Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of metastatic renal cell carcinoma with immunotherapy has resulted in objective anti-tumor responses in 15-30% of patients. To enhance the therapeutic effects of immunotherapy, it is becoming evident that this approach should be combined with other treatment modalities. In this study, a spontaneously metastasizing murine renal adenocarcinoma (Renca), transplanted under the renal capsule, was treated with either radiation therapy, immunotherapy or a combination of both. In order to distinguish between the local and systemic effects of radiation therapy, total body irradiation was compared to irradiation of the tumor-bearing kidney only, or irradiation of the whole mouse with the tumor-bearing kidney shielded. Immunotherapy was administered with interleukin-2 (IL-2) alone or with IL-2 and lymphokine activated killer (LAK) cells. Combined radiation and immunotherapy induced a better anti-tumor response than either modality alone. The best response was obtained by local tumor irradiation and IL-2 therapy and resulted in a significant reduction in primary tumor size, elimination of lung metastases and a significant increase in survival.
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PMID:Synergy of radiation therapy and immunotherapy in murine renal cell carcinoma. 140 69

Patients with head and neck squamous cell carcinomas (HNSCCs) manifest defects in cell-mediated immune function. Previous studies in this laboratory have demonstrated regional alterations in the immunocompetence of draining lymph nodes (LNs) in HNSCC patients. In this investigation, we studied functional activity of lymphocytes from lymph nodes in different locations in the radical neck dissections (RNDs) from patients undergoing operations for HNSCC. Lymphocytes from nodes close to the primary tumor ("near" lymph nodes or NLN) exhibited a significant decrease in interleukin-2 (IL-2)-activated cytotoxicity when compared to lymphocyts from distant nodes ("far" lymph nodes or FLN). In addition, co-culture experiments suggested the existence of a soluble regulatory factor, produced by lymph nodes, that inhibited the development of lymphokine-activated killer (LAK) cells in vitro. Further experiments with conditioned supernatants from the lymph node cells confirmed the presence of this soluble inhibitory factor. The inhibitory effect is significantly greater in NLNs than in FLNS. This hierarchical phenomenon suggests a regional network of immunosuppression in HNSCC patients. It is likely that tumor- and lymph node-induced suppression plays a role in limiting the efficacy of current immunotherapy protocols in human beings. A greater understanding of mechanisms of local inhibition of immune function will aid in improving adoptive immunotherapy for treatment of cancers in human beings.
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PMID:Hierarchical immunosuppression of regional lymph nodes in patients with head and neck squamous cell carcinoma. 176 90

Peripheral blood mononuclear cells (PBM) from normal donors and patients with recurrent glioma were activated initially for 48-72 h with phytohemagglutinin-P (PHA) and recombinant human interleukin-2 (IL-2), and then proliferated in vitro for up to 5 months with IL-2. These cells are termed mitogen-stimulated lymphokine-activated T killer (T-LAK) cells. We measured patterns of T-LAK cell growth, in vitro cytolytic activity on a panel of continuous and primary tumor cells, and the phenotypes of the cells in these cultures. Lymphocyte viability declined dramatically over the first 3-5 days; and then the remaining cells in these cultures began to divide and maintained a constant 30-36 h doubling time for long periods in vitro. Phenotyping revealed that cells in the initial few days of culture were heterogeneous, but became almost totally CD3 T cells after 7-10 days in culture. The T-LAK cells from individual normal donors and cancer patients demonstrated a non-genetically restricted cytolytic ability against a panel of both continuous cell lines and primary autologous and allogeneic glioblastoma cells in vitro. This technique provides a method of generating large numbers of autologous cytolytic T cells with non-restricted anti-tumor activity that can be derived from peripheral blood mononuclear cells.
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PMID:Generation of stimulated, lymphokine activated T killer (T-LAK) cells from the peripheral blood of normal donors and adult patients with recurrent glioblastoma. 201 99

