Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new approach to cancer treatment has been developed based on the adoptive transfer of activated lymphocytes into cancer patients. Lymphocytes harvested from patients by leukapheresis are converted into lymphokine-activated killer (LAK) cells by incubation with recombinant interleukin-2 (rIL-2). These LAK cells are then infused back into the patients in combination with intravenous IL-2. Among 25 patients treated with this form of adoptive immunotherapy there were 11 patients with measurable tumor reductions, including 1 complete responder. The majority of responses occurred in patients with metastatic renal cell carcinoma, melanoma and colorectal carcinoma. The toxicities of IL-2, including fluid retention and pulmonary edema, limit therapy, and laboratory investigation is now aimed toward understanding the mechanism of IL-2 toxicity. The use of LAK cells and IL-2 in cancer therapy is still in a developmental stage and needs to be refined before its role can be definitely established.
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PMID:Therapy of cancer using the adoptive transfer of activated killer cells and interleukin-2. 312 51

The sensitivity of H-2b-high and H-2b-low variants of BL6 melanoma to the cytotoxic action of NK and lymphokine-activated killer cells was investigated. BL6 mouse melanoma cells lack detectable H-2Kb and had low levels of expression of H-2Db Ag. The BL6T2 variant cells, obtained after treatment of BL6 cells with mutagen N-methyl-N-nitro-N'-nitro-soguanidine, had relatively high levels of expression of class I H-2b Ag. Poly(I:C)-stimulated spleen cells of nude mice were highly cytotoxic for BL6T2, whereas H-2b-low BL6 cells were less sensitive to NK activity in an 18-h 51Cr-release assay. Similar results were obtained after 4-h incubation of radio-labeled tumor cells with IL-2-activated effector cells. In contrast, both lines were equally sensitive to lysis by purified granules derived from rat large granular lymphocytes (LGL) or by macrophages. By using various clones selected from BL6 or BL6T2 cells, it was found that BL6 or BL6T2 clones with low H-2b Ag expression were less sensitive to lysis by NK cells than H-2b-high clones. After IFN treatment of either BL6 or BL6T2, the target cells became more resistant to lysis by either NK cells or by purified LGL granules. IFN-treated BL6 cells had substantially increased expression of H-2b Ag and in this respect became similar to untreated BL6T2. However, IFN-treated BL6 cells were more resistant than BL6T2 cells to lysis by NK cells and LGL granules, suggesting that augmentation of H-2b Ag expression and NK resistance could be two independent IFN-induced effects. With a cold target inhibition assay, it was found that BL6T2 or its H-2 positive clones were highly competitive and inhibited the cytotoxic activity of NK and lymphokine-activated killer cells against radiolabeled YAC-1 and BL6T2, whereas BL6 cells or H-2-negative clones of BL6T2 and BL6 lines showed poor competitive ability. Thus, our data indicate that the NK resistance of H-2-low BL6 cells may be due to a paucity of NK recognizable determinants. N-Methyl-N-nitro-N'-nitroguanidine treatment of BL6 melanoma cells was associated with an increase in class I H-2b Ag expression and NK sensitivity, suggesting the involvement of class I MHC Ag in the sensitivity of tumor cells to NK cell-mediated cytotoxicity.
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PMID:H-2 antigen expression and sensitivity of BL6 melanoma cells to natural killer cell cytotoxicity. 312 40

