Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This re-evaluation of a pilot study conducted nearly three decades ago (1965-1970), in which serendipity played a central role in favorable responses of hematologic malignancies to the administration of adoptive lymphocytes from both parents, has been motivated by clearer understanding. Temporary remissions marking LAK cell-driven graft-versus-leukemia (GvL) responses were observed in four of seven acute leukemia patients associated with unique self-limited graft-versus-host (GvH) reactions that were NK cell and cytokine related. Retinopathy not previously reported in a GvH setting was a consistent manifestation in these patients. Cure was achieved in an eighth patient with acute lymphoblastic leukemia after she had been given effective chemotherapy, an active role for the adoptive therapy indicated by the occurrence of a week of fever suggesting an abortive GvH reaction. Two of five patients with Hodgkin's disease also experienced favorable responses to parental leukocyte therapy, one exhibiting GvH manifestations almost identical to those seen in the acute leukemia patients when given the adoptive therapy successfully to spur recovery from severe herpes zoster that had interrupted curative radiation therapy. The GvH in the other patient was a more typical one, the key effect being an increase in circulating lymphocytes that may have contributed indirectly to cure with subsequent therapy. These and other attempts to apply GvL responses therapeutically, including those currently in favor, exemplify the shortcomings of partial mitogenic responses to alloactivation, which are dependent on engraftment, limited in scope, excessively toxic, and difficult to control. Treatment with mitogens such as PHA would be a superior alternative because of the abilities of these agents to regulate immune responses by simple modulations of dosage, scheduling, and modes of application.
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PMID:Haplotype donor-generated graft-versus-leukemia responses: serendipity revisited. 854 57

The high relapse rate of hematologic malignancy treated with autologous bone marrow transplantation (ABMT) may reflect the absence of a graft-versus-leukemia (GVL) effect usually associated with graft-versus-host disease (GVHD). The purpose of this study was to determine whether administration of interleukin-2 (IL-2) early after ABMT might induce or exacerbate acute skin GVHD. Fourteen patients at high risk for post-transplant relapse, eight with NHL and six with AML > or = first relapse, were conditioned with chemotherapy and total body irradiation (13) or chemotherapy alone (1), and received purged (10) or unpurged (4) marrow. A median of 35 days (range 25-58) after ABMT, they received a 5-day induction course of Roche IL-2 (9 x 10(6) U/m2/day) followed by apheresis, reinfusion of LAK cells, and a 10-day maintenance course of IL-2 (0.9 x 10(6) U/m2/day), all by continuous i.v. infusion. Serial skin biopsies were obtained before and after IL-2 therapy and were read blindly. Patients were studied prospectively for the development of acute cutaneous GVHD as reflected by rash ( > or = 25% body surface area), skin biopsy ( > or = grade II histologic changes) and T cell infiltration as assessed by staining of the biopsy with antibodies UCHL-1 and TIA-1. No patient had a rash before IL-2 therapy, but 12 of 14 (85%) developed a rash during the IL-2 induction course. Before IL-2 therapy, biopsies from three of 10 patients (30%) revealed histologic GVHD; after induction IL-2, biopsies from 11 of 14 patients (79%) revealed grade II acute GVHD. Biopsies from all patients with histologic GVHD after IL-2 therapy contained TIA-1 positive T cells. HLA-DR was negative in the keratinocytes of these paraffin-embedded sections. One patient died early of sepsis, one patient required and responded to topical corticosteroids and 12 had spontaneous resolution of the rash. Six patients relapsed at 3-13 months, while seven remain in complete remission 32+ to 41+ months after ABMT. The results demonstrate that IL-2 therapy after ABMT can induce effects which histologically and clinically mimic cutaneous acute GVHD in most patients. Prospective, randomized trials of IL-2 vs observation after transplantation of autologous marrow or stem cells for high-risk NHL and AML have been initiated which may allow us to determine whether this phenomenon is associated with a clinical GVL effect as reflected by a decreased relapse rate.
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PMID:Close simulation of acute graft-versus-host disease by interleukin-2 administered after autologous bone marrow transplantation for hematologic malignancy. 870 86

