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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent developments in biotechnology have resulted in a substantial renewal of cancer immunotherapy. In particular, the availability of murine monoclonal antibodies and recombinant biological response modifiers by genetic manipulation has made it possible to re-test abandoned concepts of adoptive humoral and cellular immunotherapy and to reconsider the biomodulation of the patient's immune system. Thus, the utilization of monoclonal antibodies to purge ex vivo autologous marrow from residual tumor cells has reached an advanced stage of clinical investigation in the field of autologous bone marrow transplantation for leukemia or lymphoma. Numerous promising clinical trials are being performed by the injection of monoclonal antibodies directed at tumor-associated antigens, coupled with cytotoxic agents (isotopes, drugs, toxins). In the area of recombinant technology, interferon-alpha has become the drug of choice for a particular form of chronic leukemia (hairy-cell leukemia). Interleukin-2 administered in conjunction with autologous activated lymphocytes has been shown to mediate significant anti-tumor activity in metastatic cancer patients. This review briefly describes recent clinical results obtained in cancer immunotherapy and discusses the potential of these new approaches.
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PMID:[Current possibilities in immunotherapy of cancer]. 355 Oct 61

Interleukin-2 (IL-2) is a lymphokine synthesized by some T cells following activation. Resting T cells do not express IL-2 receptors but receptors are rapidly expressed on T cells following the interaction of antigens, mitogens, or monoclonal antibodies with the antigen specific T-cell receptor complex. Using anti-Tac a monoclonal antibody that recognizes the IL-2 receptor, the receptor has been purified. The receptor is a 33 kdalton peptide that is post-translationally glycosylated to a 55 kdalton mature form. Mature receptors contain both N-linked and O-linked sugars and are both sulfated and phosphorylated. Using an oligonucleotide probe, based on the N-terminal amino acid sequence, cDNAs encoding this receptor have been cloned, sequenced and expressed. The addition of anti-Tac to in vitro culture systems blocks the IL-2 induced DNA synthesis of IL-2 dependent T-cell lines and inhibits soluble auto- and alloantigen induced T-cell proliferation. Furthermore, it prevents the generation of cytotoxic and suppressor effector T cells. The anti-receptor antibody also inhibits lectin stimulated immunoglobulin synthesis and the sequential expression of late appearing activation antigens on T cells. Normal resting T cells and most leukemic T-cell populations do not express IL-2 receptors however the leukemic cells of all patients with human T-cell leukemia/lymphoma virus (HTLV-I) associated, adult T-cell leukemia (ATL) examined expressed the Tac antigen. In HTLV-I infected cells the 42 kdalton long open reading frame (LOR) protein encoded in part, by the pX region of HTLV-I may act as a transacting transcriptional activator that induces transcription of the IL-2 receptor gene thus providing an explanation for the constant association of HTLV-I infection of lymphoid cells and IL-2 receptor expression. The constant display of large numbers of IL-2 receptors which may be aberrant in the ATL cells may play a role in the uncontrolled growth of these leukemic T cells. Patients with the Tac positive ATL are being treated with an anti-Tac monoclonal antibody directed towards this growth factor receptor.
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PMID:Interleukin-2 receptor expression in retrovirus associated adult T-cell leukemia. 610 Jun 44

Disseminated tumors growing progressively in syngeneic hosts can be eradicated by combination therapy with cyclophosphamide and adoptive transfer of specifically immune T cells. Interleukin-2 (IL-2), which induces proliferation of T cells specifically activated by antigen, has substantial therapeutic potential as a reagent for increasing the magnitude of tumor-specific T cell responses. The purpose of the present studies was to determine the effector mechanisms operative in tumor-bearing hosts by which subpopulations of immune T cells can mediate tumor eradication, and to determine if the in vivo administration of exogenous IL-2 can augment these T cell effector functions. Disseminated leukemia was eradicated by adoptive therapy with the immune Lyt 1+2- noncytolytic T cell subpopulation, under experimental conditions in which cytolytic T lymphocytes could not participate. The Lyt 1+2- subset contains helper/amplifier cells that produce endogenous IL-2 in response to tumor and effector cells that mediate delayed-type hypersensitivity reactions. The administration of exogenous IL-2 following transfer of immune T cells containing this noncytolytic subset failed to augment their therapeutic activity, implying that the amount of IL-2 being produced endogenously did not limit the antitumor response. Adoptive therapy with purified cytolytic Lyt 1-2+ T cells produced a demonstrable but limited antitumor effect. Since this cytolytic subpopulation lacked helper T cells, the limited activity observed presumably reflected a requirement for an IL-2-producing cell. Administration of exogenous IL-2 following cell transfer satisfied this requirement and markedly augmented the efficacy of adoptive therapy with Lyt 1-2+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effector mechanisms operative in adoptive therapy of tumor-bearing animals: implications for the use of interleukin-2. 623 12