Progression of human melanoma is associated with changes in antigenic phenotypes of tumor cells. To establish whether inflammatory infiltrates in progressing melanoma also change, we studied 146 cutaneous melanomas at different stages of progression. Monoclonal antibodies (MAbs) against lymphocyte and macrophage subpopulations, interleukin-2 receptor (IL-2 R), immune interferon (IFN-gamma), and the IFN-gamma-inducible, progression-associated melanoma antigens HLA-DR and gp89 were applied in situ. During the course of melanoma progression, decreased amounts of peritumoral T cells, IL-2 R-expressing lymphocytes and dermal T6+ dendritic cells were found, while increased numbers of intratumoral T cells, inflammatory (27E10+) and mature (25F9+) macrophages were associated with local progression of primary melanomas. In metastases, most infiltrate components except 25F9+ macrophages were rare. Positive correlations were observed between: (1) dermal T6+ cells and IL-2 R+ lymphocytes, and (2) presence of IFN-gamma in the infiltrate and HLA-DR and gp89 antigens on tumor cells. In all stages, HLA-DR expression on tumor cells was correlated with: (1) a shift towards T8+ lymphocytes in the infiltrates and (2) a loss of IL-2 R expression. Our data suggest mutual influences between melanoma cells and mononuclear cell infiltrates in situ.
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PMID:Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. 312 89

There is continuing interest in the possibility of immunologic intervention in the therapy of malignant disease. By employing a range of different techniques, it has been possible to show the presence of activated helper, suppressor, and cytotoxic T cells, B cells, NK precursors, and macrophages at the tumor site. The overwhelming impression from our data is that tumors may be subject to immunologic attack by heterogeneous effectors and that there is selective trapping of these effectors with corresponding depletion at the periphery. Like all inflammatory sites, however, the tumor contains both positive and negative regulatory mechanisms with the coexistence of cells with effector and suppressor functions, eg, T suppressors that modulate the proliferative response of T helpers and macrophages suppressing NK function contribute to the dynamic interplay in situ. Additional complexity is indicated by immunohistologic studies that clearly show that the stroma rather than foci of tumor cells are the site of infiltration, thereby further limiting effector function. We are now at the end of the descriptive stage of our investigations and further studies must approach the more difficult problem of modifying the host response in such a way as to alter the balance between effector and suppressor activity. A promising area of research would appear to be the use of cloned helper T cells or their products in the immunotherapy of cancer. The demonstration, by us, of selective trapping at tumor sites suggests that administration of the patients' own T cells with antitumor reactivity may serve as an efficient delivery vehicle to activate host effectors in situ. Studies in animal systems have shown the feasibility of this approach, although the failure of cultured T cells to undergo normal recirculation represents a considerable unresolved problem. Effector function by each of the tumor-infiltrating cell types described is under T cell control, and preliminary studies have already indicated the ability of helper T cells to accelerate allograft and tumor rejection. The increasing availability of gene-cloned materials with potent biologic activity opens new areas of research in cancer therapy. The lymphokines IL-2 and interferon are already undergoing clinical trials. Studies by Hersey demonstrate that administration of conditioned medium containing impure IL-2 results in the appearance of antitumor effectors in previously nonreactive melanoma patients, and Rosenberg, among others, has shown IL-2 to be a potent enhancer of alloimmune responses. Lymphokine-activating macrophages also augment antitumour responses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Human tumor-infiltrating lymphocytes: a marker of host response. 315 76

A suppressive immunoregulatory factor (IRF) produced by murine melanoma K-1735 M3 has been identified. Extracts from tissue or cultured cells grown in serum-medium were prepared by 3 M KCl extraction and partially purified by low-salt precipitation. IRF extracted from fresh tumor, cultured cells, and spent medium from the K-1735 cell line suppressed 3H-thymidine incorporation by splenocytes during mitogen stimulation. Cell viability was not impaired by IRF. IRF suppressed splenocyte proliferation, protein synthesis, murine IL-2-mediated blastogenesis, and mixed splenocyte responses. However, in vitro generation of allogenic cytotoxic cells was not suppressed. Significant inhibitory activity could not be extracted from normal tissues. IRF activity was reduced by treatment with proteolytic enzymes and neuraminidase and was bound by lentil lectin, indicating that the factor is a glycoprotein. IRF was heat-stable, yet labile to treatment with acid, base, or 2-mercaptoethanol. Inhibitory activity was partially characterized by preparative isoelectric focusing (pI 3.5-5.8), and the active moiety had a molecular size of 10-12 K according to HPLC. The HPLC-purified active fraction of IRF did not contain the immunosuppressive retroviral antigen p15(E). Splenocytes from animals treated with IRF in vivo demonstrated reduced responses to Con A and PHA in vitro. Suppressor cells were not identified. We have identified a low-molecular-weight glycoprotein from a murine melanoma, which suppresses a variety of immunologic responses in vitro and in vivo. IRF appears to be a potent mediator of tumor-induced immunosuppression in this model.
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PMID:Identification and characterization of a tumor-derived immunosuppressive glycoprotein from murine melanoma K-1735. 315 40

Peripheral blood lymphocytes (PBL) from a melanoma (Me) patient, previously shown to be unable to react against the autologous tumor (Me 28) after mixed lymphocyte-tumor culture (MLTC), were cultured in vitro with the autologous tumor in MLTC and/or with IL-2-containing supernatants. T-cell clones were then obtained by limiting dilution and by micromanipulation. Eleven clones, selected for autologous tumor (Auto-Tu) cytotoxicity, were tested for specificity on a panel of 17 cell cultures of normal and neoplastic origin, revealing a complex spectrum of lytic activities. Three groups of clones could be identified depending on the patterns of cytotoxicity. One clone (B11.12) lysed Me28 and expressed a borderline reactivity against one allogeneic Me. A second group of clones (A4, A4.18, H10, E12, C9) lysed the Auto-Tu and allogeneic Me. The last group of clones (A4.2, A4.3, A4.4, A7, B7) expressed a broader pattern of reactivity with significant cytotoxicity against targets of different histologic origin. Furthermore, the second and third groups of clones lysed K562 while B11.12 did not. The Auto-Tu-restricted reactivity of clone B11.12, confirmed by a further test on 13 allogeneic Me and on autologous IL-2 cultured lymphocytes, suggests the recognition of antigenic structures preferentially expressed on Me28. Blocking studies, performed with monoclonal antibodies (MAb), revealed that an anti-HLA class I MAb (w6/32), but not two anti-DR MAbs (L243, DI.12), could inhibit the cytotoxic activity of clones B11.12 on Me28. A significant blocking effect by w6/32 on Me28 was achieved also with clones A4.4 and H10 but not with clones A4.2, A4.3 and A7. The phenotype of all clones was T3+, T4-, T8+, HNK-I-, suggesting that the anti-tumor effectors were of the T-cell lineage. Taken together, these data indicate that it is possible to isolate anti-tumor CTL-clones after MLTC from a PBL population of a metastatic melanoma patient. Furthermore, we present evidence suggesting a role of class-I antigens in the interaction of some cloned effectors with the autologous tumor target.
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PMID:Clonal analysis of cytotoxic T-lymphocyte response to autologous human metastatic melanoma. 315 14

Killing of autologous melanoma (auto-Me) was obtained with pooled allostimulated peripheral blood lymphocytes (PBL) in 34/42 cases and found not to be due to a cross-reactivity between melanoma and allogeneic normal antigens. To see whether generation of tumour cytotoxic PBL by allostimulation was due to release of IL-2, PBL from 34 patients were divided into two aliquots and stimulated either by alloantigens or IL-2. Allostimulated PBL were cytotoxic for auto-Me in 30/34 cases (85%) whereas IL-2 generated tumour cytotoxic cells in 22/34 cases (64%). Lysis of K562, a target for monitoring NK-like activity, was obtained in 95-100% of cases with both stimuli. A similar frequency of OKT3+, OKT4+, OKT8+ and HNK1+ cells was found in PBL activated by allostimulation and IL-2, whereas a higher frequency of OKM1+ cells was evident in IL-2-stimulated PBL. Cold-target competition studies indicated that allostimulation generated at least two different types of effectors, one lytic to auto-Me but not to K562, and the other which lysed both targets. Allostimulated, FACS-separated T3- cells killed both auto-Me and K562 cells whereas T3+ cells lysed only auto-Me. It is concluded that allostimulation generated two subpopulations of auto-Me killer cells, one of the T lineage and the other NK-like, which both can destroy auto-Me targets.
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PMID:Allostimulation of patients' lymphocytes generates both T and NK-like cells cytotoxic for autologous melanoma. 316 Mar 80

Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.
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PMID:Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. 325 61

Addition of IL-4 (1,000 U/ml) to either high or low concentrations of IL-2 augmented tumor-infiltrating lymphocytes (TIL) growth from human melanoma. Weekly restimulation with irradiated tumor cells in conjunction with IL-4 allowed enhanced growth of TIL. With low-dose IL-2 (10 U/ml) and IL-4, expanded TIL had little cytolytic activity against Daudi or allogeneic tumors. Further, IL-4 augmented the total lytic activity against autologous tumors in most cases. With high-dose IL-2 (1,000 U/ml), IL-4 addition decreased nonspecific killing activity against Daudi or allogeneic melanomas in many cases, and reciprocally augmented cytolytic activity against the autologous melanoma in many cases. This suggests the possible use of IL-4 in cancer therapy, especially in adoptive cellular immunotherapy using TIL or in conjunction with IL-2 administration.
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PMID:Interleukin 4 promotes the growth of tumor-infiltrating lymphocytes cytotoxic for human autologous melanoma. 326 24

There are two strategies for evaluating the antitumor effect of IL-2. In the first approach IL-2 has been used to support the proliferation of T-effector cells or LAK cells in vitro in the hope that large quantities of these effector cells can be used therapeutically. This approach has shown some efficacy in animal models if LAK cells are administered in combination with IL-2. However, it is extremely difficult to standardize the numbers of lymphocytes and the biological activity of effector cells for clinical use. Recently the cloning of IL-2 has made available large quantities of purified recombinant IL-2 (rIL-2) for preclinical and clinical trials. Accordingly there have been recent attempts at injecting rIL-2 directly to stimulate effector cells in vivo. In this study, in vivo and in vitro augmentation of the cytotoxicity of spleen lymphocytes against syngeneic B-16 melanoma cells (induction of LAK cells) and the suppression of artificial pulmonary and liver metastases of B-16 melanoma in C57BL/6 mice was tried by subcutaneous multiple injections of high-dose human rIL-2. In addition, the immunosuppressive effect of a water-soluble nitrosourea derivative (ACNU) was determined in terms of the cytotoxicity of spleen lymphocytes, and the restoring effect of lymphokine-activated killer (LAK) cells and/or human recombinant interleukin-2 (rIL-2) on the cytotoxicities of spleen lymphocytes were examined in ACNU-treated C57 BL/6 mice. It was also tested whether the administration of LAK cells and/or rIL-2 could reduce the increased numbers of pulmonary metastases in ACNU-treated mice. The cytotoxicity of spleen lymphocytes against YAC-1 cells as well as against syngeneic B-16 and F-10 melanoma cells was augmented not only by incubation of spleen lymphocytes with human recombinant interleukin-2 (rIL-2) in vitro but also by injecting high-dose rIL-2 into C57BL/6 mice for more than 3 consecutive days. In animals injected with multiple high doses of rIL-2 subcutaneously, the numbers of tumor nodules in the lung were significantly decreased 21 days after intravenous tumor inoculation. In addition, in these groups of animals no liver metastases were observed although liver metastases were detected in 6/11 of control mice. The maximum effective dose of ACNU suppressed the cytotoxicity of spleen lymphocytes and pretreatment with ACNU enhanced the induction of artificial pulmonary metastases.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Strategy of cancer treatment using human recombinant interleukin 2 and lymphokine activated killer cells]. 348 26


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