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

Ten patients with advanced liver cancer, primary in 5 and metastatic in the other 5, were treated with lymphokine-activated killer cells, autologous (aLAK) and/or homologous (hLAK) combined with human natural IL-2. Each course of treatment lasted 10 days. For aLAK/IL-2 treatment, white cells were collected from the patients to be treated by a cell separator on Day 4 and after 3-day culture of the mononuclear cells in vitro in the presence of IL-2 (500 units/ml), the aLAK cells (1-2 x 10(9)) were transferred back to the patient on Day 7 via the hepatic artery by selective catheterization. IL-2 (20-30 x 10(4) units) was given i.v. daily on Days 1, 2, 8, 9 and 10. For hLAK/IL-2 treatment LAK cells from healthy donors (0.5-1 x 10(9)) were administered i.v. on Days 1, 4, and 7 and IL-2 (20-30 x 10(4) units) i.v. daily on Days 2, 3, 5, 6, 8, 9, 10. Patients with primary liver cancer were all treated with aLAL/IL-2, followed by hLAK/IL-2 in 3. Patients with metastatic cancer in the liver were either treated with hLAK/IL-2 alone or in combination with aLAK/IL-2. The results of the treatment as monitored by B ultrasonography, CT scan and digital selective angiography are as follows: CR in 2 (with metastatic liver cancer), PR in 4 (3 with primary and 1 with metastatic liver cancer), MR in 2 and no response in 2. On follow-up, 7 patients survived greater than 6 months and 1 (a complete responder) for greater than 12 months. Side effects were mild with transient fever up to 38.5 degrees C and general malaise.
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PMID:[Treatment of advanced liver cancer by autologous and/or homologous LAK cells combined with human natural LL-2]. 187 94

Adoptive immunotherapy in cancer has been essentially restricted to the use of lymphoid effector cells (NK, TIL, LAK) stimulated with IL-2. Differentiated macrophages represent another key effector population even more important for the immune control of cancer. We have shown that activated murine macrophages reduced primary tumors and experimental metastases. Human macrophages differentiated from circulating monocytes and activated with IFN gamma (MAK) were cytotoxic in vitro for a variety of tumor cell and caused regression of human tumors implanted in nude mice. A large scale technology has been developed for the generation of antitumor macrophages. These MAK cells (10(8) to 10(9] were injected in cancer patients in pilot clinical trials and were well tolerated. MAK treatment is technically feasible, clinically safe and presents several advantages compared to other immunotherapies.
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PMID:Adoptive immunotherapy of solid tumors with activated macrophages: experimental and clinical results. 188 50

We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.
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PMID:Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial. 191 Jun 23

In patients with metastatic malignant melanoma the distribution patterns of radiolabelled lymphokine-activated killer (LAK) cells were investigated. Peripheral mononuclear cells (PMC) were isolated from six patients. LAK cells were generated by culturing PMC in complete medium containing 1000 U interleukin (IL)-2/ml and labelled with indium 111 before retransfer. We obtained scans at 2.5, 24, 48 or 96 h after injection with a high resolution gamma-camera. Intravenously injected LAK cells distributed to the lungs, liver, spleen and bone marrow. External tumour detection of known lymph node and bone metastases was successful in four. It failed in one patient with a solitary lung metastasis and in another patient with subcutaneous metastases. Our results suggest that LAK cells show tumour homing, providing a direct interaction between tumour and cytotoxic cells. We conclude that PMC seem to retain their ability to migrate after IL-2 stimulation and 111In-labeling. This technique may be helpful for kinetics studies or external detection of metastases in patients with malignant melanoma.
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PMID:Imaging pattern of radiolabelled lymphokine-activated killer cells in patients with metastatic malignant melanoma. 204 69

