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)

Dominant rearrangements of T-cell receptor (TCR) beta-chain genes are reported among tumor-infiltrating lymphocytes (TIL). After interleukin-2 expansion of TIL from renal and lung carcinoma and melanoma biopsy tissues, rearrangements of TCR beta-chain genes were analyzed by Southern blotting. Nongermline restriction fragments, indicating dominant rearrangements, were detected among the TIL from all 6 patients with renal cell carcinoma, 17 of 20 patients with melanoma, and 3 of 6 patients with lung tumors. The restriction-fragment sizes of these dominant rearrangements were heterogeneous among the various patients. Rearrangements into C beta 1 were more common than C beta 2 rearrangements. Phenotypic analyses indicated that dominant rearrangements occurred in both CD4 and CD8 predominant TIL populations. The TIL populations that were extracted were expanded to derive large cell numbers suitable for in vivo transfer in an interleukin-2 and TIL immunotherapy program. The data indicated that the cells delivered to these patients usually were characterized by dominant populations of T-cells with selective TCR gene rearrangements. The significance of selective TCR use requires evaluation of the function and specificity of the TIL comprising these dominant populations both in their native in vivo setting and in the context of therapeutic transfer.
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PMID:Dominant rearrangements among human tumor-infiltrating lymphocytes. Analysis of T-cells derived from 32 patients with melanoma, lung, and renal cell carcinoma. 131 29

We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters. Two regimens differing in the sequence of treatment were employed, and 1-6 treatment cycles were given, depending on patient response. Two patients had a complete response (CR, 46+m, 14m), two patients a partial response (PR, 16m,6m), one a minimal response and four had a stable disease lasting 2-7 months, thus the response rate (CR+PR) was 22%. None of the following parameters, tested prior to initiation of the therapy and 1-2 days after termination of each course of IL-2, correlated with the clinical response: WBC counts (total and differential), levels of blood CD4 and CD8 T cells, NK cells, monocytes and B cells, production of IL-1 and IL-1 inhibitor by monocytes, responsiveness to 3 mitogens, NK/LAK cell activity, and serum levels of IL-1 alpha, IL-2, soluble IL-2 receptor, and TNF alpha. The only prognostic parameter was the greater increase in the level of IL-2 receptor (Tac)-bearing lymphocytes in the responding patients after 1-3 cycles of IL-2. The data suggests that non-specific immune parameters have no prognostic value for patients undergoing IL-2-based immunotherapy.
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PMID:Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response. 144 17

Tumor-infiltrating lymphocytes (TIL) were isolated from a human melanoma metastatic to the abdomen. The TIL were 99% CD3+ and 99% CD4+ and CD8-. They were dependent on interleukin-2 (IL-2) for growth, as measured in a thymidine uptake assay, and were not cytotoxic to autologous or allogeneic melanoma or K562. When co-cultured with irradiated autologous tumor cells, or tumor cell supernatants, the TIL not only did not respond, but the IL-2-dependent growth was inhibited significantly. Inhibition occurred during the first 24 hours of co-culture and persisted as long as the tumor was present. After being washed free of inhibitory tumor cells, the TIL again were able to grow in the presence of IL-2, indicating that the inhibition was not caused by irreversible toxicity mediated by the tumor. Addition of excess IL-2 did not reverse the inhibitory effect, but addition of indomethacin, an inhibitor of cyclooxygenase and prostaglandin synthesis, partially blocked the inhibition. These data show melanoma-mediated inhibition of induction and expansion of human T-cells in vitro, which may reflect one of the mechanisms of inhibition of cellular responses in vivo. These results stress the need to examine the techniques for optimal in vitro expansion of tumor-specific TIL or cytotoxic T-cells for adoptive immunotherapy.
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PMID:Human melanoma-mediated inhibition of autologous CD4+ helper tumor-infiltrating lymphocyte growth in vitro. 153 42

Tumor-infiltrating lymphocytes (TIL) were obtained from a mouse melanoma cell line (CL 62) transfected with the gene for the human melanoma Ag p97. TIL were cultured with anti-CD3 antibody and IL-2 for up to 38 days. Flow cytometry identified these TIL as Thy-1.2 + ve/CD4-ve/CD8 + ve cells. A heteroconjugated antibody 500A2 x 96.5, specific for both the CD3 Ag on TIL and the p97 Ag on CL 62 melanoma cells, was prepared using N-succinimidyl-3-(2-pyridyldithio)-propionate as a linking agent. TIL alone demonstrated low levels of cytotoxicity against autologous CL 62 tumor and also against the parental K1735 tumor and an allogeneic murine melanoma (B16). The addition of 500A2 x 96.5 heteroconjugated antibody enhanced TIL-mediated lysis of CL 62 tumor, but not of the K1735 or B16 tumors. This enhanced cytotoxicity was elicited at E:T ratios as low as 0.4:1, and in TIL cultured for 7 to 38 days. These results suggest that hetero-conjugated antibody may enhance the anti-tumor effect of TIL in vivo.
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PMID:Enhancement of in vitro tumor-infiltrating lymphocyte cytotoxicity by heteroconjugated antibodies. 153 18