There is good evidence that T lymphocytes play an important role in the graft-versus-leukemia (GVL) effect following allogeneic bone marrow transplantation (BMT) for hematologic malignancies. However, the role of natural killer (NK) cells in GVL is less clear. To further investigate a possible association of NK cells with GVL we studied 15 patients undergoing BMT for chronic myeloid leukemia (CML), correlating T-cell (CD4+ and CD8+) and NK-cell (CD16+ 56+) recovery with relapse and graft-versus-host disease (GVHD). Patients were studied on three occasions up to 9 months after BMT, for lymphocyte surface phenotype and for spontaneous and IL-2-stimulated (LAK cell) cytotoxic function. Circulating CD8+ and NK but not CD4+ cell numbers were significantly lower in five patients who relapsed compared with those remaining in remission after BMT (mean 0.03 vs 0.32 x 10(9)/l, p = 0.002 for CD8+ cells: mean 0.03 vs 0.11 x 10(9)/l, p = 0.002 for NK cells). There was no correlation of CD4+. CD8+, or NK cell numbers and development of grade-II or more acute GVHD. Spontaneous NK cytotoxic function rose to within the normal range in the first month after BMT. LAK function remained low during the study period. These results link NK cell recovery more closely with a GVL than with a GVH effect.
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PMID:Association of natural killer cell immune recovery with a graft-versus-leukemia effect independent of graft-versus-host disease following allogeneic bone marrow transplantation. 903 7

In this report we describe the characteristics of an immunosuppressive molecule from an Abelson Leukemia Virus transformed highly malignant and metastatic RAW117-H10 murine large cell lymphoma cells. Our studies have shown that the mitomycin-c treated or irradiated RAW117-H10 cells very significantly (p < 0.001) inhibited the nitrogen induced proliferation of normal Balb/c splenocytes. The cell surface extracts from the immunosuppressive RAW117-H10 lymphoma cells significantly inhibited the in vitro T cell or NK/LAK cell functions. Our in vivo studies demonstrated that there was a significant suppression of immune response in the Balb/c mice bearing RAW117-H10 cells when compared with mice bearing low metastatic parental RAW117-P cells or control mice. Subsequently we isolated and purified the main molecule responsible for this immunosuppression and found that the molecule is a glycoprotein with a molecular weight of 70 kD with an isoelectric point of 4.3, which cross reacted with antibodies to murine leukemia virus envelope gp70 molecules. Further analysis using immunoelectrophoresis, molecular probing techniques, and mannose specific lectin binding assay revealed that the immunosuppressive 70 kD molecule, is different from the wild type MLV envelope gp70 molecule and thus appears to be an altered gp70 molecule. These studies demonstrate that the metastatic lymphoma associated immunosuppression may facilitate the growth and metastasis of tumor cells. Our results also elucidate the possible mechanism(s) of retrovirus induced immunosuppression and the molecular basis of this retroviral envelope-mediated process in viral pathogenesis and tumor progression.
Leukemia 1997 Apr
PMID:Immunosuppression by metastatic lymphoma derived altered retroviral gp70 molecule. 920 41

The results of the present study demonstrate that cells with the morphologic and phenotypic characteristics of blast cells that are obtained from the peripheral blood of patients with newly-diagnosed or recurrent acute myeloid leukemia (AML) can be stimulated by gamma interferon + lipopolysaccharide (IFN/LPS) to mediate in vitro cytolysis of an NK-insensitive hepatoma cell line. The conditions of IFN/LPS induction and subsequent assessment of cytotoxicity that were employed were identical to those used conventionally to test macrophage-mediated tumor cell cytotoxicity. What was totally unexpected was that these same blast cells, in the absence of stimulation with IFN/LPS, were also found to mediate high levels of spontaneous cytotoxicity against autologous bone marrow cells and against the U937 human promonocytic leukemia cell line in vitro. This high level of spontaneous cytotoxicity against autologous bone marrow or U937 promonocytic leukemia cells was not enhanced by IFN/LPS or MCSF under conditions that stimulated cytotoxic function in normal blood monocytes and was markedly reduced by pretreatment of the blast cells with IL2 under conditions that induced potent NK/LAK-mediated cytotoxicity. Neutralizing antibodies against TNFalpha and/or IL1alpha/beta eliminated the cytolytic function of blast cells against autologous bone marrow or U937 promonocytic leukemia targets. These findings demonstrate the existence of a population of cells with the morphologic characteristics of blast cells in the peripheral blood of AML patients which has the capacity to mediate spontaneous cytolysis of autologous bone marrow cells or a promonocytic leukemia cell line. These cells may be an immature variant of normal precursors produced as a consequence of the disordered hematopoietic environment in the marrow of AML patients. Alternatively, this function may be mediated by a subset of the leukemic blasts themselves.
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PMID:Cytolytic activity of peripheral blood blast cells from patients with acute myeloid leukemia. 947 27

Killing of target cells by cytotoxic T cells is mediated by induction of apoptosis requiring functional death pathways. Kill is mediated either by the CD95 or the perforin/granzyme pathway. We found that SH-EP neuroblastoma cells are preferentially killed via CD95, while in the T leukemia cell line CEM CD95 and perforin/granzyme are involved. In both types of cell lines, cells resistant to CD95- and drug-induced apoptosis are crossresistant to cytotoxic T cell kill. Resistant cells show decreased apoptosis and deficient activation of caspases indicated by decreased cleavage of the prototype caspase substrate PARP. Preincubation with the caspase inhibitor zVAD-fmk strongly decreased LAK cell kill in sensitive cells. Although parental CEM cells could be sensitized for LAK kill by preincubation with doxorubicin, resistance could not be reverted in doxorubicin or CD95 resistant CEM cells. These data demonstrate the crossresistance in induction of apoptosis by different cytotoxic regimens in tumor cells and may have implications for the immunotherapy of tumors in which apoptosis resistance was induced by previous chemotherapy.
Leukemia 1999 Mar
PMID:Decreased sensitivity of drug-resistant cells towards T cell cytotoxicity. 1008 32

Thirteen adults with acute myeloblastic leukaemia (AML) in early 2nd complete remission (CR) were treated with recombinant interleukin-2 (IL-2) and autologous IL-2-activated peripheral blood lymphocytes (LAK cells). All 13 developed IL-2-induced in vitro lymphocytoxicity against K562 and Daudi target cells. After seven years' follow-up, there was no overall improved survival compared with a historical control group treated with chemotherapy alone. However 7/13 patients developed T-cel-associated cutaneous graft-versus-host disease (GVHD), and 4/4 of these tested showed in vitro evidence of a T-cell-mediated graft-versus-leukaemia (GVL) effects. These had significantly longer 2nd CRs and survived longer. More lymphocytes were harvested and more LAK cells were reinfused in these seven cases. Since these patients also had longer 1st CRs, their GVL response to IL-2/LAK cells could be a feature of slowly progressive disease.
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PMID:Acute myeloblastic leukaemia: graft-versus-host and graft-versus-leukaemia responses to autologous IL-2 activated lymphocytes in rapid and slow disease. 1039 74

We present data providing new evidence that poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA)-bound drugs, unlike free drugs, have both cytostatic and immunomobilizing activity (CIA). Immediately after injection, due to the high level of the drug, the main activity of the polymeric conjugate is cytotoxic and cytostatic. Later on, long-term circulating PHPMA-bound drug, at concentrations lower than its minimal inhibitory levels, mobilizes the defense mechanisms of the host. Cytotoxic and cytostatic effects of drug-PHPMA were repeatedly confirmed. The following data support the concept of the immunomobilizing activity of the N-(2-hydroxypropyl)methacrylamide (HPMA) conjugates: (a) pre-treatment with free drugs (doxorubicin, cyclosporin A) accelerates the appearance of EL4 mouse T-cell lymphoma while a similar pre-treatment with doxorubicin-PHPMA induces limited but definitive mobilization of the host's defense mechanisms; (b) mice cured of EL4 mouse T-cell lymphoma, BCL1 mouse B-cell leukemia and 38C13 mouse B-cell lymphoma by injection of doxorubicin-PHPMA conjugate targeted with monoclonal antibodies (anti-Thy 1.2 for EL4, anti-B1 for BCL1 and anti-CD71 for 38C13) and re-transplanted with a lethal dose of the same cancer cells survive without any treatment considerably longer than control mice; (c) increased NK activity and anti-cancer antibody was detected only in animals treated with doxorubicin-PHPMA conjugate; and (d) considerably increased NK and LAK activity was seen in a human patient treated for generalized breast carcinoma with doxorubicin-PHPMA-IgG.
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PMID:Acquired and specific immunological mechanisms co-responsible for efficacy of polymer-bound drugs. 1177 52

The interleukins function as intercellular hormones, possessing the ability to alter the activity of a target cell population. Interleukin-4, secreted by activated T-cells, has shown antitumor activity in vitro against multiple myelomas, lymphoma, chronic myelomonocytic leukemia, and some solid tumors. Early promising clinical studies have shown the efficacy of IL-4 in decreasing the malignant lymphocyte count and in normalizing hematologic parameters in patients with CLL and in inducing transient clinical responses in patients with non-Hodgkin's lymphoma. Interleukin-6 possesses immunomodulating properties including enhancement of NK cell activity and induction of cytotoxic T-cell activity. IL-6 has shown antitumor activity in mice injected with weakly immunogenic syngeneic tumors and has been shown to inhibit in vitro human breast carcinoma and leukemia/lymphoma proliferation through a direct tumor inhibitory effect. Clinical studies investigating the antitumor activity of IL-6 are currently in phase II clinical trials. IL-6 and IL-11 have demonstrated thrombopoietic enhancing activity in primate models and early clinical trials. These agents have a potential application in ameliorating the thrombocytopenia associated with myeloablative chemotherapy. Yet to enter clinical trials, IL-12 has been shown to enhance the lytic activity of nonspecific NK/LAK cells and appears to be more efficient than IL-2 or IFN's in enhancing NK cytotoxicity. IL-12 has also been shown to enhance specific allogeneic human CTL responses and to induce the secretion of IFN-gamma from both resting and activated T and NK cells. In summary, these interleukins are now promising agents under investigation as effective treatment strategies in the oncologic setting.
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PMID:A Review of the New Cytokines: IL-4, IL-6, IL-11, and IL-12. 1183 74

We studied the effects of the in vivo administration of interleukin-2 (IL-2) (at low doses) + GM-CSF in BALB/C mice injected intraperitoneally with LSTRA murine leukemic cell line in order to test the possible role of this immunotherapeutic approach in the eradication of leukemia. Mice were injected intraperitoneally on day -1 with different concentrations of LSTRA cells. On day 0, mice received a lethal dose of TBI of 700 cGy from a Cs(137) source, followed by a single high dose of recombinant human-granulocyte-colony stimulating factor (rh-G-CSF) (1 microg/g) intraperitoneally 2h after TBI. This procedure rescued 80% of mice but only mice injected with the lower concentration of LSTRA cells (10(3)) could be cured. The lethal dose (LD 100/60) of LSTRA in normal mice was 10(4). The subcutaneous administration of rh-IL-2 (4.000 IU/mouse per day, from day +1 to +28) + rm-GM-CSF (1 microg/kg per day) from day +7 to +28 cured mice injected with 10(4) LSTRA cells and 40% of mice injected with 10(5) cells. Mice injected with 10(6) cells died from leukemia. We observed an increase in LAK activity on days +21 and +28 without an increase in NK activity. We show that BALB/C mice injected with LSTRA cell line can be cured by in vivo activation with IL-2 + GM-CSF depending on the cell dose injected. The curability of leukemia was confirmed at the molecular level with a PCR method.
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PMID:BALB/C mice injected with LSTRA leukemic cell line are cured by in vivo treatment with IL-2 + GM-CSF. 1253 Dec 27


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