In vitro ultraviolet-B (UVB) irradiation of murine and rodent bone marrow cells prevents GVHD without compromising engraftment while inducing tolerance to donor-type allografts. In anticipation of clinical trials of UVB-modified bone marrow grafts, we studied the in vitro effects of UVB irradiation (50-300 J/m2) on human natural killer and lymphokine activated killer cells since both types of cells influence the development of GVHD and graft-versus-tumor effect. Interleukin-2-activated and untreated human lymphocytes were used as effectors in a 51Cr release cytotoxic assay against various tumor cell lines as targets. NK-mediated lysis of K562 targets was decreased by UVB irradiation of the effector cells in a dose-dependent manner. FACS analysis of CD16+ and CD56+ cells 24 hr after UVB exposure showed a UVB-dose-dependent decrease in the number of cells expressing these surface markers. UVB irradiation of lymphocytes prior to activation with high-dose IL-2 resulted in a range of 20- to 89-fold decrease in LAK precursors as measured by limiting dilution analysis using the LAK-sensitive cell line HL60. In contrast, the LAK activity of lymphocytes that had been stimulated in vitro with high-dose IL-2 prior to UVB irradiation was preserved when assayed immediately after UVB modulation; however, there was a significant decrease in lytic activity (with most samples tested) when the assay was performed 24 hr after UVB exposure. It appears that the lymphocyte response to UVB modification is dose dependent, with some cell types displaying higher sensitivity to UVB irradiation than others. These findings suggest that prevention of GVHD by UVB is due, in part, to inhibition of NK activity, and may offer a new strategy to augment the graft versus leukemia effect of UVB-modified bone marrow grafts in clinical transplantation.
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PMID:Effects of ultraviolet-B irradiation on human LAK and NK cytotoxic activity. 755 80

Acute myeloid leukemia (AML) cells express the surface adhesion proteins intercellular adhesion molecule-1 (ICAM-1, CD54) and lymphocyte function associated molecule-3 (LFA-3, CD58). Exposure to the myeloid growth-promoting cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulates expression of ICAM-1 and LFA-3 on AML cells but does not increase their sensitivity to lysis by interleukin-2-activated natural killer cells (LAK) in 51Cr assays. However when AML cells are exposed to GM-CSF prior to incubation with LAK, their subsequent clonogenic activity is significantly reduced. If a blocking antibody to ICAM-1 is added during the incubation period of AML with LAK, the inhibitory effect is completely ablated. A less pronounced effect is observed with an antibody to LFA-3. ICAM-1 is expressed on a greater proportion of CD34+ than CD34- AML cells and exposure to GM-CSF induces a significantly greater upregulation of ICAM-1 on leukemic CD34+ cells than their CD34- counterparts. These data suggest that the inhibitory effect of IL-2-activated natural killer cells on clonogenic AML cells is mediated principally via the lymphocyte function associated molecule-1 (LFA-1)/ICAM-1 interaction. Interleukin-2 upregulates LFA-1 expression on natural killer cells. Simultaneous administration of effector cell activators such as IL-2 and target cell modulators such as GM-CSF may have a therapeutic benefit in patients with minimal residual myeloid leukemia.
Leukemia 1995 Apr
PMID:GM-CSF enhances IL-2-activated natural killer cell lysis of clonogenic AML cells by upregulating target cell expression of ICAM-1. 772 3

High-dose recombinant human Interleukin-2 was given to 21 patients with acute myeloid (n = 11) or lymphoid (n = 10) leukemia in relapse. A rapid decrease in the peripheral leukemic blasts numbers was observed in six patients. We were unable to demonstrate at the bone marrow level a diminution in the percentage of leukemic blasts. However an increase in the expression of the adhesion molecule CD54/ICAM-1(LFA-1 ligand) affected the leukemic bone marrow blasts of these six patients. This increase in CD54 was found in eight of the 11 (73%) AML and four out of the ten (40%) ALL blasts and CD58/LFA-3 (CD2 ligand) to a lesser extent. This increased expression was not associated with modifications in the expression of MHC class II molecules. In vivo IL-2 also dramatically modified the bone marrow T-cell subsets via the increase of CD3+ cells expressing the CD45RO 'memory' marker (six out of the eight tested patients) or CD54 (seven out of the eight tested patients). Altogether these results demonstrate that leukemic blasts can be affected by in vivo IL-2 via mechanisms that could involve T cells.
Leukemia 1994 Jul
PMID:Modifications of leukemic blast cells induced by in vivo high-dose recombinant interleukin-2. 803 17

Adoptive immunotherapy is used to treat malignant tumors resistant to conventional therapeutic modalities. Patients with metastatic melanoma, renal cell carcinoma or mesothelioma are most likely to benefit from this treatment. Tumor infiltrating lymphocytes (TIL) contain tumor specific killer cells and are found to be the most effective. When TIL is not available or until it can be produced in sufficient amount, autologous activated lymphocytes (AAL) are an alternative. AAL are leukapheresed lymphocytes, activated by conditioned medium from OKT3 stimulated autologous lymphocytes. Subcutaneous IL-2 and oral cimetidine are also administered to support the reinfused AAL and to inhibit activation of CD8+ suppressor cells, respectively. To improve the yield and activation of reinfused lymphocytes, addition of IL-2 to the culture medium was tested in different time intervals after the onset of the culture. Interleukin-2 added in the first or second day i) improved the yield of activated lymphocytes; ii) increased the expression of activation markers CD25 (IL-2 receptor) and HLA-DR and iii) augmented killing of tumor cells. Later addition of IL-2 had no or negative effects. In vitro priming of peripheral blood mononuclear cells with autologous or allogeneic but histologically identical tumors was used to increase tumor-specificity of AAL. Autologous serum, containing antibodies specific to tumor cells, facilitated antigen presentation and yielded cytotoxic lymphocytes capable of efficiently killing tumor cells.
Leukemia 1994 Apr
PMID:Adoptive immunotherapy with activated peripheral blood lymphocytes. 815 78

Interleukin-2 (IL2) fused to ricin B chain (RTB) with modifications of amino acid residues in each of three galactose-binding subdomains (1alpha, 1beta and 2gamma) was expressed in insect cells, purified by immunoaffinity chromatography and reassociated with ricin A chain (RTA). The fusion toxin-bound human leukemic cells with IL2 receptors and the binding was competed with IL2 but not asialofetuin. In contrast, binding was not observed with receptor negative human cell lines, and the fusion molecule very weakly bound asialofetuin (Kd= 10(-6)M), indicating lectin-deficient RTB. The IL2-lectin-deficient RTB-RTA intoxicated IL2 receptor bearing cells as well as ricin or IL2-wild-type RTB-RTA. While ricin and IL2-wild-type RTB-RTA were equally toxic to receptor negative cell lines, the IL2-lectin-deficient RTB-RTA was two-two and one half logs less cytotoxic to these cell lines. The sensitivity of receptor-positive cells to the lectin-deficient fusion protein suggests that high avidity intracellular galactose binding may not be required for ricin intoxication, at least in the case of IL2 receptor-targeted molecules. Furthermore, the potent selective cytotoxicity of the fusion protein suggests that the IL2-lectin-deficient RTB-RTA and similar ricin fusion molecules directed against other leukemic cell surface receptors provide a novel class of fusion toxins for therapy of human leukemias.
Leukemia 1997 Jan
PMID:IL2 fused to lectin-deficient ricin is toxic to human leukemia cells expressing the IL2 receptor. 900 14

Allogeneic cord blood is now being widely used as a source of stem cells for hematologic reconstitution after myeloablative therapy, with reported significantly lower levels of graft-versus-host disease (GVHD) compared with the use of allogeneic bone marrow (BM). This study was undertaken to investigate biologic aspects of natural killer (NK) cell activity, as recognized effector cells of the GVHD and graft-versus-leukemia (GVL) response, from cord blood and conventional BM. NK-cell activity levels of freshly isolated cells from cord blood and BM against K562 targets were comparable. Lymphokine activated killer (LAK) cells from both hematopoietic cell sources were compared for their ability to kill target cells by necrotic or apoptotic mechanisms using specific target cell lines. Cord blood cells had significantly higher necrosis-mediated cytotoxic activity against Daudi target cells compared with BM-derived cells. Cord blood LAK cells had relatively high levels of apoptotic-mediated cytotoxicity against YAC-1 target cells, whereas BM-derived LAK cells were unable to induce apoptosis in these cells. Interleukin-2 (IL-2) induced significant granzyme B activity in cord cells in contrast to BM cells, in which very little activity was measured. Western blotting confirmed these findings, with IL-2 inducing granzyme B protein expression in cord cells but not detectable levels in BM cells. BM cells had significantly lower cell surface expression of IL-2R and prolonged culture in IL-2 was only partially able to restore their deficient apoptotic cytotoxic activity. Thus, major differences exist between cord blood-derived and BM-derived mononuclear cells with respect to their NK-cell-associated cytotoxic behavior. This could have important implications for stem cell transplantation phenomena, because it suggests that cord blood may have increased potential for a GVL effect.
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PMID:Differential cytotoxicity of cord blood and bone marrow-derived natural killer cells. 941 86

Leukemia has been treated with chemotherapy for the past 40 years with only moderate success. A growing body of evidence suggests that by augmenting the immune system more effective results may be obtained. This is highlighted by T cell reinfusions resulting in durable remissions in patients with chronic myelogenous leukemia who have relapsed after an allogeneic transplant. Interleukin-2 is the primary growth factor for T lymphocytes and is a stimulator of natural killer cell activity. It has now been shown that a limited number of otherwise refractory leukemias can be effectively treated with interleukin-2. However, there remains a lack of correlation between the biologic and clinical effects of interleukin-2. The clinical activity of interleukin-2 appears to be greatest in myeloid leukemias. A variety of dose schedules and routes of administration make it difficult to determine if interleukin-2 given to patients in clinical remission is of benefit. Large randomized studies are necessary to explore the role of interleukin-2 in leukemia.
Leukemia 1998 Nov
PMID:Interleukin-2 and leukemia. 982 39


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