As part of a phase-II clinical trial of post-operative active specific immunization (ASI) with virus-modified autologous tumour cells (AuTu) in colorectal carcinoma patients, we have analyzed in vitro anti-AuTu immune responses with lymphocytes isolated from the peripheral blood (PBL) of 5 treated patients. The PBL of 3 "responder patients", those who developed a positive DTH reaction to AuTu, when stimulated in standard in vitro autologous lymphocyte tumour-cell cultures (ALTC), showed cytotoxic anti-AuTu reactivity only in association with natural-killer-cell(NK)-like activity. We removed nonspecific cytotoxic cells (CD56-positive) from PBL of colon carcinoma or melanoma patients and positively selected T cells with strong CD8 staining (CD8hi) using FACS. Following in vitro stimulation, specific cytotoxic T cells (CTL) directed against either autologous EBV-transformed B cells (AuEBV-B) or autologous melanoma cells were identified in the CD8hi T-cell population. However, even using this novel technique, no specific CTL against autologous colon carcinoma cell lines were detected in PBL from ASI-treated patients (2 DTH responders and 2 DTH non-responders). If AuTu-specific CTL precursors existed in these blood samples, their frequency must have been very low (less than 1 in 8 x 10(4) CD8 positive T cells). Sorted CD4 T cells from these patients, in the presence of autologous antigen-presenting cells, showed no specific anti-tumour proliferative response, and in one instance we observed inhibition of proliferation in the presence of tumour cells.
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PMID:An analysis of autologous T-cell anti-tumour responses in colon-carcinoma patients following active specific immunization (ASI). 163 35

Distinct changes in the antigenic phenotypes of mononuclear cells infiltrating primary and metastatic malignant melanomas (MM) have been shown to characterize distinct steps of melanoma progression. The purpose of our study is to establish whether the growth fraction of malignant melanoma cells is related to the mononuclear cell subtypes. Using monoclonal antibody Ki67, the presence of a nuclear antigen in proliferating cells of both tumor and inflammatory infiltrate cells was established in 20 primary recurrent and metastatic cutaneous melanomas. Monoclonal antibodies against lymphocyte and macrophage subsets were also applied in situ. Numerous CD8 and CD4 positive cells and natural killer (NK) cells were detected in all the infiltrates. A low CD4+/CD8+ ratio was observed in most tumors with a high proliferative activity. The presence of positive CD1+ cells seemed also to be correlated with a high activity. Our data suggest a correlation between inflammatory cell subsets and proliferative activity of MM.
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PMID:Characterization of proliferative cells in malignant melanomas and their inflammatory infiltrates. 167 44

We have previously demonstrated that interferon (IFN) treatment of mice bearing the spontaneously metastasizing B16F10L murine melanoma on days -5 to -1 prior to surgical removal (day 0) of the primary tumor resulted in survival of greater than 50% of treated mice. The antitumor effect was correlated with an early increase of natural killer (NK) cell cytotoxicity followed by a later developing specific cytolytic T-cell response. The purpose of this study was to establish definitively the roles of NK, CD4, and CD8 cells as mediators of the antitumor/antimetastatic effects of IFN treatment by administration of anti-asialo-GM1, anti-L3T4, and/or anti-Lyt-2 antisera. Depletion of NK cells, alone or in combination with T-cells, eliminated the protective effect of IFN treatment. Depletion of both CD4 and CD8 cells, however, did not significantly alter the therapeutic effect of IFN therapy. Collectively, these data conclusively demonstrated the importance of NK cells as mediators of the IFN induced antitumor state. However, in mice depleted of CD4 cells alone, the protective effect of IFN was eliminated, in spite of the presence of intact NK cells. In vitro analysis of NK cytotoxicity on day 1 after surgery demonstrated (a) a lack of IFN induced stimulation of NK activity in CD4 depleted mice and (b) a significant increase in both baseline and IFN induced NK cytotoxicity in CD8 depleted mice. These data suggested a CD8 cell mediated inhibition of NK activity/stimulation in CD4 depleted mice, possibly responsible for the lack of response to IFN therapy in that group. These results demonstrate the importance of not only individual components of the immune system but also the interaction of these components in both the natural and IFN induced control of spontaneous B16F10L metastases.
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PMID:Role of natural killer and T-cells in interferon induced inhibition of spontaneous metastases of the B16F10L murine melanoma. 170 66

