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Biomedical subjects

M Stetler-Stevenson

Publications and source records attributed to M Stetler-Stevenson.

At least 19 recordsLinked to original sources
PubMed2006

Elevation of soluble CD307 (IRTA2/FcRH5) protein in the blood and expression on malignant cells of patients with multiple myeloma, chronic lymphocytic leukemia, and mantle cell lymphoma.

CD307 is a differentiation antigen expressed in B-lineage cells. One soluble and two membrane-bound forms have been predicted and an enzyme-linked immunosorbent assay (ELISA) for soluble CD307 established. Our goal was to determine if CD307 is expressed on the surface of cells from patients with multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and other B-cell malignancies and if soluble CD307 levels are elevated in the blood of patients with these B-cell malignancies. Cells and blood were collected from patients. Expression of CD307 was measured by flow cytometry and blood levels of soluble CD307 by ELISA. High soluble CD307 levels were detected in 21/43 (49%) of patients with MM, 36/46 (78%) with CLL and 9/24 (38%) with MCL. Soluble CD307 levels correlated with plasma cell percentages in bone marrow aspirates in MM and total white blood cells in CLL. CD307 on the cell membrane was detected by flow cytometry in 8/8 MM, 23/29 CLL and 4/5 MCL samples. Because CD307 is present on malignant cells from patients with MM, CLL and MCL, CD307 may be a useful therapeutic target for the treatment of these diseases.

Adolescent↗
PubMed2001

Diagnostic utility of flow cytometric immunophenotyping in myelodysplastic syndrome.

The myelodysplastic syndromes (MDSs) are characterized by bilineage or trilineage dysplasia. Although diagnostic criteria are well established for MDS, a significant number of patients have blood and bone marrow findings that make diagnosis and classification difficult. Flow cytometric immunophenotyping is an accurate and highly sensitive method for detection of quantitative and qualitative abnormalities in hematopoietic cells. Flow cytometry was used to study hematopoietic cell populations in the bone marrow of 45 patients with straightforward MDS. The results were compared with those obtained in a series of patients with aplastic anemia, healthy donors, and patients with a history of nonmyeloid neoplasia in complete remission. The immunophenotypic abnormalities associated with MDS were defined, and the diagnostic utility of flow cytometry was compared, with morphologic and cytogenetic evaluations in 20 difficult cases. Although morphology and cytogenetics were adequate for diagnosis in most cases, flow cytometry could detect immunophenotypic abnormalities in cases when combined morphology and cytogenetics were nondiagnostic. It is concluded that flow cytometric immunophenotyping may help establish the diagnosis of MDS, especially when morphology and cytogenetics are indeterminate. (Blood. 2001;98:979-987)

Adult↗
PubMed2001

Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia.

BACKGROUND: Hairy-cell leukemia that is resistant to treatment with purine analogues, including cladribine, has a poor prognosis. We tested the safety and efficacy of an immunotoxin directed against a surface antigen that is strongly expressed by leukemic hairy cells. METHODS: RFB4(dsFv)-PE38 (BL22), a recombinant immunotoxin containing an anti-CD22 variable domain (Fv) fused to truncated pseudomonas exotoxin, was administered in a dose-escalation trial by intravenous infusion every other day for a total of three doses. RESULTS: Of 16 patients who were resistant to cladribine, 11 had a complete remission and 2 had a partial remission with BL22. The three patients who did not have a response received low doses of BL22 or had preexisting toxin-neutralizing antibodies. Of the 11 patients in complete remission, 2 had minimal residual disease in the bone marrow or blood. During a median follow-up of 16 months (range, 10 to 23), 3 of the 11 patients who had a complete response relapsed and were retreated; all of these patients had a second complete remission. In 2 of the 16 patients, a serious but completely reversible hemolytic-uremic syndrome developed during the second cycle of treatment with BL22. Common toxic effects included transient hypoalbuminemia and elevated aminotransferase levels. CONCLUSIONS: BL22 can induce complete remissions in patients with hairy-cell leukemia that is resistant to treatment with purine analogues.

Adult↗
PubMed2001

Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis.

