Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between October 1987 and November 1988, 95 European patients with metastatic renal cell carcinoma have been treated with recombinant interleukin-2 (rIL-2) (EuroCetus) at 18 X 10(6) IU/m2/day (equivalent to 3 X 10(6) Cetus Units/m2/day) according to the West schedule in two trials. 1. Forty-two patients received rIL-2 alone. Median time between initial diagnosis and metastases was three months. Eighty-one percent of the patients had at least two involved sites at inclusion and 86% underwent prior nephrectomy. Twenty-seven patients (64%) received two successive courses. Over 80% of the planned dose was administered in 69% and 44% of patients during courses 1 and 2, respectively. Fever, hypotension, weight gain, rise in creatinine level, hepatic disturbances, anaemia and thrombocytopenia were commonly observed but resolved promptly after completion of therapy. No toxic death was recorded. Two (6%) complete responses (CR), four (13%) partial responses (PR), four stable diseases (SD) and 22 progressive diseases (PD) were observed. The response rate is 6/32 (19%); the median progression-free survival time is not reached at 218+ days (92-394). 2. Fifty-three patients received rIL-2 with lymphokine-activated killer (LAK) cells. Median time from primary diagnosis to metastases was three months. Eighty-five percent of patients had at least two involved sites though 73% had previously undergone nephrectomy. Forty patients (75%) received two successive induction courses. Most patients, i.e. respectively, 77% and 60%, were given at least 80% of the planned dose during courses 1 and 2. Median numbers of LAK cells infused were 13.1 and 11.6 X 10(9) nucleated cells per course, respectively. Toxicity was not different from that described above; no toxic death occurred; five CR (10%), nine PR (18%), 11 SD and 26 PD were observed. The response rate is 14/51 (27%) and the median progression-free survival time is not reached at 7.2+ months (3-13.1). In conclusion, rIL-2, with or without LAK cells, is obviously active on metastatic renal cell carcinoma. The difference in response rate between the two trials is not statistically significant but has to be paralleled with the difference in dose received by the patients rather than with the addition of a cellular therapy. Toxicity was always manageable and reversible. The association of rIL-2 with other lymphokines should represent a major issue to improve the response rate and will be considered in further European studies.
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PMID:Interleukin-2 with or without LAK cells in metastatic renal cell carcinoma: a report of a European multicentre study. 269 75

We have recently reported a simple and reproducible technique for the purification and rapid expansion of homogeneous populations of large granular lymphocytes expressing a natural killer cell phenotype and high levels of broad antitumor cytotoxic activity [lymphokine-activated killer (LAK) activity]. This technique exploits the observation that, in the presence of recombinant interleukin 2 (rIL-2), large granular lymphocytes/natural killer cells become adherent to plastic surfaces, actively proliferate, and acquire high levels of LAK activity. Because of their adherent properties these cells have been termed adherent LAK or A-LAK cells. The present studies investigate the antimetastatic effects of A-LAK cells in a syngeneic rat model of experimental pulmonary and hepatic metastases. For pulmonary metastases, F344 rats received i.v. injections with a natural killer-resistant mammary adenocarcinoma, MADB106, and, for hepatic metastases, animals received an intrasplenic injection of MADB106 tumor cells followed by surgical splenectomy. Three days later, the animals were treated with A-LAK cells alone, A-LAK cells plus rIL-2, or rIL-2 alone. These treatments were compared to immunotherapy using standard cultures of LAK cells (unfractionated spleen cells) and rIL-2. The results indicate that the administration of unfractionated LAK cells plus interleukin 2 (IL-2) was effective in reducing established lung or liver metastases in this rat model. However, the results also indicate that purified populations of A-LAK cells in combination with rIL-2 demonstrate dramatic and superior antimetastatic effects when compared to LAK cells cultured under standard conditions. The antimetastatic effects of standard LAK cells or A-LAK cells plus IL-2 translated into significant survival benefits compared to animals receiving no therapy or IL-2 therapy alone. Survival after therapy with A-LAK cells plus IL-2 was significantly prolonged compared to treatment with standard LAK cells. These data suggest that purified populations of LAK cells (derived from natural killer cells) may prove superior for adoptive immunotherapy in the clinical setting.
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PMID:Enhanced antimetastatic activity of lymphokine-activated killer cells purified and expanded by their adherence to plastic. 278 50