Lymphokine-activated killer (LAK) cells were generated from splenocytes of rats bearing a weakly immunogenic Dunning prostate tumor (R-3227 AT-3) and activated with recombinant interleukin-2 (rIL-2). The maximal LAK activity was obtained from splenocytes of rats bearing tumors for 10 to 14 days after incubation with 1000 U/ml./day of rIL-2 for five to eight days. The majority of these LAK cells expressed high levels of asialo GM1 (89%), laminin (83%), OX-19 (80%) and OX-8 (88%) surface markers. LAK cells exhibited higher cytotoxicity to rat prostate tumor cells and mouse lymphoma in vitro than to other non-prostate tumor cells or normal rat splenocytes and thymocytes. Splenocytes of rats bearing prostate tumors have higher LAK activity than normal splenocytes. The Winn type assay showed that Dunning prostate tumor growth was inhibited effectively by LAK cells at a tumor cell:LAK cell ratio of 1:50. The therapeutic efficacy of LAK cells in the treatment of primary solid prostate tumors and pulmonary metastases of Dunning rats was evaluated. LAK cells in combination with rIL-2 showed a greater therapeutic benefit in 1) prevention of prostate tumor metastases to lung, 2) retardation of the primary tumor growth, 3) regression of spontaneously established pulmonary metastases, and 4) prolongation of survival as compared to untreated controls or those groups treated with LAK cells or rIL-2 alone. The results of this study indicate that the conjunctive therapeutic approach of using surgical therapy to remove primary solid tumors followed by adoptive immunotherapy with LAK cells plus in vivo administration of IL-2 may be potentially valuable in the treatment of prostate tumors, particularly for the spontaneous pulmonary metastases.
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PMID:Adoptive immunotherapy using lymphokine-activated killer cells and recombinant interleukin-2 in preventing and treating spontaneous pulmonary metastases of syngeneic Dunning rat prostate tumor. 205 87

Alteration in interactions between tumor-infiltrating lymphocytes (TILs) and tumor cells after chemotherapy or immunotherapy was studied in metastatic melanoma patients. Tumors were harvested from surgical specimens 17 days after the end of chemotherapy with cisplatin, vinblastine, and dacarbazine (CVD). Tumors of nonlymph-node metastases from two responders yielded neither TILs nor tumor cells, whereas those from all four nonresponders had both TILs [(1.1-13.8) x 10(6) cells/g tumor] and tumor cells [(2.8-30.8) x 10(6) cells/g tumor). Tumors of lymph node metastases from nine patients yielded substantial numbers both of TILs and tumor cells, regardless of different clinical responses, except with one complete responder, whose tumor did not contain tumor cells. The mean increase of TILs from these tumors (n = 14) 3-4 weeks after incubation with 200 U/ml recombinant interleukin-2 (rIL-2) was 2.5-fold, whereas there was a 56-fold increase in TILs from untreated tumors (n = 3). CD3+ T cells predominated in TILs before and after expansion with IL-2. IL-2-activated TILs from five of six tumors tested displayed higher cytotoxicity against autologous tumor cells than against cells from any of three allogeneic tumors. Mean tumor cell numbers (10(6) cells/trial) obtained by serial needle biopsies for the same tumor in five patients decreased from 1.2 before therapy to 0.25 at day 4 of therapy (interferon alpha alone), and to 0.02 at day 8 (interferon alpha and IL-2). This decrease did not correlate with clinical responses. Yields (x 10(6) cells/g tumor) of TILs and tumor cells in subcutaneous melanomas obtained by excisional biopsies in one nonresponder under IL-2 therapy were respectively 0.2 and 1.1 before therapy (day 0), 0.1 and less than 0.01 during (day 7), 0.2 and less than 0.01 at the end of therapy (day 21), and 0.5 and 0.5 at the time of tumor progression (day 66). Yields of TILs and tumor cells in the other nonresponder were respectively 3 and 26 before (day 0), 16 and 3 during (day 7), and 0.4 and less than 0.01 at the end of IL-2 therapy (day 17), and 2.5 and 6 at the time of progression (day 62). TILs in these two patients before therapy proliferated well in culture with IL-2 (570- and 720-fold, respectively), and showed higher cytotoxicity against autologous tumor cells, whereas none of those from the five tumors biopsied during or at the end of IL-2 therapy proliferated. TILs at the time of progression showed modest proliferation (54- and 76-fold, respectively) and showed major-histocompatibility-complex-nonrestricted cytotoxicity. In summary, a decrease in the number of live tumor cells did not always correlate with clinical response in either therapy. CVD chemotherapy may simply impair IL-2-induced proliferation of TILs. IL-2 therapy may induce transient unresponsiveness of TILs to IL-2.
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PMID:Alteration in interactions between tumor-infiltrating lymphocytes and tumor cells in human melanomas after chemotherapy or immunotherapy. 205 68

