Evidence for eosinophil activation in cancer patients receiving recombinant interleukin-4: effects of interleukin-4 alone and following interleukin-2 administration.

Interleukin-4 (IL-4) is a T-cell-derived cytokine that may mediate murine tumor rejection through the activation of host eosinophils. In association with a Phase I clinical trial of IL-4 in cancer patients, we have examined changes in eosinophil counts and characterized systemic eosinophil degranulation. As previously reported, IL-4 administration induced a modest eosinophilia in all 17 evaluated patients. Here, we report that IL-4 therapy induced systemic eosinophil degranulation based on increases in serum major basic protein (MBP) (P = 0.018) and urine MBP (P = 0.031). The increase in serum MBP was IL-4 dose dependent (P = 0.001). Following the highest dose (600 microgram/m2/day) of IL-4 administered, mean serum MBP levels were >2000 ng/ml. Skin biopsies of rashes from patients receiving IL-4 revealed MBP deposition. Sera from eight patients receiving IL-4 at 360 and 600 microgram/m2/day exhibited eosinophil survival-enhancing activity (on days 3, 5, 7, and 9) significantly above pretreatment (on day 1) activity (P values 0. 0469, 0.0039, 0.0395, and 0.0313, respectively). This enhanced eosinophil survival could be neutralized by antibodies to IL-5, granulocyte-macrophage-colony-stimulating factor, and IL-3. The eosinophil activation demonstrated in this trial may be relevant to the clinical effects of IL-4 in cancer patients. Furthermore, an association between IL-4 and eosinophil activation should be explored in other disease states.

Taste changes experienced by patients receiving chemotherapy.

PURPOSE/OBJECTIVES: To increase knowledge about the nature, frequency, and quality-of-life (QOL) effects associated with taste changes after chemotherapy. DESIGN: Cross-sectional, descriptive. SETTING: 11 outpatient urban and suburban oncology centers. SAMPLE: 284 adults who had received at least two chemotherapy cycles. METHODS: Patients completed a taste change questionnaire and the Functional Assessment of Cancer Therapy-General, and nurses collected demographic and disease-related information. Descriptive statistics, Spearman correlations, chi-square, Mann-Whitney, and Kruskal-Wallis one-way analysis of variance were calculated. FINDINGS: Taste changes were frequent and at least moderately severe for many patients, who often reported dry mouth, decreased appetite, nausea, and vomiting. Cisplatin and doxorubicin were the agents most likely to be related to severe taste changes and to have caused greater distress from taste changes, which also were associated with decreased QOL. Oncology nurses and physicians rarely discussed taste changes with patients, who often tried changing the ways they seasoned their food. CONCLUSIONS: Taste changes are a frequent and significant problem for patients receiving chemotherapy and have negative effects on patients' QOL. Oncology nurses and physicians typically do not offer self-management suggestions to patients. IMPLICATIONS FOR NURSING RESEARCH AND PRACTICE: Repeated-measures research may provide a clearer understanding of chemotherapy-associated taste changes over time. Studies to examine strategies suggested from this and other research as well as clinical literature may determine which self-care interventions are most useful. Nurses should inform patients that taste changes may occur following chemotherapy, provide self-management information, and assess for related problems that could increase chemotherapy morbidity.

A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients.

