摘要:

Summary:Our group and others have conducted phase II trials of high‐dose interleukin‐2 (IL‐2) or IL‐2 with the adoptive transfer of in vitro activated lymphocytes in patients with advanced malignancies. Although durable complete and partial responses were seen in patients with renal cell carcinoma and metastatic melanoma, overall response rates were low and toxicity was substantial. In preclinical models, the combination of IL‐2 and interferon‐&agr; has synergistic antitumor activity. Based on these data, and our prior experience with high‐dose IL‐2 (Cetus), we conducted a trial to determine the maximum tolerated dose of IL‐2 (0.4, 0.8, and 1.2 mg/m2) administered together with a fixed dose of interferon‐&agr;2b(3 × 106u/m2) intravenously every 8 h on days 1‐5 and 15‐19. Patients were monitored in the intensive care unit and given pressor support for hypotension as needed. Twenty‐four patients were entered (6, 10, and 8 at each IL‐2 dose, respectively; 14 renal cell carcinoma, 7 melanoma, 2 colon, and 1 hepatoma). The median age was 56 years, the male to female ratio was 19:5, and performance status was 0 or 1 (Eastern Cooperative Oncology Group) in all patients. Toxicity was similar at all dose levels, but the onset was earlier in the treatment course as the dose of IL‐2 was escalated in successive cohorts; therefore, more doses were withheld at the higher dose levels. The major toxicities resulting in the interruption or stopping of treatment were hypotension requiring pressors, dyspnea, and neurotoxicity. Grade 1 or 2 fever, nausea and vomiting, fatigue, and cutaneous reactions were common at all dose levels. Reversible grade 3 or 4 transaminase elevations were also seen in most patients, but were not considered dose limiting. Three objective responses were noted in patients with renal cell carcinoma: one at dose level 2 and two at dose level 3. Dose level 2 was chosen for further phase II evaluation.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:A phase I trial of high‐dose continuous infusion rIL‐2 over 5 days and i.m. recombinant human interferon‐&agr; (rHuIFN‐&agr;2a) three times weekly in 23 patients with advanced malignancy has been completed. Cohorts of patients were treated at three different dose levels: rIL‐2 3.0 × 106u/m2plus rHuIFN‐&agr;2aeither 5.0 or 10.0 × 106u/m2, and rIL‐2 4.5 × 106u/m2plus rHuIFN‐&agr;2a5.0 × 106u/m2over 4 weeks. Dose‐limiting toxicity consisted of pulmonary and neurologic side effects, and the maximal tolerated dose was 3.0 × 106u/m2on days 1‐5 of rIL‐2, and 10.0 × 106u/m2three times weekly of rHuIFN‐&agr;2a. Four partial responses (renal carcinoma, three; endometrial carcinoma, one) were seen. In conclusion, toxicity of this schedule of rIL‐2 and rHuIFN‐&agr;2awas significant, but manageable. Further investigation is needed to define the antitumor activity of this combination.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Clinical immunotherapy trials have been performed recently where ex vivo interleukin‐2 (IL‐2)‐activated peripheral blood mononuclear cells (i.e., the “LAK” cells) have been transfused in addition to IL‐2 infusions. In such protocols, patients have received highly heterogeneous cell suspensions and the nature of the effector cells that may have contributed to tumor regression has remained unclear. In certain animal models, it has appeared that natural killer lymphocytes were the effector cell type responsible for tumor regression. To test whether NK cells could eventually be relevant for the treatment of human tumors, we have performed a feasibility trial where purified lympho‐kine‐activated natural killer (LANAK) cells have been prepared and transfused to a limited series of renal cell carcinoma patients receiving IL‐2 (continuous infusions at 3 × 106U/m2/day). Natural killer lymphocytes (1‐2 × 106) were purified from peripheral blood mononuclear cells and expanded during 4‐5 weeks in the presence of IL‐2 on microtiter plates containing feeder layers cells. In vitro, the resulting LANAK cell suspensions were 100 times (range of 2 to 103) more efficient against Daudi target cells than their autologous LAK counterparts. Twelve patients were included; 9 received the two planned courses of treatment with LANAK cells and IL‐2. Overall toxicity was relatively moderate. Besides occasional chills, there were no apparent secondary effects due to cell infusions. The mean number of LANAK cells transfused per patient was 45.1 × 109, ranging from 7 to 125 × 109. The biodistribution of LANAK cells was similar to that reported previously for LAK cells with no preferential localization to tumor sites. We conclude from this study that using well‐defined populations of effector lymphocytes is a feasible cellular therapy approach that may lead to improved understanding and efficacy of the novel immunotherapy methods.