In an attempt to further understand the biological significance of soluble IL-2 receptors (sIL-2R) in solid tumors, we have evaluated 160 cancer patients (breast: 40; lung: 66; colon: 18; stomach: 22; uterine cervix: 14) and 58 healthy subjects, as controls. Serum mean levels of sIL-2R, measured with an enzyme immunoassay, were significantly higher in cancer patients than in controls. Metastatic cancer patients showed significantly higher values than the non-metastatic ones; this difference was significant in all tumor histotypes, except small cell lung carcinoma. Moreover, in 15 patients in whom sIL-2R were evaluated either before or after radical surgery, a significant surgery-induced increase in sIL-R mean values was seen. Finally, the chemotherapy-induced rise in sIL-2R appeared to be associated with a lack of clinical response. These results seem to suggest that sIL-2R may be a marker of host biological response in patients with solid tumors, the significance of which needs further investigation.
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PMID:The biological significance of soluble interleukin-2 receptors in solid tumors. 213 75

Anti-tumour effector cells were generated through 4 days culture of normal C57BL/6 splenocytes in a medium containing concanavalin A supernatant and then fractionated with Dolichos biflorus lectin (DBA) into DBA+ (agglutinable with DBA) and DBA- (non-agglutinable with DBA) cells. The DBA- cells, infused intravenously into mice together with B16 melanoma cells, or adoptively transferred into mice 3 days after the injection of B16 cells, caused a marked decrease in the number of lung nodules, while the DBA+ cells exerted no effect. On the other hand, the DBA+ cells exhibited higher cytolytic activity in vitro than the DBA- cells in short-term 51Cr-release assays. Then, we analysed the mechanism of the strong anti-tumour activity of DBA- cells in vivo. We found that DBA- cells showed higher response to recombinant interleukin-2 (rIL-2) than DBA+ cells and proliferated very well with a small amount of IL-2. In addition, DBA- cells adhered more strongly to lung endothelial cells than DBA+ cells in response to rIL-1 or rTNF. Furthermore, DBA- cells produced larger amounts of macrophage activating factor (MAF) including IFN-gamma when cultured with B16 melanoma. Taken together, our results show that DBA- cells are effective in reducing experimental pulmonary metastases not only by the direct lytic activity but also by the indirect killing activity through the activated macrophage.
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PMID:Anti-tumour efficacy of mouse spleen cells separated with Dolichos biflorus lectin (DBA) in experimental pulmonary metastasis of B16 melanoma cells. 217 66

