ABSTRACT
Twelve patients with the acquired immune deficiency syndrome (AIDS) and Kaposi's sarcoma were treated with recombinant human gamma-interferon (rIFN-gamma). A rapid, substantial increase in the fraction of HLA-DQ-positive monocytes was noted after treatment with rIFN-gamma. The rIFN-gamma-induced increase in monocyte HLA-DQ was seen throughout the course of treatment, with the percentage of HLA-DQ-positive monocytes dropping slightly following each week's treatment with rIFN-gamma and then rapidly increasing following the next course of treatment. Although the percentage of HLA-DR-positive monocytes was unchanged (HLA-DR was expressed on greater than 80% of monocytes prior to treatment), the density of HLA-DR on monocytes also increased following rIFN-gamma treatment. Following rIFN-gamma treatment, no changes were seen in CD3, CD4, CD8 T cell numbers, in T cell subset ratio (CD4/CD8), in Leu 7 or CD16 (Leu 11) cell number, in spontaneous Ig secretion, in PHA-induced in vitro proliferation, or in NK activity. These results indicate that exposure to rIFN-gamma in vivo led to the increased expression of class II antigens on monocytes in patients with AIDS.
Subject(s)
Acquired Immunodeficiency Syndrome/immunology , HLA-D Antigens/immunology , Interferon-gamma/pharmacology , Monocytes/immunology , Sarcoma, Kaposi/immunology , Acquired Immunodeficiency Syndrome/therapy , Dose-Response Relationship, Drug , Humans , Immunity, Innate , Immunoglobulins/metabolism , Interferon-gamma/therapeutic use , Killer Cells, Natural/immunology , Leukocyte Count/drug effects , Lymphocyte Activation/drug effects , Lymphocytes/immunology , Recombinant Proteins , Sarcoma, Kaposi/therapyABSTRACT
A Phase I study of recombinant interferon-gamma (rIFN-gamma) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-gamma. rIFN-gamma was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2-4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7-12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1-1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-gamma is given at doses at or near this MTD.
Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Adjuvants, Immunologic , Interferon-gamma/toxicity , Sarcoma, Kaposi/drug therapy , Adolescent , Adult , Cytomegalovirus/drug effects , Cytotoxicity, Immunologic/drug effects , Drug Evaluation/methods , Humans , Interferon-gamma/administration & dosage , Interferon-gamma/pharmacokinetics , Killer Cells, Natural/drug effects , Leukocyte Count/drug effects , Male , Middle Aged , Recombinant ProteinsABSTRACT
A clinical trial to determine the antitumor activity of recombinant interferon-gamma (rIFN-gamma) was conducted in 36 patients with advanced colorectal cancer. Severe constitutional symptoms were seen in the first five patients who received rIFN-gamma as a 2- to 4-hour intravenous infusion, and this method of administration was therefore abandoned. One transient partial tumor regression was observed in the 31 patients who received treatment by the intramuscular route of administration. Although a clinically tolerable regimen suitable for outpatient administration was developed, rIFN-gamma given in this dose and schedule had minimal antitumor effect for the treatment of advanced colorectal cancer. NK activity was depressed within 48 hours of rIFN-gamma administration but became significantly higher than normal controls or pretreatment levels during therapy despite disease progression, indicating discordance between augmentation of this immune parameter and tumor status. Serum CA 19-9 levels were unusually high and increased significantly more than CA 125 or CEA during rIFN-gamma treatment. This observation suggests that rIFN-gamma could augment localization of anti-CA 19-9 used to diagnostically image or therapeutically target a labeled chemotherapy agent to tumor in those patients expressing this antigen.