Tissue inhibitors of metalloproteinases (TIMPs), first described as specific inhibitors of matrix metalloproteinases, have recently been shown to exert growth factor activities. It was previously demonstrated that TIMP-1 inhibits apoptosis in germinal center B cells and induces further differentiation. Interleukin-10 (IL-10) is reported as a vital factor for the differentiation and survival of germinal center B cells and is also a negative prognostic factor in non-Hodgkin lymphoma (NHL). However, the mechanism of IL-10 activity in B cells and the regulation of its expression are not well understood. IL-10 has been shown to up-regulate TIMP-1 in tissue macrophages, monocytes, and prostate cancer cell lines, but IL-10 modulation of TIMP-1 in B cells and the effect of TIMP-1 on IL-10 expression has not been previously studied. It was found that TIMP-1 expression regulates IL-10 levels in B cells and that TIMP-1 mediates specific B-cell differentiation steps. TIMP-1 inhibition of apoptosis is not IL-10 dependent. TIMP-1 expression in B-cell NHL correlates closely with IL-10 expression and with high histologic grade. Thus, TIMP-1 regulates IL-10 expression in B-cell NHL and, through the inhibition of apoptosis, appears responsible for the negative prognosis associated with IL-10 expression in these tumors.

Apoptosis↗
PubMed2001

Tissue inhibitor of metalloproteinase-1 alters the tumorigenicity of Burkitt's lymphoma via divergent effects on tumor growth and angiogenesis.

Epstein-Barr virus (EBV)-positive Burkitt's lymphoma cells and EBV-infected B cells elicit humoral factors that inhibit tumor-induced angiogenesis, resulting in tumor necrosis and regression. Of the chemokine factors identified in association with this growth behavior, none have induced complete tumor regression. We have previously identified tissue inhibitors of metalloproteinase (TIMP)-1 in various B cell lymphoma cell lines. Here we show that induction of TIMP-1 expression in an EBV-negative Burkitt's lymphoma cell line results in a biphasic, in vivo tumor growth pattern in the nude mouse that is essentially identical to EBV-positive Burkitt's lymphoma cell lines. The initial effect of TIMP-1 is to enhance tumor growth, consistent with the reported anti-apoptotic effect of TIMP-1 on B cell growth. Tumor necrosis and regression then follow the initial period of rapid, increased tumor growth. Only microscopic foci of residual, proliferating tumor cells are observed on biopsy of the tumor site. This latter effect is mediated by TIMP-1 inhibition of an angiogenic response within the developing tumor mass, as demonstrated by immunostaining and microvessel counts. These findings suggest that TIMP-1 is an important mediator of the in vivo growth properties of EBV-positive Burkitt's lymphoma.

Animals↗
PubMed2001

Coincident myelodysplastic syndrome and T-cell large granular lymphocytic disease: clinical and pathophysiological features.

Myelodysplastic syndrome (MDS) and T-cell large granular lymphocytic disease (T-LGL) are bone marrow failure disorders. Successful use of immunosuppressive agents to treat cytopenia in MDS and LGL suggests a common pathophysiology for the two conditions. Of 100 patients with initial diagnoses of either MDS or T-LGL referred to the National Institutes of Health for immunosuppressive treatment of cytopenia, nine had characteristics of both T-LGL and MDS (T-LGL/MDS). Fifteen patients with T-LGL received cyclosporin (CSA) (10 responses). Eight out of nine patients with T-LGL/MDS received CSA (two responses) and one patient received ATG (one response). Of 76 patients with MDS, eight received CSA (one response) and 68 received ATG (21 responses). The response to immunosuppression was significantly lower in patients with T-LGL/MDS and MDS than in patients with T-LGL disease alone (28% vs. 66%, P = 0.01). The proportion of T-helper cells and T-suppressor cells with an activated phenotype (HLA-DR(+)) was increased in patients with T-LGL, T-LGL/MDS and MDS, but the increase in activated T-suppressor cells in patients with T-LGL/MDS was not statistically significant. Autoreactive T cells may suppress haematopoiesis and contribute to the cytopenia in T-LGL and some patients with MDS, leading to T-LGL/MDS. The lower response rate of MDS or T-LGL/MDS to immunosuppression, compared with T-LGL alone, may reflect the older age and intrinsic stem cell abnormalities in MDS and T-LGL/MDS patients.

Adult↗
PubMed2001

Flow cytometric analysis of lymphomas and lymphoproliferative disorders.

Flow cytometry has become an important tool in the diagnosis and characterization of hematologic and lymphoid neoplasia. This technology serves as an excellent complement to microscope-based traditional diagnostic methods and adds distinctive capabilities that are unmatched by any other diagnostic methods. Flow cytometry is ideal for fluids where cells are naturally suspended but is also useful in lymphoid tissues, from which single-cell suspensions can be easily obtained. The advantages of flow cytometry are largely based on its ability to analyze very rapidly, even in small samples, multiple cell properties simultaneously, including size, granularity, surface and intracellular antigens, and DNA content. The quantitative nature of the data produced, both with regard to cell population distributions and to expression of individual cell antigens, offers objective criteria for interpretation of results. Examples of applications include the detection of clonal cells in B-cell lymphoma, the recognition of antigenic expression anomalies in B- or T-cell malignancies, the identification of malignant plasma cells, and the rapid measurement of cell cycle fractions. The unique attributes of flow cytometry allow for increased sensitivity in the detection of neoplastic cells and should contribute to improving accuracy and precision in the diagnosis and classification of lymphomas and lymphoproliferative disorders. Semin Hematol 38:111-123. This is a US government work. There no restrictions on its use.