Twenty-one head and neck squamous cell carcinoma (HNSCC) cell lines were established from 89 fresh tumor specimens in order to study the biology of HNSCC lines, establish tumors in nude mice, and evaluate the sensitivity to immunological effector cells of these tumors in vitro and in vivo in nude mice. The lines were established from explants using differential trypsinization and culture for 2 to 20 mo. The explants were derived from 11 different sites. Three pairs of lines were derived from both the primary tumor and metastatic lymph nodes in the same patients. All cultures grew as either compact or diffuse adherent monolayers, and they had a median doubling time of 86 h (range, 33 to 531 h). DNA fingerprinting confirmed that the HNSCC lines were individual isolates. Thirteen of 14 lines tested induced tumors in athymic mice. The histology of each line growing in nude mice was similar to that of the original tumor tissue. Immunocytochemistry showed keratin production in all lines tested. Aneuploidy (36 to 87 chromosomes) was present in all 16 lines studied; the median chromosome number for lines derived from primary tumors was 70, whereas for lines originating from metastatic or recurrent tumors, it was 54. Karyotypic analysis showed deletion of the short arm of chromosome 3 (3p-) in 12 of 16 cell lines and trisomy 6 in 12 of 16 lines. In addition, translocations between chromosomes 9 and 11 or 9 and 12 were each present in five of 16 lines tested. The HNSCC lines were resistant to lysis by natural killer cells, but were efficiently lysed by lymphokine-activated killer cells in 4-h 51Cr release assays. These new lines have allowed us to establish a model of local adoptive immunotherapy of HNSCC in tumor-bearing nude mice, and they provide a resource for future studies of the biology of HNSCC.
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PMID:Biology, cytogenetics, and sensitivity to immunological effector cells of new head and neck squamous cell carcinoma lines. 276 86

To examine the potential regulatory role of interferon-gamma in the cellular immune response to melanoma and its precursor lesions, we have tested the capacity of this lymphokine to enhance HLA class II antigen-dependent T lymphocyte blastogenesis, its in vitro production by autologous T cells stimulated by melanoma, and its presence in melanocytic lesions in situ. Cell lines derived from a dysplastic nevus, a radial growth phase primary tumor, a vertical growth phase primary, and metastatic lesions were induced by recombinant interferon-gamma to express increased amounts of HLA class II antigens. Such cells were then examined in radioimmunoassay for expression of HLA-DR antigens and in co-culture for their ability to stimulate proliferation of autologous T cells. Interferon-gamma treatment of melanocytic cells increased their expression of HLA-DR antigens threefold to sixfold. In parallel with these findings, co-culture of T cells with interferon-treated cells of a dysplastic nevus and a radial phase melanoma led to augmented T cell incorporation of tritiated thymidine, and this stimulation was inhibited with a monoclonal antibody to HLA-DR antigens. Despite augmented expression of HLA class II antigens (HLA-DR, -DQ, and -DP), vertical growth phase and metastatic melanoma cells failed to stimulate autologous T cells. When T cells were co-cultured with stimulating melanoma cells, culture supernatants contained significantly increased amounts of interferon-gamma (12 U/ml) in comparison with supernatants of T cells alone (4 U/ml). No interferon was detectable in cultures of melanoma cells alone. To link these in vitro phenomena to in situ events, we used murine monoclonal antibodies to interferon-gamma, the interleukin 2 receptor, and HLA-DR antigens in an immunoperoxidase system to detect interferon production and lymphocyte activation in frozen sections of lesions representative of melanocytic tumor progression. In these studies, precursor dysplastic nevi and radial phase melanomas contained the highest numbers of activated lymphocytes and stained positively for interferon-gamma. These results suggest that interferon-gamma plays a central role in the regulation of the cellular immune response to melanoma. It is produced by T cells, likely activated by tumor antigens seen in the context of HLA class II antigens. In turn, interferon-gamma production enhances expression of HLA class II antigens by melanoma and precursor cells, and such enhancement is associated with additional T cell activation in a positive feed-back loop.
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PMID:Interferon-gamma regulates the T cell response to precursor nevi and biologically early melanoma. 310 2

