Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-2 has been used after autologous BMT (ABMT) with the aim of inducing graft versus leukemia (GVL) effect. Our studies in mice have shown that IL-2 therapy induces GVL effect when employed after BMT with bone marrow (BM) that has been activated with IL-2 in vitro (ABM). The present study was carried out to define the time of optimal GVL effect after BMT so that the immunomodulatory approaches could be concentrated at the time of maximum GVL effect. Our data show that GVL effect was induced if IL-2 was instituted immediately after BMT with ABM in mice with acute myeloid leukemia; institution of IL-2 1 week after BMT with ABM did not induce GVL effect. IL-2 therapy instituted immediately or 1 week after BMT with fresh bone marrow (FBM) did not induce any GVL effect. A significant increase in the NK activity was noticed whether IL-2 was instituted immediately or 1 week after BMT, either with FBM or with ABM. To evaluate the ability of IL-2 in the eradication of residual disease from the autograft and the host, BM with variable infiltration with leukemia was activated with IL-2 and used for BMT in leukemic mice. The GVL effect of BM with minimal leukemic infiltration (absence of morphologically demonstrable disease) was comparable to the GVL effect of normal BM. These findings suggest that: (a) maximum GVL effect after BMT with ABM is concentrated in the early post-transplant period possibly because of minimal residual disease during this time; (b) an increase in the NK activity induced by IL-2 therapy may not predict for an improved GVL effect; and (c) for optimum GVL effect, BM with minimal leukemic infiltration should be activated with IL-2 before BMT.
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PMID:Graft versus leukemia effect after transplantation with interleukin-2-activated bone marrow. Correlation with eradication of residual disease. 833 64

In order to obtain T cells for adoptive immunotherapy after autologous bone marrow transplantation (ABMT) for patients with resistant hematological malignancies, a culture system was developed for growing T cells and inducing non-MHC-restricted cytotoxicity using anti-CD3 monoclonal antibody (OKT3) activation. In this investigation, we show that (1) peripheral blood lymphocytes or bone marrow mononuclear cells (BMMNC) from normal donors and cancer patients can be activated with OKT3 and grown in interleukin-2; (2) normal BMMNC activated with OKT3/IL-2 exhibited non-MHC-restricted cytotoxicity and surface markers comparable to that exhibited by normal PBL activated with OKT3/IL-2; (3) both proliferation and cytotoxic functions were IL-2-dependent; (4) PBL activated with OKT3/IL-2 after cryogenic storage grew and killed comparable to PBL activated with OKT3/IL-2 prior to cryopreservation; (5) OKT3/IL-2-activated PBL and BMMNC obtained from 5 patients with non-Hodgkin's lymphomas (NHL) and 1 patient with acute myelogenous leukemia (AML) increased cell numbers 41-75-fold in 2 weeks of culture; 5 of 6 patients with NHL or AML had PBL and BMMNC that exhibited cytotoxic activity; and (6) contaminating leukemic cells did not overgrow in OKT3/IL-2-activated cultures and could no longer be detected on cytospin specimens after 3 weeks of culture. These data show that T cells in PBL or BMMNC from ABMT candidates can be activated with OKT3/IL-2 for adoptive immunotherapy in combination with ABMT.
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PMID:Preclinical studies for adoptive immunotherapy in bone marrow transplantation. Generation of anti-CD3 activated cytotoxic T cells from normal donors and autologous bone marrow transplant candidates. 835 89

We have shown that therapy of AML patients in second remission with continuous infusion of IL-2 resulted in generation of cytotoxic lymphocytes in peripheral blood and bone marrow. However, these lymphocytes mediated cytotoxicity only against tumor cell lines, and not against AML blasts. Additional in vitro activation with higher dose of IL-2 was necessary for induction of AML blast oncolysis. This indicates that the concomitant treatment with continuous and periodic bolus IL-2 infusion may be necessary, to achieve higher levels of IL-2 and subsequently, more potent lymphocyte activation. Alternatively, it may not be possible to induce optimal antileukemia response in vivo with tolerable doses of IL-2, and the adoptive therapy with in vitro supremely activated lymphocytes may represent an option. In this article, we discuss several approaches to the supreme activation of cytotoxic lymphocytes against highly resistant AML blasts and their possibilities in leukemia therapy.
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PMID:Recent approaches to induction of cytotoxic lymphocytes against leukemia. 836 Dec 37