Subject(s)
Antigens, Tumor-Associated, Carbohydrate/metabolism , Colorectal Neoplasms/therapy , Interferon Type I/therapeutic use , Adult , Aged , Aspartate Aminotransferases/blood , Carcinoembryonic Antigen/metabolism , Colorectal Neoplasms/blood , Colorectal Neoplasms/immunology , Female , Humans , Interferon Type I/adverse effects , Killer Cells, Natural/cytology , Male , Middle Aged , T-Lymphocytes/classificationABSTRACT
A phase I trial of intramuscularly administered recombinant human tumor necrosis factor (rTNF) was conducted in 19 adult patients with advanced solid tumors. The agent was administered daily for up to five consecutive days every other week for two to four courses. Doses of rTNF ranged from 5 to 200 micrograms/m2/d. Dose-limiting toxicities were encountered at doses greater than 100 micrograms/m2/d. Toxicities included tenderness, erythema and induration at the site of injection, fatigue, fever, chills, headache, anorexia, nausea, vomiting, and diarrhea. Moderate to marked reductions in WBC and platelet counts were observed regularly at the highest dose levels, but none were clinically significant. Hepatic enzyme elevation was seen frequently, and two patients developed hyperbilirubinemia. Only one of seven patients treated with doses greater than 100 micrograms/m2/d completed the planned course of therapy. Even at the highest dose levels, serum concentrations of rTNF could only rarely be detected in the serum. No therapeutic responses were observed. The maximal tolerated dose (MTD) of rTNF in this trial was 150 micrograms/m2/d, administered for two courses.
Subject(s)
Neoplasms/drug therapy , Tumor Necrosis Factor-alpha/administration & dosage , Adult , Aged , Dose-Response Relationship, Drug , Drug Evaluation , Female , Humans , Injections, Intramuscular , Male , Middle Aged , Neoplasms/blood , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Research Design , Time Factors , Tumor Necrosis Factor-alpha/adverse effectsABSTRACT
A clinical trial was conducted to determine the tolerance and toxicity of recombinant tumor necrosis factor (rTNF) and recombinant interferon gamma (rIFN-gamma) when administered concurrently by continuous intravenous infusion to 11 patients with the AIDS-related complex (ARC). In addition, HIV culture, p24 antigen levels, and CD4 positive lymphocytes were monitored to obtain preliminary evidence of antiviral and immunologic effects. Two 5-day treatment cycles were separated by a 9-day washout period. Two patients were entered at each dosage level and each patient received the two 5-day treatment cycles at two sequential dose levels ranging from 1 to 25 micrograms/m2. Two patients did not complete their second treatment cycle--one due to the development of a rash, the second due to central venous catheter discomfort. The occurrence of phlebitis with peripheral vein administration of these agents necessitated administration via central venous catheter. With the exception of a single patient who developed severe headache at the 25 micrograms/m2 dose, severe clinical toxicities were not observed. Fever, chills, headache, and myalgias were the most significant clinical toxicities observed and all were dose dependent. The percentage fall in total granulocytes was dose dependent and ranged from 17% at the 1 microgram/mm2 dose to 48% at both the 15 and 25 micrograms/mm2 dose levels. The mean nadir granulocyte count was 1694/mm3. No significant renal or hepatic toxicity was observed. Of 22 treatment cycles the CD4 cell number was increased in 11, unchanged in 7, and decreased in 4. The mean CD4 cell number did not change significantly (176 +/- 143/mm3 pretherapy versus 279 +/- 305/mm3 posttherapy).(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
AIDS-Related Complex/therapy , Antiviral Agents/therapeutic use , Interferon-gamma/therapeutic use , Tumor Necrosis Factor-alpha/therapeutic use , Adult , Antiviral Agents/adverse effects , Humans , Interferon-gamma/adverse effects , Male , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Tumor Necrosis Factor-alpha/adverse effectsABSTRACT