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:To determine whether recombinant human &agr;‐interferon (rIFN&agr;A) could enhance tumor uptake of an antimelanoma monoclonal antibody (Mab) 96.5 in vivo, groups of nude mice bearing P97 antigen‐positive human melanoma subcutaneous xenografts were given i.m. injections of normal saline or rIFN&agr;A daily for 10 days. On day 7, mice received either 5 &mgr;g of111In‐labeled Mab 96.5 or irrelevant111In‐labeled subclass‐matched or non‐subclass‐matched control Mabs. Animals were killed 72 h later and the percent injected dose per gram (%ID/g) in tumor and normal organs was determined. There was a significant (p< 0.001) increase in 96.5 in tumors of IFN‐treated mice compared to saline‐treated mice and mice receiving irrelevant Mabs. There was also a significantly increased uptake of 96.5 in blood, heart, lung, kidney, and muscle of IFN‐treated vs. control mice (p< 0.05). This finding was most likely due to increased antigen shedding since significant differences in %ID/g were not observed between IFN‐treated and control mice bearing antigen‐negative tumors. Furthermore, P97 content in tumor and tissues of IFN‐treated mice bearing melanoma xenografts was significantly higher than in mice without tumors. In summary, IFN enhanced targeting of 96.5 via an antigen‐specific mechanism. These data confirm and extend previous studies in other tumor systems, and suggest that clinical trials of Mabs plus IFN might be useful in overcoming poor Mab localization that occurs as a result of antigenic heterogeneity in humans.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Orally administered muramyl dipeptide (MDP) was found to prime induction of endogenous tumor necrosis factor (TNF) in mice. This priming effect was observed after oral administration of MDP of more than 100 &mgr;g/mouse; the maximal time interval between oral administration of MDP and i.v. injection of OK‐432, a triggering agent for induction of endogenous TNF, was extended over 3‐10 h and then decreased after 24 h. Antitumor effect against Meth‐A, MH134, and MM46 tumor cells in mice was observed after oral administration of MDP followed by i.v. injection of OK‐432. These findings suggest that orally administered MDP can be used as a priming agent for inducing endogenous TNF in cancer patients, and that MDP, a component of enteric bacteria, must have an important role in maintaining homeostasis through activation of macrophages.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Interferons (IFN) have clinical efficacy in certain hematologic malignancies. Combining IFN with conventional cytotoxic agents has been proposed as a means of improving therapy for diseases such as chronic myelogenous leukemia (CML). In this study, we examined the effect of recombinant interferons alone and in combination with Ara‐C on normal and leukemic human hematopoietic progenitor cells (CFU‐GM) in vitro. Mononuclear cells from normal bone marrow, peripheral blood of patients with CML, or the acute nonlymphocytic leukemia cell line HL‐60 were incubated with &agr;‐, &bgr;‐, or &ggr;‐IFN (0‐1,000 units/ml) followed by the addition of Ara‐C. The survival of normal CFU‐GM was significantly increased if cells were treated with IFN 1 h before 3 h of Ara‐C exposure. Similar IFN pretreatment of CML and HL‐60 progenitors failed to protect leukemic CFU‐GM from Ara‐C‐induced toxicity. This selective protection of normal CFU‐GM may have clinical application.