BACKGROUND: Interleukin-4 (IL-4) can enhance immune function within various leukocyte populations and mediate antitumor effects in mice. In vitro, IL-4 activation of human lymphocytes is enhanced by prior exposure to interleukin-2 (IL-2). This phase I trial of continuous intravenous infusion (CI i.v.) IL-4 was performed to determine its toxicity and biologic activity. IL-2 was administered prior to a second course of IL-4 in the same patients to determine whether IL-2 exposure can enhance IL-4 effects in vivo. PATIENTS AND METHODS: Seventeen patients with non-hematologic malignancies were entered on this trial. Treatment consisted of 7 days of CI i.v. IL-4 followed by a 2 week period off therapy, then a 4 day course of CI i.v. IL-2 at 11.2 MIU/m2/day followed by 3 days rest, and then a second 7 day course of CI i.v. IL-4. IL-4 dose escalation included 40 micrograms/m2/day (6 pts.), 120 micrograms/m2/day (3 pts.), 360 micrograms/m2/day (5 pts.), and 600 micrograms/m2/day (3 pts.). RESULTS: Dose limiting toxicity occurred at 600 micrograms/m2/day of IL-4; a dose at which 2 of 3 patients exhibited a vascular leak syndrome characterized by weight gain, peripheral edema, effusions, oliguria, and diffuse rash. Pretreatment with IL-2 did not significantly enhance IL-4 toxicity in the 40-360 micrograms dose range. IL-4 treatment was associated with a modest, but significant increase in peripheral eosinophil counts (p = 0.004), but no consistent change in lymphocyte phenotype or function. Patients treated at the higher dose of IL-4 (360 micrograms) administered following IL-2, exhibited a marked increase in peripheral eosinophils after IL-4 therapy (p = 0.007). Following the second course of IL-4, we observed increases in the percent CD56+ (NK/LAK marker) lymphocytes (mean increase = 6.8%), above levels induced by the preceding IL-2 treatment (p = 0.055). A single minor durable tumor response was seen in a patient with metastatic renal cancer. CONCLUSIONS: IL-4 administered at 360 micrograms/m2/day CI i.v. over seven days is the maximum tolerated dose and is tolerable following a 4 day course of IL-2. IL-4 therapy alone is associated with a modest eosinophilia. In patients receiving IL-2 prior to IL-4, both circulating eosinophils and CD56+ cells increased above levels observed early after IL-2 treatment. Based upon these results, phase II trials of IL-4 in combination with IL-2 could be planned in 'IL-2 sensitive' malignancies.

A phase IA/IB trial of anti-CD3 murine monoclonal antibody plus low-dose continuous-infusion interleukin-2 in advanced cancer patients.

Preclinical studies have shown that anti-CD3 antibodies can enhance the in vitro activation of human T lymphocytes in combination with low-dose interleukin-2 (IL-2) and induce the in vivo rejection of murine tumors. A Phase IA/IB trial combining a murine monoclonal antibody, anti-CD3 antibody (OKT3), with low-dose continuous-infusion IL-2 was conducted in cancer patients to define the toxicity and immunologic effects of this combination. OKT3 administered weekly as a 15-min infusion at dose levels of 10, 100, 200, 400, and 600 micrograms/m2 was followed 18 h later by a 100-h infusion of IL-2 at 3 MIU/m2/day for 3 consecutive weeks. When feasible, patients also received the IL-2 course without OKT3 to assess the effects of OKT3 on the IL-2 regimen within the same patient. Thirty patients were enrolled onto the study, with 24 completing the OKT3/IL-2 course and 18 completing both OKT3/IL-2 and IL-2 alone courses. OKT3 administration was associated with acute hypotension with fevers of > 40 degrees C and in two patients cerebral vascular infarcts. At 600 micrograms/m2 OKT3, these toxicities were dose limiting. In a dose-dependent manner, OKT3 induced the transient release of tumor necrosis factor (TNF) and IL-6 into the serum and a profound lymphopenia. OKT3 did not significantly enhance the toxicity of this schedule of IL-2 administration. All solid tumor patients treated at 100-600 micrograms/m2 OKT3 showed induction of a human anti-murine antibody response prior to the third week of treatment. A patient with renal cell cancer treated at the 600-micrograms/m2 OKT3 dose level experienced a 4-month partial remission, and two mixed responses were observed in a sarcoma and a melanoma patient treated at 100- and 400-micrograms/m2 OKT3 dose levels, respectively. Most importantly, we were unable to demonstrate that the addition of OKT3 enhanced immune activation within peripheral blood based upon the magnitude of rebound lymphocytosis, increase in CD56+ or CD3+, CD25+ lymphocytes, induction of natural killer, lymphokine activated killer, or cytolytic T lymphocyte cytotoxicity, or release of serum cytokines (TNF, IL-6) or soluble CD25 (as assayed 24 h following IL-2 infusion). Therefore, this approach was ineffective at enhancing the immunologic effects of a low-dose continuous-infusion IL-2 regimen and will not be pursued further in clinical trials.