This study was undertaken to determine an immunologically active regimen for the administration of recombinant gamma-interferon (rIFN-gamma). The patient population included patients with completely resected melanoma, stage I (Clark's level IV or V) or stage II. All patients exhibited no evidence of disease (NED) at the time of the study. Patients received rIFN-gamma by intramuscular (IM) injection daily for 15 days at 0.0001 mg/m2, 0.001 mg/m2, 0.01 mg/m2, 0.1 mg/m2 (ten patients/group), or 0.25 mg/m2 (five patients). Interferon (IFN) was well tolerated, with non-dose-limiting constitutional symptoms occurring in the majority of patients at 0.1 mg/m2 and 0.25 mg/m2. All five patients receiving 0.25 mg/m2 developed elevated transaminase levels, which led to a discontinuation of therapy in one patient. Immunological activity was assessed by serial measurements of natural killer (NK) cell activity, hydrogen peroxide production by monocytes, and changes in expression of Fc receptors and human leukocyte class II antigen (HLA-DR) on monocytes. These changes were determined at baseline (X2), six to seven time points during rIFN-gamma therapy, and two times after the last dose of rIFN-gamma. No changes were observed at the two lowest doses. At the 0.01 mg/m2 dose, all parameters were elevated but not as consistently nor to the same levels as seen following administration of 0.1 mg/m2. At 0.25 mg/m2, H2O2 production was enhanced, but unlike at 0.1 mg/m2, it declined during the last few days of IFN therapy. Subcutaneous (SC) administration was compared with IM administration using the 0.1 mg/m2 dose. SC administration resulted in enhanced H2O2 production and Fc receptor expression by monocytes. More consistent elevations in peroxide generation and higher levels of Fc receptor expression were seen following SC administration. No significant difference was found between the two routes of administration. A comparison of two schedules, daily and three times weekly, suggested that monocyte activation may return to normal 72 hours after IFN administration. Of the doses tested, 0.1 mg/m2 administered daily appeared to be the most effective biological response modifier (BRM) regimen, and because of ease of administration, we favor the SC route.
Subject(s)
Interferon-gamma/administration & dosage , Melanoma/therapy , Dose-Response Relationship, Drug , Drug Administration Schedule , HLA-DR Antigens/analysis , Humans , Hydrogen Peroxide/metabolism , Injections, Intramuscular , Injections, Subcutaneous , Interferon-gamma/adverse effects , Killer Cells, Natural/immunology , Melanoma/immunology , Monocytes/drug effects , Monocytes/immunology , Monocytes/metabolism , Receptors, Fc/analysisABSTRACT
Twenty-three patients with chronic plaque-type psoriasis were treated with intramuscular administration of human recombinant interferon gamma. Patients were treated with doses of 0.01 to 0.25 mg/m2 daily (five out of seven days) for four weeks, or 0.25 mg/m2 three times weekly for one week with escalation to 0.5 mg/m2 for the subsequent seven weeks. Some patients treated with the 0.25-mg/m2 dose showed improvement coincident with their therapy. Although recombinant interferon gamma may have some therapeutic activity in certain patients' psoriasis, the magnitude of this effect is at best small. This result is in contrast to interferon alfa, which has been reported to cause an exacerbation of this disease. Staining of posttreatment biopsy specimens with a monoclonal antibody against HLA-DR antigen using an immunoperoxidase technique demonstrated HLA-DR expression by keratinocytes in some of the patients treated at the higher doses. No obvious correlation was seen between clinical improvement of the psoriasis and intensity or extent of HLA-DR antigen expression by keratinocytes in the skin biopsy specimens.
Subject(s)
Interferon-gamma/administration & dosage , Psoriasis/therapy , Biopsy, Needle , Dose-Response Relationship, Drug , Drug Evaluation , HLA-DR Antigens/analysis , Humans , Immunoenzyme Techniques , Injections, Intramuscular , Interferon-gamma/adverse effects , Phenotype , Psoriasis/immunology , Psoriasis/pathology , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Skin/immunology , Skin/pathology , Time FactorsSubject(s)
Interferon-gamma/administration & dosage , Drug Evaluation , Drug Industry , Drug Tolerance , HumansABSTRACT
Twenty-eight patients with disseminated malignant melanoma received daily im therapy with recombinant interferon-gamma. The dose was 0.25 mg/m2 on Days 1-7 followed by a daily dose of 0.5 mg/m2 if tolerated. Among 27 patients, we observed three objective partial regressions (8.3, 3.7, and 3.9+ months). The median leukocyte count nadir was 2.5 X 10(3)/mm3 (range, 1.4-5.1). Constitutional symptoms included moderate to severe fever greater than 37 degrees C (100%), fatigue (59%), chills (37%), and mild to moderate myalgias (64%). Recombinant interferon-gamma produces manageable side effects but limited efficacy as employed in this study.