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:The in vivo effects of the subcutaneous administration of the granulocyte colony‐stimulating factor (G‐CSF) on chemotherapy‐induced hematopoietic injury were evaluated in BALB/c mice. Mice treated with chemotherapeutic drugs were injected once a day for up to 12 days with 2 &mgr;g of recombinant human G‐CSF, and following this, bone marrow cellularity, spleen weight, and peripheral blood cell counts were measured 24 h after cessation of the G‐CSF treatment. Treatment of normal mice had minimal effect on the elevation of the white blood cell (WBC) count or on the hosts' resistance toK. pneumoniaeinfection. Spleen weight was significantly higher in normal mice treated with G‐CSF, and the platelet counts were slightly lower. In mice treated with cyclophosphamide (150 mg/kg), G‐CSF treatment caused an elevation of WBC and an enhancement of antibacterial resistance. Variable amounts of an accelerated recovery of neutrophils by G‐CSF treatment was also observed in nimustine hydrochloride (50 mg/kg)‐, mitomycin c (MMC) (8 mg/kg)‐, or vindesine sulfate (VDS) (4 mg/kg)‐treated mice. A significant decrease in PLT counts was observed in MMC‐ or VDS‐treated hosts given G‐CSF. These results indicate that administration of G‐CSF may facilitate hematopoietic recovery in chemotherapy‐treated cancer patients and that it may help them to increase their resistance to life‐threatening infection. Conversely, treatment with G‐CSF and chemotherapeutic drugs may cause a more severe thrombocytopenia than is observed with only chemotherapy treatment.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Thirty evaluable patients with advanced carcinoma of the pancreas received treatment with either daily × 5 bolus or continuous infusion × 5 days recombinant &ggr;‐interferon. No responses were noted. Major toxicities included fever, hypotension, and flu‐like symptoms. &ggr;‐Interferon does not appear to be an active single agent for patients with advanced pancreatic cancer.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Tumor necrosis factor (TNF) induces hemorrhagic necrosis in the Meth A mouse tumor model and has shown cytostatic and cytotoxic antitumor effects against a wide range of human tumors both in vitro and as human tumor xenografts in nude mice. Because of in vitro activity against colorectal tumors and antitumor responses in colon cancer patients in phase I trials, this phase II study was undertaken. Patients were treated with TNF administered daily for 5 days/week every other week at a dose of 150 &mgr;g/m2/day as a 30‐min i.v. infusion. One cycle consisted of 4 weeks of treatment over an 8‐week period. Twenty‐five patients have been entered into this study with three patients ineligible. The 22 eligible patients ranged in age from 38‐73 years and had initial performance status of 0 in 10 patients, 1 in 10 patients, and 2 in 2 patients. No complete or partial responses were seen. Two patients had stable disease (no response) and 18 patients progressed. Two patients had no evaluation and were assumed to have had no response. The response rate is therefore 0%, with a 95% exact confidence interval of 0% to 15%. There was one grade 4 toxicity consisting of nausea and vomiting. Most common grade 3 toxicities were chills and fever in four patients, nausea and vomiting in three patients, and anemia and elevated liver enzymes in two patients. Headache, myalgia/arthralgia, and elevated serum triglycerides were frequently seen. Mildly elevated levels of fibrin split products were seen after TNF treatment in 5/13 evaluable patients and one ineligible patient. One thrombotic episode occurring in a subclavian vein and possibly related to central line placement or TNF treatment occurred. In this dose and schedule, TNF is ineffective for the treatment of metastatic colorectal adenocarcinoma.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:The biological response modifier OK‐432, constituting cell wall fragments from a group AStreptococcusstrain and used in anticancer therapy trials, was tested for its ability to interact with different plasma proteins. The uptake of125I‐labelled protein was measured using a panel of six different plasma proteins all known to react with receptors on a majority of streptococcal strains. Of the proteins tested, plasminogen demonstrated the most substantial uptake, with uptake values ranging from 70 to 79%. A slight interaction with fibrinogen was also detected whereas no significant interaction was found with either human immunoglobulin (Ig)A, IgG, serum albumin, or mouse albumin. The results with plasminogen suggest the possibility of a new explanation of the antitumor activity described for OK‐432.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID