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At least 829 records · Page 46Linked to original sources
PubMed1991

Phase I evaluation of recombinant tumor necrosis factor given in combination with recombinant interferon-gamma.

In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients were given an intramuscular (i.m.) injection of IFN-gamma, followed 5 min later by an i.m. injection of TNF-alpha, each agent in different sites, every other day for ten doses over 20 days. Patients received 10, 50, or 100 micrograms/m2 of each agent throughout the treatment course. No dose modifications were made. Patients suffering serious toxicity had therapy stopped and were considered to be off-study. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 micrograms/m2 of both agents developed serious toxicity (one fever greater than 105 degrees F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 micrograms/m2 of IFN-gamma plus 50 micrograms/m2 of TNF-alpha. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells.

Adult↗
PubMed1992

A phase II study of recombinant interleukin-2 with or without recombinant interferon-beta in non-Hodgkin's lymphoma. A study of the Cancer and Leukemia Group B.

Interleukin-2 (IL-2) and interferon-beta (IFN-beta) have demonstrated activity against lymphoid malignancies, presumably mediated by the augmentation of lymphokine-activated killer (LAK) cell and natural killer (NK) cell activity. There is in vitro and in vivo evidence to suggest that the combination of IL-2 and IFN-beta is synergistic. The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II trial of IL-2 with or without IFN-beta in 49 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL). Overall toxicity was severe, with 17 patients experiencing life-threatening toxicity. Three patients had treatment-related deaths. Responses were noted in seven patients (17%). There were no meaningful differences between treatment arms in toxicity profile, response rate, or modulation of in vivo NK and LAK activity. We conclude that IL-2 with or without IFN-beta is not effective therapy for NHL in the doses and schedule used in this study.

Adult↗
PubMed1995

Phase I study of sequentially administered recombinant tumor necrosis factor and recombinant interleukin-2.

The purposes of this study were to determine the maximally tolerated dose (MTD) of IL-2 when sequentially administered following TNF (at its MTD), to identify any unique toxicities, and determine the immunomodulatory effects of this combination. Patients with metastatic cancer were treated with 160 micrograms/ml rTNF by rapid i.v. infusion for 5 days, followed by rIL-2 therapy daily at doses up to 18 x 10(6) IU/m2/day for 5 days and 6 x 10(6) IU/m2/day for 7 days. Cycles were repeated at 3- or 4-week intervals until progressive disease or unacceptable toxicity developed. Fifteen patients received 46 cycles of therapy (range 1-8, median 3). Major toxicities included hypotension, weight loss, and decreased performance status comparable to that reported with rIL-2 alone. No novel toxicities were identified. Two of 14 patients who received two cycles of therapy had objective responses (1 complete, 1 partial). Both occurred in patients with malignant melanoma, lasted 30 and 75 weeks, respectively, and included a complete response in liver metastasis. Dosage reductions of IL-2 were necessary for 3 patients over 11 treatment cycles (23%), and rTNF in 1 patient for 1 cycle (2%). The MTD of 5-day infusional rIL-2 was determined at 18 x 10(6) IU/m2/day. rTNF did not augment natural killer/lymphokine-activated killer activities beyond that commonly seen with IL-2 infusions. We conclude that full doses of rTNF can be combined with escalating rIL-2 infusions in an outpatient setting without additive toxicity and with clinical activity in patients with malignant melanoma.

Adult↗
PubMed1993

Enhanced antitumor effect of recombinant human tumor necrosis factor in combination with recombinant human granulocyte colony-stimulating factor in BALB/c mice.

The synergistic antitumor effect of tumor necrosis factor (TNF) and granulocyte colony-stimulating factor (G-CSF) was investigated. G-CSF was administered subcutaneously to BALB/c mice inoculated with Meth-A cells at a dose of 2.5 micrograms/day for 5 consecutive days. When TNF (1 x 10(3) U) was administered intravenously to mice which had been pretreated with G-CSF, tumor growth showed a 74.1% inhibition 17 days after the tumor cell inoculation, compared to that of untreated mice. In this experiment, G-CSF significantly (P < 0.025) enhanced the antitumor effect of TNF. The in vitro cytotoxicity of TNF (10 U/ml) towards Meth-A cells was increased about 5.2-fold in the presence of neutrophils (E/T = 50) as compared to the cytotoxicity obtained with TNF alone. A combination of TNF and G-CSF (50 ng/ml) in the presence of neutrophils, resulted in a 2.1 times greater cytotoxicity against Meth-A cells as compared to that obtained without G-CSF. Significant augmenting effects of G-CSF on superoxide (O2-) production by TNF-stimulated neutrophils were observed. These observation suggest that the neutrophil plays an important role in the antitumor action of TNF on Meth-A cells, and that the antitumor effect of TNF is enhanced by combination with G-CSF.

Animals↗
PubMed1987

Peripheral blood lymphocyte response to recombinant and non-recombinant interleukin 2 in previously treated patients with Hodgkin's disease, long-time off-therapy.

13 patients with Hodgkin's disease (HD) previously treated, 9 of whom were long-time (more than 2 yr) off-therapy, were studied for peripheral blood lymphocyte response to interleukin 2 and for lymphocyte subpopulations by means of in vitro cultures and monoclonal antibodies. The aim of the study was to ascertain the role played by interleukin 2 in the impaired cell-mediated immunity of HD patients. The results show a response of peripheral blood mononuclear cells of HD patients to either the T cell-specific polyclonal mitogens PHA and Con A or to the T cell-dependent, although B cell-specific, PWM, most significantly decreased compared to the normal response. As far as the interleukin 2 involvement in HD is concerned, our study suggests: an impaired endogenous interleukin 2 production by T lymphocytes, a most probable deficiency of the interleukin 2 receptor (Tac) expression and 3) a decrease of the number and/or of the function of NK cells no longer responsive in vitro to interleukin 2. The phenotypic analysis of peripheral blood mononuclear cells showed a slight decrease of total T cells (T3+), of the helper/inducer subset (T4+) and of the T4+/T8+ cells ratio. Our data seem to support the rationale for a therapeutical approach with interleukin 2 in controlled clinical trials also in HD patients, according to the experiments in progress in solid tumor patients.

Adolescent↗
PubMed1996

Use of human recombinant growth hormone and human recombinant insulin-like growth factor-I in patients with human immunodeficiency virus infection.

Infection with the human immunodeficiency virus (HIV) can lead to global alterations in metabolism as well as immunodeficiency. There is dysregulation of endocrine function in adults and children, the extent and magnitude correlating with disease progression. Some of the more prominent abnormalities occur in the thyroid, gonadal, and somatomedin axes. Clinical manifestations of these abnormalities are growth failure in children, which is one of the most sensitive indicators of disease progression, and a wasting syndrome in adults and children. Although there are case reports of growth hormone (GH) deficiency in HIV-infected children, most patients with growth failure have normal serum levels of GH and normal to low levels of insulin-like growth factor-I (IGF-I). Antiretrovial therapy can improve the growth rate in children for a period of time if there is a drop in viral titer, but as the viral load increases, the growth rate decreases again. Administration of GH or IGF-I to these patients can improve the growth rate and lean body mass, and in some patients improve immune function. Although studies on resting energy expenditure in HIV-infected patients have shown increases, these are not proportional to disease progression, but may be dependent upon cytokine activation and other abnormalities. Adult patients with wasting have been shown to have relatively normal total energy expenditure, but decreased intake. Appetite stimulants have been shown to have some benefit, but do not increase lean body mass. The most significant clinical benefit has come from administration of GH in short-term trials. GH and IGF-I are both able to inhibit apoptosis and reconstitute the immune system in rodents treated with ablative therapy. In addition, GH can modulate the marrow suppressive effects of zidovudine and may enhance its ability to inhibit viral reverse transcriptase. Current clinical trials are ongoing in both adults and children. GH and IGF-I may have a role in regimens intended for immune reconstruction, and could be useful as adjuvant therapy in selected patients with HIV infection.

Adult↗