Subject(s)
Interferon-gamma/therapeutic use , Melanoma/drug therapy , Recombinant Proteins/therapeutic use , Skin Neoplasms/drug therapy , Adult , Aged , Drug Evaluation , Female , Humans , Interferon-gamma/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Recombinant Proteins/adverse effects , Remission InductionABSTRACT
Tumor necrosis factor is a cytokine derived from activated macrophages. This agent is cytostatic and cytolytic against transformed human cell lines in vitro and has in vivo activity against a variety of murine tumors. We report a clinical study of the pharmacokinetics, toxicity, and biological activity of i.v. and i.m. administered recombinant human tumor necrosis factor (rTNF). Twenty patients with metastatic cancer were given rTNF in doses ranging from 1 to 200 micrograms/m2 by alternating i.m. and i.v. bolus injections with a minimal intervening period of 72 h. Each patient received a maximum of eight treatments given twice weekly over a 4-week period. With i.v. bolus administration, serum concentrations of rTNF were detected by enzyme-linked immunosorbent assay at doses of 25 micrograms/m2 or greater. The clearance of rTNF in the serum was described by a monoexponential equation with a half-life calculated to be 14-18 min. After i.m. administration, serum concentrations of rTNF were consistently detected by enzyme-linked immunosorbent assay at doses of 150 micrograms/m2 or greater. Peak concentrations were observed within 2 h and rTNF was occasionally detected, at the lower limit of sensitivity of the assay, at 24 h postinjection. rTNF was well tolerated clinically in this dose range, and there was evidence of antitumor effect.
Subject(s)
Glycoproteins/therapeutic use , Neoplasms/therapy , Adult , Aged , Breast Neoplasms/therapy , Carcinoma, Renal Cell/therapy , Colonic Neoplasms/therapy , Drug Evaluation , Female , Glycoproteins/adverse effects , Glycoproteins/metabolism , Hemoglobins/metabolism , Humans , Kidney Neoplasms/therapy , Lipid Metabolism , Male , Metabolic Clearance Rate , Middle Aged , Multiple Myeloma/therapy , Pancreatic Neoplasms/therapy , Recombinant Proteins/metabolism , Recombinant Proteins/therapeutic use , Tumor Necrosis Factor-alphaABSTRACT
A major difficulty limiting the use of immunomodulators in clinical medicine has been the complexity of the immunoregulatory network in which modulation of one component usually perturbs the entire system, thus diminishing the specificity of the approach. Lymphokine-activated killer cells infused with interleukin-2 have proved effective in inducing remissions in several advanced cancers, particularly metastatic renal cell carcinomas. The interferons have shown direct antiproliferative effects as well as specific effects on immune function. Alpha-interferon has shown impressive antitumor effects in hairy cell leukemia and significant antiviral effects in papillomavirus infection of the genital tract. Interleukin-2 has multifaceted effects on various limbs of the inflammatory and immune responses and may be the critical common denominator in the adjuvant effects of several other compounds. Monoclonal antibodies have assumed an increasing role in diagnostic and therapeutic approaches to neoplastic and immune-mediated diseases. Finally, several immunomodulators are currently being tested in the treatment of the immune defect of the acquired immunodeficiency syndrome.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Immunotherapy/methods , Acquired Immunodeficiency Syndrome/therapy , Antibodies, Monoclonal/therapeutic use , Humans , Interferons/therapeutic use , Interleukin-1/physiology , Interleukin-2/therapeutic use , Killer Cells, Natural/physiology , Lymphokines/therapeutic use , Neoplasms/therapyABSTRACT
Thirty-three patients with metastatic renal cell carcinoma were treated with recombinant human interferon gamma (rIFN gamma) in two sequential, nonrandomized phase II studies. Fifteen patients received rIFN gamma by daily i.m. injection in doses ranging from 0.25 to 1.0 mg/m2, and 18 patients received it by daily continuous i.v. infusion in doses ranging from 0.01 to 0.05 mg/m2. Partial remissions were achieved by one of 14 (7%) evaluable patients in the i.m. study and in one of 16 in the i.v. study (6%). The incidence of clinical toxicity was similar for both studies. Toxicity was severe in patients receiving rIFN gamma by the i.m. route at 1.0 mg/m2 and by the i.v. route at 0.05 mg/m2. Toxicity includes constitutional symptoms (fatigue, anorexia, weight loss), leukopenia, abnormalities in liver function tests, and hypertriglyceridemia. At the doses and schedules used, rIFN gamma had minimal therapeutic activity as a single agent in metastatic renal cell carcinoma.