IL-2 with or without autologous lymphokine-activated killer (LAK) cells, administered early after ABMT for AML may eradicate residual disease and reduce relapses. This paper reports 14 patients who received IL-2 or IL-2 plus LAK cells after ABMT for AML in first relapse or at a later stage, in two separate trials. Patients with AML in first relapse (n = 9), second CR (n = 3) or second relapse (n = 2) underwent ABMT after busulfan (BU), CY and total body irradiation (n = 11) or BU/CY alone (n = 3), with marrow that was (n = 6) or was not (n = 8) purged with 4-HC. In a previously-reported Phase I trial, eight patients received IL-2 (Roche) by continuous infusion at 0.3-3.0 x 10(6) U/m2/day x 5 days and, after 6 days of rest, 0.3 x 10(6) U/m2/day x 10 days. In a subsequent trial, five patients received IL-2 at 3.0 x 10(6) U/m2/day x 5 days, underwent leukapheresis for 3 days and received their LAK cells plus IL-2 (0.3 x 10(6) U/m2/day x 10 days). A sixth patient received only 2 days of IL-2, developed sepsis and died of multiorgan failure. All other patients had mild to moderate toxicity which was reversible. All patients developed neutrophilia, lymphocytosis and thrombocytopenia. IL-2 with or without LAK therapy was initiated 21-91 days (median 51 days) after ABMT. Severe thrombocytopenia (< 10 x 10(9)/l) occurred during the apheresis days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-2 with or without lymphokine-activated killer cells as consolidative immunotherapy after autologous bone marrow transplantation for acute myelogenous leukemia. 840 64

Leukemic cells from 21 to 197 adult patients with de novo acute myelocytic leukemia (AML) were positive for IL-2R alpha chain (IL-2R alpha), whereas IL-2R beta chain (IL-2R beta), which is responsible for IL-2 signal transduction, was not found on leukemic cells from any of these cases tested. The expression of IL-2R alpha was closely associated with that of adhesion molecules CD4, CD11b and CD22, and endopeptidase CD10. None of the IL-2R alpha (+) AML cells responded to recombinant human IL-2. These data suggest that IL-2R alpha on AML cells may not be involved in cellular proliferation as one of growth factor receptors but may have a role in the control of cell-to-cell interactions.
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PMID:Interleukin-2 receptor alpha chain on acute myelocytic leukemia cells is involved in cell-to-cell interactions. 842 75

A novel factor-dependent human myeloid leukemia cell line (GF-D8) was established from the peripheral blood of an 82-year-old man suffering from acute myeloblastic leukemia (AML). By morphology, cytochemical staining, and analysis of surface antigens, GF-D8 cells are myeloblasts of immature progenitor origin. The consensus karyotype is 45, XY, -5, 7q-, inv(7) (q31.2q36), 8q+, +8q+, 11q+, 12p-, -15, -17, + marker. The long-term survival and proliferation of GF-D8 cells is dependent on the presence of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3). Weak colony growth was observed after exposure of GF-D8 cells to stem cell factor (SCF) but not after exposure to granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), IL-1 beta, IL-2, IL-5, or tumor necrosis factor-alpha (TNF-alpha). GM-CSF- and IL-3-induced proliferation is dose dependent, with significant growth observed at concentrations as low as 0.1 ng/mL, but the combination of both factors has no synergistic effect. A significant proliferation is induced by GM-CSF and IL-3 even in serum-deprived cultures, although with a slightly decreased efficiency. GF-D8 cells were shown to express specific messenger RNAs for the alpha chains of the GM-CSF and IL-3 receptors as well as for the beta chain, common to both receptors. Interestingly, despite the absence of biologic response to G-CSF, specific transcripts for the G-CSF receptor gene were similarly identified by reverse polymerase chain reaction analysis. GF-D8 cells represent a useful tool for studying chromosome abnormalities of human AML as well as the regulation of myeloid proliferation and differentiation in vitro.
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PMID:Establishment and characterization of a new granulocyte-macrophage colony-stimulating factor-dependent and interleukin-3-dependent human acute myeloid leukemia cell line (GF-D8). 844 95

In the present study, we have investigated the leukemic cells obtained from 16 patients with acute myeloid leukemia (AML) at diagnosis for the membrane expression of p55 (alpha) and p75 (beta) interleukin-2 receptor (IL-2R) chains using specific monoclonal antibodies (mAbs), as well as for the presence of their transcripts using Northern blot analysis. In addition, immunoprecipitation of the p75 membrane molecule with TU27 and Mik-beta 1 mAbs was carried out in selected cases. The p75 IL-2R beta transcripts were detected in all cases, whereas the membrane p75 molecule was demonstrable by flow cytometry in three cases. However, data from the immunoprecipitation analysis suggest that the lack of the p75 IL-2R detection by flow cytometry might be caused by the low density of molecules per cell rather than the fact that the specific mRNA is not translated into the p75 surface molecule. In addition, a consistent membrane positivity with an anti-p55/CD25 mAb, present on fresh uncultured blasts in 37.5% of the cases, became detectable after short-term culture in 75% of cases. In each individual case, a strict correlation was found between membrane CD25 reactivity and the expression of p55 mRNA. Taken together, our data suggest that the expression of both alpha (p55) and beta (p75) IL-2R molecules is a common feature of leukemic cells in AML, and provide new arguments for reassessing the possible role of IL-2 in leukemic growth.
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PMID:Alpha (p55) and beta (p75) chains of the interleukin-2 receptor are expressed by AML blasts. 844 47

