Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal cell carcinoma (RCC) is one of the few cancers partially sensitive to biotherapy. However, involvement of T cell immunity in host-defense against autologous tumor cells remains unclear. This manuscript investigated T cell functions of interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes (TILs) from human RCCs by studying their oligoclonality, cytotoxicity, and cytokine production. IL-2-activated RCC-TILs from 17 of 33 cases (52%) (p < 0.01 vs. IL-2-activated patients' peripheral blood mononuclear cells, PBMC) displayed oligoclonal expansion as determined by seven different monoclonal antibodies (mAbs) to T cell receptor (TCR) V alpha or beta regions after 2 to 5 weeks in culture. By comparison, IL-2-activated PBMC from only 1 of 15 healthy donors (7%), 3 of 23 patients (13%), and IL-2-activated lymphocytes from nontumorous kidney from 1 of 8 (12.5%) cases (V beta 5.1) did. Specifically, IL-2-activated RCC-TILs showed oligoclonal expansion of V alpha 2+ cells (8/33 cases, p < 0.05 vs. IL-2-activated patient's PBMC), V beta 5.1+ cells (6/33), V beta 8+ cells (4/33), V beta 12+ cells (4/33), and V beta 6.7+ cells (2/33). Oligoclonal expansion of plural TCR V regions was observed in 6 of 33 cases. IL-2-activated RCC-TILs from 4 of 16 cases produced higher levels of interferon-gamma (IFN-gamma) in culture with autologous tumor cells than with allogeneic tumor cells. Those from 11 of 16 cases did not produce IFN-gamma in response to autologous tumor cells, and the remaining case produced it in a major histocompatibility complex (MHC)-nonrestricted manner. IL-2-activated RCC-TILs with oligoclonal expansion in 4 of 5 cases showed IFN-gamma production in response to the corresponding anti-TCR V region mAb as well as anti-CD3 mAb. IL-2 and IL-4 were not detected in any cases tested. IL-2-activated RCC-TILs displayed cytotoxicity relatively restricted to autologous tumor cells in only 1 of the 16 cases evaluated, MHC-nonrestricted cytotoxicity in 12 cases, NK activity in one case and no cytotoxicity in two cases. In summary, IL-2-activated RCC-TILs demonstrated the oligoclonality in approximately half of the cases (17 of 33, 52%), but rarely displayed either autologous tumor-specific-IFN-gamma production (4 of 16 cases) or -cytotoxicity (1 of 16 cases).
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PMID:T cell functions of IL-2-activated tumor-infiltrating lymphocytes from renal cell carcinoma. 147 75

Previous studies on continuous hepatic artery infusions of recombinant interleukin-2 (IL-2) have shown that in a nontumor-bearing animal a continuous infusion given in a circadian "day cycled" pattern was much less toxic and could be given with 10 times higher doses of IL-2 than if the constant pattern of infusion was used. In the present study, circadian-patterned continuous hepatic artery infusions of IL-2 were used in hepatoma-bearing rats. Doses of 10 mg/m2/day could be tolerated when IL-2 was given in a "day cycle" rhythm. Control animals were given 1 mg/m2/day of constant infusion IL-2, which was the highest hepatic artery infusion dose tolerated at a constant rate without mortality in nontumor-bearing animals. Animals treated with the constant infusions of IL-2 had a 37.5% mortality rate and a 25% objective response rate in measurable tumor size. Animals receiving the "day cycle" had no mortality and a 100% objective response rate. The conclusion was that "day cycled" circadian-patterned continuous hepatic artery infusions of IL-2 could be given with much lower toxicity and much improved tumor response rates than constant continuous infusions.
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PMID:Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2. 147 73

The effect of solid-phase anti-CD3 antibody activation and cryopreservation was evaluated on thirteen samples of tumor-infiltrating lymphocytes (TILs) derived from epithelial ovarian cancer. Seven preparations of TILs were cultured with or without solid-phase anti-CD3 antibody in addition to 100 units/ml of recombinant interleukin-2 (rIL-2). The proliferation rate of all of the seven TIL preparations stimulated by anti-CD3 antibody on the fourth or fifth day of culture was 3.4 to 9.8 times greater than that of lymphocytes cultured with rIL-2 alone. Furthermore, in an experiment with five TIL samples activated with anti-CD3 antibody, three of them showed augmented cytotoxic activity against autologous fresh tumor cells. The population of CD3+/CD8+ TILs was increased after 4-5 weeks of cultivation and CD8+ lymphocytes amounted to over 70% in all of seven preparations tested, whereas two of seven preparations not activated by anti-CD3 antibody were CD3+/CD4(+)-dominant. In addition, nine preparations of TILs cultured with rIL-2 were cryopreserved for several weeks; after recovery from cryopreservation, no major change was observed in cell surface markers, in growth rate or in cytotoxic activity. These results suggest that cryopreserved and/or anti-CD3 antibody-activated lymphocytes could conveniently be employed in a clinical trial of adoptive immunotherapy employing TIL.
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PMID:Solid-phase anti-CD3 antibody activation and cryopreservation of human tumor-infiltrating lymphocytes derived from epithelial ovarian cancer. 148 50

Peripheral blood mononuclear cells obtained from 24 primary lung cancer patients were stimulated with anti-CD3 monoclonal antibody (alpha CD3MoAb) followed by culture with recombinant interleukin-2. The optimal concentration of alpha CD3MoAb for stimulation was 50 ng/ml in the liquid phase, and the sensitization culture was commenced at a cellular concentration of 1 x 10(6)/ml. Patients entered into this study were 14 cases of adenoca rcinoma, 7 of squamous cell carcinoma, and 3 of small cell carcinoma. After 4-6 days of stimulation with alpha CD3MoAb followed by culture with RIL-2 for 5-7 days, the cellular expansion was 3.7 folds (mean). Surface marker analysis of the cells revealed significant increments of CD3+, CD8+, HLA-DR+, and IL-2R+ cells after sensitization culture. In 2 cases, fresh autologous tumor cells could be obtained from surgical specimens. Effector cells generated in those 2 cases did not show significant cytotoxic activity against autologous tumor cells in 4 hr 51Cr release assay. In 5 cases, cytotoxicity against established lung cancer cell lines, STC-1 and L0301, were analyzed. In all cases, effector cells showed significant cytolytic activity against both targets. The sensitization culture utilizing alpha CD3MoAb was easy to perform and feasible for the majority of patients, and it is considered that utilization of this culture system would be worth while for adoptive immunotherapy in primary lung cancer patients.
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PMID:[Generation of effector cells from primary lung cancer patients by stimulation with anti-CD3 monoclonal antibody followed by culture with recombinant interleukin-2]. 148 32

Experimental and clinical studies were conducted on lymphokine-activated killer (LAK) cell therapy for advanced renal cell carcinoma (RCC). The traffic assay using radiolabeled LAK cells indicated short-term but appreciable accumulation of LAK cells in the tumor site when trans-arterially infused. By contrast, systemically infused LAK cells were localized not to the tumor tissue but to the lung. Therefore, we began treatment of the patients with extrapulmonary metastases by means of regional arterial administration of LAK cells and those who had pulmonary metastases by a systemic LAK therapy. Regimen of Interleukin-2 (IL-2) administration was bolus infusion of 5 x 10 U IL-2 twice daily. Frequency of LAK cell administration varied from one to three times a week depending upon the patient's condition. Eight out of 16 metastases, such as bone, muscle, and lymph node metastases, in 9 patients treated by arterial LAK therapy showed regression. Side effects during LAK therapy were not serious. Past history of having chemotherapy was an unfavorable factor that could reduce the sensitivity to LAK therapy. Our laboratory study showed the production of Interferon (IFN)-gamma and Tumor Necrosis Factor (TNF)-alpha by LAK cells when preincubated with RCC cells, which may indicate the mechanism of LAK cell-mediated antitumor activity in vivo. The study also showed that LAK cells as well as monocytes preincubated with the supernatant of LAK cells damaged normal endothelial cells in vitro, which suggested the possibility that LAK therapy risks increasing the frequency of brain metastasis by damaging the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Lymphokine-activated killer (LAK) therapy for advanced renal cell carcinoma: clinical study on arterial LAK therapy and experimental study on LAK cell activity]. 148 87

We have developed a new technique for detecting binding of interleukin 2 (IL-2) to cells. This technique involves incubating the cells with IL-2 and then analysing the cell surface with specific anti-IL-2 antibodies and flow cytometry. This binding was only detected on tumor cells that possessed the p55 subunit of the IL-2 receptor. The role of p55 was ascertained by inhibition of the binding with a monoclonal antibody to p55. Although p55 is necessary for cytometrically detected IL-2 binding, further studies demonstrated that p55 is not sufficient. Thus, cytometrically-detected binding is likely to involved the contribution of other IL-2 surface receptors. Interleukin-2 binding to peripheral blood T lymphocytes and to a non-transformed T-cell clone was also detected cytometrically and it was shown that this binding is regulated by the activation status of the cells. Whereas IL-2 binding to quiescent T cells could not be detected, upon activation abundant binding was seen. The functional consequences of this type of cellular binding were studied. Interleukin-2 binding to cells during a short pulse was shown to have significant long-term consequences both for T-cell proliferation and for the enhancement of major histocompatibility complex (MHC)-non-restricted cytotoxicity.
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PMID:Cytometrically detected specific binding of interleukin 2 to cells. 149 54