Subject(s)
Carcinoma, Renal Cell/therapy , Interferon-gamma/therapeutic use , Kidney Neoplasms/therapy , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/secondary , Drug Evaluation , Female , Humans , Infusions, Intravenous , Injections, Intramuscular , Interferon-gamma/adverse effects , Kidney Neoplasms/blood , Male , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic useSubject(s)
Interferon-gamma/therapeutic use , Sarcoma/therapy , Adult , Aged , DNA, Recombinant , Drug Evaluation , Female , Humans , Interferon-gamma/adverse effects , Male , Middle Aged , Sarcoma/mortality , Sarcoma/pathologyABSTRACT
We report a phase I study of the biological effects, tolerance, and pharmacokinetics of 6- and 24-hour iv infusions of recombinant interferon-gamma (rIFN-gamma) in cancer patients. Twenty-one patients received the 6-hour iv infusion regimen at doses ranging from 0.016 to 0.65 mg/m2/day. Forty-one patients received the 24-hour iv infusion regimen at doses ranging from 0.01 to 0.05 mg/m2/day. Fever and flu-like symptoms were the most common side effects and were seen at all dose levels. The maximum tolerated dose was 0.16 mg/m2 for the 6-hour regimen and 0.01 mg/m2/day for the 24-hour regimen. A dose-dependent granulocytopenia was observed at doses greater than or equal to 0.05 mg/m2/day. A marked increase in beta2 microglobulin occurred by Day 5 of treatment in almost all patients, regardless of the dose level. Consistent serum levels of rIFN-gamma were achieved only at doses of 0.325 mg/m2/day of the 6-hour infusion. The mean serum concentrations at this dose ranged from 18 to 83 units/ml as measured by bioassay (0.64-2.4 ng/ml by enzyme-linked immunoassay). Antibody against rIFN-gamma did not develop in any patient. During the short period of evaluation of this study, one patient with renal cell carcinoma achieved a partial response, and three patients with renal cell (two) and lung carcinoma (one), respectively, achieved minor responses. This study will form the framework for phase II efficacy trials of iv rIFN-gamma.
Subject(s)
Interferon-gamma/administration & dosage , Neoplasms/therapy , Recombinant Proteins/administration & dosage , Adult , Aged , Antibodies/analysis , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Evaluation , Female , Humans , Interferon-gamma/adverse effects , Kinetics , Male , Middle Aged , Neoplasm Metastasis , Neoplasms/blood , Neoplasms/pathology , Recombinant Proteins/adverse effects , Research Design , beta 2-Microglobulin/analysisABSTRACT
Combinations of interferon-alpha and interferon-gamma demonstrate synergistic antiviral and anti-proliferative activity in vitro. Therefore, we initiated a clinical study of combination interferon therapy in humans. Eighteen patients with metastatic solid tumors received daily intramuscular (IM) injections of recombinant interferon-alpha-A (IFN alfa-2a, Roferon-A; Hoffman-LaRoche, Nutley, NJ) and recombinant IFN-gamma (rIFN-gamma) for 6 weeks. The dose levels were 0.5, 1.0, 2.0, and 5.0 X 10(6) U/m2/d of each interferon. A minimum of two patients were entered sequentially at each dose level. Fever, chills, fatigue, and a greater than or equal to 50% drop in granulocyte counts were observed at all doses. Severity of symptoms corresponded to increasing dose levels. In contrast to the tachyphylaxis to these symptoms that usually develops in patients treated with the individual interferons, many patients on this study experienced persistent fever and worsening fatigue over 6 weeks. The maximum tolerated dose was 1 X 10(6) U/m2/d of each interferon. One patient with renal-cell carcinoma achieved a partial remission (duration, 3 months). Enzyme-linked immunoassay analysis in all four patients for whom complete data were available revealed that peak blood levels of IFN alfa-2a on day 22 were about tenfold higher than on day 1. Because of the possibility of cumulative toxicity, the recommended starting dose for further studies is 0.5 X 10(6) U/m2/d of each interferon, with escalation to 1.0 X 10(6) U/m2/d after 1 month if tolerance is acceptable. Phase II investigations to explore the antitumor efficacy of this regimen are planned.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/therapy , Adult , Aged , Antibodies/analysis , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Diseases/chemically induced , DNA, Recombinant , Dose-Response Relationship, Drug , Drug Evaluation , Enzyme-Linked Immunosorbent Assay , Female , Gastrointestinal Diseases/chemically induced , Hematologic Diseases/chemically induced , Humans , Interferon Type I/administration & dosage , Interferon-gamma/administration & dosage , Kinetics , Male , Middle Aged , Neoplasms/blood , Neoplasms/immunology , Research DesignABSTRACT
Animals suffering from malignancy or chronic infection develop characteristic metabolic abnormalities, including a well-defined hypertriglyceridemic state. These abnormalities have been attributed to release of one or more mediators from activated macrophages. We report that cancer patients receiving RIFN-gamma, a potent macrophage activator, at doses of greater than or equal to 0.25 mg/m2/d i.m. show marked increases in triglyceride but not in cholesterol levels (pretreatment triglyceride level of 180 +/- 190 mg/dl [mean +/- SD] vs. a day-14 level of 370 +/- 242 mg/dl, n = 23, p less than 0.001 by the paired t test). This hypertriglyceridemia was characterized by an increase in very low-density lipoproteins and a decrease in plasma post-heparin lipase activity, consistent with defective triglyceride clearance (mean pretreatment lipase level of 2.1 mumol/ml/h vs. a day-14 level of 1.2 mumol/ml/h, n = 6, p = 0.02 by the paired t test). rIFN-gamma did not directly inhibit lipoprotein lipase enzymatic activity in vitro. Other possible mechanisms of action, such as suppression of lipase by an rIFN-gamma-induced mediator released from activated macrophages, or a direct effect of interferon on lipase biosynthesis, require further investigation. Our observations provide evidence that factors produced by the immune system can regulate lipid metabolism in man.
Subject(s)
Interferon-gamma/pharmacology , Lipoprotein Lipase/blood , Neoplasms/metabolism , Recombinant Proteins/pharmacology , Triglycerides/blood , Adult , Aged , Female , Glycoproteins/blood , Humans , Interferon-gamma/adverse effects , Male , Middle Aged , Neoplasms/therapy , Tumor Necrosis Factor-alphaABSTRACT
We report the results of a phase I study of the tolerance and biologic activity of intramuscularly (IM)-administered recombinant interferon-gamma (rIFN-gamma). Forty-four patients with metastatic cancer were given rIFN-gamma at doses ranging from 0.01 to 2.5 mg/m2/d for 42 days. The most common side effects were fever, flulike symptoms, night sweats, and granulocytopenia. The maximum tolerated dose was 0.5 mg/m2/d. Administration of rIFN-gamma resulted in modulation of immune system functions, including induction of major histocompatibility complex-associated antigens on blood leukocytes, an increase in blood surface immunoglobulin-bearing B cell and natural killer (NK) cell number, and NK cell cytotoxicity. Serum lysozyme, determined as an estimate of tissue macrophage activity, also increased. Serum assays for anti-interferon antibodies were negative in all patients. Five of eight evaluable patients with lymphoproliferative disorders showed objective evidence of tumor regression consisting of partial responses (two patients), and minor responses (three patients). These data suggest that further phase II studies of IM-administered rIFN-gamma are indicated.
Subject(s)
Interferon-gamma/administration & dosage , Neoplasms/drug therapy , Agranulocytosis/chemically induced , Antibodies/analysis , Body Weight , Chemical and Drug Induced Liver Injury , Drug Evaluation , Fever/chemically induced , Humans , Immunity/drug effects , Injections, Intramuscular , Interferon-gamma/adverse effects , Interferon-gamma/therapeutic use , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , beta 2-Microglobulin/analysisABSTRACT
Evidence that interferon-gamma may be a physiologic macrophage-activating factor, and that macrophage activation may be defective in lepromatous leprosy, led us to test the effects of intradermal injection of low doses of recombinant interferon-gamma in six patients with this disease. Interferon-gamma, 1 or 10 micrograms, was administered daily by jet gun for three days into a single cutaneous lesion. A biopsy specimen was taken from the injection site on the sixth study day and compared with specimens obtained previously from a site where no injection had been made or where excipient alone had been injected in the same way as the interferon. Interferon-gamma elicited local effects similar to certain features of delayed-type hypersensitivity reactions or tuberculoid leprosy, including induration, T-cell and monocyte infiltration, keratinocyte proliferation, diminution of epidermal Langerhans cells, and dermal and epidermal cell HLA-DR (Ia) antigen expression. At some of the sites of interferon-gamma injection, there was also an apparent decrease in acid-fast bacilli. Before treatment, monocytes from patients with lepromatous leprosy released 48 percent as much hydrogen peroxide as did monocytes from controls in response to phorbol myristate acetate, and 36 percent as much as those from controls in response to Mycobacterium leprae. When recombinant interferon-gamma was injected, these responses became normal. No toxic effects were observed. These observations suggest that interferon-gamma can mediate certain manifestations of delayed-type hypersensitivity or cell-mediated immunity in vivo, and that recombinant interferon-gamma should be tested for possible therapeutic effects in certain nonviral infectious diseases.
Subject(s)
Interferon-gamma/therapeutic use , Leprosy/therapy , Adult , Female , HLA-DR Antigens , Histocompatibility Antigens Class II/analysis , Humans , Hydrogen Peroxide/metabolism , In Vitro Techniques , Injections, Jet , Interferon-gamma/administration & dosage , Interferon-gamma/adverse effects , Langerhans Cells/pathology , Leprosy/immunology , Leprosy/pathology , Male , Middle Aged , Monocytes/metabolism , Monocytes/pathology , Mycobacterium leprae/isolation & purification , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Skin/microbiology , Skin/pathology , T-Lymphocytes/pathologyABSTRACT
Fifteen patients with advanced malignancy were treated with recombinant interferon gamma (rIFN-gamma) (specific activity approximately 2 X 10(7) units/mg, purity greater than 99%) given by 1-hour iv infusion three times a week for 6 weeks, at fixed dose levels of 0.1, 0.5, 1.0, or 2.0 mg/m2/day. The common side effects were constitutional symptoms, including fever, chills, myalgias, and headache, but these were less severe than those observed following daily 6-hour iv infusions. Significant changes in blood cell counts and routine serum chemistries were not observed, but there was a dose-dependent increase in serum triglyceride levels. The maximum safely tolerated dose achieved was 1.0 mg/m2/day. Peak serum interferon levels occurred at the midpoint of the infusion and were dose-dependent. rIFN-gamma was rapidly cleared from serum and no detectable activity was found 2 hours after the infusion. Two patients, both with B-cell malignancies, showed objective evidence of tumor regression during the treatment. Treatment was associated with an increase in serum levels of beta 2-microglobulin and the H2O2 secretory capacity of peripheral blood monocytes. We conclude that rIFN-gamma administered by short iv infusion can induce biological activities and causes less toxicity than when given by prolonged iv infusion.