Metastatic cancer was treated with interleukin 2 and lymphokine-activated killer cells with the addition of the cyclooxygenase inhibitor ibuprofen in an attempt to reduce side effects in 13 patients (eight male and five female). Twenty-six patients treated with only interleukin 2 and lymphokine-activated killer cells formed the control group. After interleukin 2 administration, a significantly increased number of lymphokine-activated killer cells were transfused in ibuprofen-treated patients. Cytotoxic effects were not significantly different in the treated and untreated groups. With regard to cell phenotype, both groups of patients manifested significant activation of the immune system as measured by T10 and OK1a. Symptom scores were dramatically reduced in patients treated with ibuprofen. Temperature above 37 degrees C were rare. Ibuprofen did not significantly alter rate of response in this immunotherapy trial (38% vs 42%). Ibuprofen is now routinely used in all of our current immunotherapy trials.
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PMID:Ibuprofen causes reduced toxic effects of interleukin 2 administration in patients with metastatic cancer. 278 76

Immunotherapy with recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells (LAK) has become a new form of therapy that has been shown to induce remissions in patients with renal cell carcinoma and melanoma. Despite encouraging results, this form of therapy has been associated with increasing toxicity, often requiring therapy in an intensive-care unit. In this report severe intrahepatic cholestasis occurred in two patients receiving rIL-2 and LAK cells. This form of cholestasis appeared to be directly related to rIL-2 administration at a doses of 2 x 10(6) U/m2 and 3 x 10(6) U/m2 t.i.d. A liver biopsy showed moderate hepatocellular bile stasis, with lobular and portal inflammation. All other studies for potential cause of this cholestasis were negative, including studies for metastatic disease. When therapy was discontinued, evidence for cholestasis and bile stasis resolved. We conclude that rIL-2 is a drug with a potential to induce severe hepatic injury that is reversible upon cessation of therapy with rIL-2. Further care should be exercised when rIL-2 is administered to patients with abnormal liver function.
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PMID:Severe intrahepatic cholestasis in patients treated with recombinant interleukin-2 and lymphokine-activated killer cells. 278 19

Spleen cells of C57BL/6N mice bearing lung metastases were induced to the cytotoxic state by subcutaneous injection of recombinant human interleukin-2 (IL-2) at a minimum dose of 5 x 10(4) U/mouse three times a day for 3 consecutive days. A single intraperitoneal injection of lentinan alone at concentrations of up to 10 mg/kg body weight did not render spleen cells cytotoxic to P-29 cells, but a combination of subthreshold doses of these agents (5 x 10(4) U/ml IL-2 and 5 mg/kg lentinan) induced significant in vivo lymphokine-activated killer activity in spleen cells of tumor-bearing mice. Similarly, spleen cells from mice treated i.p. with lentinan became cytotoxic on in vitro treatment with IL-2. The in vitro responsiveness of spleen cells to IL-2 was maximal 3 days after i.p. injection of lentinan. Synergism between IL-2 and lentinan was also observed in mice bearing spontaneous lung micrometastases: neither IL-2 (less than 5 x 10(4) U/mouse) nor lentinan (less than 2.5 mg/kg) alone had a therapeutic effect, but multiple injections of IL-2 with a single injection of lentinan resulted in significant inhibition of spontaneous pulmonary metastases. From these results we conclude that IL-2 and lentinan in combination are more effective than either one alone for inducing destruction of pulmonary metastases.
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PMID:Synergistic induction of lymphokine (IL-2)-activated killer activity by IL-2 and the polysaccharide lentinan, and therapy of spontaneous pulmonary metastases. 278 52