The role of cisplatin (CP) and FK-565 in monocyte-mediated up-regulation of lymphokine-activated killer (LAK) cell induction by interleukin-2 (IL-2) was examined. Treatment of peripheral-blood mononuclear cells (PBMC) with CP or FK-565 in the presence of IL-2 resulted in a significant increase in LAK activity against NK-resistant Raji cells, as assessed by the 4-hour 51Cr release assay, depending on the dose of CP, FK-565 and IL-2. Up-regulation of IL-2-induced LAK activity by CP/FK-565 was significantly higher in whole PBMC as compared to PBMC depleted of monocytes. Addition of different numbers of monocytes to cultures of lymphocytes plus IL-2 along with CP or FK-565 resulted in a significant up-regulation of LAK activity depending on the number of monocytes added. Pretreatment of monocytes for 2 h with CP or FK-565 before addition of lymphocytes plus IL-2 resulted in significant up-regulation of LAK activity as compared to untreated monocytes. Culture supernatant of CP- or FK-565-treated monocytes also significantly up-regulated IL-2-induced LAK activity of lymphocytes. The results of the present investigation suggest that up-regulation of LAK activity by CP and FK-565 in human PBMC is monocyte-mediated. Further, our data demonstrate that tumor necrosis factor and IL-1 play an important role in the up-regulation of LAK activity by monocytes that have been pretreated with FK-565 or CP. These results indicate that CP and FK-565 may be useful in modulating the immune response during treatment of neoplasia with IL-2 and LAK therapies.
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PMID:Role of human blood monocytes in up-regulation of lymphokine (interleukin-2)-activated killer cell activity with cisplatin and FK-565. 149 19

Evidence is presented for the existence of a serum factor(s) (SF), which inhibits the growth of both the interleukin-2 (IL-2)-dependent cell line CTLL and the 2-day generation of CTL cells. This activity is found in the serum of both nude and euthymic mice and its suppressive effect can be detected about 18 hours after addition to CTLL cultures. The inhibitory activity elutes from a Sepharose 6B gel after the gamma globulin fraction (100-150 kD), and is precipitated by ammonium sulfate at 60 w/v% saturation. IL-3-mediated bone marrow colony formation is not inhibited by SF. It also does not suppress the growth of a panel of different tumor cell lines. The spleen cell responsiveness to both Con A and LPS activation is greatly reduced in the presence of SF. However, binding of radiolabelled IL-2 to CTLL cells was not blocked by SF, although the activity was greatly reduced by absorption to these cells. Our data support the existence of factor(s) in sera that may have a regulatory role on IL-2-mediated functions.
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PMID:Normal mouse serum-derived factor(s) which inhibits growth of the interleukin-2-dependent cell line CTLL. 149 96

Published data indicate that when recombinant interleukin-2 (rIL-2) is administered to children as a 15-min i.v. bolus, doses of 18 x 10(6) IU/m2 are poorly tolerated, requiring intensive care unit (ICU) management of IL-2-induced hypotension. We administered rIL-2 as a 1- or 2-h i.v. infusion to 11 children with malignancies refractory to conventional therapy. IL-2 was given every Monday/Wednesday/Friday for 3 weeks. Four children received 12 x 10(6) IU/m2/dose, four received 18 x 10(6) IU/m2/dose, and three received 24 x 10(6) IU/m2/dose (1 Cetus Unit = 6 IU). Fever, chills, flushing, nausea, vomiting, transient weight gain, and oliguria were observed at all three dose levels (not dose-limiting toxicities). Cardiovascular toxicity was significantly reduced compared to the bolus regimen. Mild hypotension was observed at all three dose levels; however, there was no severe dose-limiting hypotension. Because of reduced cardiovascular toxicity, IL-2 was safely administered on an outpatient basis. This regimen induced marginal transient increases in natural killer cell activity and lymphokine-activated killer cell activity. No measurable clinical tumor response was observed in any of the 11 children. The maximum-tolerated dose has not been reached. This regimen allows for a considerable cost reduction (outpatient care instead of ICU care) and safety, making further clinical trials on the use of IL-2 in children more feasible.
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PMID:Phase I study of recombinant human interleukin-2 for pediatric malignancies: feasibility of outpatient therapy. A Pediatric Oncology Group Study. 150 55

Several strategies have been used to stimulate the growth of tumor-specific T cells in place of tumor antigen. One approach is to use pharmacologic agents to activate the second messenger pathways of T-cell activation. In the present study, we examined the ability of the protein kinase C activator bryostatin 1 (B) plus the calcium ionophore ionomycin (I) to stimulate the growth of lymphocytes obtained from the axillary lymph nodes (DLN) draining a progressively growing intradermal plasmacytoma tumor. Draining lymph node cells were initially cultured with autologous tumor cells and 20 U/ml of interleukin-2 (IL-2) for 7 days. The lymphocytes were then incubated with various concentrations of bryostatin 1 plus 1 microM ionomycin and cultured for an additional 14 days in IL-2. DLN cells initially cultured with autologous tumor and then restimulated with 5 nM bryostatin 1 and 1 microM ionomycin exhibited marked in vitro proliferation and 15-fold expansion of cell numbers over 2 weeks. The cells expanded with B/I were predominantly CD8+ T cells and retained specific in vitro cytotoxicity against autologous tumor. When adoptively transferred to mice with established liver metastases, DLN cells restimulated with B/I-mediated specific tumor regression.
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PMID:Bryostatin 1 activates T cells that have antitumor activity. 150 56


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