Spontaneous regression occurs in a small proportion of malignant melanomas, and it is important to understand the processes involved in its induction as this may give a guide to future therapies for this disease. We have examined 36 primary malignant melanomas (19 regressing, 17 non-regressing) and identified the cellular phenotypes and activation states of the cells infiltrating regressing and non-regressing primary melanomas by immunochemistry. We have found a significantly increased number of CD3-positive cells and an increased ratio of CD4/CD8-positive cells infiltrating regressing compared to non-regressing tumors. In addition, the expression of the interleukin 2 receptor, an activation marker for T cells, was increased. However, there were no significant differences in class II MHC, CD1, intercellular adhesion molecule 1 (ICAM1), or melanoma-associated differentiation-antigen expression in these tumors. These data are consistent with melanoma regression being induced by activated CD4 T cells and do not seem to be related to the differentiation markers we have examined on these tumors.
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PMID:Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma. 171 19

Lymphocyte clones were isolated from CD4+ peripheral-blood lymphocytes (PBL) of melanoma (Me) patient 9923 (HLA-DR7, DQw2, w6), co-cultured for 30 days with autologous accessory cells, allogeneic Me (Me 1811) (HLA-DR7, DQw1, w2), IL-1 beta (2 U/ml) and IL-2 (15 IU/ml). The 55 clones tested displayed a CD3+, CD4+, CD8-, T-cell receptor (TCR) alpha/beta+, gamma/delta- phenotype. Twenty clones were assayed for proliferation in the presence of Me 1811 and B-lymphoblastoid cell line (LCL) 1811, both expressing HLA-class-I and -II (DR7 and DQw2 shared with patient 9923), intercellular adhesion molecule-1 (ICAM-1) and lymphocyte-function-associated antigen-3 (LFA-3) molecules. Eight clones were found to be reactive to Me 1811 but not to LCL 1811. Specificity analysis of these 8 clones revealed that each of them proliferated only to Me 1811, not to other 14 Me and 12 different LCL, suggesting recognition of melanoma-associated antigen (MAA) expressed on the stimulating Me. One clone (103) was analyzed in more detail. A wider specificity analysis showed that it reacted to Me 1811 but not to 10 other Me expressing or not HLA-DR7, 5 normal melanocyte cultures (2 of them typing HLA-DR7-positive when exposed to interferon-gamma--IFN-gamma), 4 tumors other than Me and 20 different LCL. Clones did not show proliferation in the presence of autologous Me cells. Clone proliferation in response to Me 1811 was significantly inhibited by monoclonal antibodies (MAbs) directed to CD3, TCR alpha/beta, TCR beta chain V12, CD4 and HLA-DR. Moreover, following stimulation with Me 1811, clone 103 showed increased surface expression of CD25 (IL-2 receptor) and CD71 (transferrin receptor) and produced significant amounts of IL-2 and IFN-gamma. The supernatant taken from co-culture of clone 103 with Me 1811 augmented the cytotoxicity of PBL 9923 and other allogeneic PBL against K562 and Me 1811. Thus, the lymphocyte clone 103 is a CD4+ Th clone which uses its CD3/TCR alpha/beta complex to recognize an MAA in conjunction with HLA-DR7. Availability of this type of reagent may prove useful to identify and characterize MAA recognized by T lymphocytes.
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PMID:Human allogeneic melanoma-reactive T-helper lymphocyte clones: functional analysis of lymphocyte-melanoma interactions. 183 14

After a 5-day period of continuous intravenous infusion of recombinant interleukin 2 (rIL-2) in seven patients with malignant melanoma or gastric or pancreatic cancer, different lymphocyte subsets were separated from patients' blood and tested ex vivo for cytotoxic activity against various tumour cell lines. Lytic activity was mediated by CD3+CD56+, CD3-CD56+, CD3-CD2+ and CD8+CD56+ lymphocytes. No cytotoxic activity could be observed within the CD3+CD56-, CD3+CD2+ or CD4+ T cell subsets. To characterize CD56+ cytotoxic cells further, the expression of other antigens on this population was analysed before and after IL-2 therapy. CD3, CD4, CD16 and CD57 antigens were weakly expressed, and the IL-2 receptor (CD25) was not detectable on these cells either before and after treatment with IL-2. In contrast, increased expression of CD2. CD8 and HLA-DR antigens occurred following therapy. The divergence of CD3 and CD8 antigen expression after IL-2 therapy was caused by an increase in CD3-CD8+ cells, detectable as a low-density CD8+ subset. This study shows that cytotoxic activity of in vivo IL-2-activated killer cells is predominantly, but not exclusively, mediated by CD3-CD56+ lymphocytes, partially coexpressing the CD8 antigen and lacking the expression of CD16 antigens.
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PMID:Cytotoxic activity and phenotypic characteristics of lymphocyte subsets after therapy of cancer patients with interleukin-2. 187 92


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