In a murine pulmonary metastases model, interleukin-2 (IL-2), a lymphokine capable of expanding all classes of T lymphocytes, synergizes with interferon-alpha (IFN-alpha) to reduce established metastases and prolong survival. We tested whether indomethacin (INDO), which inhibits synthesis of prostaglandin E2 (a potent immunosuppressor), could further augment the antitumor efficacy of these lymphokines. Age-matched C57BL/6 mice bearing pulmonary micrometastases of a weakly immunogenic fibrosarcoma MCA-106 were treated intraperitoneally for 6 consecutive days, starting on day 3 with (1) saline solution, (2) IL-2 (50,000 units twice a day), (3) IFN-alpha A/D (50,000 units per day), and (4) IL-2 and IFN-alpha A/D. Half of each treatment group was given plain water and the rest INDO-treated (14 micrograms/cc) drinking water throughout the duration of the experiment. Pulmonary metastases were enumerated on day 21. IFN or INDO alone had little effect, whereas IL-2 reduced metastases and prolonged survival. All combination treatments, including INDO/IFN, decreased metastases and prolonged survival except INDO/IL-2/IFN in which several early deaths negated any significant survival prolongation. Early mortality (less than 21 days) was seen with IFN/INDO (8.3%), IL-2/IFN (7.7%), and IL-2/IFN/INDO (8.3%) indicating toxicity of these treatments. Spontaneous proliferation of splenocytes from non-tumor-bearing mice treated for 5 days showed that INDO combined with IL-2 or IFN enhanced proliferation measured 3 days after cessation or treatments. A striking reduction in T-cell marker (Thy 1.2+) in groups treated with IL-2/IFN, INDO/IL-2, INDO/IFN, and INDO/IL-2/IFN 3 days after cessation of IL-2 and IFN suggests that a non-T-cell is amplified when INDO is combined with IL-2 or IFN. These results show that INDO can enhance efficacy of IL-2 or IL-2/IFN. Furthermore, INDO/IFN offers an equi-efficacious, albeit similarly toxic, alternative to IL-2 treatment of tumors and may be useful clinically.
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PMID:Indomethacin-enhanced immunotherapy of pulmonary metastases using IL-2 and IFN-alpha. 278 16

From January 1987 to February 1988, 15 stage IV melanoma patients were treated with two courses of bolus injection of rIL-2 plus LAK cell infusions at the National Cancer Institute of Milan. The original treatment regimen included a first course of rIL-2 administration (400 micrograms/m2 bolus injection 3 times a day [TID] for 4 days) and a second course of rIL-2 administration (800 micrograms/m2 bolus injection TID for 7 days) separated by 4 consecutive daily leukaphereses. Autologous lymphokine activated killer (LAK) cells were reinfused into each patient on three occasions during the second period of rIL-2 administration. Due to the appearance of grade III-IV neurological, hepatic and cardiopulmonary toxicity, 7 patients discontinued dosing before the end of treatment, one patient desired to be withdrawn and one patient died from rapidly progressive disease, although complications of rIL-2 administration may have contributed to her death. Only 6 patients completed the schedule without evidence of major intolerance, even though the planned dose during the second course of rIL-2 was reduced to 400 micrograms/m2. The complete duration of treatment ranged from 11 to 19 days. The total dose of rIL-2 injected ranged from 12.6 to 30.4 mg. The number of infused LAK cells ranged from 15.5 x 10(9) to 60 x 10(9)/patient. Two of the 14 evaluable patients showed a minor anti-tumor response. In 5 patients new metastases in other sites were documented from 2 to 5 months after completion of dosing. No apparent association was found between progression of the disease (or the appearance of new metastases) and the total dose of rIL-2 injected, the number of LAK cells administered or the number of days of treatment. By December 1988, all patients had died of their disease in a period ranging from 3 to 14 months from the last injection of rIL-2. The lack of significant clinical responses in this study and the high toxicity of this treatment lead us to conclude that at least as far as melanoma patients are concerned, adoptive immunotherapy with rIL-2 plus LAK cells (as described here) is not a justifiable treatment option unless new evidence presents itself.
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PMID:A phase II study of the administration of recombinant interleukin 2 (rIL-2) plus lymphokine activated killer (LAK) cells in stage IV melanoma patients. 278 45

Our previous studies demonstrated that the incubation of human peripheral blood lymphocytes or murine splenocytes in recombinant interleukin 2 (RIL 2) resulted in the generation of lymphokine-activated killer (LAK) cells capable of lysing a broad spectrum of fresh tumors in short-term chromium-release assays. Moreover, injections of LAK cells plus RIL 2 were highly effective in eliminating established 3 day metastases in the lung and liver (1-3). We have examined several parameters to define whether or not the cytolytic activity of LAK cells as measured in vitro correlated directly with the in vivo anti-tumor efficacy of adoptively transferred LAK cells. LAK cells plus RIL 2 could mediate marked reductions of established pulmonary metastases in mice rendered T cell deficient by adult thymectomy and lethal, total body irradiation followed by reconstitution with T cell-depleted bone marrow and spleen cells. Thus there was no requirement for additional T lymphocytes of host origin for successful therapy with adoptively transferred LAK cells plus RIL 2. Fresh splenocytes depleted of T cells by anti-Thy-1.2 monoclonal antibody plus complement generated LAK cells that were as highly lytic to fresh tumor in vitro and were as effective in reducing established pulmonary metastases as those generated from untreated or complement-treated splenocytes. Thus the precursor to LAK cells with anti-tumor activity in vitro and in vivo did not express the Thy-1 antigenic marker. In contrast, treatment of LAK effector cells (those generated from a 3-day incubation of fresh, normal splenocytes in RIL 2) with anti-Thy-1.2 antibody plus complement reduced or abolished their in vitro cytolytic activity. However, when combined with the systemic administration of RIL 2, these T cell-depleted, non-lytic LAK cells remained as effective in reducing the number of established pulmonary metastases upon adoptive transfer as untreated or complement-treated lytic LAK cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo: direct correlation between reduction of established metastases and cytolytic activity of lymphokine-activated killer cells. 287 Nov 6