In this review we have considered the role of ABMT for the acute leukemias. It is apparent from data around the world that ABMT is a curative therapy for patients with both AML and ALL after primary treatment failure. Other than allogeneic BMT, ABMT may be the only curative therapy following relapse, especially in AML. The role of ABMT in first CR is less well defined. There are few data to support the widespread use of ABMT in first CR for ALL. Moreover, the improved survival of adults with ALL with current intense multiagent regimens will probably obviate the need to continue clinical trials of ABMT for ALL in first CR. For patients with AML in first CR, however, it seems that ABMT may well lead to improved rates of DFS compared with chemotherapy alone. Almost every published report describes better DFS for patients who underwent ABMT compared with historical or contemporary controls who were treated with chemotherapy. One note of caution is that as chemotherapy evolves, the increment in survival currently observed from ABMT may diminish, thus rendering ABMT less obviously necessary. On the other hand, from an economic standpoint, ABMT could prove to be cost-effective, because a short, intense treatment that is effective may prove to be less costly than the current extended period of chemotherapy. Because ABMT is becoming safer, it would seem reasonable to continue its use in patients with AML at high risk for relapse (secondary AML, adverse cytogenetics, and so on) while awaiting the outcome of the randomized clinical trials currently underway that are seeking to define the role of ABMT for the general population of patients with AML after initial remission is achieved. Meanwhile, further definition of the relative value of the various purging regimens, preparative regimens, and adjunctive therapy (i.e., IL-2, mAb) warrants study.
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PMID:Autologous bone marrow transplantation for adult acute leukemia. 844 59

In in vivo allogeneic bone marrow transplantation studies with the Brown Norway (BN) rat as recipient and the WAG/Rij rat as allogeneic donor a significant graft-versus-leukemia (GVL) effect is observed. Studies were performed to investigate whether lymphokine-activated killer (LAK) cells play a role in this GVL effect. Splenocytes from WAG/Rij and BN rats were activated in vitro by recombinant human interleukin-2 (rhIL-2) for 5-6 days. The cytolytic activity of these LAK cells was tested on four rat solid tumor cell lines, i.e. an ureter carcinoma, a rhabdomyosarcoma, and two lung tumors, and on leukemic cells derived from the BN rat acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia (L4415). The panel of target cells also included the murine cell lines P815 and YAC. Both WAG/Rij and BN LAK cells were not capable of lysing the leukemic cells in contrast to significant cytolytic activity on the rat solid tumor cell lines and P815 and YAC. BNML cells showed to be resistant to lysis by human NK cells. Phenotypical analysis of the rat LAK population revealed a decrease in the CD4/CD8 ratio compared to the unstimulated splenocyte population. Rat LAK cells displayed no antibody-dependent cellular cytotoxicity (ADCC) on the leukemic cells, whereas IL-2-stimulated human peripheral blood cells showed moderate ADCC activity on the leukemic cells. To investigate whether cytokines play a role in lysis of leukemic target cells, graded numbers of LAK cells and leukemic cells were co-cultivated for seven days in an agar-based colony culture system. This resulted in moderate suppression of leukemic colony formation. From the current in vitro studies it appears that the graft-versus-leukemia observed in in vivo allogeneic bone marrow transplantation studies is probably not due to a direct leukemic cell kill by LAK cells.
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PMID:In vitro resistance of the brown Norway rat acute myelocytic leukemia (BNML) to lymphokine-activated killer activity. 848 27

Myeloablative chemo (+/- radio) therapy and rescue with ABMT has been used as final consolidation therapy in 18 patients with AML in first remission. In seven (6 autologous, 1 syngeneic) marrow reinfusion was followed by iv IL-2. One patient, who commenced IL-2 4 days after BMT, died from pulmonary oedema due to the capillary leak syndrome. Thereafter, treatment with IL-2 was delayed until the platelet count reached 30 x 10(9)/l. All patients developed reversible hypotension (treated with infusion of colloid), but treatment was otherwise well tolerated. With 21-58 months (median 32 months) from the time of ABMT there has been one relapse (actuarial risk 17%, 95% confidence intervals (CI) 3-31%). The disease-free survival is 71% (95% CI 38-100%). Eleven patients with comparable remission induction and consolidation therapy, and an identical interval between diagnosis and ABMT (5-11 months, median 6 months) received an autograft without immunotherapy. With 24-45 months (median 29 months) follow-up the actuarial disease-free survival is 36% (95% CI 8-64%), the actuarial relapse risk is 54% (95% CI 18-90%). We conclude that immunotherapy given after ABMT to patients with AML in first remission when the platelet count exceeds 30 x 10(9)/l is safe and may induce an immunological environment which results in the elimination of residual leukaemia.
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PMID:Immunotherapy with interleukin 2 after ABMT in AML. 850 74


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