The murine monoclonal antibody (A9), raised to the human squamous cell carcinoma (SCC) cell-line UM-SCC-1, defines a squamous cell antigen associated with aggressive biologic behavior of SCC cell lines in vivo and in vitro. In the present investigation, A9 antigen was detected in tissue sections from 37 consecutive, previously untreated patients with SCC of the head and neck. All tumors were positive for A9 binding, although three distinct patterns (reflecting different intensities of A9 expression) were identified. The intensity of A9 expression was independent of primary tumor site, tumor differentiation, keratinization, or growth pattern. The frequency of high expression (Pattern 1) grew with increasing T class, N class, and tumor stage, and was associated with loss of blood group expression in the tumor and with low levels of lymphocyte infiltration in the tumor. Strong A9 expression had a statistically significant association with low nuclear grade (i.e., tumors with more mature and fewer enlarged nuclei, P = 0.019), low vascular/stromal response (i.e., patchy response rather than continuous, P = 0.014), and impaired in vitro lymphokine production by peripheral blood leukocytes (P = 0.0011). Of greatest interest, however, was the strong association of high A9 expression with shortened disease-free interval (DFI) (P = 0.085) and survival (P = 0.081) relative to patients with weak A9 tumor staining (Patterns 2 and 3). Similarly, the loss of blood group antigen expression was strongly associated with decreased DFI (P = 0.038) and survival (P = 0.062). While neither Pattern 1 A9 expression nor loss of blood group reach statistical significance in prediction of survival, the combination of Pattern 1 A9 expression and loss of blood group expression in primary tumors was significantly associated, both with decreased disease-free interval (P = 0.017) and with decreased overall survival (P = 0.011) (median length of follow-up = 22 months). The length of follow-up (LFU) ranged from 2 to 38 months, with a median LFU of 22 months. While the number of patients (37) is small, the significant association between the expression of these cell-surface markers with relapse and survival indicates that immunohistologic staining of the primary tumor will be an important prognostic indicator useful in identification of individual patients at greatest risk of recurrence or early death from head and neck cancer, independent of tumor size, site, or stage at presentation. These markers may thus provide means of selecting patients who should receive adjuvant therapy and more intensive monitoring for the early detection of recurrent disease.
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PMID:Expression of A9 antigen and loss of blood group antigens as determinants of survival in patients with head and neck squamous carcinoma. 310 4

Natural interleukin-2 is a lymphokine with an immunoregulatory function. The recombinant interleukin-2 (rIL-2) is cloned from a human lymphoblastoid T-cell line for this trial. The gene is expressed in E-coli, allowing production of large quantities of rIL-2. This study is an open label phase I-II trial designed to evaluate the toxicity and efficacy of a rIL-2 in disseminated renal cell carcinoma. After surgical resection of the primary tumor, 3 X 10(6) units/m2 day rIL-2 is administered by 2-hr IV infusions daily for 5 days every other week for a total of eight cycles. At the conclusion of eight cycles of therapy, the patients were re-evaluated for response. Patients with complete and partial responses were eligible to receive an additional eight cycles every other week. Patients demonstrating progressive disease during this study were withdrawn. The toxicities of the high-dose rIL-2 included transient hypotension, pyrexia, malaise, and skin rashes. The transient hypotension responded to fluid replacement, and the other toxicities also responded to symptomatic treatment. The early results in ten patients indicate two partial and one complete response. We have concluded that administration of high-dose interleukin-2 has acceptable toxicities with encouraging response and deserves a phase III study.
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PMID:A phase I-II study of high-dose recombinant human interleukin-2 in disseminated renal-cell carcinoma. 326 82