Flow Cytometry↗
PubMed2000

Diagnosis of unexpected acute myeloid leukemia and chronic lymphocytic leukemia: a case report demonstrating the perils of restricted panels in flow cytometric immunophenotyping.

We report on the flow cytometric identification of concomitant acute myeloid leukemia and chronic lymphocytic leukemia in cytology specimens submitted with minimal clinical information. A 64-year-old man presented with fever and progressive dyspnea on exertion. Chest X-ray and computed tomography scan showed a left upper lobe pulmonary mass. Pulmonary capillary pullback specimens were collected to determine infectious verses neoplastic etiology. The pulmonary capillary pullback specimens showed atypical mononuclear cells with enlarged, slightly irregular nuclei; visible nucleoli; and basophilic cytoplasm. Flow cytometric analysis of the specimen for lymphoma was requested. Flow cytometric immunophenotypic studies showed that 78% of the cells were CD34 positive, CD45 dim positive and CD11c positive, consistent with acute myeloid leukemia. About 0. 75% of the cells expressed CD5 as well as dim CD20 and were monoclonal for kappa light chains: consistent with chronic lymphocytic leukemia/small lymphocytic lymphoma. At this time the clinician communicated a history of myelodysplastic syndrome of refractory anemia subtype. Peripheral blood was obtained for further immunophenotyping and the patient was immediately treated for his acute myeloid leukemia. This case demonstrates that a diagnostic antibody panel should allow evaluation of all cell types as per the U.S./Canadian consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry (Stewart et al.: Cytometry 30:231-235, 1997). Published 2000 Wiley-Liss, Inc.

Acute Disease↗
PubMed2000

Cyclin D1 overexpression in a model of human breast premalignancy: preferential stimulation of anchorage-independent but not anchorage-dependent growth is associated with increased cdk2 activity.

Cyclin D1 is frequently overexpressed in human breast ductal carcinoma in situ (DCIS) specimens, which confer a high risk for the development of infiltrating ductal carcinoma. If causally involved in the genesis of human breast malignancy, cyclin D1 may represent an interesting target for chemopreventive approaches, as it sits at the junction of many growth factor and hormonal pathways. We have used the MCF-10A human breast cell line, derived from a mastectomy containing a low risk premalignant lesion, as a model system. Three cyclin D1 transfectants exhibited physiologically relevant levels of transgene overexpression, but no coordinate overexpression of other cell cycle related genes. Proliferation assays, flow cytometry, and cdk enzymatic assays of anchorage-dependent proliferation indicated only a minimal and transient effect of cyclin D1. In contrast, cyclin D1 overexpression significantly stimulated anchorage-independent colonization in soft agar or methylcellulose, accompanied by greater Gl-S progression. The cdk4 activity of the control- and cyclin D1 transfectants in colonization assays was comparable, but the cdk2 activity was higher in the latter. Injection of control- and cyclin D1 transfected MCF-10A cells in matrigel into nude mice failed to produce tumors within 1.5 years. The data suggest that cyclin D1 overexpression is an early feature of breast neoplastic progression, and can contribute to cancer development through the promotion of colonization.

Animals↗
PubMed2000

Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies.

PURPOSE: To evaluate the toxicity, pharmacokinetics, immunogenicity, and antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Patients with CD25(+) hematologic malignancies for whom standard and salvage therapies failed were treated with LMB-2 at dose levels that ranged from 2 to 63 microg/kg administered intravenously over 30 minutes on alternate days for three doses (QOD x 3). RESULTS: LMB-2 was administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at the 63 microg/kg level was reversible and included transaminase elevations in one patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in nine patients at the maximum-tolerated dose (40 microg/kg QOD x 3); toxicity was transient and most commonly included transaminase elevations (eight patients) and fever (seven patients). Only six of 35 patients developed significant neutralizing antibodies after the first cycle. The median half-life was 4 hours. One hairy cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin's disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2 to 5 log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly. All four patients with HCL responded to treatment. CONCLUSION: LMB-2 has clinical activity in CD25(+) hematologic malignancies and is relatively nonimmunogenic. It is the first recombinant immunotoxin to induce major responses in cancer. LMB-2 and similar agents that target other cancer antigens merit further clinical development.

Adult↗
PubMed2000

Development of lymphoproliferative disorder of granular lymphocytes in association with hairy cell leukemia.

Lymphoproliferative disorder of granular lymphocytes (LDGL) is a low grade T-cell disease characterized by clonal expansion of large granular lymphocytes of either T cell or natural killer (NK) cell lineage that express the cytotoxic T-cell/NK cell antigens CD16, CD56 and/or CD57. LDGL has been described in association with other malignancies, leading to theories of a common abnormal stem cell as well as development of the LDGL as an immune response to a primary tumor. We have studied 32 patients with hairy cell leukemia (HCL). In 15 patients (47%) we detected an increase in cells expressing cytotoxic T-cell/NK cell antigens. In 10(31%) patients these cells were of T cell lineage, while 5 patients (16%) had increased NK-cells. T cell clonality was detected by PCR in all cases with increased cytotoxic T-cells in which adequate DNA was obtained from peripheral blood. Since in 2 patients the LDGL was not present at diagnosis but developed during follow up, our data suggests that clonal LDGL may develop in response to the HCL. The significance of LDGL in the setting of HCL and flow cytometric evaluation of HCL versus LDGL will be discussed.

Adult↗
PubMed2000

Hairy cell leukemia, a B-cell neoplasm that is particularly sensitive to the cytotoxic effect of anti-Tac(Fv)-PE38 (LMB-2).

Anti-Tac(Fv)-PE38 (LMB-2) is a recombinant, single-chain immunotoxin composed of the variable domains of the anti-Tac (anti-CD25) monoclonal antibody fused to a truncated form of Pseudomonas exotoxin (PE). Until now, this agent has been reported to be very cytotoxic toward T-cell but not B-cell leukemic cells freshly obtained from patients and is being tested clinically in patients with CD25+ malignancies of both B- and T-cell origin. Hairy cell leukemia (HCL) is a B-cell malignancy in which the cells are usually CD25+ and their ex vivo sensitivity to LMB-2 was unknown. Malignant cells from the first HCL patient to be tested were very sensitive to the cytotoxic effect of LMB-2 in vitro (IC50, 1.1 ng/ml), and this patient responded clinically to LMB-2 administered systemically. Therefore, we decided to assess the potential clinical utility of LMB-2 in other patients with HCL. We tested fresh leukemic cells from nine additional CD25+ HCL patients. LMB-2 was very cytotoxic ex vivo in all patients with IC50s as low as 0.5 ng/ml. Malignant cells freshly obtained from patients with chronic lymphocytic leukemia were also sensitive to LMB-2 but not as sensitive as cells from HCL patients. These results indicate that CD25+ HCL is a B-cell neoplasm that is particularly sensitive to LMB-2, and this agent may be useful in patients who have failed standard therapies.

Adult↗
PubMed2000

A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma.

This study used an 8-day continuous infusion regimen of a 1:1 mixture of two immunotoxins (ITs) prepared from deglycosylated ricin A chain (dgA) conjugated to monoclonal antibodies directed against CD22 (RFB4-dgA) and CD19 (HD37-dgA; Combotox) in a Phase I trial involving 22 patients with refractory B cell lymphoma to determine the maximum tolerated dose, clinical pharmacology, and toxicity profile and to characterize any clinical responses. Adult patients received a continuous infusion of Combotox at 10, 20, or 30 mg/m2/192 h. No intrapatient dose escalation was permitted. Patients with > or =50 circulating tumor cells (CTCs)/mm3 in peripheral blood tolerated all doses without major toxicity. The maximum level of serum IT (Cmax) achieved in this group was 345 ng/ml of RFB4-dgA and 660 ng/ml of HD37-dgA (1005 ng/ml of Combotox). In contrast, patients without CTCs (<50/mm3) had unpredictable clinical courses that included two deaths probably related to the IT. Additionally, patients exhibited a significant potential for association between mortality and a history of either autologous bone marrow or peripheral blood stem cell transplants (P2 = 0.003) and between mortality and a history of radiation therapy (P2 = 0.036). In patients with CTCs, prior therapies appeared to have little impact on toxicity. Subsequent evaluation of the ITs revealed biochemical heterogeneity between two lots of HD37-dgA. In addition, HD37-dgA thawed at the study site tended to contain significant particulates, which were not apparent in matched controls stored at the originating site. This suggests that a tendency to aggregate may have resulted from shipping, storage, and handling of the IT that occurred prior to preparation for administration. It is not clear to what extent, if any, the aggregation of HD37-dgA IT was related to the encountered clinical toxicities; however, the potential to aggregate does suggest one possible basis for problems in our clinical experience with HD37-dgA and leads us to the conclusion that non-aggregate-forming formulations for these ITs should be pursued prior to future clinical trials.

Adult↗
PubMed2000

Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) toward fresh malignant cells from patients with B-cell leukemias.

Chemical conjugates of anti-CD22 monoclonal antibodies and toxins have been used to treat CD22+ hematological malignancies. A new anti-CD22 recombinant immunotoxin RFB4(dsFv)-PE38, composed of the Fv portion of the monoclonal antibody RFB4 fused to a truncated form of Pseudomonas exotoxin A, is being developed to target CD22+ tumor cells. To explore the potential clinical utility of this recombinant toxin in treating patients with B-cell malignancies, the fresh cells of patients were incubated ex vivo with RFB4(dsFv)-PE38. Specific cytotoxicity was demonstrated in the malignant cells of 25 of 28 patients with a variety of B-cell malignancies, including acute and chronic lymphocytic leukemias and large cell, mantle cell, and follicular lymphomas. The IC50S, the concentrations necessary for 50% inhibition of protein synthesis, were 3-10 ng/ml in five patients and 10-50 ng/ml in seven patients. Cytotoxicity correlated with cell death upon direct examination of the malignant cells. Significant cytotoxicity was observed with cells containing as few as 350 CD22 sites/cell. A more active derivative of RFB4(dsFv)-PE38, RFB4(dsFv)-PE38KDEL, was produced and was slightly to more than 10-fold more cytotoxic toward patient cells and about twice as toxic to mice. Thus, RFB4(dsFv)-PE38 was specifically cytotoxic toward malignant cells from patients with B-cell leukemias. These data support the testing of RFB4(dsFv)-PE38 in patients with CD22+ leukemias and lymphomas, which is presently under way.

Antibodies, Monoclonal↗
PubMed1999

Increased peripheral blood gamma delta T-cells in patients with lymphoid neoplasia: A diagnostic dilemma in flow cytometry.

We have observed increased numbers of non-neoplastic gammadelta-T-cells in the peripheral blood of a series of patients with non-Hodgkin's lymphoma not of gammadelta-T-cell origin. The majority of normal gammadelta-T-cells are negative for surface CD4 and CD8 and a subpopulation does not express CD5, two immunophenotypic findings strongly suggestive of neoplasia in alpha beta T-cells. In addition, they express cytotoxic T-cell/Natural killer cell antigens. In this study, up to 22% of PBLs were CD4 and CD8 negative gammadelta-T-cells and up to 33% PBLs were CD5 negative gammadelta-T-cells. In addition, as high as 42% of PBLS were gammadelta-T-cells expressing cytotoxic T-cell/Natural killer cell antigens, suggestive of a large granular lymphoproliferative disorder. Failure to recognize that these are normal gammadelta-T-cells could lead to the erroneous diagnosis of peripheral blood involvement with a T-cell neoplasm, especially in the setting of a history of non-Hodgkin's lymphoma. Cytometry (Comm. Clin. Cytometry) 38:280-285, 1999. Published 1999 Wiley-Liss, Inc.

Adult↗
PubMed1999

Responses in refractory hairy cell leukemia to a recombinant immunotoxin.

We report major responses in 4 of 4 patients with hairy cell leukemia (HCL) who have recently been treated on a phase I trial with the recombinant immunotoxin LMB-2. The immunotoxin, designed to target CD25(+) malignancies, is composed of the Fv portion of the anti-Tac (anti-CD25) antibody, fused to a 38-kD truncated form of Pseudomonas exotoxin A, and has previously been called anti-Tac(Fv)-PE38. All 4 HCL patients were resistant to standard and salvage therapies for HCL, including 2-chlorodeoxyadenosine (CdA) and interferon alpha, and all patients responded to LMB-2 after a single cycle. One patient treated with 2 cycles had a complete remission (CR), with regression of HCL cells from the blood and marrow and resolution of splenomegaly and pancytopenia. As is typical for patients in CR after treatment with CdA, minimal residual disease was detectable by flow cytometry of the bone marrow aspirate. This patient has not relapsed after 11 months. Three other patients had 98% to 99.8% reductions in malignant circulating cells. These results represent a proof of principal that targeted therapy with recombinant Fv-containing proteins can be clinically useful. LMB-2 may be an effective new therapy for patients with chemotherapy-resistant CD25(+) HCL.

ADP Ribose Transferases↗