Murine and human lymphocytes incubated in recombinant interleukin 2 (RIL 2) generate a population of cytotoxic cells (lymphokine-activated killer cells [LAK]), which are able to lyse a wide array of fresh tumor cells but do not lyse fresh normal cells. Intravenous administration of these cells with the concomitant administration of RIL 2 can eliminate established pulmonary and hepatic metastases in mice. To characterize the cell that has in vitro LAK activity, we subdivided murine lymphocytes by lysing select subpopulations with the use of complement and antibodies against lymphocyte surface markers or by fluorescence-activated cell sorting. Thy-1.2-negative splenocytes were found to generate near normal amounts of LAK activity after RIL 2 incubation. Small and inconsistent LAK cell activity was generated from Thy-1.2-positive splenocytes. Ia-positive and surface immunoglobulin-positive splenocytes had little or no LAK precursor capability and did not appear to be necessary for LAK activation. Treatment of splenocytes with anti-asialo GM1 (anti-ASGM1) heterosera and complement markedly decreased their ability to generate LAK activity. At the effector stage, cytotoxic cells were of the Thy-1.2-positive, Ia-negative phenotype. Ia-depleted cells were separated into subpopulations bearing or not bearing the gamma Fc receptor (gamma FcR). The majority of cytotoxicity resided in gamma FcR-positive cells. Thus the precursors of murine LAK cells are "null" lymphocytes bearing neither T nor B cell surface markers but develop the Thy-1.2 cell surface marker in vitro, in association with the development of lytic activity for fresh tumor cells after stimulation by RIL 2.
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PMID:Murine lymphokine-activated killer (LAK) cells: phenotypic characterization of the precursor and effector cells. 287 87

The systemic administration of lymphokine activated killer (LAK) cells and recombinant interleukin-2 (RIL-2) is effective in reducing the number of established pulmonary and hepatic metastases from multiple murine tumors and has recently been shown to be effective in mediating the regression of metastatic cancer in humans as well. The generation of sufficient numbers of LAK cells for the effective therapy of human tumors remains a major obstacle to the widespread application of this immunotherapeutic approach. We have thus studied methods for the in vitro expansion of LAK cells effective in immunotherapy. Our previous studies used LAK cells generated in culture with RIL-2 for 3 days. LAK cells cultured in RIL-2 for 5 or 7 days were not significantly different from cells cultured for 3 days either in the number of cells obtained, their in vivo cytotoxicity or their in vivo therapeutic effectiveness. When day 3 LAK cells were transferred to fresh culture medium containing 1000 U/ml of RIL-2, a highly reproducible expansion of these cells was obtained. By day 5, cell numbers expanded 9.6 +/- 0.8-fold (mean +/- SEM; n = 36) and by day 8, cells expanded 15.1 +/- 1.0-fold (n = 19). In 4 h 51Cr release assays against fresh tumor target cells, day 3 LAK cells had a mean of 13 lytic units/10(6) cells in 24 experiments. Day 5 expanded LAK cells had a mean of 30 lytic units/10(6) cells in 13 experiments (P less than 0.05 compared to day 3 LAK cells) and day 8 expanded LAK cells had a mean of 11 lytic units/10(6) cells in 6 experiments (P = NS compared to day 3 LAK cells) When day 5 and day 8 expanded LAK cells were infused in vivo with RIL-2, they were found to significantly reduce the number of experimentally induced pulmonary metastases as effectively as non-expanded conventional day 3 LAK cells. Similar findings were documented in experiments against hepatic metastases. These experiments demonstrate that LAK cells could expand a mean of 15-fold in vitro in RIL-2 and maintain their anti-tumor therapeutic effectiveness when adoptively transferred. These experiments suggest methods for generating increased numbers of cells for use in the adoptive immunotherapy of human cancers and may substantially reduce the need for repeated leukophereses of cancer patients undergoing this therapy.
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PMID:Optimal methods for generating expanded lymphokine activated killer cells capable of reducing established murine tumors in vivo. 287 49


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