Previous studies have indicated the efficacy of adoptive immunotherapy utilizing recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells in the treatment of advanced neoplastic disease. However, this therapeutic approach is associated with considerable toxicity, primarily due to the systemic administration of rIL-2. The present study was undertaken to determine the efficacy of a newly developed water-soluble glucan, when administered in combination with LAK cells, in the therapy of experimental hepatic metastases. Mice were challenged subcutaneously (1 X 10(4) cells) with reticulum cell sarcoma M5076 on day 0. Therapy was initiated on day 15, when a palpable primary tumor mass and hepatic micrometastases were evident, and continued at 3-day intervals up to day 54. Sarcoma-bearing mice received glucan (250 mg/kg) intravenously, either alone or in combination with LAK cells (1 X 10(7)/mouse). Control mice received 5% (wt/vol) dextrose in water. Glucan-LAK cell therapy significantly suppressed primary tumor growth, inhibited the progression of hepatic metastases and prolonged survival in sarcoma-bearing mice. Splenocytes, incubated with rIL-2 for 72 h, exhibited significant natural killer (NK) cell activity and were cytotoxic to sarcoma cells in vitro. Glucan-LAK cell administration resulted in significant increases in splenic NK cell activity and Kupffer cell-mediated tumoricidal activity. In addition, bone marrow proliferation was enhanced following the co-administration of glucan and LAK cells. Due to its nontoxic nature and immunostimulating properties, soluble glucan may prove to be an attractive biological response modifying agent for utilization in adoptive immunotherapy of advanced neoplastic disease.
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PMID:Soluble glucan and lymphokine-activated killer (LAK) cells in the therapy of experimental hepatic metastases. 328 99

Antigenic differences between primary tumors and their cervical lymph node metastases of 12 patients with head and neck cancers were examined by measuring their sensitivity to cytotoxic lymphocytes (CL). Cytotoxicity was induced by autologous mixed lymphocyte (CL). Cytotoxicity was induced by autologous mixed lymphocyte tumor cell culture (MLTC), and further cultivation with recombinant interleukin-2 (rIL-2). The effector cells which were used in this study consisted of OKT3+8+ and OKT3+4+ subpopulations. Their cytotoxic nature was different from lymphokine activated killer cell (LAK cell) activity. Cytotoxicity of CLs stimulated by autologous primary tumor cells (CLP) was observed in 7 out of 12 patients (58.3%). In contrast, cytotoxicity of CLs stimulated by metastatic tumor cells (CLM) was observed in 4 out of 12 patients (33.3%). In the cases in which both CLP and CLM were successfully induced, cross-reactivity tests and cold target inhibition tests were performed. These results suggested that a reduction in immunogenicity had occurred at the metastatic site, and sensitivity against autologous CL was different between primary and metastatic tumor cells.
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PMID:Differences of sensitivity to autologous cytotoxic lymphocytes between primary tumor and its cervical lymph node metastases. 350 23

Macrophages were isolated by adherence from an early-passage chemically-induced tumor in C57BL/6 mice and from its spontaneous lung metastases. Cytolytic activity was measured as release of [3H]-thymidine from prelabelled tumor cells and cytostasis in a postlabelling assay. Normal, unstimulated peritoneal macrophages exhibited low but significant non-specific cytotoxic activity at attacker to target (A:T) ratios greater than or equal to 20:1, whereas stimulation of tumor-cell proliferative capacity was consistently observed at A:T ratios less than or equal to 2.1, Macrophages from the peritoneal cavity of tumor-bearing mice, from the primary tumor or from polled secondaries had baseline cytotoxic or growth-enhancing (depending on the A:T ratio) potential similar to that of control peritoneal macrophages. In vitro exposure to endotoxin, lymphokine supernatants or partially purified fibroblast interferon augmented the tumoricidal activity of normal and tumor-associated macrophages; tumor-associated macrophages showed no evidence of enhanced responsiveness to these activating stimuli. Tumor cells from the primary neoplasm and its spontaneous metastases were equally susceptible to macrophage tumoricidal activity. It is inferred from in vitro data that the relatively low numbers of non-activated macrophages present within poorly immunogenic metastasizing tumors may have no direct effect or actually stimulate tumor-cell proliferative capacity at the primary tumor site; conversely, disseminating tumor cells might encounter sufficient numbers of mononuclear phagocytes in the circulation and in lungs to permit the expression of macrophage cytotoxicity, at least during the early steps of metastasis formation.
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PMID:In vitro effects on tumor cells of macrophages isolated from an early-passage chemically-induced murine sarcoma and from its spontaneous metastases. 728 17


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