The adoptive transfer of tumor-infiltrating lymphocytes (TIL) with the concomitant administration of IL-2 has been shown to mediate the regression of established 6- and 14-d murine hepatic and pulmonary metastases. For successful immunotherapy with TIL, however, pretreatment with either cyclophosphamide (CP) or whole body irradiation (WBX) was required. The exact mechanism of CP and WBX augmentation of TIL antitumor activity remains unknown, but the elimination of Ts cells has been frequently invoked as an explanation. To address this possibility and to determine if local tumor irradiation (LTX) could synergize with TIL as well as WBX, we investigated the effect of LTX on the therapeutic efficacy of TIL and IL-2 in the treatment of multiple 7-d murine hepatic metastases. Experiments studying the treatment of a weakly immunogenic murine adenocarcinoma, MC-38, showed prolonged survival of mice treated with the combination of IL-2, TIL, and either LTX or WBX, compared with treatment with radiation alone or radiation plus IL-2 controls (p less than 0.0001). In addition, therapy with LTX and IL-2 prolonged survival, compared with LTX administration alone, whereas therapy with WBX combined with IL-2 did not alter survival. This augmentation of TIL-mediated antitumor activity was dependent on the dose of radiation used. To assess the possibility that tumor-associated Ts cells inhibit the function of adoptively transferred TIL in animals with 7-d metastatic tumor and are eliminated by WBX and LTX, we repeated the above experiments leaving some tumor unirradiated. Mice underwent either LTX or limited LTX, which included only the right side of the liver (LTX1/2). The number of right- and left-sided metastases were then individually counted. These studies showed that the reduction in the number of right-sided metastases was identical between the two groups and that the presence of left-sided tumor in the LTX1/2 group did not suppress the observed antitumor activity of TIL against irradiated tumor. Additional evidence against the elimination of suppressor cells as an important mechanism in radiation-induced augmentation of TIL antitumor activity was provided by experiments studying the effectiveness of TIL in thymectomized, lethally irradiated, and reconstituted B mice. Unless CP was administered before the adoptive transfer of TIL, therapy with IL-2 and TIL in these B mice was ineffective in the absence of demonstrable T lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synergistic antitumor activity of tumor-infiltrating lymphocytes, interleukin 2, and local tumor irradiation. Studies on the mechanism of action. 229 78

The MCA 102 sarcoma has been defined by a variety of immunologic studies as a tumor lacking intrinsic immunogenicity. Nevertheless, we have recently demonstrated the feasibility of generating therapeutically effective lymphocytes for adoptive immunotherapy of this tumor. Procedures to achieve this required in vivo priming of syngeneic mice to elicit preeffector cells followed by in vitro sensitization (IVS) with tumor cells in the presence of IL-2. By selective depletion of T cell subsets in vivo, we identified the involvement of both CD4+ (L3T4+) and CD8+ (Lyt-2+) T cells in mediating tumor regression. The CD4+ cells exerted their helper function via the secretion of IL-2 because antitumor effects abrogated by depletion of CD4+ cells could be reconstituted by exogenous IL-2. In order to elicit preeffector cells with reactivity against the MCA 102 tumor, we found that in vivo sensitization could be accomplished with either the MCA 102 or MCA 106 tumor but not with the MCA 101 or MCA 105 tumor. Analysis of specificity of tumor stimulation during IVS of MCA 102 tumor-primed preeffector cells demonstrated cross-reactivity between not only the MCA 102 and MCA 106 tumors but also the MCA 105 tumor whereas the MCA 101 tumor was ineffective. In adoptive immunotherapy, transfer of IVS cells generated from MCA 102 tumor-primed and stimulated lymph node cells was able to mediate reductions of pulmonary metastases established from the MCA 102, MCA 105, and MCA 106 tumors but not from the MCA 101 tumor. We conclude that regression of the MCA 102 tumor is probably mediated through T cell recognition of a set of common tumor-associated Ag shared by several other syngeneic tumors. Immunologically, the tumor-associated Ag are characteristically different from classical tumor-specific transplantation Ag (TSTA) because immunity to TSTA on the MCA 105 or MCA 106 tumor does not cross-react with the MCA 102 tumor. Thus, this study demonstrates that Ag other than TSTA on chemically induced tumors can serve as target molecules for T cell-mediated adoptive immunotherapy.
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PMID:Effector phenotype and immunologic specificity of T-cell-mediated adoptive therapy for a murine tumor that lacks intrinsic immunogenicity. 236 40


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