. Following injection into mice bearing 1-2 cm3 SW2 xenografts, SWA11 showed strong selective accumulation in the small cell heterotransplants with a tumour to blood ratio of 7.5:1 at day 4. Other tumour to organ ratios were similarly high at 19:1, 22:1 and 12:1 for liver, kidney and spleen respectively. The absolute amount of SWA11 which localised was 10.5% of total injected material per gram tumour at day 2 and this level did not markedly decrease by day 4. The high ability of SWA11 to localise to SCC xenografts was confirmed by external gamma scintigraphy. The potential application of SWA11 as a model system for in vivo radioimmunotherapy is discussed.

Animals↗
PubMed1989

Establishment of a human in vitro mesothelial cell model system for investigating mechanisms of asbestos-induced mesothelioma.

Normal human mesothelial (NHM) cells were transfected with a plasmid containing SV40 early region DNA. Individual colonies of transformed cells from several donors were subcultured for periods of 5 to 6 months and 60 to 70 population doublings (PDs) before senescence, in contrast to a culture lifespan of approximately 1 month and 15 PDs for NHM cells. One such culture, designated MeT-5A, escaped senescence and has been passaged continuously for more than 2 years. These cells had a single integrated copy of SV40 early region DNA in their genome, expressed SV40 large T antigen, and exhibited features of mesothelial cells including sensitivity to the cytotoxic effects of asbestos fibers. One year after injection subcutaneously or intraperitoneally in athymic nude mice, these cells remain nontumorigenic, and therefore are a potential model system for in vitro fiber carcinogenesis studies.

Animals↗
PubMed1988

Reduction of systemic fungal infections in patients with hematological malignancies, neutropenia, and prolonged fever by early amphotericin B therapy.

A rate on autopsy of up to 30% systemic fungal infections and difficulties in diagnosing systemic mycosis antemortem have led to the empiric use of amphotericin B in patients with hematological malignancies, prolonged fever, and neutropenia. Routine empiric antifungal treatment was initiated in our institution in 1982. Amphotericin B was given to granulocytopenic patients with hematological malignancies with (a) unremitting fever after 48-72 h of antibiotic treatment, (b) recurrent fever during antibiotic treatment, or (c) with newly detected pulmonary infiltrates, sinusitis, skin and retinal lesions suggestive of a fungal infection. With this approach the rate of systemic fungal infections decreased significantly from 10% (27 of 270 patients; 1973-1981) to 4% (6 of 153 patients; 1982-1986, P less than 0.02). The reduction of systemic fungal infections was most prominent in patients with acute myelogenous leukemia, where its proportion decreased from 16% (16 of 98 patients; 1973-1981) to 4% (2 of 50 patients; 1982-1986, P less than 0.023). Our data support the hypothesis that the incidence of systemic fungal infections in patients with hematological malignancies and especially in acute myelogenous leukemia can be reduced significantly by empirical treatment with amphotericin B.

Adult↗
PubMed1988

Tumor-associated membrane sialoglycoprotein on human small cell lung carcinoma identified by the IgG2a monoclonal antibody SWA20.

A mouse IgG2a monoclonal antibody, SWA20, defining a tumor-associated cell surface antigen on small cell carcinoma of the lung (SCC) was generated. The reactivity of the antibody with cell lines was examined by indirect immunofluorescence staining and solid phase radioimmunoassay and the reactivity with tissues by immunoperoxidase staining. The antibody reacts with a proportion of small cell carcinoma cell lines (4 of 8) and tissues (7 of 12), but not with other pulmonary or extrapulmonary cell lines (0 of 30) or tumor tissues (0 of 78). The antibody was unreactive with primary cultures of normal bronchial epithelial cells, RBC, and WBC. Immunoperoxidase staining of normal tissues showed rare antigen-positive cells in suprabasal layers of bronchial epithelium and less than 10% of positive cells in colon epithelium. Immunoblots of SCC extracts demonstrated antibody reactivity with a doublet band at Mr 40,000, a broader band at Mr 100,000, and a band at Mr 180,000. The antigen was not present in crude lipid extracts of SCC cells. Solid phase radioimmunoassays and immunoblots showed binding competition with the lectin Triticum vulgaris, sensitivity of the antigen to neuraminidase, and a partial sensitivity to treatment with periodate. The antigen was coexpressed on SCC cell lines with the antigen sGP90-135 defined first by antibody LAM8 (R. Waibel, C. J. O'Hara, and R. A. Stahel. Cancer Res., 47:3766-3770, 1987) but differed from it by lack of reactivity with Lea-positive saliva and partial resistance to periodate treatment. There was no binding competition between radiolabeled antibodies SWA20 and LAM8 to SCC target cells. The IgG2a antibody SWA20 identifies a previously undescribed tumor-associated surface membrane antigen, sGP100, expressed selectively on a proportion of SCC.

Antibodies, Monoclonal↗